Talk:Temazepam/Archive 2

Plagiarism

The "Toxicity" section appears to have been plagiarized from the Introduction and Discussion sections of Buckley et al (1995) “Relative toxicity of benzodiazepines in overdose.” (available here). See this diff where it is added and this comparison to current revision, essentially unchanged. At some point, the source itself is later added to back up one of the plagiarized sentences in paragraph 5, but this is clearly a violation of WP:COPYVIO. St3vo (talk) 02:13, 20 June 2008 (UTC)

The "Pregnancy" section is also copied word-for-word from temazepam's prescribing information, available here. It was added shortly after the Toxicity section (diff). The source is referenced at the end, but I don't believe lifting 3 paragraphs verbatim is permitted (I'm not familiar with the relevant policy for drug monographs). St3vo (talk) 02:42, 20 June 2008 (UTC)

It needs rewording if that is the case then.--Literaturegeek | T@1k? 03:29, 20 June 2008 (UTC)

Agreed. I'm just trying to document everything that needs prompt attention (perhaps via {{editprotected}}?)St3vo (talk) 03:51, 20 June 2008 (UTC)

Same for "Pharmacokinetics", see the Clinical Pharmacology section of the monograph here, and the diff...St3vo (talk) 03:47, 20 June 2008 (UTC)

...and "Special Precautions", see Precautions section here, diff. Again, the source of the material is cited at the end of the paragraph, but I really don't think that justifies copying the text of the monograph in its entirety. Regardless of the intention, it should be reworded and appropriately sourced. St3vo (talk) 04:16, 20 June 2008 (UTC)

...and "Interactions", see "Interactions with Other Medicines (page 5) here, diff. Same Australian monograph, taken without citation in this instance. St3vo (talk) 04:49, 20 June 2008 (UTC)

St3vo, could you please also take the time to go through the edits I applied, and proofread that? (They are all not in the current revision, see history) 70.137.161.241 (talk) 04:55, 20 June 2008 (UTC)

I intend to look through everything; at the moment, I'm just trying to figure out where the nitrazepam->temazepam switches in article titles came from (see the section above), but I will do my best to proofread all the edits tomorrow. Best, St3vo (talk) 05:13, 20 June 2008 (UTC)

I'm shamefully unsure of the copyright status of drug monographs, apart from third-party provider ones (Cerner Multum, Lexi-comp etc.) I'm torn between nuking the copy-and-pasted sections altogether, protection be damned (fluoxetine was summarily deleted a while back when it was found to contain copyvio content) and leaving it in for discussion and rewording. Any thoughts? Fvasconcellos (t·c) 21:26, 20 June 2008 (UTC)

Here http://en.wikipedia.org/w/index.php?title=Temazepam&diff=220181687&oldid=220180004

the reference changed from "nitrazepam withdrawal" to "nitrazepam and temazepam withdrawal" 70.137.161.241 (talk) 06:31, 20 June 2008 (UTC)

I'd recommend immediately moving the copyrighted text to Talk:Temazepam/sources and putting it back in the article once it has been rewritten. Tim Vickers (talk) 14:28, 21 June 2008 (UTC)

Am doing. Fvasconcellos (t·c) 16:19, 21 June 2008 (UTC)

cross tolerance with barbiturates

text says barbiturates can be substituted for temazepam. ref says flurazepam can be substituted for barbiturates, which is the other way around. Find a clinical reference for "barbiturates can be subststituted for temazepam" or state it the other way around, like in the ref. Actually for the cross tolerance both ways have to be referenced, it is not perfectly symmetrical, because barbs and benzos act by a different mechanism, as you explained. So they don't fully overlap 70.137.161.241 (talk) 15:14, 20 June 2008 (UTC)

You created this argument on the nitrazepam page where you make up rules as you go along, like to reference it you have to have a study showing swapping barb for specific benzo and specific benzo for barb etc. You know that this is impossible to find two studies like this and your argument will win out for you. You have been involved in research and development of drugs and have degrees in pharmacology. Every pharmacologist knows that benzodiazepines are cross tolerant with barbiturates. On the nitrazepam page the ref was actually about swapping people on nitrazepam to barbs but that wasn't good enough etc. The reality is you don't want the reader to know that benzos work similarly to barbiturates (which have a bad name). My reality was I thought that it was a useful and productive encyclopedia fact for the tolerance section. Why not use this reference?[1]--Literaturegeek | T@1k? 07:41, 21 June 2008 (UTC)

As for the use of flurazepam and it being misrepresented for temazepam. the ref should either be removed or the wording temazepam be changed to "benzodiazepine hypnotics" or else replace it with my reference.--Literaturegeek | T@1k? 07:45, 21 June 2008 (UTC)

Reference title alterations

I believe I have found the 3 reference alterations, which were the most disconcerting revelations of this mess in my opinion. I am not making any judgments at this time - these are just the raw diffs to establish what occurred and when.

1. Here Thegoodson changes the wording of the title of Viukari et al, 1978 (PMID 24980) from "fosazepam" to "temazepam" and adds a statement on temazepam withdrawal causing sudden violent death, backed up by a preexisting ref for nitrazepam (later changed by anon in #3). I do not have access to this paper, so I can't verify this claim, but it looks dubious.

2. Here Thegoodson changes "nitrazepam" to read "temazepam" in 2 places, once in the text and once in the ref immediately following (Tarao et al, 1992; PMID 1737083).

3. Here an anonymous editor, 70.48.214.28, changes the wording of the title of Kitabayashi et al, 2001 (PMID 11900604), from "nitrazepam" to "temazepam."

I'll be away this weekend, but I'd be interested in hearing any explanations for why these refs were changed...accidents happen, but if Wikipedia is to be at all respectable, we really need citations to match up. St3vo (talk) 20:15, 20 June 2008 (UTC)

Yes, I'd already found the problematic citations by following 70.'s edits, but the above diffs show this was a) clearly not an accident and b) not a one-time occurrence. I'd be very, very interested in explanations from Thegoodson as well. Fvasconcellos (t·c) 20:43, 20 June 2008 (UTC)

I'm also disturbed by the addition of a reference that dealt with the effects of chlordiazepoxide, midazolam and nitrazepam (PMID 2894998) to support a statement that tolerance developed to temazepam. Tim Vickers (talk) 21:13, 20 June 2008 (UTC)

Tolerance

I've rewritten this section to reflect what I think the references show. Tim Vickers (talk) 21:13, 20 June 2008 (UTC)

Old version

Although tolerance to the sleep inducing properties of temazepam develops within a matter of days, so too does tolerance to the residual performance impairment. After 6 days of use, tolerance to temazepam's sleep inducing effects and performance impairing effects occurs. One study demonstrated tolerance to the sleep promoting effects of nitrazepam and temazepam after 7 days nightly administration. Quality of sleep was found to be increased after the first nights administration of either nitrazepam or temazepam but by day 7 quality of sleep was found to have returned to baseline suggesting the development of complete tolerance after 7 days use. In mice tolerance to the anticonvulsant properties of temazepam developed profoundly and rapidly over 6 days, although some anticonvulsant effects were still apparent after 6 days administration.

First draft of new version.

Chronic or excessive use of temazepam may cause drug tolerance, and this drug is not recommended for long-term use. Studies examining the short-term use of temazepam over six days saw no evidence of tolerance. Another study examined the short-term effects of the accumulation of temazepam or nitrazepam in elderly patients. Here, the authors concluded that elderly patients showed little tolerance during the accumulation of the drugs and that temazepam and nitrazepam had similar overall effects. In longer-term use, tolerance can develop towards the ability of this drug to maintain sleep, so that the drug loses effectiveness. However, this is not seen in all cases, and tolerance to benzodiazapines may develop selectively to some, but not all, of these drugs' effects. Other researchers have suggested that temazepam may produce tolerance less rapidly than other benzodiazepines with longer drug half-lives in the body, but there is little agreement amongst experts on if the benzodiazipines differ in their ability to induce tolerance. In light of such conflicting data, a recent review by Professor Malcolm Lader at King's College London concluded that for benzodiazipines in general "long-term efficacy remains controversial".

Discussion of this proposed new wording

• I am taken aback by the difference in meaning and context, particularly since you mostly used the same references. Since I don't have access to the full text of these studies, I can't verify the wording myself, but if that's what the sources say, that's what should be in the article. Fvasconcellos (t·c) 14:49, 21 June 2008 (UTC)

Oppose

Sorry but I disagree with the summary. It is very misleading to the reader. The studies you are citing are only 6 - 7 days studies (edit I see that you have a couple of more long term studies). It disagrees with many other papers and the FDA and committee on safety of medicines. It is true that temazepam is still effective after 6 - 7 days but after 1 week most papers find tolerance occurs rapidly and completely as does the FDA and CSM. FDA and CSM findings trump individual studies. Most individual studies into sleep meds are often carried out by their manufacturers. I can provide citations for this. I would rather go with the FDA and CSM.

This is what I think would be more accurate.

Temazepam shows a rapid development of tolerance.[2] Tolerance to temazepam begins to develop after 1 week's use.[3] A 22 day study of temazepam demonstrated a raid development of tolerance to temazepam. Temazepam is effective in short term use but intermediate term use shows a rapid development of tolerance.[4] Tolerance seems to occur more quickly when used in gelatine capsules than tablet form temazepam.[5] Temazepam is still effective with no evidence of tolerance after 6 days of continuous nightly usage. The FDA reports that benzodiazepine hypnotics including temazepam lose their sleep promoting properties in 3 - 14 days as does the committee on the safety of medicines, Institute of Medicine (USA), White House Office of Drug Policy and the National Institute on Drug Abuse.[6], [7] A study in 11 young male subjects showed that significant tolerance occurs to temazepam's thermoregulatory effects and sleep inducing properties after 1 week of use of 30 mg temazepam. Body temperature is well correlated with the sleep inducing or insomnia promoting properties of drugs.[8]

Although I do see how the references did seem to be misquoted.--Literaturegeek | T@1k? 15:39, 21 June 2008 (UTC)

Also drugs.com, I don't think should be used to say drug tolerance occurs occasionally if the FDA and CSM says it occurs typically if not always. The FDA and CSM is definitely more authoritative.--Literaturegeek | T@1k? 15:47, 21 June 2008 (UTC)

Erm, the first two studies in the "new version" were not short-term. PMC 1400899, which incidentally was a short-term study, states that no evidence of tolerance was seen with temazepam. Fvasconcellos (t·c) 15:52, 21 June 2008 (UTC)

Nope it says no evidence that tolerance occurs with quazepam. It says rapid development of tolerance to temazepam. What it says for temazepam and triazolam is this: "In comparison to triazolam and temazepam, quazepam is more effective with short-term use, and with continued use it maintains its efficacy in contrast to both of these drugs which show rapid development of tolerance."--Literaturegeek | T@1k? 15:56, 21 June 2008 (UTC)

In the 2nd link in my new version it says hypnotic effects deminished. The abstract for temazepam says: "Hypnotic effects were found for both drugs in the early phase, but diminished for both in the late phase".

I am not sure what you are reading? Maybe you misread the abstract?--Literaturegeek | T@1k? 15:59, 21 June

No, I'm talking about Tedeschi et al., "The effect of repeated doses of temazepam and nitrazepam on human psychomotor performance". You're talking about PMID 2905824. Fvasconcellos (t·c) 16:01, 21 June 2008 (UTC)2008 (UTC)

Oh, I know the paper you are talking about. Yes they say that tolerance does not occur over 6 days and I do not dispute that, but if you scroll down to the bottom paragraph they quote the FDA findings that say benzodiazepine hypnotics lose their effectiveness after 3 - 14 days. So that would mean that temazepam loses its effectiveness not less than a week but not more than 2 weeks. Within 2 weeks but not before 1 week.--Literaturegeek | T@1k? 16:07, 21 June 2008 (UTC)

I just edited into my new version that temazepam is effective for 6 days with no evidence of tolerance as the paper says. I just used the paper for the FDA findings, sorry, cleared up confusion.--Literaturegeek | T@1k? 16:10, 21 June 2008 (UTC)

OK. *sigh* I'm still seeing contradictory information, not to mention these are relatively old studies. Isn't anyone studying benzos anymore? :) Aren't there any good meta-analyses out there? Fvasconcellos (t·c) 16:16, 21 June 2008 (UTC)

That 1980 review is a good general reference, thank you Literaturegeek. I've rewritten the proposed text above to try to incorporate all these findings and give a balanced view - it seems like you get no tolerance with short-term use and whether or not you see tolerance in the long term depends on what outcome you are examining and how intensively the people are dosed. Tim Vickers (talk) 17:08, 21 June 2008 (UTC)

I don't come across much new research into benzo tolerance. It has all been researched extensively already over the decades.--Literaturegeek | T@1k? 19:57, 21 June 2008 (UTC)

Second draft of new version

You watered down my papers :=( LOL. Ok I made a new version.

Chronic or excessive use of temazepam may cause drug tolerance, which can develop rapidly, so this drug is therefore not recommended for long-term use. In 1979 the Institute of Medicine (USA) and the National Institute on Drug Abuse stated that most hypnotics lose their sleep-inducing properties after about 3 to 14 days. Indeed, some studies have observed tolerance to temazepam after as little as one week's use. However, another study examined the short-term effects of the accumulation of temazepam over 7 days in elderly patients. Here, the authors concluded that elderly patients showed little tolerance during the accumulation of the drug. Other studies examining the short-term use of temazepam over six days and saw no evidence of tolerance.

In use longer than 1-2 weeks, tolerance will frequently develop towards the ability of temazepam to maintain sleep, so that the drug loses effectiveness. However, not all studies agree. For example, in one study that examined the drug sensitivity of people who had used temazepam for 1-20 years, the responses of these chronic users to the drug was no different from that of controls. This was in contrast to the tolerance that developed with the related benzodiazepine lorazepam, and the authors speculated that this difference may be due to the shorter half-life of temazepam, or to differences in how the two drugs were usually administered. Another study that examined the efficacy of temazepam treatment on chronic insomnia over three months saw no drug tolerance, with the authors even suggesting that the drug might become more effective over time. These studies are complicated by the possibility that tolerance may develop selectively to some, but not all, of the drug's effects. In light of such conflicting data, a recent review by Professor Malcolm Lader at King's College London has noted that for benzodiazipines in general "long-term efficacy remains controversial", but recommended they continue to be limited to short-term treatments.

I am still don't agree about using two papers to dispute health regulatory bodies, one of which used only 11 patients on temazepam and they were paid to take part in the trial. They were recruited from an advertisement in the newspaper. As money may have been a motive to take part in the trial, how do we know that people motivated by money wouldn't be selling their temazepam and this could explain the discrepency. It is easier if wanting benzos to sell on to boost your income to fake insomnia to a doctor than to fake anxiety but I am speculating. The paper said that those on lorazepam were more likely prescribed lorazepam for anxiety associated insomnia than temazepam. Also they screened out psychiatric illness and people had to be on either only temazepam or only lorazepam, if they were taking their temazepam every day for 1 - 20 years, why no day time withdrawal symptoms (psychiatric illness) like anxiety, depression agoraphobia etc etc? Maybe they weren't taking the pills but were selling them? Maybe another explaination? The authors towards the end state that The efficacy of lorazepam or temazepam as a hypnotic after chronic use cannot be determined from this study, although this was the most frequent self-admitted indication for use. Only 11 people. The other trial, I would like to see the full text paper but it is interesting.--Literaturegeek | T@1k? 18:15, 21 June 2008 (UTC)

Could this explain why some papers disagree on whether tolerance occurs? Or could it be poor methadology? Or could I be wrong? Anyone's guess, but here is an interesting reference.

The Journal of Clinical Sleep Medicine published a paper which had carried out a systematic review of the medical literature concerning insomnia medications and raised concerns about benzodiazepine receptor agonist drugs, the benzodiazepines and the Z-drugs that are used as hypnotics in humans. The review found that almost all trials of sleep disorders and drugs are sponsored by the pharmaceutical industry. It was found that the odds ratio for finding results favorable to industry in industry-sponsored trials was 3.6 times higher than non-industry-sponsored studies and that 24% of authors did not disclose being funded by the drug companies in their published paper when they were funded by the drug companies. The paper found that there is little research into hypnotics that is independent from the drug manufacturers.

That's not something we can speculate about. If a paper has been published in a peer-reviewed journal it is unquestionably a relaible source. Tim Vickers (talk) 19:05, 21 June 2008 (UTC)

Ok, how about my version which includes the two papers which say tolerance does not occur. Is it ok compromise?--Literaturegeek | T@1k? 19:19, 21 June 2008 (UTC)

I read relaible source. It says that All articles must adhere to Wikipedia's neutrality policy, fairly representing all majority and significant-minority viewpoints that have been published by reliable sources, in rough proportion to the prominence of each view.

"rough proportion to the prominence of each view."

I think that the majority view is that tolerance develops to temazepam's hypnotic properties seeing as all the health bureaucracies when reviewing the evidence indicate this, so I think my version represents the majority view in the peer reviewed literature more fairly while still mentioning the more minority view that tolerance does not develop.--Literaturegeek | T@1k? 19:40, 21 June 2008 (UTC)

I think we're very close to finding a perfect form of words, either is certainly a big imporvement over the previous verion! The only problem is that the FDA/White House opinions that are cited in the 1980 review are opinions that were published in 1979, almost 30 years ago. I'm hesitant to use this to make a statement about current views on this drug. What do you think of PMID 10622686, which notes the controversy over long-term use of benzodiamidines and reviews the current evidence? Tim Vickers (talk) 20:34, 21 June 2008 (UTC)

Professor Malcolm Lader is one of the world experts on benzodiazepines. He is or should I say was one of the most senior psychopharmacologists in the UK and spent many years studying benzos.--Literaturegeek | T@1k? 20:42, 21 June 2008 (UTC)

Good, do you have access to the full text of that ref? If you need the Pdf just e-mail me through my userpage. Tim Vickers (talk) 20:47, 21 June 2008 (UTC)

I read the full text of the papers quoted here. The international panel paper was on anxiety and temazepam is indicated for insomnia and virtually never prescribed for anxiety. Secondly it was sponsored by the manufacturers of benzodiazepines. Hoffmann-La Roche, Inc., The Upjohn Company, and Wyeth-Ayerst International jointly supported the survey with an unrestricted educational grant. They only discussed benzodiazepines in terms of anxiety so it can't be used to discuss tolerance to hypnotic properties of temazepam. The lader paper only said tolerance to the anxiety properties is controversial. The lader paper actually quotes a study where it was demonstrated by EEG that hypnotic properties of benzodiazepines return to normal within 4 weeks usage of benzodiazepines. The use and abuse paper again only questions in theoretical terms that tolerance to the anxiety properties may not develop but says that tolerance to the sedative properties does occur.

This wiki temazepam article has been criticised for using refs for other benzodiazepines other than temazepam (eg nitrazepam) so I don't think we can use these references especially as they appear to be being taken out of context and the papers actually back my view up that hypnotic properties disappear within a few days to a few weeks and that there is no controversy over tolerance to hypnotic effects. It really is an established fact and proven scientifically via EEG findings as well that hypnotic properties disappear within weeks of continued use of benzo sedative hypnotics. I really am not happy putting misinformation into this article regarding tolerance. The lader article is pretty good though I think. I think lader explains it well though about rebound insomnia and withdrawal anxiety etc being mistaken for a return of the underlying condition by patients and doctors and being mistaken for continued efficacy.--Literaturegeek | T@1k? 21:50, 23 June 2008 (UTC)

The lader paper actually quotes a study which showed that longer term use of benzos, I think 6 or weeks actually while initially helping anxiety actually caused their condition to worsen, and trial subjects became more symptomatic than controls or those on antidepressants. But that is talking about anxiety treatment though and temazepam is indicated for insomnia.--Literaturegeek | T@1k? 22:05, 23 June 2008 (UTC)

Apologies for being a nuisance. :+(--Literaturegeek | T@1k? 22:12, 23 June 2008 (UTC)

I've tried merging the two versions, no point in having two parallel drafts. My first effort at stitching the two together, so have a go at rounding off the rough edges. Tim Vickers (talk) 22:35, 23 June 2008 (UTC)

General concerns

I am actually less concerned about the plagiarized sections from the drug fact sheet. The information is probably most reliable part of this article. (I didn't touch these) I am concerned about unreliable information, like "euphoria was consistently reported, temazepam is extremely euphoric" [ref]. Opening the ref shows incidence of euphoria of 1.5%, much less than headache 9.5% (if I remember correctly) I am also concerned about many other references, which are incorrectly cited. I am also concerned about anecdotal evidence, like "a patient of a psych ward showed brain problems", and biased-collective studies "100 patients of a psych ward showed on average more mental problems than healthy controls", cited as proof for causality of negative effects by temazepam. Furthermore I am concerned about cloak and dagger books of investigational journalism, the evening news, news papers, information leaflets for school childeren (which don't even mention temazepam) and police reports of e.g. some hicktown being cited as reference. I am also concerned about the inclusion of lengthy discussion of some in vitro experiments, which don't lead themselves to anything but conjectures. (I removed some of those, e.g. under unphysiological conditions, in a methanol solution of less than 2,5% (!), without agreed relevance to pharmacological actions.) This looks like reports from the "Journal of irreproducible results", and if WP articles are subverted with that kind of work, we can forget the whole idea of WP. Many of the citations look like scientific april fool jokes. I previously said, I don't want an article which tells me that my sleeping pills are dangerous MKULTRA and KGB torture drugs and being used to keep soviet prisoners in a vegetative state. I don't want to know that they turn me into a criminal in a "Jekyll and Hyde" manner, lead to testicular shrinkage (stop, that was nitrazepam, see there), brain rot and dementia, are the favorite of Nepalese junkies, and are mainly found in the pockets of dead criminals in the morgue, by Glasgow police. These are sleeping pills, for heavens sake. 70.137.161.241 (talk) 02:08, 21 June 2008 (UTC)

I know, everybody is a scientist. Thats the idea of WP, thats why I am editing. I would however prefer if the usage of police reports as scientific reference is a little limited to an appropriate part (what is appropriate will have to be agreed) of the article. Maybe we can use the 100 police report references in a scientific article about knuckle dusters and night sticks. Everybody is a scientist, the police too. And the Glasgow police in particular. 70.137.161.241 (talk) 02:26, 21 June 2008 (UTC)

Let's focus entirely on the article here, and the sources involved. Please list the sources and statements that you have concerns about. It may be helpful to create sections on this talkpage that deal with specific changes of parts of the text, as I have done above. Please offer specific comments and identify better sources. Tim Vickers (talk) 02:55, 21 June 2008 (UTC)

For a list of my concerns, look at history. I have done a series of 34 edits, which are removed from the current version. I have deleted references, which I found erroneous or otherwise insufficient. For instance the whole KGB antics and MKULTRA stories, all references from newspapers, etc. This belongs into this discussion. Alone the verifiability of a claim by some reference is not enough. Here a list of edits. Look that up in history. They are all now deleted from the current version. They revrted to before these edits. an old version, and then locked. Look at it.

1. (cur) (last) 17:35, 18 June 2008 70.137.159.55 (Talk) (70,066 bytes) (deleted depersonalization. The title is "depersonalization after nitrazepam withdrawal" and misrepresented as "after nitrazepam AND TEMAZEPAM withdrawal. FORGERY(!) the 3rd time.)
2. (cur) (last) 17:27, 18 June 2008 70.137.159.55 (Talk) (70,418 bytes) (deleted reference. it is not about temazepam but lorazepam,lormetazepam, nitrazepam.)
3. (cur) (last) 17:23, 18 June 2008 70.137.159.55 (Talk) (70,890 bytes) (deleted reference, it is not about temazepam at all but misrepresented(!) It is about flurazepam. Title forged(!))
4. (cur) (last) 17:19, 18 June 2008 70.137.159.55 (Talk) (71,394 bytes) (deleted reference. It doesn't mention temazepam at all.)
5. (cur) (last) 17:08, 18 June 2008 70.137.159.55 (Talk) (71,899 bytes) (deleted unsourced statements. The reference doesn't talk about that, it is the UK law, not about US, Singapore, etc.)
6. (cur) (last) 14:49, 18 June 2008 70.137.159.55 (Talk) (73,127 bytes) (Undid revision 220070878 by Thegoodson (talk))
7. (cur) (last) 12:00, 18 June 2008 81.105.181.48 (Talk) (96,678 bytes) (Changed infobox 'UK legal' to Class C; see relevant subsection of talk page)
8. (cur) (last) 03:50, 18 June 2008 Thegoodson (Talk | contribs) (96,679 bytes) (Delete work again, and you will no longer be editing after I am done with you...)
9. (cur) (last) 02:56, 18 June 2008 70.137.153.251 (Talk) (73,128 bytes) (deleted tolerance in mice. the study is about nitrazepam, no word about temazepam. erroneous citation!)
10. (cur) (last) 02:48, 18 June 2008 70.137.153.251 (Talk) (73,657 bytes) (added detail from reference)
11. (cur) (last) 02:27, 18 June 2008 70.137.153.251 (Talk) (73,601 bytes) (corrected: after 6 days tolerance to temazepam did NOT occur, from the reference. erroneous citation!)
12. (cur) (last) 02:16, 18 June 2008 70.137.153.251 (Talk) (73,755 bytes) (added in Victoria)
13. (cur) (last) 01:46, 18 June 2008 70.137.153.251 (Talk) (74,093 bytes) (added "in Victoria" from reference. This is not a general phenomenon)
14. (cur) (last) 01:17, 18 June 2008 70.137.153.251 (Talk) (74,034 bytes) (deleted obscure "british study", unsourced statement)
15. (cur) (last) 01:08, 18 June 2008 70.137.153.251 (Talk) (75,241 bytes) (deleted permanent brain damage. The ref is about nitrazepam, not temazepam. They have not seen the patient before. Anecdotal, inconclusive. doesn't provide causality.)
16. (cur) (last) 01:01, 18 June 2008 70.137.153.251 (Talk) (76,158 bytes) (corrected citation from reference: brain damage)
17. (cur) (last) 00:48, 18 June 2008 70.137.153.251 (Talk) (76,059 bytes) (deleted "wobble rave..." ref by Parrott. please provide original reference. This is only cited by Ashton, not her result.)
18. (cur) (last) 00:27, 18 June 2008 70.137.153.251 (Talk) (76,776 bytes) (deleted injection into eyes. This is urban legend. Ashton cites with permission from secondary source,not her result. Please provide primary reference.)
19. (cur) (last) 00:23, 18 June 2008 70.137.153.251 (Talk) (76,914 bytes) (deleted insufficient references: Where published, reviewed?)
20. (cur) (last) 22:58, 17 June 2008 70.137.153.251 (Talk) (77,875 bytes) (corrected: incidence of euphoria=1.5% according to FDA, rarely reported, less than diarrhea and headaches)
21. (cur) (last) 22:39, 17 June 2008 70.137.153.251 (Talk) (77,964 bytes) (deleted reference which was a TV program)
22. (cur) (last) 22:31, 17 June 2008 70.137.153.251 (Talk) (79,298 bytes) (deleted references which were newspaper articles and the evening news)
23. (cur) (last) 22:25, 17 June 2008 70.137.153.251 (Talk) (81,682 bytes) (deleted reference, which was a newspaper article)
24. (cur) (last) 22:21, 17 June 2008 70.137.153.251 (Talk) (82,369 bytes) (deleted reference, which was a newspaper article)
25. (cur) (last) 13:59, 16 June 2008 70.137.174.90 (Talk) (83,039 bytes) (deleted full agonist. ref does not talk about temazepam, but nitrazepam vs. a partial agonist)
26. (cur) (last) 13:44, 16 June 2008 70.137.174.90 (Talk) (83,378 bytes) (deleted duplicate, see drugbox)
27. (cur) (last) 13:38, 16 June 2008 70.137.174.90 (Talk) (83,521 bytes) (deleted Utilization (in Australia only) too narrow, anecdotal. Worldwide would be maybe(!) interesting)
28. (cur) (last) 13:27, 16 June 2008 70.137.174.90 (Talk) (84,135 bytes) (deleted military use, unsourced statement)
29. (cur) (last) 13:19, 16 June 2008 70.137.174.90 (Talk) (84,713 bytes) (sumarized vasopressin/ACTH action and deleted the copy of the whole experiment abstract)
30. (cur) (last) 13:10, 16 June 2008 70.137.174.90 (Talk) (86,322 bytes) (deleted duplicate, see pharmacology)
31. (cur) (last) 13:04, 16 June 2008 70.137.174.90 (Talk) (86,661 bytes) (deleted duplicate, see pharmacokinetics)
32. (cur) (last) 12:51, 16 June 2008 70.137.174.90 (Talk) (86,737 bytes) (deleted KGB antics. refs are sensational bestseller books, investigational journalism, not scientific lit.)
33. (cur) (last) 12:43, 16 June 2008 70.137.174.90 (Talk) (89,101 bytes) (deleted ref[10], it is not about temazepam, but is a leaflet for school children about the dangers of presciption drugs)
34. (cur) (last) 02:33, 16 June 2008 70.137.174.90 (Talk) (90,393 bytes) (deleted cross tolerance with barbiturates. The ref states the other way around, and not with temazepam but flurazepam)
35. (cur) (last) 23:47, 15 June 2008 70.137.174.90 (Talk) (90,997 bytes) (deleted cognitive behavioral tharapy. doesn't belong here. It is "What else can one do to improve sleep?")
36. (cur) (last) 23:40, 15 June 2008 70.137.174.90 (Talk) (93,575 bytes) (deleted opioid effect. direct opioid receptor binding has never been described. This is a speculation based on inhibition of endogenous opioids in rats.)
37. (cur) (last) 23:35, 15 June 2008 70.137.174.90 (Talk) (94,005 bytes) (deleted 3T3 cells. Only mentioned in a side note. They talk about rat thymoma interaction with peripheral benzodiazepines, not temazepam)
38. (cur) (last) 22:16, 15 June 2008 70.137.174.90 (Talk) (94,452 bytes) (deleted cholinesterase inhibition. in vitro, at what concentrations? has never after been shown to be pharmacologically relevant.)
39. (cur) (last) 22:06, 15 June 2008 70.137.174.90 (Talk) (94,842 bytes) (deleted neurosteroid interaction. chemical experiment with enzymes in vitro, at unphysiological concentrations. ref does not claim secured pharmacological action, just conjectures.)

70.137.161.241 (talk) 03:22, 21 June 2008 (UTC)

Please stop cluttering the benzodiazepines with a collection of refs to arbitrary pubmed articles. These are largely reports of some experiments, which have been carried out sometime, somewhere and for some reason on rats, mice and brain slices. Also communications of a really interesting and bizarre case observed in some psych ward. For almost every such article you will find a match which comes to contrary conclusions. Please limit the contribution to agreed conclusions, as found in pharmacology books and the FDA profiles, avoid anecdotal reports, speculative results, could have, may be involved, has one time been observed, is suspected, is being investigated, could have a theoretical connection, is still controversial and disputed etc. Not everything which has sometimes been suspected, investigated, speculated or observed is relevant to pharmacology and should be included. Virtually everything has some time been suspected, investigated, speculated or observed. We have again do discuss the encyclopedia level of factuality and notability. The mere existence of a report somewhere is no evidence for that. Also a compromise of the kind Claim A is still disputed. Claim B is still disputed etc etc. doesn't help. We cannot copy the complete set of pubmed hits on temazepam here and claim them all as still under investigation and leading to contradicting results. Those have not reached the level of relevant and agreed facts. We have to limit this article to encyclopedic, established facts. The claim, that its all from peer reviewed journals is no counterargument. —Preceding unsigned comment added by 70.137.161.241 (talk) 03:06, 21 June 2008 (UTC)

This http://en.wikipedia.org/w/index.php?title=Temazepam&oldid=220181687 is a revised version of the text, before my edits were reverted Please look at it. I didn't yet arrive at most of the police/drug abuse chapter 70.137.161.241 (talk) 03:32, 21 June 2008 (UTC)

I agree with many of the changes you made there. The long section on the detailed pharmacological effects of benzodiazepines in general needed to be removed. The tolerance section was completely wrong (please comment above on if my proposed replacement is any better), and the long discussion of cognitive therapy is misplaced in this article. However, the section on criminality does need to be kept, if re-written in a less sensationalist tone. Tim Vickers (talk) 03:39, 21 June 2008 (UTC)

Criminality, Eins, zwei, Polizei

The section on criminality has to be cleared of anecdotal reports. The fact is that benzos and temazepam are drugs, which are with some incidence being misused. In the case of temazepam, the focus on illegal use, street use is essentially in people who have not legitimate access to alcohol, like underage youth, and in people from societies where alcohol use is traditionally frowned upon or illegal due to religious law. There the use of an "alcohol pill" sells in an illegal mass market. (Nepal, south east asia, Malaysia) Some notability of reported confiscations in the order of 100s pills. (Normally thats not noteworthy, one family pack) These are results of extremely restrictive laws in Singapur, Brunei, some other arabic states. The overall importance of this is approximately described by DEA reports, which list these drugs as drugs of concern. We don't need to elaborate on this with 50% of the article filled with repetitive citations from dozens of drug related bulletins. One concise chapter summarizing the DEA report is enough. Please no stories from "Glasgow morgue", "Edinburgh concerned pharmacists", "Victoria health department advisory", "Heather Ashtons speech before the pharm critical grass roots organization" etc. etc. etc. This are all repetitions. The whole part of this article is a repetition of death, amputation, crime, death, amputation, crime and so forth. The DEA has already summarized it correctly, with an additional good deal of concern and caution. We don't need to further support this position by endless repetitions. 70.137.161.241 (talk) 04:07, 21 June 2008 (UTC)

In fact I had to grin subversively, reading about confiscation reaching from 20 pills upward in Singapore. I think we really should not care, if they raise the possession of 20 sleeping pills to a capital crime, to be punished with 20 years of prison or death. That is an artifact of their hysterical law. They also punish spitting, have signs "no pissing, its a felony" in the elevator and limit the number of potted plants on the balcony. Violation is a misdemeanor. 70.137.161.241 (talk) 04:25, 21 June 2008 (UTC)

I hope, after reading the diff list of my edits, you see more clearly what I was talking about in my remarks. They were really to the point, and about this article. This discussion has been going on for months. The crime chapter is not only sensational in wording, but also bloated out of proportion to its importance by endless citations of anecdotal and police reports, see above my remarks about this. We could continue like this ad infinitum. Where is the report of the sheriffs office in Timbuktu, the coroner in (list of suburbs of all cities above 100000) Not to forget, what the park ranger in Lesoto experienced, when he confiscated pills, etc. etc. This chapter is scalable in size arbitrarily. The counter argument is not that the citations are not true! The counterargument is that nobody gives a shit about these anecdotes, once the overall picture has been summarized in 3 sentences. It is just not notable information. Otherwise please include the case history of every addict of temazepam, who has ever lived. And include those which can not be found now later, after more thorough investigations, or state that the results are still inconclusive because the materials are not complete. 70.137.161.241 (talk) 04:55, 21 June 2008 (UTC) 70.137.161.241 (talk) 04:55, 21 June 2008 (UTC)

Tim, what edits of my list you do NOT agree with? 70.137.161.241 (talk) 05:09, 21 June 2008 (UTC)

I don't like the way that in some of those edits you removed entire sections with the reason given that you thought the source was unreliable. Just tag any such sources with {{Verify credibility}} or remove the citation and add the {{Fact}} template. This gives other editors a chance to find better sources. Tim Vickers (talk) 14:20, 21 June 2008 (UTC)

There is a big chunk of stories referenced here:

One in five risking death or amputation. The Independent - London (13 May, 1995). Retrieved on 2008-02-18. Deadly craving for 'jellies' leads to crime wave. The Independent - London (19 August, 1995). Retrieved on 2008-02-18. Deadly 'jellies' flood city from Eastern Europe; Police chiefs fear drug-fuelled crime surge as home-made tablets hit streets again. Evening Times (10 October, 2003). Retrieved on 2008-02-18. Frontline Scotland Pure Lethal (BBC Television program). ? (25 January, 2000). Retrieved on 2008-03-01.

I propose to remove these. Living in the US, I am aware of the questionable quality of journalism and the evening news. "Weapons of mass destruction found in Iraq", "Joints dipped in embalming fluid from funeral home", "Clairvoyant predicting terror attack", "Bible contains all the future in encrypted format" etc. etc. "Hitler was taking 1g of atropine every day". No kidding. What these illiterates write is not a scientific reference. 70.137.161.241 (talk) 19:56, 21 June 2008 (UTC)

My views

Chatroom

Is it really necessary to fill discussion pages up over and over again with endless arguments by this anon user. I realise that now I am filling up the talk page but I have had problems with this anon user for months and months and feel I have to say what I have to say.

I think that people are over-reacting to references which have been misrepresented, such as nitrazepam being swapped for temazepam. Don't misinterpret me I do think that it was pushing it a bit to use a reference for nitrazepam in an article on temazepam. I think that it is important to remember that benzodiazepines tend to have the exact same side effects and withdrawal effects as one another. In the British National Formulary for example it will say for side effects of benzodiazepines other than diazepam "See under diazepam". All benzodiazepines bind to benzodiazepine receptors located on the alpha1 alpha2, alpha3 and alpha5 subunits of the GABAa receptor. The main difference is elimination half life between the benzos. With that being said some benzos tend to be worse than others or better than others depending on how you look at it and their can be subtle differences between benzodiazepines. I support either removing references which do not refer to temazepam or else ammending them to say "benzodiazepine drugs have been found to,,," instead of "temazepam has been found to,,," or whatever. So remove or ammend I support either. I think that the problems of the temazepam article really does not warrant this huge amount of drama and filling up of talk pages with endless arguing and absorbing huge amounts of time and emotions of various editors and admins on behalf of this anon editor.--Literaturegeek | T@1k? 09:32, 21 June 2008 (UTC)

I would also like to remind the admins that when I was reverting anon's edits, that I have not contributed heavily to this article and thus am not familiar with the abstracts used. I can now see that the anon is disguising their bias now better by mixing it with some genuine edits. I did break the 3 revert rule though and am guilty of that.--Literaturegeek | T@1k? 09:58, 21 June 2008 (UTC)

Changes I support or oppose

I will edit this list as the debate progresses. I so far;

• Support, either removing refs which refer to nitrazepam and not temazepam, or else I support ammending it to say "benzodiazepines" (see above topics for further explaination). I think that it is probably better they are removed though.
• Weak support, the removal of cognitive behavioural therapy section. It is an edit which I made.
• Oppose the censoring of temazepam's use by intelligence agencies.
  • I agree this could stay in the article, as long as we don't focus unduly on it and it's properly referenced. I also think it should be in a separate section, i.e. not in "History". Fvasconcellos (t·c) 16:19, 21 June 2008 (UTC)
• Oppose removing temazepam's injection in the eye by an addict.
  • This page has a picture of said addict's eye after injection of temazepam, and gives a reference "Thompson et al. 1993" which unfortunately is not complete enough to identify the source. Meodipt (talk) 06:47, 22 June 2008 (UTC)

Source here: http://www.pubmedcentral.nih.gov/pagerender.fcgi?artid=1679637&pageindex=1 Open the link. I do however doubt that this is encyclopedia type material, I see it as anecdotal. Also I remember having read this earlier, since the 70s, with varying substances and at varying places. So it must have happened more than once, or my memory is betraying me. 70.137.161.241 (talk) 14:05, 22 June 2008 (UTC)

• Oppose suggesting tolerance occurs occasionally and using 6 day clinical trials without using trials which last longer than 6 days which show rapid development of tolerance. Also this is in direct opposition to FDA, CSM and just about every other health body.--Literaturegeek | T@1k? 15:41, 21 June 2008 (UTC)
  • I'd like to point out Tim's proposed version was indeed cited to two long-term trials, in addition to mentioning short-term ones. Fvasconcellos (t·c) 16:17, 21 June 2008 (UTC)

Copy-pasted content

I am going to be bold and remove copy-pasted content, such as full article abstracts and copy-pasted drug monograph sections, from the article. This page has enough going on as it is, and I think copyright concerns, whether legitimate or unfounded, are serious enough for this to take precedence. We can always return constructive content to the article later. Fvasconcellos (t·c) 14:38, 21 June 2008 (UTC)

• I agree. Tim Vickers (talk) 14:39, 21 June 2008 (UTC)
• I support, due to copyrite concerns.--Literaturegeek | T@1k? 14:46, 21 June 2008 (UTC)

Pharmacology

I propose moving the following paragraph from the "Pharmacology" section into the main benzodiazepine page, and leaving a brief note in the article:

Temazepam and other benzodiazepines may influence neurosteroid metabolism and progesterone levels which in turn may influence the functions of the brain. The pharmacological actions of benzodiazepines at the GABAa receptor are similar to those of neurosteroids. Neuroactive steroids are positive allosteric modulators of the GABAa receptor, enhancing GABA function. Many benzodiazepines (diazepam, medazepam, estazolam, nitrazepam flunitrazepam and temazepam) potently inhibit the enzymes involved in the metabolism of neurosteroids. Long-term administration of benzodiazepines may influence the concentrations of endogenous neurosteroids, and thereby would modulate the emotional state. Factors which effects the ability of individual benzodiazepines to alter neurosteroid levels depend on the molecular make up of the individual benzodiazepine drug. Presence of a substituent at N1 position of the diazepine ring and/or the chloro or nitro group at position 7 of the benzene ring contribute to potent inhibition of the isoenzymes, and in turn a bromo group at position 7 (for bromazepam) and additional substituents (3-hydroxy group for oxazepam and tetrahydroxazole ring for cloxazolam and oxazolam) decrease the inhibitory potency of benzodiazepines on neurosteroids.

The following statements in the section also need to be placed in some sort of context (clinical relevance? research possibilities?), otherwise they're just factoids:

Temazepam also has an inhibitory effect on cholinesterase. Temazepam also inhibits Swiss 3T3 cells.

—Fvasconcellos (t·c) 14:53, 21 June 2008 (UTC)

Swiss 3T3 cells: They are only mentioned in a side note of the reference. The reference is about rat thymoma cell binding of an experimental peripheral benzodiazepine receptor ligand, not temazepam, and doesn't mention temazepam at all.

1. (cur) (last) 23:35, 15 June 2008 70.137.174.90 (Talk) (94,005 bytes) (deleted 3T3 cells. Only mentioned in a side note. They talk about rat thymoma interaction with peripheral benzodiazepines, not temazepam)

Acetylcholinesterase inhibition: The abstract doesn't mention conditions and concentrations of this in vitro chemical experiment. Pharmacological consequences in vivo have not been described afterwards. It seems to be one of the experiments, which lead themselves to nothing. Benzodiazepines as future insecticides maybe?

1. (cur) (last) 22:16, 15 June 2008 70.137.174.90 (Talk) (94,452 bytes) (deleted cholinesterase inhibition. in vitro, at what concentrations? has never after been shown to be pharmacologically relevant.)

Propose to remove for above reasons. Opinions? 70.137.161.241 (talk) 04:29, 23 June 2008 (UTC)

Opioid mechanism: This is a reference about inhibition of some behavioral effects (locomotion) of benzodiazepines in rats, by naloxone. Naloxone antagonizes behavioral effects of many substances and other effects, including the effects of electro-shocks, via inhibition of endogenous opioids. See pubmed [related] hits. The article is more about the effects of naloxone vs. rat locomotion, than benzodiazepines. Direct opioid receptor binding of temazepam or its metabolites has never been described. The reference used nitrazepam, not temazepam.

1. (cur) (last) 23:40, 15 June 2008 70.137.174.90 (Talk) (93,575 bytes) (deleted opioid effect. direct opioid receptor binding has never been described. This is a speculation based on inhibition of endogenous opioids in rats.)

Propose to delete. Other opinions please. 70.137.161.241 (talk) 04:29, 23 June 2008 (UTC)

Interaction with neurosteroids: Yamamoto, Shintani et al This is an in vitro experiment with enzymes, under unphysiological conditions (in a solution containing less than 2.5% methanol.) Reading it I can see no pharmacological relevance, this are just proposals for future research in their conclusions. IMO this is a reference which has not reached the stage of agreed factuality and relevance for inclusion in an encyclopedia. I can not see the statements in the article to be derived from this paper. Please someone proofread the article against the reference, and see if i missed something. 70.137.161.241 (talk) 15:07, 21 June 2008 (UTC)

1. (cur) (last) 22:06, 15 June 2008 70.137.174.90 (Talk) (94,842 bytes) (deleted neurosteroid interaction. chemical experiment with enzymes in vitro, at unphysiological concentrations. ref does not claim secured pharmacological action, just conjectures.)

70.137.161.241 (talk) 04:29, 23 June 2008 (UTC)

Yes, the most recent review I can find on neurosteroids (PMID 10662535) doesn't mention these findings at all, or cite Yamamoto et al. None of the other papers that cite this publication (link) show any in vivo relevance. Doesn't seem very important. Tim Vickers (talk) 17:16, 21 June 2008 (UTC)

I propose to remove the reference and its projected pharmacological consequences from the pharmacology paragraph. It is just speculative and cannot be derived from the ref.

I also propose to add "and blunts the ACTH stressor response in rats" to the vasopressin release statement. I think this got lost in the cleanup of the lengthy laboratory procedure of the vasopressin release experiments. See my edit in history, where I concluded the result. 70.137.161.241 (talk) 17:40, 21 June 2008 (UTC)

Yes, it was lost in the cleanup. How about simplifying it to "and decreases stress-induced ACTH secretion", which would be a bit more lay-friendly? Fvasconcellos (t·c) 17:54, 21 June 2008 (UTC)

Thats good. Also look at the neurosteroid. It really doesn't lead itself to the article. 70.137.161.241 (talk) 18:01, 21 June 2008 (UTC)

It might do ok in the main benzo article. The pharmacology section is a bit lacking.--Literaturegeek | T@1k? 18:58, 21 June 2008 (UTC)

It doesn't lead itself to the pharmacology of benzodiazepines either. It is just a chemical experiment. See remarks of TimVickers above. The conclusions drawn in the temazepam article are not supported by the ref. So they shouldn't reappear in the benzodiazepines article either. The ref simply doesn't say that, and nobody else has drawn in vivo or human pharmacology conclusions either. 70.137.161.241 (talk) 19:13, 21 June 2008 (UTC) 70.137.161.241 (talk) 19:13, 21 June 2008 (UTC)

So, is everyone clear on removing the neurosteroid paragraph? Fvasconcellos (t·c) 21:12, 23 June 2008 (UTC)

I added that neurosteroid paragraph. I agree to it's removal. I am not happy with the tolerance proposals at all though above :=(.--Literaturegeek | T@1k? 22:09, 23 June 2008 (UTC)

Journalism, the evening news, the BBC

One in five risking death or amputation. The Independent - London (13 May, 1995).

Deadly craving for jellies leads to crime wave. The Independent - London (19 August, 1995).

Deadly jellies flood city from Eastern Europe; Police chiefs fear drug-fuelled crime surge as home-made tablets hit streets again. Evening Times (10 October, 2003).

Frontline Scotland Pure Lethal (BBC Television program). (25 January, 2000).

I propose to remove these. Living in the US, I am aware of the questionable quality of journalism and the evening news. "Weapons of mass destruction found in Iraq", "Joints dipped in embalming fluid from funeral home", "Clairvoyant predicting terror attack", "Bible contains all the future in encrypted format" etc. etc. "Hitler was taking 1g of atropine every day". No kidding. These are not scientific references. 70.137.161.241 (talk) 14:21, 22 June 2008 (UTC)

The Independent and BBC are very reliable sources, probably roughly equivalent to the NYT and NPR in your country (although I'd rank the BBC a bit higher myself!). The only question in my mind is if this problem is notable enough to be mentioned in a worldwide encyclopaedia. Tim Vickers (talk) 14:56, 22 June 2008 (UTC)

For the injection of "jellies", speaking personally I know this has been a problem highlighted by the media in Scotland and there is some academic literature on the topic, so I think we should mention it. See link 1, link 2 link 3. See also link 4 and link 5, which suggests this is also a problem in Australia, which resolves the notability problem for me. Tim Vickers (talk) 15:10, 22 June 2008 (UTC)

Yes, mention. But not by endless repetition of reports from 100 places, repeated over 5 pages. I may remind that the citations are not complete ever. They mentioned Nepal, but they forgot the incidence in New Guinea and Ruanda. etc. hope you see what I mean to say. This can be summarized in few sentences. See above my remarks of "criminality, eins, zwei, polizei". It is indeed a question of notability, as I said there. The volume of such citations is entirely scalable ad infinitum. Wiki is about everything and its all true. But we have to summarize, not bloat by repetition of anecdotal and police reports and the news and the border post and and and and.... 70.137.161.241 (talk) 15:32, 22 June 2008 (UTC)

I agree, we need to give a broad overview that outlines all the important points, not a collection of factoids. Tim Vickers (talk) 16:20, 22 June 2008 (UTC)

Not only the crime chapter is bloated by factoids with unclear relevance to the topic at hand. The pharmacology chapter and others too suffer from that, including the complete laboratory procedure for the vasopressin/ACTH rat experiment, now to be summarized in one short sentence. Including the neurosteroid section, with an overinterpreted chemical experiment, including single case of braindamaged patient encountered in some hospital. (they have not seen him before his drug abuse of 30 years, so causality cannot be derived) This was finally my reason to do a series of 34 bold edits, to get a discussion of these issues. The edits are all reverted, but at least we have a discussion rolling. 70.137.161.241 (talk) 16:48, 22 June 2008 (UTC)

Very true, but Wikipedia:BOLD, revert, discuss cycle might have been a better way to approach this! Anyway, I'm sure the article will be improved by this, we seem to be coming to general agreement on several points. Tim Vickers (talk) 16:51, 22 June 2008 (UTC)

Thats what I tried. But it became Wikipedia:BOLD, revert, no discussion cycle. 70.137.161.241 (talk) 17:59, 22 June 2008 (UTC)

Page unprotection?

Hi everybody. Since the discussion on this talkpage now seems quite constructive, and the previous edit-warring has been acknowledged as a regrettable example of how things can sometimes get out of hand, what do people think about unprotecting the page? We could start by removing the cognitive therapy section, which I think we all agree isn't directly relevant to temazepam. I've got to stress though that any further edits will have to go slowly, and with careful discussion and drafting on the talkpage. Tim Vickers (talk) 17:00, 22 June 2008 (UTC)

• Agree 70.137.161.241 (talk) 17:19, 22 June 2008 (UTC)
• Tentatively, yes. I'm a bit concerned that TheGoodSon hasn't been around in a couple of days and may not even be aware of how the discussion is progressing, but I'm also of the opinion that full protection should not be extended beyond what is strictly necessary. Fvasconcellos (t·c) 18:18, 22 June 2008 (UTC)
• Neutral--Literaturegeek | T@1k? 19:31, 22 June 2008 (UTC)
• Support. I think we're making quite a bit of headway here, and if *all* parties can agree to be levelheaded, that momentum would really be beneficial to the renovation of this article. St3vo (talk) 22:52, 22 June 2008 (UTC)

OK, I've removed the protection. Let's take this slowly and check on the talkpage that people are OK with changes before making them. Anybody using reversion, rather than discussion, to influence the article will be blocked from editing. Tim Vickers (talk) 20:59, 23 June 2008 (UTC)

Braindamage

Delete the reference about braindamage by temazepam. This is an anecdotal report about an abuser of NITRAZEPAM (not temazepam), in whom persistent braindamage was suspected after withdrawal. Severe hypoperfusion of the brain was seen. The doctors had not seen him before his 30 year nitrazepam abuse. The results are inconclusive, no causality is provided, it is the extreme case of biased collective study with N=1, a single patient who came in very ill.

ref Kitabayashi et al.

I propose to delete, as such anecdotal single patient case doesn't give evidence for the rather general statement in the article. The development of persistent neurological/braindamage by bemzodiazepines is at best a disputed claim, by no means an established fact. See discussion above, about braindamage, Karolinska study, contradicting studies, biased collective studies. Please other opinions. I think the ref doesn't lead itself to the general statements. 70.137.161.241 (talk) 01:54, 24 June 2008 (UTC)

Seems reasonable; I'm sure there are higher-quality references to support this particular statement, although "sudden and violent death" is very unencyclopedic wording in my opinion. I don't think the article should give much emphasis to anecdotal reports, animal studies, or studies about other benzodiazepines with conclusions/results not generalizable to temazepam. Fvasconcellos (t·c) 01:58, 24 June 2008 (UTC)

The "sudden and violent death" claim was added by Thegoodson at the same time as one of the ref alterations, and I think it's safe to remove without further discussion. I definitely support removing Kitabayashi et al and agree with 70's concerns re: biased collective studies, but as temazepam shares considerable pharmacology with the other hypnotics like nitrazepam and flunitrazepam, I think we should state something like, "There is evidence that long term abuse of hypnotics like temazepam may lead to permanent brain damage..." and go on to describe the evidence both for and against as in sections above. Refs specifically looking at temazepam are strongly preferred, of course, but the concerns seem well-represented in the literature and I'm inclined to present the whole picture rather than throwing out multiple reliable sources. St3vo (talk) 03:36, 24 June 2008 (UTC)

Yes, going from a single case of nitrazepam withdrawal to saying high doses of benzodiazepines will cause brain damage is untenable. Tim Vickers (talk) 03:26, 24 June 2008 (UTC)

Removed. Fvasconcellos (t·c) 00:51, 25 June 2008 (UTC)

Swiss 3T3 cells

Swiss 3T3 cells: They are a laboratory mouse tumor cell line. They are only mentioned in a side note of the reference. The reference is about rat thymoma cell binding of an experimental peripheral benzodiazepine receptor ligand, not temazepam, and doesn't mention temazepam at all.

(cur) (last) 23:35, 15 June 2008 70.137.174.90 (Talk) (94,005 bytes) (deleted 3T3 cells. Only mentioned in a side note. They talk about rat thymoma interaction with peripheral benzodiazepines, not temazepam)

Propose to delete, no relation to topic at hand: in vivo or human pharmacology, temazepam. Please other opinions.

Remove, no possible in vivo significance. Tim Vickers (talk) 18:25, 25 June 2008 (UTC)

Acetylcholinesterase inhibition

Acetylcholinesterase inhibition: The abstract doesn't mention conditions and concentrations of this in vitro chemical experiment. Pharmacological consequences in vivo have not been described afterwards. It seems to be one of the experiments, which lead themselves to nothing. Benzodiazepines as future insecticides maybe?

(cur) (last) 22:16, 15 June 2008 70.137.174.90 (Talk) (94,452 bytes) (deleted cholinesterase inhibition. in vitro, at what concentrations? has never after been shown to be pharmacologically relevant.)

Propose to remove for above reasons. Please other opinions. 70.137.161.241 (talk) 02:19, 24 June 2008 (UTC) 70.137.161.241 (talk) 02:22, 24 June 2008 (UTC)

This is serum cholinesterase, not acetylcholinesterase. Tim Vickers (talk) 00:12, 25 June 2008 (UTC)

Not really. Per abstract they look at BOTH, red cell cholinesterase=Acetylcholinesterase AND plasma cholinesterase=Butyrilcholinesterase=Pseudocholinesterase. However, the abstract doesn't mention conditions and concentrations of the experiment, for the observed in vitro inhibition. I guess unphysiological. No in vivo or human pharmacological consequences known IMO or described afterwards. Please correct me. 70.137.161.241 (talk) 01:15, 25 June 2008 (UTC)

Yes, it just looks like a factoid to me. I couldn't find any papers citing this publication, but that might be because it was so old. Tim Vickers (talk) 02:44, 25 June 2008 (UTC)

Proposed Pharmacology

Old revision: with edits

Temazepam is classed as a 1,4 benzodiazepine, with the chemical name 7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1-4-benzodiazepin-2-one. (duplicate, see drug box) It is structurally most closely related to diazepam and oxazepam. In its clinical effects however, temazepam is most closely related to nimetazepam, nitrazepam, and flunitrazepam. [11] It is a white, crystalline substance, is very slightly soluble in water and sparingly soluble in alcohol. It is lipophilic and is metabolized hepatically via oxidative pathways. (duplicate see Pharmacokinetics) The main pharmacological action of temazepam is the enhancement of the increase the effect of the inhibitory neurotransmitter GABA at the GABAA receptor. Temazepam is a powerful agonist of the α1 subunit of the GABAA receptor. Positive Modulation of the α1 subunit of the receptoris associated with sedation, motor-impairment, ataxia, and reinforcing behavior.[12] The half life of temazepam is 8-22 hours.[13] (duplicate, see drugbox and Pharmacokinetics) It is a full agonist of the benzodiazepine receptor.[14] (probably true, but the reference is nitrazepam) duplicate

In rats, temazepam triggers the release of vasopressin into paraventricular nucleus of the hypothalamus.[15]and reduces the stress-induced release of ACTH in rats.

Temazepam also has an inhibitory effect on cholinesterase,[16] (likely a pharmacologically irrelevant in vitro experiment) and inhibits mouse Swiss 3T3 cells lab culture.[17] (certainly irrelevant, ref is about an experimental chemical on rat tumor cells, not temazepam}

New proposed revision: Temazepam is structurally most closely related to diazepam and oxazepam. (it is 1-methyl- oxazepam, or a hydroxy-diazepam. I buy that)

In its clinical effects however, temazepam is most closely related to nimetazepam, nitrazepam, and flunitrazepam. [3] The ref abstract doesn't yield that. Full text somebody? (I believe we would have to show that it has in common with the other ones a pronounced binding to the a1 subunit, and pronounced sedative effect vs. day anxiolytics. No reference.)

It is a white, crystalline substance, is very slightly soluble in water and sparingly soluble in alcohol.

The main pharmacological action of temazepam is to increase the effect of the inhibitory neurotransmitter GABA at the GABAA receptor. Positive modulation of the GABA receptor by the α1 subunit of the receptor is associated with sedation, motor-impairment, ataxia, and reinforcing behavior.[12]

Temazepam triggered the release of vasopressin into the rat hypothalamic paraventricular nucleus and they don't yet exactly know how reduced stress-induced secretion of ACTH in a dose-dependent manner in rats.[6]

Stress results in release of adrenocorticotropic hormone (ACTH) from the pituitary into the general bloodstream, which results in secretion of cortisol and other glucocorticoids from the adrenal cortex. These corticoids involve the whole body in the organism's response to stress and ultimately contribute to the termination of the response via inhibitory feedback.[8] copied from WP: Stress

Consequently it may be speculated that a reduced secretion of ACTH in response to stress leads to a reduction of the whole body stress response. Own conjecture, a reference for that somebody?

70.137.161.241 (talk) 06:32, 26 June 2008 (UTC)

 —Preceding unsigned comment added by 70.137.161.241 (talk) 23:58, 24 June 2008 (UTC) 

70.137.161.241 (talk) 00:29, 25 June 2008 (UTC) Please other opinons and edits. 70.137.161.241 (talk) 02:45, 24 June 2008 (UTC) 70.137.161.241 (talk) 00:43, 25 June 2008 (UTC)

This revision looks good. Could there be a sentence on the implications of its actions on ACTH, or at least a statement that implications are unknown? Also, perhaps a word on what clinical effects it shares with nitrazepam et al? St3vo (talk) 22:23, 24 June 2008 (UTC)

Utilization

The utilization chapter only mentions the presciption use in Australia. No relation or conclusions, a single sprinkle of anecdotal fact. Propose to delete, until a useful embedding and conclusion arises. As such it appears as a useless factoid to me. Other opinions?

I agree, we need to expand and clarify the main paragraphs on what this drug is prescribed for. This seem a strange add-on to this section that deals with use in Australia, I don't think it is used for different purposes in Australia, so I don't see the point of focusing on one country here. Tim Vickers (talk) 00:05, 25 June 2008 (UTC)

With this in mind: deleted 70.137.161.241 (talk) 06:32, 26 June 2008 (UTC)

Military use

Another factoid. This is not exactly what I associate with military use. The other explanations about Modafinil and Zombieclone Zaleplone are tangential to the article IMO. Whole chapter unsourced, of questionable relevance and notability, certainly doesn't deserve a chapter of its own. Hell, if it were Sarin, maybe. Next we devote a whole chapter elsewhere to the military use of the US Army std. (ACME brand) toothpaste and not to forget the US Army std. foot balm (also ACME ) they use to treat blisters. Propose to delete. Other opinions? 70.137.161.241 (talk) 05:57, 24 June 2008 (UTC)

I'd guess from my Google searches that this was added in response to the USAF friendly-fire incident with the Canadians in Afghanistan. However, the drugs those reports focused on were amphetamines, with sleeping pills mentioned in passing. Makes sense - you're not going to give fighter pilots sedatives! I'd cut this myself, this is a article on worldwide use of this drug, the US military is not a significant part of the market. Tim Vickers (talk) 23:39, 24 June 2008 (UTC)

A military use that could be significant is the use of temazepam for the treatment of seizures caused by nerve agents. See link. Tim Vickers (talk) 00:13, 25 June 2008 (UTC)

The link doesn't open. Its pay-per-view. 70.137.161.241 (talk) 17:54, 26 June 2008 (UTC)

Normally they would give a hell of a dose of diazepam for that, thats easier available everywhere and long acting. 70.137.161.241 (talk) 06:32, 26 June 2008 (UTC) Until then: deleted. 70.137.161.241 (talk) 06:32, 26 June 2008 (UTC)

"Toxicity" section

Would anyone object to merging this section (which still appears to contain text copied verbatim from research articles—I'll check on that in a moment) into "Overdose"? There's certainly some overlap, and I really don't see any content in here that merits a standalone section. Fvasconcellos (t·c) 00:55, 25 June 2008 (UTC)

I believe all but the first sentence is plagiarized from the intro/methods/discussion sections of Buckley et al 1995...but I support the merging of that sentence :) St3vo (talk) 01:10, 25 June 2008 (UTC)

Go ahead. Cut and merge. Tim Vickers (talk) 01:13, 25 June 2008 (UTC)

Done. There was indeed very little that could be saved. I've also removed the following statement from the "Overdose" section, as it was redundant to the paragraph preceding it, but now I think it may actually be a better fit (prose is nearly always better than a "laundry list"):

Overdose of temazepam may result in excessive sedation, impairment of balance and speech. This may progress in severe overdoses to respiratory depression or coma and possibly death. The risk of overdose is increased if temazepam is taken in combination with alcohol, opiates or other CNS depressants. Temazepam overdose responds to the benzodiazepine receptor antagonist flumazenil.

I'd appreciate a look at my attempted rewrite and suggestions for further improvement. Fvasconcellos (t·c) 02:47, 25 June 2008 (UTC)

Tim, look at reply AChE, also at proposed Pharmacology. Your opinions? 70.137.161.241 (talk) 01:45, 25 June 2008 (UTC)

Dependence

Abrupt withdrawal after long term use from therapeutic doses of temazepam may result in a very severe benzodiazepine withdrawal syndrome. There are reports in the medical literature of at least six psychotic states developing after abrupt withdrawal from temazepam including delirium after abrupt withdrawal of only 30 mg of temazepam and in another case, auditory hallucinations and visual cognitive disorder developed after abrupt withdrawal from 10 mg of temazepam, 5 mg of nitrazepam and 0.5 mg of triazolam. Gradual and careful reduction of the dosage, preferably with a milder long-acting benzodiazepine such as clonazepam or diazepam, or even a milder short to intermediate acting benzodiazepine such as oxazepam or alprazolam, was recommended to prevent severe withdrawal syndromes from developing. Other strong hypnotic benzodiazepines, whether short, intermediate or long-acting are not recommended.[40]

ref Terao et al.

The reference doesn't talk about temazepam, nitrazepam and triazolam. They talk about nitrazepam and triazolam only, together with sleep deprivation. I don't see the article statements derived from the reference. The reference is in Japanese. Propose to remove. Unsourced statement. Ref anecdotal N=2, biased collective, unrelated, different substance, says it is extremely rare and noteworthy. (exotic?)

Maybe instead add a reference where a Japanese slit his belly open under the influence of temazepam. 70.137.161.241 (talk) 18:19, 25 June 2008 (UTC)

Death, the coroner, statistics, mixed intoxication, drowning etc.

I may remind that the frequently cited coroners reports are extremely difficult to interpret. A few thoughts:

They are an extreme case of biased collective=the dead ones found somewhere. Causality is not provided.

They have to be corrected for the circumstances, which are frequently unclear: Example: Elderly vagrant found dead under a bridge, with temazepam in blood. Question: Natural death with coincident temazepam use? Exposure with coincident temazepam? Malnourishment with temazepam? Unclear virus infection with temazepam? Combination of those? No causality provided.

Statistics: If temazepam had absolutely no connection to mortality at all, like a breath mint, we would still find cases of natural death, with ingestion of a breath mint, just by intersecting the sets "natural death" with "breath mint user". No causality provided, just dead breath mint users.

Mixed intoxication: Alcohol in particular has a narrow "therapeutic margin". Do we count this as a temazepam death when temazepam is found?

Drowned suicide victim: Is this a temazepam death?

Statistics,correlation with common cause: Intersection of biased collective=skid row population etc., higher incidence of death in those, drug use in those leads to an appearance of causality on careless interpretation. This is a statistic fallacy. (skid row has a high mortality), (skid row uses drugs) -> (drugs cause mortality.) No causality provided.

I propose to use such reports only with great care to derive any causality. Propose to delete a lot of conclusions based on that. Other opinions? 70.137.161.241 (talk) 19:46, 25 June 2008 (UTC)

To illustrate the point: Sudden Death and Benzodiazepines.

Article American Journal of Forensic Medicine & Pathology. 17(4):336-342, December 1996. Drummer, Olaf H. Ph.D; Ranson, David L. D.M.J.

Abstract: A study of 16 deaths associated with toxic concentrations of benzodiazepines during the period of 5 years leading up to July 1994 is presented. Cases where other drugs, including ethanol, had contributed to the death were excluded. All cases were subject to a full macroscopic and microscopic examination by pathologists, and all cases were subject to a full toxicological work-up. Preexisting natural disease was a feature of 11 cases. In the remaining five cases, death was caused solely by benzodiazepines. There were 14 suicides. Nitrazepam and temazepam were the most prevalent drugs detected, followed by oxazepam and flunitrazepam. Minimum toxic femoral blood concentrations of 7-aminonitrazepam, 7-aminoflunitrazepam, and oxazepam were estimated as 0.5, 0.2, and 2 mg/L, respectively. Relating these deaths to prescription rates in Victoria suggest that flunitrazepam may be inherently more toxic if misused than other benzodiazepines currently available on the Australian market.

Concluding: In a study of 16 deaths over 5 years, they found 11 times preexisting disease. 14 were suicides. In 5 cases benzodiazepines were the sole cause of death. Flunitrazepam may be inherently more toxic than other benzodiazepines.

Of course, suicide is part of an extremely unhealthy lifestyle, biased collective again. —Preceding unsigned comment added by 70.137.161.241 (talk) 08:04, 27 June 2008 (UTC) Questions and comments: Does anybody have access to the full source for details? How did they determine causality and at what doses? IMO the LD50 is so high that it is hard to kill yourself. This remains unclear to me and needs a closer investigation IMO. So, how many were temazepam, at what concentration and estimated dosis? 70.137.161.241 (talk) 20:52, 26 June 2008 (UTC)

Cleaned up

Pharmacology: previously discussed points, duplicates from Pharmacokinetics, Drug box; another Nitrazepam/Temazepam switch: Podhorna et al. Is about Ro 19-8022 vs. nitrazepam in angry mice, not temazepam. Doesn't say temazepam is a full agonist.

Indications: Duplicate from Dependence, Tolerance. duplicate ref Podhorna et al. see above.

Side effects: corrected "frequent euphoria, more than other ..." into an objective "incidence 1.5%" thats what the ref says.

Please opinions. Please don't revert without discussion. 70.137.161.241 (talk) 01:36, 26 June 2008 (UTC)

Looks good to me - no objections. St3vo (talk) 02:56, 27 June 2008 (UTC)

Vasopressin

There is still an open point with the rat stress vasopressin experiment. ref says benzodiazepine causes vasopressin release into paraventricular nucleus. Another reference says it blocks vasopressin release (into the body I presume)

http://cat.inist.fr/?aModele=afficheN&cpsidt=2955611

So are these refs to be explained by the closed feedback loop regulation, that the release into this nucleus blocks the release into the body? Who knows more? Please comment. 70.137.161.241 (talk) 06:48, 27 June 2008 (UTC)

Ok. So AVP in the plasma was unaffected. ref hypothesizes that release of AVP into paraventricular nucleus inhibits ACTH release. This would be a proposed new mechanism of ACTH release inhibition. Previous refs cited by ref thought it is the other way around. ref proposes to do further investigations. Reduction of ACTH stress response is secured. Reduction of cortisol response has been described elsewhere, also in humans. That is safe to include, if we collect references about that. Propose to delete the vasopressin theory, until agreed facts are established and they know how the feedback exactly works. Until then: delete. Other opinions? (I am not a brain surgeon or rocket scientist neuroscientist, but some here are!) 70.137.161.241 (talk) 07:54, 27 June 2008 (UTC)

Here a ref from the ref. Benzodiazepines attenuate the pituitary-adrenal responses to corticotrophin-releasing hormone in healthy volunteers, but not in patients with Cushing's syndrome.

Korbonits M; Trainer P J; Edwards R; Besser G M; Grossman A B

Clinical endocrinology, (1995 Jul) Vol. 43, No. 1, pp. 29-35. Journal code: 0346653. ISSN: 0300-0664. . English.

OBJECTIVE: The corticotrophin-releasing hormone (CRH) stimulation test has become established as a powerful tool in differentiating the source of ACTH in patients with Cushing's syndrome. Psychiatric symptoms are common in patients with Cushing's syndrome, and many patients with psychiatric illnesses may show disturbances of function of the pituitary-adrenal axis; both of these groups of patients may be receiving benzodiazepine drugs when presenting for evaluation of their possible endocrine problems. Both animal and human studies suggest that interactions occur between benzodiazepines and the hypothalamo-pituitary-adrenal axis. We have therefore evaluated the effects of a benzodiazepine drug on the pituitary-adrenal response to CRH. DESIGN: We have investigated the effects of 20 mg oral temazepam or placebo on serum cortisol and plasma ACTH after the administration of 100 micrograms i.v. human CRH in 12 healthy volunteers and in 9 patients with Cushing's syndrome. RESULTS: Temazepam significantly inhibited the peak serum/plasma levels and area under the curve for circulating cortisol and ACTH in normal subjects after CRH, but there was no such difference after temazepam in patients with Cushing's syndrome. CONCLUSIONS: Our results have shown that temazepam inhibits the pituitary-adrenal responses to human CRH in normal subjects, but not in those with Cushing's syndrome. We believe that inhibition of endogenous AVP by temazepam is the most likely explanation for our findings in healthy volunteers: the hypercortisolaemia in Cushing's syndrome suppresses the release of both endogenous CRH and AVP in portal blood which then results in abolition of the temazepam induced reduction in the pituitary-adrenal response to exogenous CRH, as seen in our patients. These effects of benzodiazepines should clearly be taken into account in patients using these compounds while undergoing endocrine assessment.

Cushings reference: I understand in cushings the CRH and the ACTH from the anterior pituitary is already downregulated by cortisol. Cortisol acting on the anterior pituitary and the hypothalamus with negative feedback. Exogenous CRH can not overcome the effect of cortisol on anterior pituitary I think. Maybe I am wrong. Or the anterior pituitary secretes ACTH independent of cortisol level and CRH, due to a tumor.So I don't see how CRH stimulation differentiates both. This reference also says temazepam reduces the stress response of ACTH and cortisol in healthy controls. We can include that in the article

The rat AVP reference: I understand that AVP and CRH from the hypothalamus act synergistically on the anterior pituitary, to release ACTH in the forward path of the loop. Do they say in the ref that AVP from the paraventricular nucleus acts in the paraventricular nucleus (in the hypothalamus) to downregulate CRH release to the pituitary by negative feedback? So there would be a little negative feedback circuit loop there too, and temazepam facilitates this downregulation, by increasing AVP release to the hypothalamus? And it is a hypothesis? Do I understand the right picture? And previously they thought temazepam would act on the neuronal input to the hypothalamus only, but now they postulate a new detail of the action on the feedback circuit? Please comments. Strange that another ref in the ref says that stress triggers the release of AVP into the paraventricular nucleus. I must be missing a detail there. Is it magnocellular neurons vs. parvocellular neurons acting in opposite sense under temazepam, and one feeds to the anterior, the other to the posterior pituitary and one of them also acts in negative feedback to the hypothalamus? Please comments. 70.137.161.241 (talk) 08:27, 27 June 2008 (UTC) 70.137.161.241 (talk) 09:16, 27 June 2008 (UTC) 70.137.161.241 (talk) 10:00, 27 June 2008 (UTC)

I must say a little block diagram of the proposed feedback mechanism would have helped my understanding. Besides, also in the WP articles on the topic, HPA etc. It is a multiplr feedback system after all and a bunch of blobs connected by interaction arrows explains more than a verbose description. 70.137.161.241 (talk) 11:22, 27 June 2008 (UTC)

To summarize, I believe the blunting of ACTH stress response and resulting cortisol response is a fact of clinical importance. We can include that, I propose. Opinions?

The release of AVP into the nucleus is a proposed mechanism of action and is research, not yet fully understood in detail by the researchers, pointing to future investigations. Too early to include as factual mechanism, dangling as a factoid. Input from WP-neuroscientists welcome. I am only the electrician here. 70.137.161.241 (talk) 11:55, 27 June 2008 (UTC)

Pharmacology

There are a few open points. I saw Tim Vickers proposed simplification to the most elementary level. I didn't so far implement it, because I hesitate to remove material, which is not obviously irrelevant, highly speculative research or conjectures or proposals for further research, or erroneously cited, anecdotal, unrelated. However, I applied some edits which seem safe with above in mind. Open points:

1. Their text suggests a more pronounced effect of sedation, ataxia, amnesia vs. anxiolytic and anti-seizure activity in the sleeping pills temazepam, nitrazepam, nimetazepam, flunitrazepam. (Compared to day-tranquilizers) Thereby their pharmacological effect would be closely related. The abstract of the ref doesn't yield that. I have no full text. They further suggest that this is due to differences in binding to subunits a1, a2... of the benzodiazepine binding site. It sounds plausible, but I was not able to confirm or reject, lacking full text. Can you please help and comment?

2. Their text mentions AVP release into rat paraventricular nucleus and consequent reduction of ACTH release by temazepam under stress. My opinion is, that the AVP part of this is a proposed new mechanism, is research and points to further investigations. They don't yet fully understand the mechanism and say so. I have described my fight with that above. Please comment. My opinion is that the reduction of ACTH release is important, as it further down diminishes the cortisol response to stress. So I thought to keep it. Has also been observed with other benzodiazepines in humans. Could you please take a look? Comment?

Looks good to me; it is now concise, understandable, and doesn't violate anyone's copyright. Fvasconcellos (t·c) 00:21, 1 July 2008 (UTC)

Here the ref, which doesn't lead itself to the statements about temazepam, nitrazepam, flunitrazepam, nimetazepam being related (abstract doesn't yield it)

Studies of the electronic structure and biological activity of chosen 1,4-benzodiazepines by 35Cl NQR spectroscopy and DFT calculations

K. Bronisza, M. Ostafina, Corresponding Author Contact Information, E-mail The Corresponding Author, O. Kh. Poleshchukb, J. Mielcarekc and B. Nogaja

Department of Physics, Adam Mickiewicz University, Umultowska 85, 61-614 Poznan, Poland

Department of Chemistry, Tomsk Pedagogical University, Komsomolskii 75, 634041 Tomsk, Russia

Faculty of Pharmacy, University of Medical Sciences, Grunwaldzka 6, 60-780 Poznan, Poland

Abstract

Selected derivatives of 1,4-benzodiazepine: lorazepam, lormetazepam, oxazepam and temazepam, used as active substances in anxiolytic drugs, have been studied by 35Cl NQR method in order to find the correlation between electronic structure and biological activity. The 35Cl NQR resonance frequencies (νQ) measured at 77 K have been correlated with the following parameters characterising their biological activity: biological half-life period (t0.5), affinity to benzodiazepine receptor (IC50) and mean dose equivalent. The results of experimental study of some benzodiazepine derivatives by nuclear quadrupole resonance of 35Cl nuclei are compared with theoretical results based on DFT calculations which were carried out by means of Gaussian’98 W software.

Keywords: Benzodiazepines; Anxiolytic drugs; Nuclear quadrupole resonance (NQR) spectroscopy; DFT calculations

Comment:

So they look at 2 benzodiazepines, lorazepam and oxazepam; Plus their 2-methyl derivatives lormetazepam and temazepam. Not nitrazepam and nimetazepam.

Delete, doesn't lead itself to a comparison between temazepam and nitrazepam. Doesn't yield the article statements.

But I totally doubt that such complex things like t 0.5 can be correlated with simple electronic properties, given the complexities of metabolism, generally.

I also doubt that binding to receptor subtypes can be theoretically derived from electronic properties. But maybe it would be possible to develop heuristics. The receptors are just too complex to be modeled in a partial differential equation, IMO.

I also doubt that equivalent doses may be calculated from electronic properties, given the complexities of such a composite measure and the organism. Given the complexities of even defining equivalent doses.

Overall: The claims seem rather exotic to me. A hoax?

And: They are not leading themselves to the article

Please comment. I am not familiar with quadrupole resonance, will try to find out. Propose to delete: unrelated. Find a clinical reference, otherwise. 70.137.161.241 (talk) 07:38, 28 June 2008 (UTC) 70.137.161.241 (talk) 08:42, 28 June 2008 (UTC) 70.137.138.55 (talk) 04:42, 29 June 2008 (UTC)

If you e-mail me through my userpage with the PMID number of the reference you need I should be able to get you the full text Pdf. Tim Vickers (talk) 15:46, 29 June 2008 (UTC)

I've had a look at this paper and it is an attempt to correlate the electronic structure of the benzodiazepines with their affinity for their receptor. It proposes that the polarity of the chlorine substituents as important in the structure-activity relationship. I don't know if you want to include this. Tim Vickers (talk) 17:59, 30 June 2008 (UTC)

It was used to support that "temazepam is pharmacologically most related to nitrazepam, nimetazepam, flunitrazepam". I think the ref doesn't say that, as you describe. Deleted. 70.137.138.55 (talk) 18:49, 30 June 2008 (UTC)