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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/06/09 07:03:41」(JST)

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Pentylenetetrazol, also known as pentylenetetrazole, metrazol, pentetrazol (INN), pentamethylenetetrazol, Cardiazol or PTZ, was a drug used as a circulatory and respiratory stimulant. High doses cause convulsions, as discovered by the Hungarian-American neurologist and psychiatrist Ladislas J. Meduna in 1934. It has been used in convulsive therapy, but was never considered to be effective, and side-effects such as seizures were difficult to avoid. Its approval by the FDA was revoked in 1982.^[1]

Mechanism

The mechanism of pentylenetetrazol is not well understood, and it may have multiple mechanisms of action. In 1984, Squires et al. published a report analyzing pentylenetetrazol and several structurally related convulsant drugs. They found that in vivo convulsant potency was strongly correlated to in vitro affinity to the picrotoxin binding site on the GABA-A receptor complex. Many GABA-A ligands are effective anticonvulsants, such as the sedatives diazepam and phenobarbital, but presumably pentylenetetrazol has the opposite effect when it binds to the GABA-A receptor.^[2]

Several studies have focused on the way pentylenetetrazol influences neuronal ion channels. A 1987 study found that pentylenetetrazol increases calcium influx and sodium influx, both of which depolarize the neuron. Because these effects were antagonized by calcium channel blockers, it was concluded that pentylenetetrazol acts at calcium channels, and it causes calcium channels to lose selectivity and conduct sodium ions as well.^[3]

Uses

Pentylenetetrazol has been used experimentally to study seizure phenomena and to identify pharmaceuticals that may control seizure susceptibility. Pentylenetetrazol is also a prototypical anxiogenic drug and, has been extensively utilized in animal models of anxiety. Pentylenetetrazol produces a reliable discriminative stimulus which is largely mediated by the GABA_A receptor. Several classes of compounds can modulate the pentylenetetrazol discriminative stimulus including 5-HT_1A, 5-HT₃, NMDA, glycine, and L-type calcium channel ligands.^[4]

Recently, Stanford University researchers have renewed interest in PTZ as a candidate for pharmacological treatment of Down syndrome. Published in the April 2007 issue of Nature Neuroscience, their brief communication outlined an experiment designed to test the underlying theory proposed to explain the purported efficacy of GABA_A antagonists in restoring the declarative memory deficits associated with the mouse model of human Down Syndrome. Ts65Dn mice injected with a 2-week regimen of either of two compounds picrotoxin or bilobalide (both GABA antagonists) showed marked improvements in both exploration and recognition of novel objects over controls injected with only saline. These results were duplicated in a second experiment with mice fed either plain milk or a combination of milk and a non-epileptogenic dose of PTZ daily for 17 days. PTZ-fed mice achieved novel object task scores comparable to wild-type (normal) mice. These improvements persisted at least 1 to 2 months after the treatment regimen. Not surprisingly these compounds' efficacies were accompanied by the normalization of Long-term potentiation in the dentate gyrus one month after the end of treatment, further suggesting persistent drug-mediated improvements in learning and memory.^[5]

The finding of pentylenetetrazol's effectiveness in treating a mouse model of Down syndrome has led 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 pentylenetetrazol.^[6]

Alternatives

In 1939, pentylenetetrazol was replaced by electroconvulsive therapy as the preferred method for inducing seizures in England's mental hospitals. However, it wasn't disapproved of in the United States until 1982.

References

^ Minkel JR (February 25, 2007). "Drug May Counteract Down Syndrome". Scientific American. Retrieved 2007-03-20.
^ Squires RF, Saederup E, Crawley JN, Skolnick P, Paul SM (1984). "Convulsant potencies of tetrazoles are highly correlated with actions on GABA / benzodiazepine / picrotoxin receptor complexes in brain". Life Sci. 35 (14): 1439–44. doi:10.1016/0024-3205(84)90159-0. PMID 6090836.
^ Papp A, Fehér O, Erdélyi L (1987). "The ionic mechanism of the pentylenetetrazol convulsions". Acta Biol. Hung. 38 (3–4): 349–61. PMID 3503442.
^ Jung ME, Lal H, Gatch MB (2002). "The discriminative stimulus effects of pentylenetetrazol as a model of anxiety: recent developments". Neurosci. Biobehav. Rev. 26 (4): 429–39. doi:10.1016/S0149-7634(02)00010-6. PMID 12204190.
^ Fernandez F, Morishita W, Zuniga E, Nguyen J, Blank M, Malenka RC, Garner CC (2007). "Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome" (PDF). Nat. Neurosci. 10 (4): 411–3. doi:10.1038/nn1860. PMID 17322876.
^ Ruby NF, Hwang CE, Wessells C, Fernandez F, Zhang P, Sapolsky R, Heller HC (2008). "Hippocampal-dependent learning requires a functional circadian system". PNAS USA 105 (40): 15593–8. doi:10.1073/pnas.0808259105. PMC 2563080. PMID 18832172.

English Journal

Alpha-asarone from Acorus gramineus alleviates epilepsy by modulating A-Type GABA receptors.

Huang C, Li WG, Zhang XB, Wang L, Xu TL, Wu D, Li Y.SourceInstitute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China; Neuroscience Division, Department of Biochemistry and Molecular Cell Biology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
Neuropharmacology.Neuropharmacology.2013 Feb;65:1-11. doi: 10.1016/j.neuropharm.2012.09.001. Epub 2012 Sep 10.
Alpha (α)-asarone is a major effective compound isolated from the Chinese medicinal herb Acorus gramineus, which is widely used in clinical practice as an antiepileptic drug; however, its mechanism of action remains unclear. In this study, we have characterized the action of α-asarone on the excit
PMID 22975146

The mu-opioid receptor-selective peptide antagonists, antanal-1 and antanal-2, produce anticonvulsant effects in mice.

Fichna J, Socała K, Nieoczym D, Gach K, Perlikowska R, Janecka A, Wlaź P.SourceDepartment of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland.
Progress in neuro-psychopharmacology & biological psychiatry.Prog Neuropsychopharmacol Biol Psychiatry.2013 Jan 10;40:126-31. doi: 10.1016/j.pnpbp.2012.07.020. Epub 2012 Aug 11.
The activation of the mu-opioid receptors (MOR) in the central nervous system has a proconvulsant effect and seizures are a common side effect of high doses of short acting opioids, like morphine or fentanyl. However, the correct assessment of the role of MOR blockade in the initiation and propagati
PMID 22918032

Japanese Journal

Effects of Antiepileptics on Behavioral and Electroencephalographic Seizure Induced by Pentetrazol in Mice

WATANABE Yusuke,TAKECHI Kenshi,FUJIWARA Akinori,KAMEI Chiaki
Journal of pharmacological sciences 112(3), 282-289, 2010-03-20
NAID 80020902056

Anticonvulsant Effect of (RS)-1-Aminoindan-1,5-dicarboxylic Acid on Pentetrazol-Induced Kindled Seizures in Mice

Watanabe Yusuke,Kaida Yuko,Takechi Kenshi,Kamei Chiaki
Biological & Pharmaceutical Bulletin 33(4), 647-652, 2010
… The present study was undertaken to clarify the effect of group I metabotropic glutamate receptor (mGluR) antagonist, (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA) on pentetrazol-induced kindled seizures. … In order to induce kindling, pentetrazol at a dose of 40 mg/kg was injected intraperitoneally once every 48 h. … Behavioral and electroencephalographic (EEG) seizures were observed for 20 min following pentetrazol administration. …
NAID 130000248013

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★リンクテーブル★

リンク元	「呼吸興奮薬」「ペンテトラゾール」

「呼吸興奮薬」

Pentylenetetrazol
Systematic (IUPAC) name
	6,7,8,9-Tetrahydro-5H-tetrazolo(1,5-a)azepine
Clinical data
Identifiers
CAS Registry Number	54-95-5
ATC code	R07AB03
PubChem	CID: 5917
ChemSpider	5704
UNII	WM5Z385K7T
KEGG	D07409
ChEBI	CHEBI:34910
ChEMBL	CHEMBL116943
Chemical data
Formula	C6H10N4
Molecular mass	138.171 g/mol
	SMILES C12=NN=N[N]1CCCCC2;
	InChI InChI=1S/C6H10N4/c1-2-4-6-7-8-9-10(6)5-3-1/h1-5H2 ; Key:CWRVKFFCRWGWCS-UHFFFAOYSA-N ;
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　　[★]

英: respiratory stimulant, respiratory stimulants
関

延髄に直接作用して呼吸興奮と血圧上昇作用を示す。臨床応用は限られる (SPC.272)
過量：唾液分泌過多、悪心、嘔吐、不整脈、けいれん (SPC.272)

頚動脈体や大動脈体および延髄の化学受容器を刺激して呼吸興奮を起こす。即効性で持続時間は短い (SPC.272)

lobeline

気道粘膜、食道および胃粘膜を刺激して反射的に呼吸興奮を起こす (SPC.272)

アルコール飲料、アンモニア

英: respiratory stimulants

「ペンテトラゾール」

　　[★]

英: pentetrazol
同: ペンチレンテトラゾール pentylenetetrazol

痙攣薬

GABA-A遮断

特徴

構造

作用機序

ピクロトキシンと同様な作用機序
GABA_A受容体を拮抗阻害→膜の過分極↓→興奮性↑

薬理作用

漸進性、非同調的、間代性けいれん
てんかん脳波を誘発

動態

適応

注意

禁忌

副作用

相互作用

[sciam-1] Minkel JR (February 25, 2007). "Drug May Counteract Down Syndrome". Scientific American. Retrieved 2007-03-20.

[2] Squires RF, Saederup E, Crawley JN, Skolnick P, Paul SM (1984). "Convulsant potencies of tetrazoles are highly correlated with actions on GABA / benzodiazepine / picrotoxin receptor complexes in brain". Life Sci. 35 (14): 1439–44. doi:10.1016/0024-3205(84)90159-0. PMID 6090836.

[3] Papp A, Fehér O, Erdélyi L (1987). "The ionic mechanism of the pentylenetetrazol convulsions". Acta Biol. Hung. 38 (3–4): 349–61. PMID 3503442.

[4] Jung ME, Lal H, Gatch MB (2002). "The discriminative stimulus effects of pentylenetetrazol as a model of anxiety: recent developments". Neurosci. Biobehav. Rev. 26 (4): 429–39. doi:10.1016/S0149-7634(02)00010-6. PMID 12204190.

[5] Fernandez F, Morishita W, Zuniga E, Nguyen J, Blank M, Malenka RC, Garner CC (2007). "Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome" (PDF). Nat. Neurosci. 10 (4): 411–3. doi:10.1038/nn1860. PMID 17322876.

[6] Ruby NF, Hwang CE, Wessells C, Fernandez F, Zhang P, Sapolsky R, Heller HC (2008). "Hippocampal-dependent learning requires a functional circadian system". PNAS USA 105 (40): 15593–8. doi:10.1073/pnas.0808259105. PMC 2563080. PMID 18832172.

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案内

pentetrazol