Tohoku J. Exper. Med., 1963, 81, 96-106 Evaluation of a New Muscle Relaxant Diallyl-nor-toxiferine (Ro 4-3816) By Kenichi Iwatsuki, Tsuneo Yusa and Minoru Inagaki Department of Anesthesiology,Tohoku UniversitySchool of Medicine (Receivedfor publication,October 1963) Diallyl-nor-toxiferine (Ro 4-3816), a derivative of toxiferine was tested experimentally and clincially. The drug appeared to be approximately 1.5 times more potent than d-tubocurarine when it was tested on vital capacity and grip strength. By measuring the changes of tidal volume under light general anesthesia, the recovery of respiratory depression due to this drug was found relatively rapid following the administration of 100 ƒÁ/kg. and 150 ƒÁ/kg., with the average duration of action for 15 and 25 minutes respectively. In a series of 150 anesthesias mostly for intra-abdominal operations the drug proved to be very advantageous because of its relatively short acting and easily controllable properties. There was no evidence of ganglionic blocking effect or histamine release in doses necessary to produce surgical relaxation. It could be used safely under halothane anesthesia. At the end of operation there were 20 cases (13%) of residual curarization, which was reversed effectively by tensilon or neostigmine. In view of these results diallyl-nor-toxiferine seems to be one of the most useful muscle relaxants available today. Diallyl-nor-toxiferine (Ro. 4-3816) is a derivative of Calabash curare alkaloid C-toxiferine 1, prepared from toxiferine by the substitution of an allyl radical in each of the two quaternary ammonium groups. Its chemical structure is shown in Fig. 1. Previous pharmacological studies (Waser & Harbeckl)) as well as clincial observations (Hiigin & Kissling2), Frey & Seeger3), Vega4), Seeger et al.s>, Lund & Stovner6), Foldes et al.al7),Alders)) have revealed that this drug is a short acting non-depolarizing muscle relaxant with less ganglionic blocking effect and histmaine release. The pharmacological properties of this drug in comparison with toxiferine and d-tubocurarine in animals are shown in Table I . In man it is reported to be approximately 1.5-1.7 times more potent than d-tubocurarine6)l0) and 4-5 times less potent than toxiferine7). We have tested this new muscle relaxant experimentally and clinically. This paper presents the results obtained with this drug in a conscious volunteer as well as the observations made in clinical cases. 岩 月賢一,遊 佐津 根雄,稲 垣 稔 96 Evaluation of a New Muscle Relaxant Diallyl-nor-toxiferine (Ro 4-3816) 97 Fig. 1. Chemical structure of diallyl-nor-toxiferine. TABLE I. Pharmacological Properties of Diallyl-nor-toxiferine in Comparison with Toxiferine and d-Tubocurarine * Waser & Harbeck' ** Hoffmann-La Roche Inc .9) 98 K. Iwatsuki et al. Diallyl-nor-toxiferine is supplied in dark ampules containing 10 mg. of powder, which was dissolved in 5 ml. of distilled water for clinical use. EXPERIMENTAL STUDIES The effect of diallyl-nor-toxiferinewas tested in a conscioussubject and was comparedwith that of d-tubocurarine. When 80ƒÁ/kg. of diallyl-nor-toxiferine was injected intravenously in 10 seconds period, ptosis and diplopia appeared around 20 seconds after the injection; then as shown in Fig. 2, vital capacity and grip strength decreased with the maximal drop of 70% and 85% respectively about 2 minutes later. Vital capacity returned rapidly up to 90% of the initial level within 6 minutes, but it took 15 minutes for the recovery of grip strength and 45 minutes for the complete disap pearance of ocular symptoms. A same dose of d-tubocurarine caused a less decrease in vital capacity and grip strength, but the time required for recovery was almost the same as that of diallyl-nor-toxiferine (Fig. 2). D-tubocurarine in a dose of 1.5 times as much, i.e. 120ƒÁ/kg. caused a similar decrease in grip strength , but the time for recovery was rather shorter in diallyl-nor-toxiferine than d-tubocurarine (Fig. 3). Fig. 2. Changes of vital capacity and grip strength after the i .v. administration of 80ƒÁ/kg. of diallyl-nor-toxiferine and 80 ƒÁ/kg . of d-tubocurarine in a conscious subject . CLINICAL STUDIES Material and Method Diallyl-nor-toxiferine was used in 150 patients aging from 19 to 84 years old (95 male and 55 female) for the production of muscular relaxation mostly for Evaluation of a New Muscle Relaxant Diallyl-nor -toxiferine (Ro 4-3816) 99 Fig. 3. Changes of vital capacity and grip strength after the i .v. administration of 80 ƒÁ/kg. of diallyl-nor-toxiferine and 120 ƒÁ/kg. of d-tubocurarine in a conscious subject. TABLE ‡U. Site of Operation intra-abdominal surgery. The sites of operation were shown in Table ‡U. After an ordinary premedication with meperidine and atropine, anesthesia was induced with thiopental and succinylcholine and then it was maintained with a semi-closed nitrous oxide and oxygen supplemented with a small amount of ether (4-5%). Halothane (0.5-1.0%) and methoxyflurane were also used in some cases. After the level of general anesthesia had been stabilized, the relaxant was injected. During the operation respiration was assisted rather than controlled. In certain cases the duration of action of the drug was observed by measuring tidal volume (a mean of 5-10 respirations) with Monaghan or Wright ventilation meter every 3 minutes after the injection. This test was performed before starting the operation whenever possible to avoid any effects upon respiration. 100 K. Iwatsuki et al. RESULTS The initial doses were 100 ƒÁ/kg., 150 ƒÁ/kg. and 200 ƒÁ/kg., depending upon the expected duration of operation and 2 mg. (30-50 ƒÁ/kg.) were supplemented repeatedly as required for maintaining muscular relaxation, usually in 20-30 minutes interval. The results were satisfactory in all cases. The doses required are shown in Table ‡V. The average doses were 9.6 mg. for the operation within 30-60 minutes, 11.2 mg. within 1-2 hours, 15.3 mg. within 2-3 hours and 16.5 mg. over 3 hours. TABLE ‡V. Duration of Operation and Average Dosage of Diallyl-nor-toxiferine The degree and the duration of action were various according to the doses administered. A 100 ƒÁ/kg. dose caused no apnea and tidal volume decreased by 75% at the maximum about 3 minutes after the injection, then it returned rapidly to the control level within 15 minutes in the average (Table IV, Fig. 4). A 150 kg. dose produced apnea of several minutes in about 40% of the cases and tidalƒÁ/ volume returned to the control level within 25 minutes in the average (Table IV, Fig. 5). When a 200 ƒÁ/kg. dose was used, about two-thirds of the cases developed apnea and it took 40 minutes in the average for the recovery of tidal volume (Table IV, Fig. 6). A supplementary dose of 2 mg. (30-50 ƒÁ/kg.) produced muscular relaxation for 15-25 minutes without causing any apnea, but when it was repeated, the duration of action became gradually prolonged as shown in Table V, indicating some cumulative effect of this drug. It was demonstrated more remarkably, when the same dose was administered repeatedly, even after TABLE IV. Duration of Respiratory Depression and Incidence of Apnea Due to Various Doses of Diallyl-nor-toxiferine Evaluation of a New Muscle Relaxant Diallyl-nor-toxiferine (Ro 4-3816) 101 Fig. 4. Changes of tidal volume after ;the administration of 100ƒÁ/kg . of diallyl-nor toxiferine. Fig. 5. Changes of tidal volume after the administration of 150 ƒÁ/kg. of diallyl-nor toxiferine. the action of a previous dose apparently disappeared. Such a tendency was almost similar to that of d-tubocurarine, suggesting that there might be no remarkable difference in the cumulative effect between these two muscle relaxants. The results are shown in Fig. 7 and Fig. 8. Ether and halothane have been reported to potentiate the action of diallyl nor-toxiferine. The dosage required and the duration of action were compared between GOE (4-5% concentration of ether) and GOF (0.5-1.0% concentration of halothane) in similar abdominal cases. As shown in Table VI no remarkable differences could be found between them. Therefore the potentiating effect upon 102 K. Iwatsuki et al. Fig. 6. Changes of tidal volume after the administration of 200ƒÁ/kg. of diallyl-nor toxiferine. TABLE V. Average Duration of Respiratory Depression Following Repeated Supplementary Doses (2 mg. of Diallyl-nor-toxiferine) Fig. 7. Changes of tidal volume following repeated admi nistration of diallyl-nor-t oxiferine (100 ƒÁ/kg.). Evaluation of a New Muscle Relaxant Diallyl-nor-toxiferine (Ro 4-3816) 103 Fig. 8. Changes of tidal volume following repeated administration of d-tubocurarine (100 ƒÁ/kg.) TABLE VI. Comparison of the Effect and the Dosage of Dially-nor-toxiferine between GOE and GOF the action of diallyl-nor-toxiferine seemed to be almost same in ether and halothane. Generally speaking it was impressive that peritoneal closure could be done easily even at the time when the respiration returned almost normal. The respiratory sparing effect seemed to be one of the characteristic features of this drug. There were 20 cases in which the administration of succinylcholine was necessitated to facilitate closure of the peritoneal cavity. Blood pressure and pulse rate were not affected by this drug actually, even under halothane anesthesia (200 ƒÁ/kg. under 2% halothane). There were 6 cases which showed a transient increase in tidal volume immediately following a sup plementary dose. There were also 5 cases which developed hiccups after the administration of the drug. But it is too small in number of the cases to determine whether these phenomena are specific for this drug.