實驗的 肝吸蟲症 家兎에 對한 Niclofolan 誘導體의 治療效果 및 毒性 = Therapeutic Effects of Niclofolan Derivatives on Experimental Clonorchiasis Rabbits and its Toxicity

국문 초록 (Abstract)

Niclofolan(5.5'-Dichloro-2.2'-hydroxy-3.3'-D-initro-Biphenyl이 肝吸蟲症에 有效하나 副作用이 强하고 人體에 對한 毒性도 아는 바가 적어 널리 使用되지 않고 있다.
Niclofolan의 誘導體에서 毒性이 적은 藥物을 얻기 爲한 試圖로서 于先 noclfolan 構造內에 NO_2 基가 肝吸蟲症 治療效果 및 毒性에 미치는 影響을 알기 爲하여 niclofolan의 Nitro基(NO_2) 中 한個 또는 두個를 Amino基(NH_2)로 置換한 5.5'-Dichloro-2.2'- Dihydroxy-3-Nitro-3'-Amino-Bipheny(Ani-clofolan)와 5.5'-Dichloro-2.2'-Dihydroxy-3.3'-Diamino-Biphenyl(Amiclofolan)의 肝吸蟲症 治療效果 및 毒性을 niclofolan의 그것과 比較觀察하여 다음과 같은 結論을 얻었다.
人工感染 肝吸蟲症토끼에서 niclofolan은 5㎎/㎏를 3日間 經口投與에서 顯著한 效果를 볼 수 있으나 aniclofolan에서는 50㎎/㎏에서도 效果가 적었고 amiclofolan에서는 50㎎/㎏에서도 效果를 볼수 없었다.
試驗管內에서의 肝吸蟲成蟲에 對한 殺蟲作用은 niclofolan 은 10^-5g/m 濃度에서 12時間에 100%, aniclofolan는 10^-5g/㎖ 濃度에서 36時間에 各各 100%의 殺蟲效果를 보였으며, amiclofolan에서는 10^-4濃度에서 48時間에 50%의 殺蟲率을 보였으며, 10^-6濃度에서는 48時間에 15%의 殺蟲率로서 對照群과 差異가 없어졌다.
血壓 및 呼吸에 對한 作用은 Niclofolan (0.63㎎/min/㎏)을 또는 aniclofolan(3.15㎎/min)를 繼續注入했을 때 血壓은 漸次 上昇하였으나 注入後 15分 및 40分頃後에는 血壓이 急激히 下降하고 죽었다. 呼吸은 投藥을 繼續함에 따라 처음 漸次 亢進되다가 後에는 漸次로 抑制되었다.
Aminoclofolan投藥群에서는 3.15㎎/min/㎏를 繼續投與했을 때 血壓은 처음 漸次 徐徐히 上昇하였으나 藥物注入 80分까지 죽지 않았으며 呼吸은 漸次 多少亢進되었다.
摘出腸管에 對한 作用은 一般的으로 緊長度가 減少되었으며 高濃度에서는 藥物適用後 數分內에 漸次 振幅이 減少되고 運動은 完全히 停止되었다. 數分內에 停止되는 藥의 濃度는 niclofolan 5×10EXP(-7)g/㎖ aniclofolan은 10^-5g/㎖, amiclofan 5×10EXP(-5)g/㎖이었다.
一般狀態 및 肝機能에 대한 作用은 Niclofolan 10㎎/㎏ 6日 投藥 期日中 食慾 및 其他行動에 異狀을 보지 못하였고 20㎎/㎏를 3日間 投藥하는 동안은 食慾 및 運動減退 혹은 죽기도하였다.
Aniclofolan 및 amiclofolan를 各各 50㎎/㎏ 6日間 投藥時에는 何等의 異狀을 볼 수 없었다. 肝機能은 niclofolan 20㎎/㎏ 投與群에서는 GOT 및 GPT가 上昇하는 例를 볼 수 있었고 niclofolan 10㎎/㎏, aniclofolan 50㎎/㎏, amiclofolan 50㎎/㎏投藥群에서는 特記할 異狀이 없었으며 全實驗動物에서 肝 및 腎臟의 組織學的 異狀 所見을 볼 수 없었다.
以上의 實驗成績을 綜合하면 niclofolan의 肝吸蟲症 治療效果 및 毒性은 構造內의 nitro基(NO_2)를 amino基(NH_2)로 置換하였을 때는 減少되었으며 NH_2 한계보다 2個를 置換하였을 때가 더욱 減少하였다.
以上 結果로 보아 niclofolan의 肝디스토마 治療效果를 爲해서는 構造內에 NO_2의 存在가 絶對必要하며 治療效果가 增强될 때는 毒性도 增加됨을 볼 수 있었다.

다국어 초록 (Multilingual Abstract)

Niclofolan(5.5＇-Dichloro-2.2＇-Dihydroxy-3.3＇-Dinitro Biphenly) has been used in the treatment of fascioliasis in animals and it was proved to be effective for paragonimiasis and clonorchiasis in man, However, because of it's side effect and toxicity it has remained in clinical trial stage.
In this study, as one of the efforts to fine out a less toxic drug from the niclofolan analogous, it was attempted to know the structure activity relationship, especially, the role of the nitro group in the structure of niclofolan for the therapeutic effect and toxicity.
For this purpose, three compounds, niclofolan, aniclofolan and amiclofolan, were compared for therapeutic effect and toxicity.
In the rabbits artificially infected with Clonorchis sinensis thereapeuitc effets were observed with niclofolan(5㎎/㎏/day for 3 days) highly effective, aniclofolan (50㎎/㎏/day) less effective, while Amiclofolan ineffective, orally.
In vitro test, one hundred percent of vermicidal effect was observed with niclofolan in concentration of 10^5g/㎖ within 12 hrs and with aniclofolan 10^5g/㎖ within 36 hrs. Whereas, fifty percent of vermicidal effect was observed with amiclofolan in the concentration of 10^4g/㎖ within 48hrs.
Infusion of niclofolan(0.63㎎/㎏/min) and aniclofolan(3.15㎎/㎏/min) into the vein of rabbit, it caused gradual stimulation of respiration followed by depresion and a suden death after 15 and 40 minutes of infusion respectively.
In the group infused with amiclofolan(3.15㎎/㎏/min), it also caused gradual elevation of blood pressure, but the rabbits remain alive even after 80 minuts of infusion, and also respiration was stimulated slightly.
On the isolated rabbit intestine, niclofolan analogous caused gradual decrease in tonus and ampiltude of movement and then finally complete ceastion of motility. The concentration of these drugs in which caused cessation of motility within a few minutes were 5×10EXP(-7)g/㎖ of niclofclofolan, 10^-5g/㎖ of aniclofolan and 5×10EXP(-5)g/㎖ of amiclofolan.
In the five rabbits given niclolofolan in a dose of 20㎎/㎏/day for 3 days, the rabbits became excited at an early stage and was depressed later and on of the five animals was expired. Elevation of GOT in two rabbits and GPT in one rabbit were noted, but there was no signification histological change in the kidney and the liver in any of rabbits.
In those groups received niclofolan (10㎎/㎏/day), or aniclofolan(50㎎/㎏/day) for 6 days respectively, no behavioral changes were noted during the treatment. Even after treatment, no alternation were noted in the serum total protein, alkaline phosphatase, GOT, GPT and histological finding in the liver and the kidney.
With the above result, it can be summerized that niclofolan which has two nitro group in the structure, has the most potency in the respect to therapeutic effect of clonorchiasis and toxicitv. Amiclolfolan which has tow amino group, has the least effect and toxicity. Aniclofolan which has one nitro and one amino group be placed between them.
Form these results, it suggest that the presence of nitro group in the structure of niclofolan is indispensable for the therapeautic effect of clonorchiasis and toxicity.