@misc{oai:az.repo.nii.ac.jp:00003812,
 author = {沼本, 輝孝 and Numamoto, Terutaka},
 month = {2014-04-16, 2014-08-18},
 note = {Amphetamine and methamphetamine hydrochloride are analpetics. They differ from morphine, but show dependence. It is a well-known problem that they cause narcomania at doses exceeding the limit.

 Methamphetamine has not only adrenergic but also potent analpetic effects. The latter effect together with bronchiectactic effect and respiration accelerating action was first reported by Alles and has been used for treatment of obesity, fatigue, paroxymal sleep, Parkinson's disease, depressive syndrome, and introxication of central inhibitors. However, no reports have been published on correlation between dependence on these drugs including methamphetamine hydrochloride and histopathological findings. We compared α-phenyl-α-N-(β-phenylisopropyl-amino-acetonitrile (AN_1) and methamphetamine hydrochloride for amphetamine-like dependenc, histopathologic changes caused by them, and relationship between dependence and these changed in the crab-eating macaque, Macaca irus. AN_1 is a mental stimulant and has a basic structure of phenylalkylamine.

 In this study correlation between AN_1 and methamphetamine hydrochloride concerning dependence and histopathologic findings was investigated with the following points emphasized:

  I. Acute intoxication symptoms
 II. Test of dependence
     1. Influence on body weight
     2. Change of symptoms during continuous administration
     3. Withdrawal phenomena
III. Histopathological examination
     1. Histopathologic changes in central nervous system
     2. Histophatologic changes in peripheral organs

 I. Acute intoxication symptoms

AN_1 group:
 A single subcutaneous injection of AN_1 caused yawning, scratching the body, trembling, grooming, mumbling, biting, licking the foot, etc. at doses of 1 and 2 mg per kg body weitht. At a dose of 5 mg/kg such symptoms as barking, unsteady eyes, loss of calmness, tremors, lying on the back, lying on the side, licking the cage and continuously putting out the tongue appeared in addition to the above symptoms.

Methamphetamine hydrochloride group:

 A single subcutaneous injection of 1 mg/kg of the drug caused aggressive movement, corediastasis, loss of calmness in addition to the symptoms found in a single administration of the same dose of AN_1. At a dose of 2 mg/kg paralysis of the lower half of body and sitting like a dog were odditionally observed. At a dose of 10mg/kg continuous yawning, sitting with legs akinbo, moving the body before and after, and biting the foot and cage were observed besides the symptoms mentioned above.

 II. Test of dependence

 Monkeys were injected with a drug twice a day for the first 7 days and every 8 hours thereafter. On the 15th day levallorphan tartrate was subcutaneously injected at a dose of 0.5 mg/kg to investigate the possibility of morphine-like dependence. The animals were observed for 8 hours to confirm the presence or absence of withdrawal symptoms.

 After observing the symptoms following the injection of levallorphan tartrate (lev), administration of the test drug was continued with the same frequency. Three subcutaneous injections daily were carried out for a total period of 45 days. Then the animals were put under observation for 152 hours to investigate whether or not spontaneous withdrawal symptoms appeared.

1. Influence on body weight

AN_1 group:
 Injection of 0.5 mg/kg twice during the first week and then 3 times daily supressed body weight gain until the 39th day. However, body weight increased after that. At a dose of 2 mg/kg a slight decrease in food intake and body weight occurred during ghe first week when animals received 2 injections daily. Body weight decreased by 4.8% after the 7th day when animals received 3 injections daily. During Lev induction and spontaneous prohibition no changes were observed in body weight.

Methamphetamine hydrochloride group:

 Two injections daily caused slight decrease in body weight. Three injections daily starting on the 8th day gave rise to a 17.9% decrease followed by a 10.8 to 8.8% decrease. During Lev induction body weight did not vary. During spontaneous prohibition a 8.8 to 2.3% reduction in body weight occurred. The body weight increased with the lapse of time after termination of methampetamine hydrochloride injection.

2. Change of symptoms during continuous administration

AN_1 group:

 The symptoms observed after a single injection of either 0.5 or 2 mg/kg disappeared after 35 days.

Methamphetamine hydrochloride group:

 The symptoms disappeared in 4 to 5 hours after the 30th day of 3 injections daily.
 One animal died on each of the 12th and 13th days of 3 injections daily.

3. Withdrawal phenomena

AN_1 group:
 Lev injection did not induce withdrawal symptoms. Symptoms of grade 1 to 2 occurred with spontaneous prohibition.

Methamphetamine hydrochloride group:

 Lev injection did not induced withdrawal symptoms. Spontaneous withdrawal symptoms appeared in 20 to 40 hours following the cessation of consecutive daily injections and were grade 5 to 6: such symptoms as grooming, staring at
 one point, continuous barking, and biting the cage appeared.

 III. Histopathological examination

 No changes to be specially mentioned were not found in a macroscopic examination of various organs.

1. Histologic changes in central nervous system

AN_1 group:
 The cerebral cortex was free of significant alternation. BETZ giant cells in the anterior central convolution enlarged to some degree. No changes were observed in the thalamus. Faintly stained cellular bodies were scattered in the brainstem nerve nucleus. The diencephalon showed little change. In the pons nuclei varied in size and large nerve cells swelled or shrinked. Some cells atrophied slightly in the hippocampus major, red nucleus, and black substance. In the cerebellum partial dissolution or disappearence of nuclei occurred at a dose of 0.5 mg/kg and degeneration of Purkinje's cells and carvenous white substance were found at a dose of 2 mg/kg. The pituitary gland was unaltered.

Methamphetamine hydrochloride group:
 In the cerebral cortex wide congestion covering the whole meninges, odema around cerebral nerve cells, and vacuolization around medullary oligoglia cells were found. Swlling of BETZ cells in the anterior central convolution was more conspicuous when compared with that in AN_1 group. In the thalamus edematous necrosis of the cerebral parenchyma was found. Although the brain-stem nerve nucleus was the same as in the AN_1 group. congestion of arterioles was more evident in some animals. No significant changes were found in the diencephalon. The pons showed severe congestion. The same changes as those in the AN_1 group were found in the hippocampus major, red nucleus, and black substance. The cerebellum showed xanthoma, epithalaxia, and degenerative necrosis in the chorioid plexus of the third ventricle, extensive congestion of the meninges, and disordered cortex in addition to the changes found in the AN_1 group. The pituitary gland was unaltered.

2. Histologic changes in peripheral organs

AN_1 group:
 Degeneration of hepatic cells was sporadically found and markedly swollen veins were found in some animals. No significant chantes occurred in the kidney. The mesenchymal system was unstable and hemosiderosis was found in the spleen. The adrenal gland showed no significant changes. Spermatogenesis was disturbed in the testis.

Methamphetamine hydrochloride group:
 Degeneration of hepatic cells of the same degree as that in AN_1 group occurred. Congestion of gromerulus was found in some animals. Unequal glomerular mesangium was observed in one animal. The changes in the spleen was more important than in the AN_1 group. The adrenal gland showed hemorrhaging and regression in some animals. Spermatogenesis was disturbed to a greater degree than in the AN_1 group.

 The following conclusions were deduced from the above results:

 1) AN_1 and methamphetamine caused similar symptoms in a single large dose, though their extent was more slight with the former.

 2) Repeated administration of AN_1 suppressed body weight gain and produced slight tolerance.

 3) Injection of levallorphan did not induce withdrawal phenomena, indicating AN_1 is free from morphine-like dependence.

 4) Spontaneous withdrawal symptoms were very slight. AN_1 differed from methamphetamine hydrochloride which causes severe changes.

 5) In the histopathological examination AN_1 caused degenerative changes of nerve cells in the anterior central convolution, brain-stem nerve nucleus, pons, hippocampus major, red nucleus, and black substance of the mesencephalon. However, it differed from methamphetamine hydrochloride in not causing vasomotor changes in the cerebral cortex, meninges, thalamus, chorioid plexus, kidney, spleen and adrenal gland. Spermatogenesis was suppressed by both drugs.

 Accordingly, it was concluded that AN_1 is not so safe as a general medical agent., 中枢興奮薬の1種にamphetamineおよびmethamphetamine-HCIがある。これらはmorphineとは異なっているが依存性をもっている。すなわち、量的度合を越えるといわゆる麻薬中毒にかかると言う難題があることは、すでに周知のことであろう。
　methamphetamine-HCIはアドレナリン作用の性格に加えて、強力な中枢興奮作用を有する。中枢興奮作用はALLESが気管支拡張、呼吸刺激とともにはじめて報告し、肥満、疲労、発作性睡眠、PARKINSON氏病、抑うつ性症候群および中枢抑制薬中毒などの治療に使用されるようになった。しかし、methamphetamine-HCIを含めて依存性と病理組織学的所見の検討との相関を検討した報告は見られない。そこで、精神賦活薬α-phenyl-α-N-(β-phenylisopropyl)-amino-acetonitrile(AN_1)は基本骨格としてphenylalkylamineをもつもので、このamphetamine様の依存が存在するか、あるとすれば病理組織学的の特性はどのようか、依存性との関係はどうかの3点をカニクイザルを用いてmethamphetamine-HCIと比較検討することを目的とした。
　本論文では
　I. 急性中毒症状
　II. 依存性試験
　　1. 体重におよぼす影響
　　2. 連続投与中における症状の推移
　　3. 禁断症状
　III. 病理組織学的検索
　　1. 中枢の組織学的変化
　　2. 末梢の組織学的変化
　以上の観点からサルを用い、AN_1とmethamphetamine-HCIの依存性と病理組織学的所見の相関性を実験成績にもとづいて比較論述した。
　I. 急性中毒症状
　AN_1群：1回皮下注射により、1および2mg/kgではあくび、体をかく、身ぶるい、grooming、口をもぐもぐさせる、咬む、足をなめるなどがあらわれ、5mg/kgでは啼鳴、目をキョロキョロさせ、落ち着きなく、振せん、背臥、横臥、金網をなめる、舌を連続的に出す症状が加わった。
　methamphetamine-HCI群：1回皮下注射により、1mg/kgではAN_1 1mg/kg投与群と同様の症状のほかに攻撃性、瞳孔散大、落ち着かないが加わった。2mg/kgでは、上記の症状のほか、後軀の麻痺、犬座姿勢が加わった。10mg/kgでは連続的なあくび、両足をなげ出して坐り、身体を前後左右に動かす、金網および足を咬む症状が加わった。
　II. 依存性試験
　サルに薬物を最初の7日間は1日2回、以後8時間間隔で1日3回連続皮下注射し、15日目にmorphine様依存の可能性があるかどうかを検するため、levallorphan tartrate (Lev) 0.5mg/kgを全群に1回皮下注射して、Lev誘発による禁断症状の有無を8時間にわたり観察した。
　Lev誘発の後の症状観察後、再び前記の注射を続け、通算1日3回連続45日間皮下注射したのち投与を中止し、以後152時間にわたり自然禁断症状の有無を観察した。
　1. 体重におよぼす影響
　AN_1群：0.5mg/kgを1日2回および3回連続投与39日間までは体重増加を抑制したが、その後は増加した。Lev誘発および自然禁断によって体重変化はおきなかった。2mg/kgでは1日2回でわずかな飼料摂取量低下と体重減少、1日3回で7日目から4.8%の減少が認められた。Lev誘発および自然禁断では体重変化はおきなかった。
　methamphetamine-HCI群：1日2回連続投与ではわずかな体重減少であったが、1日3回で7日目から17.9%の減少、その後10.8～8.8%少なかった。Lev誘発により変化はなく、自然禁断中に8.8～2.3%減であった。methamphetamine-HCI中止によって時とともに増加した。
　2. 連続投与中における症状の推移
　AN_1群：0.5および2mg/kg投与で1回皮下注射の症状は、35日の後半で消失した。
　methamphetamine-HCI群：1日3回連続投与開始30日以後4～5時間で症状が消失し、1日3回連続注射12および13日目には、それぞれ1例づつ斃死した。
　3. 禁断症状
　AN_1群：Lev誘発によって禁断はおきなかった。自然禁断においては grade 1～2を示した。
　methamphetamine-HCI群：Lev誘発によって禁断はおきなかった。自然禁断は連続注射中止20～40時間後から現われ、grade 5～6を示した。すなわち、grooming、1ヵ所を見つめる、連続的な啼鳴、金網を咬む症状があらわれた。
　III. 病理組織学的検索
　諸臓器の肉眼的観察において特記すべき変化は見られなかった。
　1. 中枢の組織学的変化
　AN_1群：大脳皮質の変化は少なかった。中心前回のBETZ巨細胞に多少の腫大をおこすものがあった。視床には変化なかった。脳幹神経核に胞体の淡染のものが散見された。間脳も変化に乏しかった。橋では核不同。大きい神経細胞の膨化または縮少が見られた。海馬角、赤核、黒質では軽度萎縮の細胞があった。小脳では0.5mg/kgで核の一部融解、消失、2mg/kgでは、プルキンエ細胞変性および白質の海綿状態が認められた。下垂体には変化なかった。
　methamphetamine-HCI群：大脳皮質全般の脳膜に広汎なうっ血、皮質神経細胞周囲性水腫および髄質オリゴグリア周囲の空庭形成を認めた。中心前回のBETZ巨細胞の腫大出現はAN_1より強かった。視床に水腫性脳実質壊死を認めた。脳幹神経核はAN_1と同じであったが、小動脈の充血の強い例があった。間脳は変化が乏しかった。橋にはうっ血が強かった。海馬角、赤核、黒質の変化はAN_1と同じであった。小脳では第4脳室の脈絡叢組織に黄色腫瘤、上皮剝離、変性壊死、小脳脳膜のうっ血が強く広汎であり、AN_1の所見のほかに皮質に乱れがあった。下垂体には変化なかった。
　2. 末梢の組織学的変化
　AN_1群：肝細胞の退行変性が散見され、これに静脈系の怒張を示す例があった。腎は著変なかった。脾は間葉系の不安定化、ヘモジデリン症があった。副腎は著変なかった。精巣に造精障害が見られた。
　methamphetamine-HCI群：肝細胞の退行変性はAN_1と同程度であった。腎糸球体うっ血を示す例があった。糸球体メサンギウム不平等が1例あった。脾の変化はAN_1より大であった。副腎に出血例、退縮例があった。精巣の造精能障害の度合はAN_1より大であった。
　以上の成績にもとづき
　1) AN_1大量1回投与では、methamphatamine-HCIより軽いが同性格の症状を現わした。
　2) 反復投与によって体重増加の抑制が認められ、軽度ながら耐性発現が認められた。
　3) levallorphan誘発による禁断症状は見受けられず、AN_1にはモルヒネネ様の依存性はなかった。
　4) 自然禁断症状はきめて軽度で、methamphetamine-HCIごとき強い変化はなかった。
　5) 病理組織学的には、中心前回、脳幹神経核、橋、海馬角、赤核、黒質の中脳の神経細胞に退行変性が認められたが、methamphetamine-HCIのもつ大脳皮質、脳膜、視床、脈絡叢および腎、脾、副腎の血管運動性の変化に乏しかった。また、造精能がいずれも抑制された。したがって、これらのことから本薬剤は、一般医薬品として安全性に乏しいと結論づけた。},
 title = {α-Phenyl-α-N-(β-Phenylisopropyl)-Amino-Acetonitrile(AN_1) のサルにおける依存性と病理組織学的所見の相関性の検討},
 year = {}
}