Tohoku J. Exper. Med., 1963, 81, 96-106

Evaluation of a New 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 anesthesia. At the end of operation there were 20 cases (13%) of

residual curarization, which was reversed effectively by tensilon or . 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 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 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. Those which required antagonisits at the end of operation were 14 among 140 cases in which anesthesia was maintained under assisted respiration and 6 among 10 cases under controlled respiration. Ten mg. of tensilon 1 or 2 times or 0.5-1.5 mg. of neostigmine were effective in all cases to reverse residual curarization.

Recurarization, neostigmine resistant curarization or any other untoward side 104 K. Iwatsuki et al.

reactions were not encountered in this series.

DISCUSSION

Diallyl-nor-toxiferine is a new muscle relaxant with a non-depolarizing type. According to the previous report1) it appears to be 1.5-2 times more potent than

d-tubocurarine on vital capacity and grip strength in conscious subjects. This

was confirmed in this study. In anesthetized subjects it was reported to be 1.5-1.7

times more potent than d-tubocurarines)10) and 4-5 times less potent than toxifer

ine7). In the preliminary studies Hiigin and Kissling2) used 75 ƒÁ/kg. of diallyl

nor-toxiferine as an initial dose and 25-15 ƒÁ/kg. were supplemented every 10-12

minutes. The information issued by Hoffmann-La Roche CO). recommended 125 ƒÁ/kg. as an initial dose and 30 ƒÁ/kg. as a repetition dose given every 15-20

minutes under nitrous oxide, oxygen and thiopental anesthesia. Foldes et al.7)

used the same doses and confirmed that these doses were adequate to produce good

surgical relaxation with minimal postoperative respiratory depression . They advised to use it under assisted rather than controlled respiration. Ether and

halothane potentiate the action of this drug, therefore it is recommended to

reduce the dose by 30-50% under ether and 40-70% under halothane anesthesia. Foldes7) observed that under halothane anesthesia similar effects

could be achieved with a 80 ƒÁ/kg. initial dose and 20 ƒÁ/kg. fractional doses given

about every 20 minutes. According to our experiences an initial 100-150 ƒÁ/kg .

dose seemed to be adequate for most operations, but 200/ƒÁ/kg . could be used for longer operations. A supplementary 2 mg. dose was given every 20-30 minutes , if required.

Diallyl-nor-toxiferine has been claimed to be relatively short acting and easily controllable. It was true with a single dose of 100-150 ƒÁ/kg ., but 200 kg. or more might cause severe respiratory depression ƒÁ/ , sometimes lasting over 40 minutes. Therefore it seemed advisable to use 100-150 ƒÁ/kg . as an initial dose except for a long operation, supplemented with a small fractional dose . Assisted respiration appears to be more advantageous than controlled respiration in order to reduce the dose and to avoid a prolonged effect . A cumulative tendency, although far less than in toxiferine, still could be observed in this drug . According to the studies by Lund and Stovner10) , a cumulative effect of this drug was similar to that of d-tubocurarine . Hiigin and Kissling2) reported that

1 mg. of diallyl-nor-toxiferine was equipotent to 2 mg . of d-tubocurarine, but in later stages of its application it became equipotent to 3 mg . of d-tubocurarine because of its cumulative effect. Blood pressure and pulse rate were not affected by this drug and no other untoward side reactions such as bronchospasm or increased salivation and bronchial secretions were encountered in this series . An absence of ganglionic blocking action and histamine release in clinical doses is a great advantage as Evaluation of a New Muscle Relaxant Diallyl-nor-toxiferine (Ro 4-3816) 105 compared with d-tubocurarine, particularly in halothane anesthesia as well as in asthmatic and allergic conditions. We had 20 cases (13%) which required antagonists against residual curarization at the end of operation, which could be reversedeffectively with 10 mg. of tensilon or 0.5-1.5 mg. of neostigminepreceded by atropine. It has been emphasized that there were few cases which required antagonists after the use of diallyl-nor-toxiferine;for examples, 14% reported by Seeger5)and 10-16.2 % by Foldes7). However,no differencecould be found by Lund and Stovner10)in the ability of neostigmineto reverse residual curarization after diallyl-nor-toxiferine and d-tubocurarine.

SUMMARY AND CONCLUSIONS

Diallyl-nor-toxiferine (Ro. 4-3816) is a new non-depolarizing muscle relaxant.

The drug was tested experimentally and clinically. It appeared to be approxim

ately 1.5 times more potent than d-tubocurarine when it was tested on vital capacity and grip strength. In a series of 150 clinical cases the drug was used

to obtain muscular relaxation mostly for abdominal surgery. Anesthesia was

maintained with nitrous oxide, oxygen supplemented with a small amount of ether

in the majority of cases. Halothane was used also in some cases. The initial

doses were 100 ƒÁ/kg, 150 ƒÁ/kg. and 200 ƒÁ/kg., depending upon the expected dura

tion of operation and 2 mg. (30-50 y /kg.) were supplemented every 20-30 minutes.

The results were satisfactory in all cases. By measuring the changes of tidal volume, 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. But a dose of 200 kg. caused apnea for several minutes in the majority of cases and it took ƒÁ/40

minutes for the recovery. A cumulative effect could be observed after its repeated administration. Blood pressure and pulse rate were not affected by this drug,

even under halothane anesthesia. It seemed impressive that peritoneal closure

could be performed easily in many cases, even after the respiration returned almost normal. There were 20 cases which required antagonists at the end of

operation. Ten mg. of tensilon or 0.5-1.5 mg. of neostigmine were effective to

reverse residual curarization. No other untoward side reactions were encountered

in this series. Diallyl-nor-toxiferine seems to be more advantageous than d

tubocurarine because of its relatively short acting and easily controllable

properties as well as an absence of ganglionic blocking action and histamine release in clincial doses. It can be used safely under halothane anesthesia. The

drug appears to be a highly useful muscle relaxant well worthy of further clinical

trials. 106 K. Iwatsuki et al.

Acknowledgment

The sauthor exress thanks to Hoffmann-La Roche Inc., for the kind supply of dially-nor-toxiferine for this study.

References

1) Waser, P.G. & Harbeck, P.H., Anaesthesist, 1962, 11, 33. 2) Hugin, W. & Kissling, P., Schweiz. med. Wschr., 1961, 91, 455. 3) Frey, R. & Seeger, R., Anesth. Analg. Rdanim., 1961, 18, 469. 4) Vega, D., El Dia Med. Urug., 1961, 27, 3557. 5) Seeger, R., Ahnefeld, F. & Hauenschild, E., Anaesthesist, 1962, 11, 37. 6) Lund, I. & Stovner, J., Acta anaesth. stand., 1962, 6, 85. 7) Foldes, F.F., Brown, I.M., Lunn, J.N., Moore, J. & Duncalf, D., Ane8th. et Analg., 1963, 42, 177.8 ) Alder, A., Anaesthesist, 1963, 12, 172. 9) Diallyl-nor-Toxiferine Ro 4-3816: Beschreibung fur die Klinik, Hoffmann-La Roche Inc., Basle, Switzerland. 10) Lund, I. & Stovner, J., Acta anaesth. stand., 1962, 6, 161.