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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 10 of 10. This is the beginning of the thread.
Posted by medievil on January 17, 2007, at 12:23:09
its time for ppl to try an NMDA antagonist for benzo's, some ppl have no problems with tolerance but others do!! so this might be the solution for them!!!
NMDA recepter really is the tolerance bad guy!!Effect of NMDA antagonists on rapid tolerance to benzodiazepines.
* Khanna JM,
* Chau A,
* Shah G.Department of Pharmacology, University of Toronto, Canada.
We have reexamined the effect of NMDA antagonists [(+)MK-801 and ketamine] on rapid tolerance to chlordiazepoxide. (+)MK-801 and ketamine blocked the development of rapid tolerance to chlordiazepoxide, but this effect was dependent on the dose ratio of the NMDA antagonist to that of the benzodiazepine used to produce rapid tolerance. Furthermore, NMDA antagonists blocked both learned and unlearned tolerance to chlordiazepoxide. It appears that in addition to impairment of memory and learning, NMDA antagonists may also influence some other mechanism involved in the production of drug-tolerance.
Diazepam dependence prevented by glutamate antagonists.
* Steppuhn KG,
* Turski L.Research Laboratories of Schering AG, Berlin, Germany.
Long-term treatment leads to tolerance to and dependence on benzodiazepines. Abrupt termination of benzodiazepine administration triggers the expression of signs of dependence. Mice withdrawn from chronic treatment with diazepam showed a time-related evolution of anxiety, muscle rigidity, and seizures between days 4 and 21 after treatment discontinuation. A period between withdrawal days 1 and 3 was symptom-free. Surprisingly, during this "silent phase" the susceptibility of mice to alpha-amino-3-hydroxy-5-tert-butyl-4-isoxazolepropionate (ATPA) and kainate seizures and the magnitude of monosynaptic reflexes mediated by non-N-methyl-D-aspartate (NMDA) mechanisms were enhanced. In apparent contrast, the "active phase", between withdrawal days 4 and 21, was characterized by increased susceptibility to NMDA seizures and enhanced magnitude of polysynaptic reflexes, which are NMDA dependent. Treatment of mice with alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) antagonists 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466) or 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline but not with the NMDA antagonist 3-[(+/-)-2-carboxypiperazin-4-yl]-propyl-1-phosphonate (CPP) during the silent phase prevented signs of dependence. In contrast, treatment with CPP but not with GYKI 52466 during the active phase prevented the symptoms. The development of tolerance to and dependence on diazepam was prevented by concurrent treatment of mice with CPP but was not prevented by GYKI 52466. These data indicate that NMDA-dependent mechanisms contribute to the development of tolerance to diazepam and to the expression of signs of dependence in mice after termination of long-term treatment with diazepam. Nevertheless, the non-NMDA-mediated silent phase is essential for triggering the symptoms. Therefore, AMPA antagonists may offer a therapeutic approach for preventing dependence on benzodiazepines that is an alternative to NMDA antagonism.
Posted by dbc on January 17, 2007, at 16:58:10
In reply to Benzodiazepine tolerance can be prevented!, posted by medievil on January 17, 2007, at 12:23:09
Im afraid not.
Benzodiazepine discontinuation is characterized by a syndrome of increased activity and reduced seizure threshold that is similar to effects mediated by the glutamatergic system. To elucidate the involvement of the glutamatergic system in benzodiazepine tolerance and discontinuation, we administered lorazepam, the NMDA antagonist CPP, and the combination of these compounds either concomitantly or consecutively to mice via osmotic pumps and evaluated pentylenetetrazole-induced seizure threshold, open-field activity, and benzodiazepine receptor binding during and after chronic administration. Animals receiving lorazepam alone developed partial tolerance at 7 days and complete tolerance at 14 days to the anticonvulsant effects of lorazepam. This effect was partly attenuated by CPP coadministration with lorazepam. This combination produced only partial tolerance. A reduction in seizure threshold was observed 4 days after discontinuation of lorazepam alone. This effect was abolished by coadministration of CPP with lorazepam and by CPP administration during the withdrawal period. Benzodiazepine binding in most structures examined was significantly reduced at 14 days during chronic lorazepam administration (versus 1 day), and coadministration of CPP did not alter this decrement. After lorazepam discontinuation, binding was increased at 4 and 7 days versus chronically treated animals and versus vehicle within the cerebral cortex. This effect was abolished by coadministration of CPP as well as by CPP administration during the lorazepam withdrawal period. These data support the involvement of the glutamatergic system in benzodiazepine tolerance and discontinuation.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9399331&dopt=Abstract
It works for opiates though.
Posted by Phillipa on January 17, 2007, at 17:54:19
In reply to Re: Benzodiazepine tolerance can be prevented!, posted by dbc on January 17, 2007, at 16:58:10
So I'd say that if a person takes benzos for over 30yrs and doesn't raise the dose and sometimes lowers it they do not have tolerance? Love Phillipa
Posted by dbc on January 17, 2007, at 19:00:59
In reply to Re: Benzodiazepine tolerance can be prevented!, posted by Phillipa on January 17, 2007, at 17:54:19
Some drugs have the opposite effect of tolerance like amphetamines and cocaine. Sometimes if you take relatively the same dose you'll get a sensitization effect. I dont know if this is the same for benzos.
Posted by Phillipa on January 17, 2007, at 19:41:17
In reply to Re: Benzodiazepine tolerance can be prevented!, posted by dbc on January 17, 2007, at 19:00:59
Like if a benzo never made you tired and now it does is this what you mean? Cause unless I'm extremely upset that's whats happening. Love Phillipa
Posted by medievil on January 18, 2007, at 10:58:11
In reply to Re: Benzodiazepine tolerance can be prevented!, posted by dbc on January 17, 2007, at 16:58:10
"Im afraid not."
so it just slows it down? hmm common guys find something to completely prevent tolerance!
nmda antagonists work great for amphetamines too, i wonder if they will prevent poop out of several meds!
reverse tolerance is something that makes you requere less of a med to get the same effect
like first time of cocaine aint all that great usually, but second time is better etc.. you dont need to increase the dose
but this usually doesnt occur with something taking daily
Posted by kelv on January 18, 2007, at 21:32:06
In reply to Re: Benzodiazepine tolerance can be prevented!, posted by medievil on January 18, 2007, at 10:58:11
All well and good!
I'v heard about Robitussin (DXM) as one for Amphetamine tolerance, and using Antacids to prolong Amphetamines effects, but never for Benzos.*Could you list some NMDA antaganonists i can easily get?
Posted by medievil on January 19, 2007, at 7:21:08
In reply to Re: MEDIVEL?, posted by kelv on January 18, 2007, at 21:32:06
i saw an abstract recently about an nmda agonist accelerating ethanol tolerance, i really do think glutamate is the major tolerance controller to everything!
well you said it yourself DXM, acamprosate, lamictal or amantadine might be other options you might consider, but i dont know if their anti glutamate action is strong enough, combining 2 might be a solution for that not sure
Posted by kelv on January 19, 2007, at 20:31:41
In reply to Re: MEDIVEL?, posted by medievil on January 19, 2007, at 7:21:08
> i saw an abstract recently about an nmda agonist accelerating ethanol tolerance, i really do think glutamate is the major tolerance controller to everything!
>
Is that why L-Glutamine has had success with lessoning Alcohol desire?
Posted by medievil on January 20, 2007, at 3:28:47
In reply to Re: MEDIVEL?, posted by kelv on January 19, 2007, at 20:31:41
i think thats because alcohol itself stimulates glutamate, not sure about this one
where's this chemist guy?!
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