Talk:Nitrazepam

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1 Not much info?
2 Nilandron
3 Clutter
4 Protected
5 Benzene carcinogenicity
6 toxicity of breakdown products in storage, aging
7 Crazy Boris
8 Cyproheptadine in rats
9 Cross tolerance with barbiturates
10 neurotoxic
11 Utilization
12 inclusion bodies
13 Hopeless
14 opioid mechanism
15 Toxicity

[edit] Not much info?

Does anyone know much about this drug? I'm not a frequent user of drugs by any means, but having tried Temazepam, Diazepam, and Alprazolam, I was prescribed Nitrazepam the other day. I cannot seem to find much info on peoples experiences with this, and wikipedia seems quite light on information too with this particular benzo. Timeshift 17:18, 8 February 2007 (UTC)

[edit] Nilandron

Doing a search for this trade name, some say it's nilutamide, some way it's nitrazepam, so removing for now. Timeshift 11:57, 9 February 2007 (UTC)

[edit] Clutter

Please stop cluttering the benzodiazepines with a collection of refs to arbitrary pubmed articles. Those are largely reports of some experiments, which have been carried out sometime, somewhere and for some reason on rats, mice and brain slices. 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 etc. Not everything which has sometimes been suspected, investigated, speculated or observed is relevant to pharmacology and should be included. Avoid bot-like inclusion of search results. pubmed is not a source but an Augias-Stable of unfinished research and a playground for students. Example: You conclude that nitrazepam "is related" to quinazolines, by being investigated together with quinazolines in one citation. You conclude that it is a hapten, by being mentioned in an article about immuno assay tests. These are not relevant articles for pharmacology. Of course it is a hapten in an immuno assay test! That is how antibody based immuno assays work! But this has nothing to do with its pharmacology. Please limit yourself to agreed facts, like the FDA profiles. And the intention is to arrive at something which looks more like the FDA fact sheet. You have included unrelated, anecdotal, spurious, loosely associated references, to include claims of neurotoxicity, reproductive toxicity, carcinogenesis etc. These are not agreed facts, but you have presented them as peer reviewed facts. This is vandalism. —Preceding unsigned comment added by 70.137.178.160 (talk) 20:43, 2 April 2008 (UTC)

Jossi: Will you please discuss this, before reverting and clearing POV? 1. Nitrazepam is not related to quinazolines, and the ref does not claim that. 2. Nitrazepam is not a hapten. The ref investigates the use of haptens to create antibodies against benzodiazepines and quinazolines. For piss-test strips. 3. FDA would not have approved Nitrazepam if it were carcinogenic or neurotoxic. The animal experiments don't lead themselves to agreed conclusions. This are not FACTS. 4. The Mouse sperm experiments are at a dose of 80mg/kg, this has no agreed relation to pharmaceutical use. Please discuss this before doing blind reverts. And I am harassing nobody, just improving the article, such that it is halfway scientific. 70.137.178.160 (talk) 09:41, 4 April 2008 (UTC)

I removed the hapten as I agree that that is disputable. You are obsessed with quinazolines. As soon as quinazolines is removed from an article you then get obsessed with something else and cause more mayhem. Wikipedia is not meant to be a patient information leaflet. It is not meant to be medical advice. Josi undid your edits. He is an administrator, please respect administrators decisions. If you have a problem with an admins decisions please take it up with that administrators rather than reverting in this case josi's reverts. I tried to reason with you on the temazepam talk page and you replied with something to do with sacrifice's to some God you make with a thousand heads and 10,000 eyes? What do you sacrifice? Why did you bring that up? I don't understand the relevance? The FDA did not approve nitrazepam!!! It is not available in the USA! It is an encyclopedia entry. It is not a patient information leaflet. You are harassing me, you are causing disruption. I have been spending about 4 hours every day for the past 3 days trying to defend myself from your accusations accusing me of all sorts and listening to your crazed rants and trying to sort through your major deletions. You have not contributed a single addition to wikipedia. You are just obsessed with deleting stuff. I have had enough of it. I don't have 4 hours every day to waste dealing with you. I am sick of it. You drove me up the walls tonight on the temazepam article which ended up getting locked to stop you editing it anymore. When is this going to stop?--Literaturegeek (talk) 10:12, 4 April 2008 (UTC)

To come back to the facts, I followed your references to male reproductive toxicity. I have elucidated on this in the article. The experiments have been performed with doses corresponding to human doses of 300 (!) to 1200 (!) 5mg tablets per day (for a 75kg human) on Sprague-Dawley rats, with doses corresponding to human doses of 500 (!) 5mg tablets per day on mice. It is questionable if these experiments have any relevance to human pharmacology, or any relevance at all. I have added this to the article. There you have now an addition, to make good for the deletions. Furthermore the cytotoxicity has been detected under simultaneous irradiation with UV light in hamster cells. I have faithfully added the facts of the references to the article, to put things in proportion. Since 1996 no further supporting evidence has been found. Seems I can help you a bit in writing scientific articles. Please don't revert, without checking the facts. 70.137.178.160 (talk) 11:19, 4 April 2008 (UTC)

Listen, I tried to be nice and accepted some of your edits. But you can't calculate rat to human pharmacokinetics the way you did saying that mg/kg it is the same in rats as humans, especially without a citation. Rats metabolise drugs at vastly different rates than humans. Lets use diazepam for an example, it is the most researched benzodiazepine to date. Here is a citation where the half life of diazepam in rats is shown to vary from between 1 - 3 hours.[1]. Here is a citation for the half life of diazepam in humans which is 20 - 100 hours [2]. Ok, now please don't turn this talk page into an instant message board arguing this. Please accept that rats metabolise benzodiazepines much much much faster than humans. I can't keep doing this following you around baby sitting your edits. If you really want to start hacking away at a wiki article then use citations. You are setting the record here for deletions in a 3 day period but you have yet to contribute one single sentence backed up with a citation. You can't keep jumping from article to article, delete, delete, delete and revert, revert, revert and flagging multiple articles as "neutrality disputed" every time your edits get undone by an admin or other editor. It has to stop. Some of your suggestions have some merit, some of them are crazy like your edit to chlordiazepoxide.[3] Please if you want to participate and help develop wikipedia become a contributer. If you are just gonna blast your way through article to article, editing and deleting huge volumes of content to suit your POV without using citations then you are gonna cause endless friction. Some of your edits here to nitrazepam have been good. It was good to add in about the UV light to give more detail to the nature of the experiment and to put things in proportion for the reader. I accept that edit.--Literaturegeek (talk) 12:43, 4 April 2008 (UTC)

You say it yourself, rats are fast metabolizers. This is the reason, why they are also showing different damages e.g. by activated metabolites, oxidative radical damage. This together with the fact that they may use different metabolic pathways than a human at all (in some detail, for some step) means, that the results cannot be carried over to human pharmacology. So the results are not necessary meaningful. Thats what I wrote earlier in my remarks. And that is what is also agreed, if you will ask the opinion of some recognized reviewer. It is the reason why I called these results speculative, and proposed to leave them out, until confirmed by other materials, statistics. 70.137.178.160 (talk) 14:24, 4 April 2008 (UTC)

To say it in different words, you have really funneled the equivalent of 1000s of tablets per day through their metabolism, generating an activated and toxic metabolite in high concentrations. Thats why the results are speculative for human pharmacology. Ask somebody. 70.137.178.160 (talk) 14:32, 4 April 2008 (UTC)

Here you go arguing about nothing. I left your edit which says about the results impact on humans are unknown and may have no relevance to humans etc. I agreed with that edit! It is in the article! I agree the relevance to humans is unknown and may have no relevance and it now clearly says that in the article. So why are you arguing about it? There are no human tests done on nitrazepam carcinogenicity. There are peer reviewed literature which show an increased rate of cancer in chronic users of sedative hypnotics in general though, human users. I can dig it out if necessary. I believe I have the full text somewhere. I think you just love winding me up for the fun of it. Are you that guy I banned off of my website? He is from San Francisco, california same as where your ip address says you are from. Are you here just to constantly annoy me? Very strange that you are spending 4 or 5 hours arguing relentlessly point after point all over benzo wiki pages with me and only me. Why not someone else?--Literaturegeek (talk) 14:40, 4 April 2008 (UTC)

Why not somebody else? 1. Because you have brought these points in. 2. Because you respond to my concerns. And: No its not me whom you have banned. This is a metropolitan area with 6 Mio. people. I am in Silicon Valley, part of that metropolitan area. Everybody is welcome to respond to my edits. Besides: you need less or no citations to strip off questionable references and conclusions than to bring them in. This is not a symmetrical process! 70.137.178.160 (talk) 14:51, 4 April 2008 (UTC)

Whatever, Your edits have yet to be backed up by a citation. You do zero research and just delete based on your POV and what you think that the reality of the literature and facts are based on your biased POV. Here incase you think I am talking nonsense. Here is a citation of sedative hypnotics in prescribed users increasing cancer in humans. [4]

I have the full text paper of this peer reviewed article.[5]. I can't post the whole paper here due to copyrite restrictions but here is a little exerpt from it in bold.

It is concerning that the preponderance of infection in participants randomized to benzodiazepine agonists in controlled trials, quite obvious in FDA NDA data, has never been discussed in the published hypnotics literature, so far as could be found. Infection is associated with other benzodiazepine agonists besides eszopiclone. Moreover, excess cancers among both human participants and laboratory rodents randomized to hypnotics in controlled trials has never been discussed in the published literature, though it is rather evident in the FDA NDAs. Perhaps Scharf et al. presented the first hypnotics trial to mention the occurrence of cancers in the drug groups, though indeed this was certainly not the first hypnotics trial in which incident cancers have been observed. 15 Similarly, over a dozen epidemiologic studies have reported an association of hypnotic use with excess mortality. A surprising feature of the latest epidemiologic study was that the risk ratio for zolpidem tended to be a bit higher than for older benzodiazepines. 16 No hypnotic manufacturer has attempted to refute the epidemiology by conducting trials to show that their product produces no excess mortality. WHAT HAS NIH AND THE VETERANS ADMINISTRATION (VA) BEEN DOING?

Because of your constant criticism of my editing patterns, I have been accused of not having access to full text papers by fellow editors. I have full access to the british medical journal and can log in right now if I wish and other access to full text's through libraries.--Literaturegeek (talk) 15:06, 4 April 2008 (UTC)

You see, so you are trying to defame my editing patterns and make it out that I am being a deceptive editor and don't know what I am talking about and blah blah. You are determined to destroy my reputation on here. I have happily and quietly edited away on wikipedia for well over a year and enjoyed helping to expand the wiki articles with little problem and now you come in causing absolute mayhem trying to destroy me and my reputation. You are doing an amazing job for someone who has yet to use a citation to back up your biased POV. Fortunately I can back up everything with citations.--Literaturegeek (talk) 15:13, 4 April 2008 (UTC)

ok. This citation seems to be for Zombieclone and Zombiedeme... and some again on rodents, which may mean nothing because of the fast metabolizer story. I am not out to destroy you and your reputation, how could I. I am out to strip speculative, loosely associated, anecdotal and unrelated material out, to arrive at a more solid article. The process is asymmetrical. You prove, before you include. I need no citations, I just ask for agreed facts. Your citation says, more investigation should be carried out, but it doesn't conclude if I saw right. And on a comparatively new substance. Not Mogadan from 30 years ago, last century. 70.137.178.160 (talk) 15:31, 4 April 2008 (UTC)

Maybe it is time for a fundamental discussion of what encyclopedia-level facts are, compared to e.g. the level required for inclusion in a peer reviewed journal. 70.137.178.160 (talk) 15:43, 4 April 2008 (UTC)

Maybe it is time you give me a freaking break!!!! Here, another link for you on cancer.[6] When are you going to give me peace!?!?!--Literaturegeek (talk) 15:54, 4 April 2008 (UTC)

Enough. You have both descended to edit warring, criticizing one another and throwing accusations around, abusing boldface and CAPS and conspiracy theorizing, and no one is actually discussing (as in having a productive, two-way conversation) what could actually be done to improve these articles. Please, step back from editing for a while while your tempers cool off, and come back to the articles' Talk pages when you're ready to have an actual discussion. Meanwhile, in danger of making matters worse, I would like you both to read this nice, enlightening essay on Staying cool when the editing gets hot. Fvasconcellos (t·c) 16:24, 4 April 2008 (UTC)

Literaturegeek: Your full text link on newer substances concludes, that "the evidence was insufficient to convince FDA of carcinogenicity". The reviewers were not convinced. Ramelteon had the same tendencies, in spite of not being a benzodiazepine receptor agonist, but a melatonin receptor agonist.

Maybe its time for a fundamental discussion of what encyclopedia level facts are vs. criteria for inclusion in a peer reviewed journal and speculative research, needing further investigation.

As almost everything has been speculated in research over time, it is easy to concoct an Anslinger-like horror campaign, by incessantly mentioning the medication together with e.g. brain damage, testicular damage, cancer, mutations, date rape, addiction, crime and depravity, in all cases conceding that these points are not fully conclusive, need further investigation. But this is not encyclopedia-level fact and evidence. 70.137.178.160 (talk) 16:30, 4 April 2008 (UTC)

[edit] Protected

The page is now protected for 10 days days. During this time, please try and find common ground and arrive to a version that all can live with. If you cannot, this is a good time to pursue dispute resolution such as third opinions or requests for comments. If you are ready to resume editing or to contest the protection, place a request at WP:RFPP. ≈ jossi ≈ (talk) 16:16, 4 April 2008 (UTC)

Maybe its time for a fundamental discussion of what encyclopedia level facts are vs. criteria for inclusion in a peer reviewed journal and speculative research, needing further investigation.

The FDA killed 100,000 americans with viox. When overwhelming evidence of the cardiotoxicity came to their attention a vote was almost won by the FDA panel to keep the evidence supressed and to carry on the slaughter and keep viox on the market as "safe and effective". Only one single vote saved more victims from Viox and got the data released. Many on the panel had shares in the manufacturer of viox. Do you not watch the news? Look into it, it was all over the news and lots of law suits. But regardless you will argue and argue. You picked that statement out of that article and took it out of contect. You still haven't justified your enormous amount of damage you have done to multiple benzodiazepine articles with your vandalism. Much of your vandalism still needs to be undone.--Literaturegeek (talk) 16:42, 4 April 2008 (UTC)

Literaturegeek, please be careful with inflammatory statements and accusations of vandalism. Vandalism has a strict and established definition on Wikipedia, and any good-faith effort, however misguided, is specifically excluded. Fvasconcellos (t·c) 16:48, 4 April 2008 (UTC)

I am being careful, check his talk page, he has had bots and admins contact him about vandalism and his edits having to be reversed etc.--Literaturegeek (talk) 16:51, 4 April 2008 (UTC)

Yes, I have. Warnings come in several levels. 70. has been notified of unconstructive edits being reverted; no editor has warned him of vandalism. Edits should only be considered as such if they are deliberate, bad-faith efforts to damage the encyclopedia. Although many folks are quick to label any apparent "worsening" of an article as vandalism (I've done so myself), that is inappropriate. Fvasconcellos (t·c) 16:56, 4 April 2008 (UTC)

Fair enough, I understand. Significant damage to multiple articles I guess I should have said. Peace lol!--Literaturegeek (talk) 17:04, 4 April 2008 (UTC)

[edit] Benzene carcinogenicity

Toxicity: That benzene is carcinogenic is undisputed. However, this doesn't carry automatically over to benzene compounds. Benzene compounds are ubiquitous in the body chemistry. (Amino acids, nucleic acids, hormones etc.) Consequently I removed attempts to derive nitrazepam carcinogenicity from benzene carcinogenicity. These are attempts to conclude by plausible but false analogy. The whole chain of logic conclusions based on this is faulty and not supported by the references. 70.137.182.40 (talk) 09:27, 17 May 2008 (UTC)

The relevance anon 70. is that a known carcinogen is fused with other compounds to form benzodiazepines and that benzodiazepines cause cancer, so that is the relevance. Have you any citations that benzene makes up amino acids, nucleic acids, hormones? I am not saying that you are wrong, I just am not aware of that. I guess your argument is that it is speculative of whether the benzene fused molecule in benzodiazepines is the mechanism for cancer in animals and humans that benzos cause. You will be pleased that I left the benzene stuff deleted, the toxicity section was probably too big anyway. I asked you once before to stay off my talk page but you were back on it last night vandalising it with unprovoked vile slanderous personal attacks on another editor. Please don't start fights with other members on my talk page again. I reverted your vandalism to my talk page. I expect pharmaceutical company academics to be more professional than that.--Literaturegeek | T@1k? 20:08, 17 May 2008 (UTC)

What or how much personal gain do you get from following me around, even edits to my talk page? Just curious.--Literaturegeek | T@1k? 20:14, 17 May 2008 (UTC)

I see you tried to delete quinazolones/quinazolines mention from the article. I added a citation that leo sternbach synthesised benzodiazepines from quinazolines. I can add more citations if you like. Very few academics have any knowledge of quinazolines. How do you know of them? Why do they bother you?--Literaturegeek | T@1k? 20:23, 17 May 2008 (UTC)

That benzodiazepines can be synthesized from quinazolines I would not call a chemical relation. You can extend the quinazoline 6-ring to the benzodiazepine 7-ring. True but irrelevant in the context. Benzene stuff and carcinogenicity: Look at Wikipedia "epinephrine", "serotonin", "phenylalanine" as examples. ((-: The benzene is the thing with the 6 corners in the structure :-))The nucleotides I take back. They are hetero ring systems. 7-amino-nitrazepam is actually a misnomer, not a rational name. It is the 7-amino metabolite of nitrazepam, but contains no nitro group, but the amino group "instead". This is not original research, but some of your references say that. The reference about this reaction is about reduction of the nitro compound by microflora in the rat cecum, at dosages of 300mg/kg. This is not original research but the reference says that. Humans have no such cecal metabolism. Look that up in literature about laboratory animals. These are well known differences between rats, guinea pigs and rabbits vs. human physiology. One of them the huge cecum with a specialized microflora to digest cellulose in the animals, but not in the human. You should mention the fact that this are animal experiments. As always - we agreed on that before - the results of such detailed metabolic studies can not directly be carried over to human physiology. In particular if the cecum is involved. Please revert to my addition, mentioning that. Besides, thats only my lay opinion. I am only the electrician here. You should see our scientists. 70.137.144.27 (talk) 20:59, 17 May 2008 (UTC)

Benzene stuff and carcinogenicity: If I correctly remember the reason why benzene is carcinogenic is: The symmetry of the molecule allows a certain resonance of the electrons, leading to the formation of an epoxid metabolite. This is very reactive and attacks nucleic acids. The symmetry of the benzene molecule is not preserved in its compounds, it is destroyed by substitutions, except in some special symmetric patterns of substitution. So the metabolic path leading to a carcinogenic metabolite is very specific to benzene and very sensitive to the detail of the molecule. Look up more details in some std text of toxicology. 70.137.144.27 (talk) 21:24, 17 May 2008 (UTC)

The majority of depressant drugs and anticonvulsants are similar to quinazolines/quinazolones in structure, I added a full text citation. I don't know why this is a big deal considering so many drug classes are similar to quinazolines it doesn't give nitrazepam or benzos in general a bad name. I accept your argument regarding benzene carcinogenicity and will not add the claims back into the article. You are right that benzene ring is in various neurotransmitters. I have learnt something new! :=) I can't help the name given to the metabolic compound of nitrazepam. That is what it is known as in the peer reviewed literature. Nonbarbiturates bind to barbiturate receptors, so one would argue why are they called barbiturates just because they aren't the classical barbiturate molcule? See my point but that is the classification given in the literature. I can't change that. It says clearly Animal above the animal studies, it is a main subsection and then below it it says human for human related studies. I don't see how anyone could get confused. I will look into the cecal metabolism. It would need a citation.--Literaturegeek | T@1k? 01:47, 20 May 2008 (UTC)

There is no doubt that benzodiazepines are similar to quinazolines. They are not related other than that both are 7- and 6- membered ring systems with 2 nitrogens, fused to a benzene ring. Both also allow development of corresponding analogs to some degree. These are e.g. hypnotics. No SARs have been found in this paradigm, so one of your previous references concludes that benzodiazepines have to be treated as a separate entity for pharmacology. Mentioning is again scenic routing through the topic, doesn't contribute to the topic at hand. We had this discussion with chlordiazepoxide before. Do we need to repeat this for each benzodiazepine? 70.137.149.100 (talk) 01:43, 20 May 2008 (UTC) You have reverted one of my edits - about rat cecal metabolism - without explanation. Pls explain. 70.137.149.100 (talk) 01:43, 20 May 2008 (UTC) One of your references is about bacterial benzodiazepine metabolism in DEAD BODIES. 70.137.149.100 (talk) 01:43, 20 May 2008 (UTC) Please don't revert my edits without explanation or discussion. 70.137.149.100 (talk) 01:43, 20 May 2008 (UTC)

I think Goodsons introduction to toxicity was better and free of some errors, you have reintroduced. —Preceding unsigned comment added by 70.137.149.100 (talk) 01:48, 20 May 2008 (UTC)

I think you already answered some things. The quinazolones are really irrelevant, I mean the analogy leads itself to nothing, is redundant, scenic routing. As a criticism to your writing style: (Not meant personal) You frequently proudly add such dangling facts to the article, which more obfuscate than elucidate any coherent line of argument. The rat cecum and dog endothelial studies are really in the intro of tox, not the animal part. I am afraid you are overgeneralizing there. At least it is worth a discussion. I want to give you a friendly reminder, how much with a grain of salt rat cecal metabolism can be transferred to human pharmacology. Humans have no such cecum. Read it up, you will come across this discussion over and over. 70.137.149.100 (talk) 01:58, 20 May 2008 (UTC)

More benzene examples- Hormones: thyroxine, triiodothyronine, melatonin; Amino acids: tryptophane, tyrosine; Neurotransmitters: tyramine, dopamine, norepinephrine. There are much more. 70.137.149.100 (talk) 02:06, 20 May 2008 (UTC)

Your reference talks about rat cecal metabolism. 70.137.149.100 (talk) 02:09, 20 May 2008 (UTC)

Link http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=242207 . Rat cecum cellulose digesting bacteria. Rats living on laboratory filter paper! Don't try this at home with yourself! Humans don't have that! And we can't do that, otherwise we could simply munch old paper and live of that. 70.137.149.100 (talk) 02:27, 20 May 2008 (UTC)

http://www.rmca.org/Articles/coprophagy.htm - not a scientific article but an introduction to rat "coprophagy" and cecal metabolism as an analog of the ruminant "chewing the cud", for digesting cellulose. Written by a biologist for rat owners. Humans are no ruminants either way around. In humans the cecum is very reduced, partly to the rudimentary "vermiform appendix". In rats it is a full functioning and prominent and comparatively huge part of the digestive tract. See also WP article "cecum". Probably good enough to show some physiological differences to humans. 70.137.149.100 (talk) 02:46, 20 May 2008 (UTC)

Ok anon, I might remove the quinazolones bit. Just kind of been busy past couple of days. I also hit a major depression brought on by yourself. My feelings were hurt when you said that Roche only sent their electrician to challenge my edits. Don't you realise how hurtful that is? LOL You need to ask for a promotion! Ok on to serious stuff now. I will review the toxicity section in the next day or two and maybe edit it down. I have a comment, about rats and human digestion. Humans do digest things via their intestines. Eat a couple of cans of baked beans and see how the ananaerobic bacteria like it in your large bowel! Don't try this technical experiment in an enclosed space though! Which of my references is in dead bodies? I need to read up on rat and human metabolism a bit more. Not an area that I am familiar with. I will read that paper on rat digestion tonight. I don't doubt that there is a different makeup in gut bacteria in different species of animals though.--Literaturegeek | T@1k? 19:41, 21 May 2008 (UTC)

Quinazolines deleted and removed sentence about nitrazepam's degradation in dead bodies.--Literaturegeek | T@1k? 19:55, 21 May 2008 (UTC)

As a retired electrician I am almost living on a diet of baked beans. Taste better every day. 70.137.149.100 (talk) 07:49, 22 May 2008 (UTC)

[edit] toxicity of breakdown products in storage, aging

Deleted related statements. Doesn't belong here, because we are not discussing "decayed" tablets and ampules, like the reference. Reference about activation of benzophenone to a carcinogenic metabolite doesn't mean that substituted benzophenones are possibly activated the same way. Same like with benzene and substituted derivatives: This is very sensitive to the details and symmetries of the molecule. Same for the quinolones. In normal metabolism the things are different. So leave it out, until metabolic products are identified as carcinogenic. 70.137.149.100 (talk) 08:57, 20 May 2008 (UTC)

http://books.google.com/books?id=Rno1rYxR264C&pg=PT235&lpg=PT235&dq=differences+rat+human+metabolism+&source=web&ots=OKS8jD4wkr&sig=1bTtOeh760SrPFZnH0cbNw_usWs&hl=en look at this reference for rat metabolism. From "Shayne Cox Gad" "Animal models in toxicology" google books. result of google search "Shayne Gad animal models toxicology". Read the rat chapter online. It also contains interesting discussion of spontaneous tumors in rats. Claims incidence of 80% spontaneous testicular tumors in aging F344 rats. Claims spontaneous testicular damage in aging F344 rats, and much more. Unfortunately the book is 150$, but you might be interested. I just looked diagonally and didn't yet read the full rat chapter. ref shows how much with a grain of salt rat tumor and metabolism studies relate to the human. After reading you will likely be critical of many animal results and possible pitfalls. (In my lay opinion, I am only the electrician here) 70.137.149.100 (talk) 22:18, 21 May 2008 (UTC)

7-aminonitrazepam is not the free radical. 70.137.149.100 (talk) 23:11, 21 May 2008 (UTC)

Kripke says: The data doesn't mean that we can have confidence, that new hypnotics are causing cancer. For the animal studies see the google book about animal studies above, in particular about rats and cancer, metabolism. Generally the human studies prove correlation with morbidity, but not causality. 70.137.149.100 (talk) 00:33, 22 May 2008 (UTC)

[edit] Crazy Boris

Please Crazy Boris will you not revert my edits without discussion, because they "seem to be unconstructive", I am proofreading the section against the references here and correcting errors. 70.137.149.100 (talk) 02:22, 23 May 2008 (UTC)

[edit] Cyproheptadine in rats

Cyproheptadine improves sleep quality in a rat experiment. Careful with generalizing this to humans: Rats are night-active. Melatonin acts as a stimulant on them. (See Kripke paper) 70.137.149.100 (talk) 04:56, 23 May 2008 (UTC)

The authors of the study recommended it for insomnia humans based on their rat sleep study results. You are right in what you say though. I accept your edit.--Literaturegeek | T@1k? 06:56, 25 May 2008 (UTC)

[edit] Cross tolerance with barbiturates

Reference says "barbiturates can be substituted BY benzodiazepine", you state the other way around. For a cross tolerance both directions have to be referenced. Deleted. 70.137.149.100 (talk) 04:59, 23 May 2008 (UTC)

Barbiturates are well known to be cross tolerant with benzodiazepines and vice versa in human and animal studies and this is why phenobarbital is used in detox centers. Personally I am not fussed whether it stays or goes. I dunno why the drug companies make a big deal out of this, because any GABAa positive modulator will have a degree cross tolerant with another GABAa positive modulator substance. corticosteroids, barbs, alcohol etc. Anyway I know it really bothers you that it is in the article and it isn't a big deal for me whether it remains in this article or not, soooo,,,,, I accept your deletion.--Literaturegeek | T@1k? 07:02, 25 May 2008 (UTC)

[edit] neurotoxic

Deleted "neurotoxic" vs. clobazam. Seemingly this is the only author thinking that. "neurotoxic" means "destroying nerve cells" and that is not what he describes. He describes dose limiting side effects of sedation in 1,4 benzodiazepines. These are not "neurotoxic" in above definition. See WP "neurotoxic". (translation? french? different definition of neurotoxic?) 70.137.149.100 (talk) 17:51, 23 May 2008 (UTC)

I believe benzos at therapeutic doses taken for years do have a degree of neurotoxicity from reading the literature, however, you are right the author is describing side effects rather than neuronal damage or death and thus I am willing to accept your deletion. Am I in a good mood today or what? :=) --Literaturegeek | T@1k? 07:05, 25 May 2008 (UTC)

[edit] Utilization

this section contains anecdotal data from Edinburgh residential homes, Tasmania and Australia, mostly about benzodiazepines in general. If this is so important, complete it with a list of all countries and move it to a special article, or move it to the articles about Edinburgh and Tasmania etc. I propose to delete this. Same for the Temazepam article. Please other opinions. 70.137.149.100 (talk) 21:30, 23 May 2008 (UTC)

I am sorry but I reject this deletion. The drug companies state clearly in their data sheets that benzos are recommended for short term use only due to risks of tolerance, dependence and withdrawal problems and other risks. Therefore, I don't think that the tasmania reference should have been deleted. I think that you deleted it because the abstract described prescribing levels as "disturbingly high". You selectively deleted that reference only from that section. I believe prescribing levels and utilisation of nitrazepam are relevant to the article.--Literaturegeek | T@1k? 07:17, 25 May 2008 (UTC)

Let me elaborate, with scenic routing, why I deleted that. I agree with the opinion that benzos, benzo-like sleep medicines, sedative weak neuroleptics, sedatives in general are or have been overused in many residential homes for long term "maintenance" of old people. This is in my opinion being done, to ease the job of the nurses. Let me be blunt. They want to prevent that at night flocks of agitated old people with organic brain syndromes, dementia and day-night reversal are stumbling around in a half conscious state of psychomotor agitated delirium, slobbering, bitching and moaning, actuating the night bell. The pitfall is of course, that benzodiazepines and other sedatives in such people have a tendency to produce paradoxical agitation and agitated delirium in themselves. So there is not only day-night reversal but also paradoxical disinhibition and reversal of the sedative action. This is hard do differentiate from reversal caused by long term use and habituation for decades to the medicines. They try then to give weak and sedative neuroleptics, sedative antidepressants or antihistaminics instead, but these either have strong anticholinergic side effects themselves or necessitate addition of anticholinergics like e.g. Artane, to mask the extrapyramidal side effects and motoric unrest (akathisia) produced by the neuroleptics. The anticholinergics or anticholinergic side effects of the sedatives may in themselves produce delirium and agitation again. Withdrawal may not be in order for some such patients, because they may not benefit from that in their remaining life (end stage of Alzheimers etc.). It is a devilish situation, half of the symptoms are eased by the medication, but the other half is caused by them. The medicine is the cure and the disease at the same time in such patients. But some of them may be indeed helped by reducing or withdrawing the sedatives. Frequently the diagnosed dementia may be in fact (at least in part) iatrogenic pseudo dementia, caused by the medication. This is a very valid concern of yours, if I understand right. To get this right would need effort and dedicated doctors. Such retirement homes may look like the first stage of hell. Patients may need to be strapped to the beds, to prevent falls. And above all these retirement homes may run from an almost bankrupt state social system and may simply have "no money" to offer anything better or more dignified to their patients, who will produce no gain to anybody any more. I believe mostly poor people are dieing like that. (I am not a social critic, just realistic) Thats why I prefer to keep my money, rather than giving it to a state run mandatory system and have them decide whats good for me. Your "utilization" chapter gives only a few sprinkles of anecdotal evidence for the situation, which is however probably found world wide. To address this situation in an article needs probably more complete and broad evidence. "Sedatives in residential homes". The few sprinkles Australia, laughably Tasmania (some island somewhere), Norway, Edinburgh are samples but just too anecdotal to be accepted as proof. But I know that you are right with your concerns. They just have to be expressed more boldly and with more facts, or they remain unimportant side notes, too unimportant to mention, pending more evidence. Probably this would need a complete article. In the utilization chapter it is just lost and doesn't get the bold factuality it deserves, including the medical trade off. I am not "Roche", but old, and I am fearing the future. Will it look like that, maybe in 10-20 years? 70.137.149.100 (talk) 09:32, 25 May 2008 (UTC)

I think frequently the doctor will decide that letting the patient sleep, or keeping him in a semi-vegetative state is the last thing he can do, short of "putting the patient to sleep". Because otherwise the patient will try to free himself of the leather straps, moaning, or stumble around in a half conscious state and fall over and over, or fall out of the bed, breaking his brittle bones, and then not recover from that. 70.137.149.100 (talk) 09:53, 25 May 2008 (UTC)

The differences in utilization of sedatives between residential homes may be caused by the fact that some residential homes specialize on patients with advanced dementia. These do not recognize their relatives, they think the nurses are their relatives, they repeat utterings incoherently, try to walk around aimlessly, fall over and over, have a tendency to suffocate on food, soil themselves. They need to be locked up, because they may try to go "home" to a place where they lived 50 years ago, in search for and calling for spouses or relatives, who died decades ago, driven by an aimless unrest and unspeakable fear. Nobody can talk any reason into them, because they don't understand or immediately forget. Addiction, tolerance and habituation to medications may be a different trade off against the benefit of a patient who is not screaming in terror because of his zombie like state, and who will anyway soon die of the end stage of brain destruction. 70.137.149.100 (talk) 21:28, 25 May 2008 (UTC)

[edit] inclusion bodies

deleted this reference. related reference shows same without medications. reference is inconclusive about this. fits storage disease. See discussion on clonazepam page of the same reference. 70.137.149.100 (talk) 02:34, 24 May 2008 (UTC)

I am willing to accept this deletion.--Literaturegeek | T@1k? 07:18, 25 May 2008 (UTC)

[edit] Hopeless

This article is as hopelessly cluttered with tangential, unrelated and anecdotal references, as the Temazepam article is. It needs a major rewrite. "Mode of action" duplicates info in Pharmacology. The whole article is focused on dangerous side effects, with many repetitions. For the moment I give up 70.137.149.100 (talk) 23:48, 23 May 2008 (UTC)

I don't agree with your criticism. I think the article is pretty good and is scientifically referenced accurately. Whilst it is not up to the standard of a featured article and is not perfect, it is certainly better than many other benzo articles.--Literaturegeek | T@1k? 07:25, 25 May 2008 (UTC)

The article needs to gain in factuality, setting it apart from fiction, speculation and extrapolation. See my remarks on "Utilization". The matter has dimensions, which are lost in the article. 70.137.149.100 (talk) 03:12, 26 May 2008 (UTC)

[edit] opioid mechanism

Added "endogenous", "in rats". No direct opioid mechanism has ever been described. neither nitrazepam nor its metabolites bind to opioid receptors. Mu-antagonists reverse the locomotor effects of many substances and even the after effects of electrical shocks. See pubmed "related" refs. This belongs more to the pharmacology of naloxone vs. rat locomotion, not to nitrazepam. Other related refs show different and inconclusive results. Another dangling fact. 70.137.145.75 (talk) 12:10, 2 June 2008 (UTC)

[edit] Toxicity

Intro section: deleted this, pending more evidence. Formation of superoxide radicals and radical oxidative damage is to some extent physiological and safeguarded by a cell mechanism. see menadione, which is a provitamin and also generates superoxide. See WP "superoxide dismutase", if I remember correctly, for the safeguard. Very interesting. It is a quantitative question, if this is really contributing to toxicity or not, if the superoxide generation can "outrun" the dismutation. For some animal models it is conjectured as the mechanism of toxicity by the ref. (rat) or only proven that the superoxide radical is being generated at all, intracellular. (dog endothelial cells. The article is about spin trapping of radicals). But the refs didn't state the mechanism and the toxicity as a secured and agreed fact cross species. It is agreed that superoxide radical in general causes damage, that is the reason that the cell has the dismutase to catch it. So it belongs so far only into the animal section as a proposed mechanism. As a general intro it is speculative, according to the refs. Or did I miss something? The general conclusion: "NTZ generates superoxide; superoxide damages the cell; -> NTZ is cell toxic" is false. It depends on the rate. Please derive your reinsertion. "reason not valid" seems too little. 70.137.145.75 (talk) 09:57, 3 June 2008 (UTC) 70.137.145.75 (talk) 10:44, 3 June 2008 (UTC)

For a rat poison which is much more toxic for the rat than for e.g. dogs (rather selective), which contains a 4-nitrophenyl group and which has a conjectured mechanism by oxidative radical damage: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=181623, see structure formula. It seems as if the rat in particular has problems with the metabolism. In humans it destroys the pancreas B-cells, is neurotoxic and causes diabetes. This is an example of species dependence of toxicity, 4-nitrophenyl, aromatic nitro compound. 70.137.145.75 (talk) 11:25, 3 June 2008 (UTC)

A very similar substance, only the pyridil-methyl entity replaced by a second 4-nitrophenyl group, is being used as a feed additive in chicken, and therefore found sometimes (rarely I hope) in eggs and fried chicken. It has very low toxicity in rats. Of course this is all really tangential, but shows how careful one has to be with the details of the formula. The p-nitrophenyl group or the character as a nitro-aromatic compound means nothing. Its the very little detail that is important. 70.137.145.75 (talk) 14:52, 3 June 2008 (UTC)

http://www.inchem.org/documents/jecfa/jecmono/v041je10.htm here the formula of the nitroaromatic chicken additive and the rat study result. (As nitro as nitro can be!) No cancer etc. its all healthy! (So to say, but I don't want such fried chicken or eggs.) Look at that! I am surprised myself. And look at the daily dose. The nitro-aromatic theory is dead I guess. 70.137.145.75 (talk) 15:09, 3 June 2008 (UTC) 70.137.145.75 (talk) 15:13, 3 June 2008 (UTC)

Deleted mortality of elderly men, correlated with the use of anxiolytics combined with analgetics. The causality is not provided. Did the analgetics or the anxiolytics or their combination cause the heart attacks? Or did they take anxiolytics and analgetics because they were suffering from chest pain and anxiety to begin with? Maybe because they e.g. were being harassed at the workplace by some young insolent yuppie snots to the point of heart disease, as is frequently heard of? And maybe they had no background to deal with those? Or how would be the speculation? Deleted until we know. Again useless dangling facts, tangential. 70.137.145.75 (talk) 07:40, 4 June 2008 (UTC)