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Pentylenetetrazol chemical structure
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Pentylenetetrazol (PTZ) is the International Nonproprietary Name of Metrazol (aka Cardiazol in Europe) and also known as pentetrazol or pentamethylenetetrazol. It is a drug used as a circulatory and respiratory stimulant. Larger doses cause convulsions, thus it was commonly used in shock therapy during the 40s and 50s, as first used by the Hungarian-American neurologist and psychiatrist Ladislas J. Meduna in 1934. Early in his work Meduna replaced camphor with pentylenetetrazol (Metrazol), an intravenous agent that induced seizures immediately compared with the long delay of 15 to 45 minutes after intramuscular camphor.
He first published his results in 1935 and then his major text in 1937. Die Konvulsionstherapie der Schizophrenie describes the results in 110 patients. Of these patients about half recovered. The results were much better for patients who were ill less than a year compared to those who had been ill for many years.
His results were quickly reproduced in many other centers around the world and this form of therapy became widely used and recognized as the first effective treatment for schizophrenia.
It later proved largely ineffective, and side-effects such as seizures are difficult to avoid. Its approval by FDA was revoked in 1982. but by then its use had been replaced by electrical stimulation, as in ECT
Pentylenetetrazole has been used experimentally to study seizure phenomenon and to identify pharmaceuticals that may control seizure susceptibility. PTZ is also a prototypical anxiogenic drug and, has been extensively utilized in animal models of anxiety. PTZ produces a reliable discriminative stimulus which is largely mediated by the GABAA receptor. Several classes of compounds can modulate the PTZ discriminative stimulus including 5-HT1A, 5-HT3, NMDA, glycine, and L-type calcium channel ligands.
Recently, it has been shown that pentetrazol at non-epileptic doses, along with two other compounds (Picrotoxin and bilobalide) can restore the cognitive function (learning and memory) of a mouse model of Down syndrome by inhibiting GABAA receptor without inducing seizures. These results caused renewed interest in pentetrazol as a potential drug candidate for Down syndrome, although clinical trials are probably still a couple of years away..
The finding of pentetrazol's effectiveness in treating Down Syndrome has lead to it being explored as a means of correcting other learning deficiencies. Specifically, hamsters denied their natural circadian rhythm (though not denied sleep) had their memory restored to near-normal levels when treated with pentetrazol.
In 1939, Metrazol (also known as Cardiazol) was replaced by electroconvulsive therapy as the preferred method for inducing seizures in England's mental hospitals.
- ↑ 1.0 1.1 includeonly>JR Minkel. "Drug May Counteract Down Syndrome", Scientific American, February 25, 2007. Retrieved on 2007-03-20.
- ↑ Entry for Pentylenetetrazole in the MeSH database
- ↑ Jung M, Lal H, Gatch M (2002). The discriminative stimulus effects of pentylenetetrazol as a model of anxiety: recent developments. Neurosci Biobehav Rev 26 (4): 429–39.
- ↑ Fernandez F, Morishita W, Zuniga E, Nguyen J, Blank M, Malenka R, Garner C (2007). Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nat Neurosci.
- ↑ Ruby et al.; Hippocampal-dependent learning requires a functional circadian system; Proceedings of the National Academy of Sciences of the United States of America, 2008, vol. 105, no. 40,15593-15598
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