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咳嗽反射と鎮咳作用(薬)に関する基礎的研究
https://az.repo.nii.ac.jp/records/3179
https://az.repo.nii.ac.jp/records/317944ad3d5c-a491-47e2-b8f1-ef066f573774
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diss_dv_otsu0126 (51.7 MB)
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diss_dv_otsu0126_jab&rev (742.2 kB)
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diss_dv_otsu0126_eab (572.9 kB)
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| Item type | 学位論文 / Thesis or Dissertation(1) | |||||||||
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| 公開日 | 2013-01-29 | |||||||||
| タイトル | ||||||||||
| タイトル | 咳嗽反射と鎮咳作用(薬)に関する基礎的研究 | |||||||||
| タイトル | ||||||||||
| タイトル | The fundamental studies on the cough-reflex and antitussive action (agents) | |||||||||
| 言語 | en | |||||||||
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| 言語 | jpn | |||||||||
| 資源タイプ | ||||||||||
| 資源タイプ | thesis | |||||||||
| 著者 |
黒田, 喜代志
× 黒田, 喜代志
× Kuroda, Kiyoshi
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| 内容記述タイプ | Abstract | |||||||||
| 内容記述 | 咳嗽反射(咳発作)は呼吸器系疾患では最も頻繁に遭遇する病症であり，対症療法的に咳発作を軽減するために鎮咳剤を使用することは臨床医学・臨床獣医学のみならず畜産学上においても極めて有用であることは周知の事実である。一方これらの領域において確実な効果が期待出来る薬剤は麻薬性のcodeine phoshate (codeine)のみで他の多くの鎮咳剤は不確実であることもよく知られている。しかし麻薬性薬剤の使用は麻薬取締法に基く取り扱い上の不便のみならず，それ以上に呼吸抑制，消化器障害(便秘)，循環器障害(血圧低下)，耐性形成，依存性(身体的，精神的)形成など医用上の厄介な有害作用を随伴すると同時に，さらに薬物乱用，凶悪犯罪等社会的あるいは国家的問題を引き起す可能性を有している。この様な理由から，鎮痛薬のみならず鎮咳薬についても非麻薬性で確実に奏効する新薬の開発が古くから社会的に要求されて来た。 著者はStühmer and Funkeにより新規に合成されたα-(isopropyl)-α-(β-dimethylaminopropyl) phenylacetonitril;isoaminile について薬理学的および毒性学的に詳細に検討し，この社会的要求をほぼ満足し，学術的にも興味深い新事実を発見したので以下その概要を記す。 1. 鎮咳薬の開発研究には鎮咳作用を動物を用いて測定出来る評価法の確立が先決である。この点に関し，a)咳嗽犬法(Kasé)，b)咳嗽猫法(加瀬，由井薗)，c)猫前喉頭神経電気刺激法(Domenjoz)，d)モルモット・アンモニア水エアロゾル吸入法(Winter and Flataker)を改変し，その有用性について比較検討した。その結果，a)は評価法に必要な条件(本文参照p. 3)をすべて満し，鎮咳活性物質のprimary screening法および効力検定法として最も優れ，次いで，b)，c)の順に実用性を認め，d)は今回実施した条件下では不適当であると言う結論に達した。 2. 上記評価法a)，b)，c)さらに猫延髄電気刺激法(Borison)を用い，isoaminileの鎮咳活性を総体的に検討した結果，クエン酸塩およびシクラミン酸塩はいずれも大差なく，50%鎮咳有効量(AtD_50値)で比較した場合codeineにほぼ匹敵し，現在頻繁に臨床使用されているdextromethorphan hydromide (d-methorphan)，noscapine hydrochloride (noscapine)に比べはるかに強力であることが判明した。(Fig. 1およびTable 1) 3. Isoaminileの鎮咳作用における安全域:safety margin(イヌのLD_50値/イヌのAtD_50値)は，クエン酸塩およびシクラミン酸塩いずれも10以上であり，codeineに比べ小さいものの，d-methorphanやnoscapineに比較するとはるかに大きく，選択性および安全性に優れている(Table 1)。 4. Isoaminileの鎮咳作用は，a)麻薬拮抗薬levallorphan bitartrate(levallorphan)により何ら影響されない(Fig. 2)。b)イヌに長期間連続投与(40日間)した場合にも耐性を形成しない(Fig. 3)。c)codeineとの間に交叉耐性を形成しない(Fig. 4)。 5. Isoaminileは，a)イヌに長期間連続投与(40日間)後，isoaminileの投薬を突然中止した場合，またisoaminileの代りにlevallorphanを代替投与した場合，いずれも禁断症状を発現しない。b)ラットに長期間連続投与(77日間)中に，isoaminileの投薬を突然中止した場合，またisoaminileの代りにlevallorphanを代替投与した場合，いずれも禁断症状(体重減少)を発現しない。c)morphine hydrochloride(morphine)依存ラットにおいて，morphineの投薬を突然中止した際誘発される禁断症状を全く防止しない。 6. Isoaminileのマウス，ラット，イヌにおける主な中毒症状は自発運動亢進，振せん，後肢の運動失調，間代性および強直性痙攣であり共通性が多く，そのLD_50値は「塩」の相違による差異，動物の性の相違による差異(sex difference)，動物の種属の相違による差異(species difference)を示さない。またマウスのLD_50値で比較すると，isoaminileの急性毒性は皮下投与法ではcodeineとほぼ等しいが，静脈内投与法・経口投与法ではcodeineに比し弱い。 7. Isoaminileは高用量(中毒症状発現用量)において鎮痛作用(d'Amour-Smith法，Haffner法)を発現する。しかし本作用はcodeine，morphineの場合とは全く異りlevallorphanにより何ら影響されない。 8. Isoaminileは高用量(中毒症状発現用量)において，a)脊髄マウスの後肢を温水に浸漬した際誘発される後肢の反射性屈曲挙上反応，b)脊髄ネコの後根を電気刺激した際前根に誘発される脊髄反射活動電位(mono synaptic action potential，polysynaptic action poteatial)を明らかに抑制する。 9. Isoaminileは高用量(鎮咳有効量の5～10倍あるいはそれ以上)において，意識レベル低下作用，麻酔増強作用，抗痙攣作用，抗振せん作用など中枢神経系全体に対し抑制的に作用する。 10. Isoaminileは生体気管支筋の緊張には影響しないが，histamine dihydrochlorideにより惹起した気管支筋痙攣に対しては緩解作用を示す。 11. Isoaminileはprocaine hydrochlorideに匹敵する局所麻酔作用を有する。 12. Isoaminileの呼吸器系，循環器系，消化器系，自律神経系に対する作用はcodeineに比べ極めて軽微である。 13. Isoaminileをラットに亜急性的投与(連続28～33日間)した際の最大安全量は推定常用量の50～75倍である。 14. Isoaminileをラットに慢性的投与(連続136日間)した際の最大安全量は推定常用量の10～20倍である。 15. Isoaminileをイヌに慢性的投与(連続180日間)した際の最大安全量は推定常用量の7.5～11.3倍である。 以上，3～15に要約した薬理学的，毒性学的研究結果から総合的に判断し，isoaminileは鎮咳薬として使用するかぎり長期間連用した場合にも安全性は十分確保出来るであろうと言う結論に達した。 次いで咳嗽反射の反射弓(Fig. 5)に対する作用を順次詳細に検討することにより，本化合物の作用機作(作用部位)の解明を企て，以下の成績を得た。 1． 中枢，特に脳幹に到達するような経路に投与すると，静注量よりはるかに少量で同程度の鎮咳効果をあらわし得た。この成績より作用点が中枢であることが推定される。 2． Procaineに匹敵する局所麻酔作用を有しているが，局所適用以外の投与方法では，a)気道粘膜内の咳のreceptorを，また，b)肺のstretch receptorをも麻酔する作用はなかった。 3． 前喉頭神経の電気刺激により孤束核に誘発され，シナプス後電位と推定される電位はisoaminileによって影響されなかった。この所見と2のa)の所見より，isoaminileは咳嗽反射の求心路には作用しないことが判る。 4． 丘間切断による除脳の前後において，isoaminileの鎮咳効果は不変であった(Fig. 6)。故にisoaminileの作用は上位中枢の影響をうけない。さらに，2.のb)の知見より肺のstretch receptorによる調節系を介して作用をあらわすものでないことが判る。 5． 咳嗽反射の遠心路，すなわち，脊髄から呼吸筋に達する経路には全く作用しない。 6． in vivoの実験で，気管支筋の正常時の緊張には影響しないが，histamineによる収縮をやや多量投与で緩解し得る。 以上の知見を総合すると，isoaminileの作用点は「咳中枢」以外ではあり得ない。さらに次の2つの所見から，「咳中枢」そのものに作用することを間接的に証明した。 7． 延髄の一定部位を電気刺激して起こした，いわゆる中枢性の咳を，末梢刺激で起こした咳と同様に抑制する(Fig. 7) 8． 前喉頭神経頻数刺激によって誘発される反回神経のburst状放電を抑制する(Fig. 8)。すなわち，孤束核-凝核間の統合回路(この中に咳中枢ニューロンがあると推定される)をcodeineと同様に抑制する。 9． Isoaminileが麻薬性鎮咳薬codeineと異なる点は，麻薬拮抗薬によって拮抗されないこと(Fig. 2)，呼吸中枢は作用しない(Fig. 7)ことである。 以上，isoaminileの鎮咳作用発現の作用機序は，「咳中枢」の選択的な抑制によるものであり，気管支筋の緩解作用にはそれ程寄与していないであろうという結論に達した。 以上総合すると，本研究の成果は臨床効果と相関する実験的評価法を比較検討し，その結果にもとづき古くから社会的に要求されていた強力で安全性に優れた非麻薬性新規鎮咳薬isoaminile (Perocan^[○!R]，シクラミン酸塩製剤:昭和44年9月3日許可，クエン酸塩製剤:昭和49年1月12日許可)を開発し，さらに本化合物の作用機作を解明したことである。 （以下図表） |
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| Abstract | ||||||||||
| 内容記述タイプ | Other | |||||||||
| 内容記述 | It is a common knowlege that the coughing (cough paroxysm) is a pathognomonic symptom of respiratory disease. Use of antitussive agents for suppressing the cough paroxysm as the symptomatolytic treatment is profitable extremely in the domain of clinical veterinary science, animal husbandry (zootechny) and clinical medicine. On the other hand, it is well known that codeine phosphate (codeine) can be expected to give a certain effect on the clinical application while many of non-narcotic antitussives are ineffective. Further, the use of narcotic antitussives is controlled by the "Narcotics Control Law" and induces the side-effects (adverse reactions) such as respiratory suppression, alimentary disturbance (constipation), circulatory disturbance (postural hypotension), development of tolerance and dependence (physical or psychic). In addition, it can possibly bring about social- or national-troubles such as drug-abuse and atrocious crime. For these reasons, the development of not only a new analgesics but also antitussives that are non-narcotic and effective certainly, has been demanded socially for a long time in each domain. From reasons of above mentioned, isoaminile ; α-(isopropyl)-α-(β-dimethylaminopropyl)phenylacetonitril was synthesized newly in order to overcome these disadvantages by Stühmer and Funke, and the antitussive activities and other pharmacological and toxicological properties of isoaminile were investigated in detail by the author. The results satisfied generally the social demand of above-noted and also induced some important new findings in chemical and life science. The following is a summary. 1. First of all, evaluating method of antitussive activity in animals must be established for the development of a new antitussive agent. In comparative methodology, a) "coughing dog" method (Kasé) was most excellent as primary screening and/or evaluating method, and b) "coughing cat" method (Kasé and Yuizono) and c) the electric stimulation method of cat's superior laryngeal nerve (Domenjoz) followed in order of the practical use, and ultimately d) the inhalation method of ammonia-aerosol in guinea-pig (Winter and Flataker) was unsuitable under the conditions practised in this time. 2. Using the above noted procedures a) b) c) and further the electric stimulation method of cat's dorso-lateral part of the medulla (Borison), the antitussive activities of isoaminile were examined generally. The antitussive activities of isoaminile had no difference between "citrate" and "cyclamate", and was approximately equal to that of codeine in compared with the median antitussive effective dose (AtD50 value), and was more potent than those of dextromethorphan hydrobromide (d-methorphan) and noscapine hydrochloride (noscapine) which had been frequently for clinical treatments. (Fig. 1 and Table 1). 3. The safety margin (dog's LDSO value/dog's AtD50 value) of isoaminile, both "citrate" and "cyclamate" was larger than ten. This was small compared with that of codeine, but was larger than those of d-methorphan and noscapine. From the above results, it is suggested that isoaminile is excellent substance in antitussive activity and in selectivity. (Table 1). 4. The antitussive action of isoaminile had no influence by the treatment of narcotic antagonist; levallorphan bitartrate (levallorphan)(Fig. 2), and had no development of tolerance by repeated administration for a long time (for 40 days)(Fig. 3), and had no development of crosstolerance between that of codeine (Fig. 4). 5. a) After repeated administration to dogs for a long time (for 40 days), the dogs had no withdrawal symptoms in both cases that isoaminile was abstinenced suddenly and that levallorphan was substituted instead of isoaminile. b) After repeated administration to rats for a long time (for 77 days), the rats had no abstinence syndrome (body weight loss) in both cases that isoaminile was stopped suddenly and that levallorphan was given in place of isoaminile. c) The abstinence syndroms of morphine hydrochloride (morphine) dependent-rats could not be prevented by the substitution of isoaminile. 6. The main common poisoning syndromes in mice, rat and dogs induced by isoaminile were increase in spontaneous movement, tremor, ataxia of hind-limbs, clonic and tonic convulsions. There were no difference of the median lethal dose.(LD50 value) of isoaminile between different "salts" and species of animal used. Comparing with LD50 values in mice, acute toxicity of isoaminile was nearly equal to codeine by subcutaneous injection, but was less than codeine by intravenous and oral administration. 7. Isoaminile had an analgesia-like effect (d'Amour-Smith and Haffner's methods) in high dosage with poisoning syndromes, but this phenomenon was different completely from those of codeine and morphine that is antagonized by levallorphan. 8. In high dosages with poisoning symptoms, isoaminile had a marked inhibitory effect on the flexer response of a hind-leg of spinal mice which were steeped in warm water and also on the spinal action potentials of spinal cats. 9. With high dosages more than approx. 5 to 10 times of antitussive effective dose, isoaminile produced a moderate inhibitory effect on the central nervous system such as depression of consciousness-level, prolongation of anesthesia, anti-convulsive effects and anti-tremor effect. 10. In vivo, isoaminile had no influence on the normal tension of bronchial muscle, but had a dilating effect on the bronchial-spasm induced by histamine dihydrochloride (histamine). 11. Local anesthetic actions of isoaminile were equal to that of procaine hydrochloride. 12. The effects of isoaminile on the respiratory system, circulatory system, alimentary tract system and autonomic nervous system were much less compared with that of codeine. 13. The safety maximal losage in the subacutely treated rats (successive oral administration of isoaminile for 28 to 33 days) was approx. 50 to 75 times as much as the presumptive clinical daily dose. 14. The safety maximal dosage in the chronically treated rats (successive oral administration of isoaminile for 136 days) was approx. 10 to 20 times as much as the presumptive clinical daily dose. 15. The safety maximal dosage in the chronically treated dogs (successive oral administration of isoaminile for 180 days) was approx. 7.5 to 11.3 times as much as the presumptive clinical daily dose. In conclusion, judging from-the results of pharmacological and toxicological studies, it is suggested that isoaminile is more excellent antitussive agent in the safety as much low acute and chronic toxicity than codeine. Furthermore, an attempt was made in order to clearly demonstrate the mode (site) of antitussive action of isoaminile by examining the effects on the cough reflex arc (Fig. 5) in order and in detail. The following is a summary. 1. When isoaminile was given by the routes directly getting to the brain stem such as the cerebello-medullar cistern, far smaller doses were sufficient to obtain the same effect as that by intravenous administration. 2. It exerted no effects on both of the sensory receptors for cough reflex in the tracheal mucosa and the pulmonary stretch receptors in spite of possessing a local anesthetic action as potent as that of procaine. 3. It had no effect on the evoked postsynaptic potentials in the solitary tract nucleus by electrical stimulation of the ipsilateral superior laryngeal nerve. 4. The antitussive effect of isoaminile was not influenced by decerebration after mid-collicular transection (Fig. 6). 5. It had no effect on the descending respiratory pathways extending from the cervical cord to the respiratory muscles. 6. It possessed a spasmolytic action on histamine-induced contraction of bronchial muscles in doses more than antitussive effective dose, though it showed no effect on the normal tone of bronchial muscles. 7. It depressed the centrally-induced coughs in antitussive effective dose which was surely able to depress peripherally-induced coughs. On the other hand, it had no pronounced effect on the respiratory center with the same dose. (Fig. 7). 8. It significantly diminished the burst discharges of the recurrent nerve induced by frequent electric stimulation of the superior laryngeal nerve as active as that of codeine (Fig. 8). That is to say, isoaminile may suppress the integrating polysynaptic pathway, probably acting as special central substrates important for cough production and localizing between the solitary tract nucleus and the ambiguous nucleus. 9. Its central antitussive action was clearly differentiated from that of codeine in the mode of action, and it was conformed by following results. a) Antitussive activity of isoaminile was not inhibited by a narcotic antagonist; levallorphan (Fig. 2). b) It had no influence on the respiratory center activity even in much larger doses than antitussive effective dose (Fig. 7). In conclusion, it is suggested that the antitussive action of isoaminile is due to selective depression of cough center <per>___- <se>___-. Putting the generalization finally. The achievements in this study were as follow. 1) Establishment of evaluating method of antitussive activity in animals, which was closely correlated to clinical efficacy. 2) Development of new non-narcotic antitussive agent; isoaminile (Perocan^[○!R], "cyclamate" was permitted on 3th September 1969, "citrate" was permitted on 12th January 1974) which was excellent in the potency and safety, and had been demanded socially for a long time. 3) Explanation of mode of antitussive action of isoaminile. This clearly indicates that not only it contributes to clinical veterinary medicine, animal husbundry science (zootechny) and clinical medicine but also it furnisches new important knowlege in following viewpoints on the physiology, pharmacology, pharmacy, toxicology and veterinary medicine. 1) Synthesis of new non-narcotic antitussives(analgesics) from the narcotic parental compounds (basic structure). 2) Physiology of cough-reflex, in particular, natural relation of "cough-center" and respiratory center, 3) Explanation of "cough-center" in cellular level. 4) Interaction between antitussive action and analgesic action. 5) Interaction between antitussive action and narcotic property. |
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| 学位名 | ||||||||||
| 学位名 | 獣医学博士 | |||||||||
| 学位授与機関 | ||||||||||
| 学位授与機関名 | 麻布大学 | |||||||||
| 学位授与年月日 | ||||||||||
| 学位授与年月日 | 1978-03-27 | |||||||||
| 学位授与番号 | ||||||||||
| 学位授与番号 | 乙第126号 | |||||||||
| 著者版フラグ | ||||||||||
| 出版タイプ | AM | |||||||||
| 出版タイプResource | http://purl.org/coar/version/c_ab4af688f83e57aa | |||||||||
