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Toxicity and Efficiency of a New Local Anesthetic*
TO X IC ITY AND EFFICIENCY OF A NEW LOCAL ANESTHETIC* By L E O N A R D S. FO SD IC K a n d H A R O L D L. H A N S E N , Chicago, 111.
IN C E E inhorn ,1 in 1909, discovered procaine and its various salts, many local anesthetics have been prepared. T h e object in the preparation has been two-fold: ( 1) to prepare a local anesthetic that would be b etter and more nearly ideal than procaine, and ( 2 ) to discover if possible some relationship between anes thetic efficiency, toxicity and chemical structure. M any of the new er anesthetics are good for many types of operations and, in some respects, are probably better than procaine. T h e la tte r is still the most widely used local anesthetic. In regard to the relationship between anesthetic efficiency, toxicity and chemical structure, much work has been done but little has been accomplished. In view of the fact that sulphur oc cupies its characteristic position below oxygen in the periodic table and hence in many respects is sim ilar to oxygen, w e 2 thought it would be interesting to pre pare and study compounds analogous to the procaine series w ith the ester oxygen replaced by a sulphur. As expected, these compounds all have marked anesthetic properties, both for topical anesthesia and for injection when soluble.
S
*Read at the Seventy-Fifth Annual Session of the American Dental Association in con junction with the Chicago Centennial Dental Congress, Aug. 11, 1933. 1. Einhorn and U hlfelder: Ann., 371: 131, 1909. 2. Hansen, H. L., and Fosdick, L. S.: J. Am. Chem. Soc., 55:2872, 1933. Jour. A .D .A .,O cto b er, 1934
As in the case of the procaine series, all of the esters prepared, with the excep tion of the salts of the alkamine ester, were insoluble in w ater and could not be conveniently studied. T h e following work is an investigation of the anesthetic efficiency and toxicity of thiocaine hydro chloride (diethylaminoethyl p-amino thiobenzoate hydrochloride), a salt of the only alkamine ester as yet prepared. E X P E R IM E N T A L P R O C E D U R E
T h e anesthetic efficiency was deter mined by the gold fish method ,3 the “wheal test” and the rabbit’s cornea method. F or the gold fish method, fish of the common variety, weighing from 2 to 4 gm., were used. T hey were kept in tanks at about 20 C. with no sudden change in temperature, and, when ready for use, were transferred by means of a cloth net to the anesthetic solution, which was of the same temperature. T h e fish were used only once to eliminate the possibility of their developing tolerance for the drug. T h ree gold fish were transferred to a 600 c.c. beaker containing about 250 c.c. of the solution to be used, and the time required to anesthetize them was noted by the usual method of pressure applied to the tail by means of a glass stirring rod. W hen the fish did not respond to pressure, it was considered that anesthesia 3. 1926.
1777
Adams et al.: J. Am. Chem. Soc., 48:6,
1778
T h e Journal of the American D en ta l Association
was complete and the time was noted with a stop watch. T h e solutions used were procaine hy drochloride 1 :500 and thiocaine hydro chloride 1 :500 and 1 :1000. T h e time of anesthesia for procaine hydrochloride as obtained by Dailey and co-workers 4 and by us was checked and found to be four teen minutes. T h e procedure of the “wheal test” is as follows : A sterile procaine solution in iso tonic salt was made up to a 2 per cent strength. Sterile thiocaine hydrochloride
H ealthy rabbits were procured and a few drops of anesthetic solution was dropped in the conjunctival sac in each eye. T h e solutions used were 1 per cent cocaine hydrochloride and 1 per cent thio caine hydrochloride. Cocaine hydrochlo ride solution was placed in one eye of the T
able
2.— R
P a tie n t 1 2
T
able
1.— R
w it h
Goldfish 1 2 3 4 5 6 7 8 9 10 11
G o l d F is h E x p e r i m e n t T h i o c a i n e H y d r o c h l o r id e esults of
T im e fo r Anesthesia M in . Sec. 2 10 2 10 2 2
10
2 2 2 2 2
21 21 21
3 3
5
12
3
13 14
3 4
15
5
5 5 5
Procaine 2 1 P e r Cent P er Cent M in . M in . 28 33 23* 33
3 4 5
C once n tra tio n
Ph
1 :5 0 0 1 :5 0 0
6.5 6.5 6.5
1 :5 0 0 1 :5 0 0 1 :5 0 0 1 :5 0 0 1 :5 0 0 1 :5 0 0 1 :5 0 0 1 :1 ,0 0 0 1 :1 ,0 0 0
6.5 6.5 6.5 6.5 6.5 6.5
1 :1 ,0 0 0
6.4 6.4 6.4
1 :1,000 1 :1 ,0 0 0
6.4 6.4
1 :1 ,0 0 0
6.4
Average for thiocaine hydrochloride, 1 :500, 2 minutes 10 seconds. Average for thiocaine hydrochloride, 1:1,000, 3 minutes 48 seconds. Average for procaine hydrochloride, 1:500, 14 minutes.
solutions were made up in isotonic salt of the concentrations of 1, 0.5 and 0.2 per cent. A wheal was produced on the arm by injecting 0.3 c.c. of each solution subcutaneously. T h e wheal was then pricked from time to time w ith a sharp probe and when pain could be detected, it was considered th at the anesthesia was over.
esults o f W h e a l T t i o n o f A n e s t h e s ia
6
able
D
ura
T hiocaine O.S 0.2 P er Cent P er Cent M in . Sec. M in . — 5 31 — 30
38
43
37
25 37
37 43
25 31
34 38
42 30 32
29 21
34
28
Average *Poor wheal. T
est;
3.— T
e sts w i t h
R
31 32
a b b i t ’s
C o rnea
T h io c a in e 1 P e r C ent Cocaine 1 Per Cent D u ra tio n O nset ' D u ra tio n Onset R abbit M in . Sec. M in . M in . Sec. M in . 1 1 20 1 30 14 2
55 40
3 4
45 52
25 23
1
5
Average T
18 28 26
able
4.—
T
o x ic it y
H Ï--K g . 640 400 320 275 225 200 175
T
1 2
11 25
2
40 20 15
22
1
55
18
ests w it h
T
h io c a in e
y d r o c h l o r id e
N o. M ic e Used 5
6 10 10 10 10 10
Dead 5 5 8 5 3 3 0
M o rta lity P er Cent 100 83 80 50 30 30 0
rabbit, while thiocaine hydrochloride so lution was placed in the other eye. Tim e for th e onset of anesthesia as well as the duration was determined by brushing the eye w ith a stiff bristle and noting the presence or absence of the winking reflex. T h e toxicity was determined by the 4. Dailey, H. T ., and Benedict, H. C .: D. use of white mice according to the Cosmos, 71:704 (July) 1929.
Fosdick and Hansen— Efficiency of N e w Local Anesthetic method of Schmitz and Loevenhart ,5 w ith the modification of Dailey .4 Sterile technic was employed as much as such animal w ork permits. T h e work of Dailey was first checked in respect to procaine and was found to be satisfactory. Fresh solutions of thiocaine hydrochlo ride were made up and the concentra tions varied by dilution w ith distilled w ater. T h e concentrations were adjusted so th at each mouse received approxi mately the same volume of fluid, not more than 1 c.c. being injected in any mouse.
1779
T h e mice were weighed and the cal culated amount of drug was injected, the results being shown in T able 4.
never such a wide variation th at it would be impossible to tell the relative efficiency. I t follows from the foregoing that the anesthetic efficiency of thiocaine hydro chloride is from four to six times that of procaine hydrochloride when used for injection and approximately twice as powerful as that of cocaine when used as a topical anesthetic. T h e toxicity is be tween two and three times as great as that of procaine, depending on whether it is classified on the basis of minimum lethal doses or per cent m ortality and is approximately one half as toxic as cocaine on either basis. T h e results th at we have obtained were checked in the clinic on various types of injections w ith satisfactory re sults. In all clinical cases, a 0.5 per cent solution was used. T h e anesthesia was obtained in tw o minutes and had a dura tion of about th at of procaine. T h e topi cal effect has been observed in the eye clinic w ith favorable results. Borate of thiocaine is now being stud ied and other alkamine esters of the same type are now being prepared.
COM M ENT
C O N C L U S IO N
RESU LTS
T h e results of the gold fish experi ments are summarized in T able I. T h e results for the wheal test are sum marized in T able 2 . T h e results obtained by the rabbit’s cornea are shown in T ab le 3. T O X IC IT Y
1. T h e toxicity and anesthetic effi ciency of thiocaine hydrochloride has been determined. 2. T h e substitution of sulphur for oxygen in an ester linkage produced a 5. Schmitz, H. L., and Loevenhart, A. S.: J. Pharm. Exper. Ther., 24:159, 167 (Sept) compound more toxic and w ith more an esthetic efficiency. 1924. T h e foregoing results show clearly th at the actual anesthetic efficiency of the drug varies somewhat w ith the method used for its determination. T h ere is
IN C E E inhorn ,1 in 1909, discovered procaine and its various salts, many local anesthetics have been prepared. T h e object in the preparation has been two-fold: ( 1) to prepare a local anesthetic that would be b etter and more nearly ideal than procaine, and ( 2 ) to discover if possible some relationship between anes thetic efficiency, toxicity and chemical structure. M any of the new er anesthetics are good for many types of operations and, in some respects, are probably better than procaine. T h e la tte r is still the most widely used local anesthetic. In regard to the relationship between anesthetic efficiency, toxicity and chemical structure, much work has been done but little has been accomplished. In view of the fact that sulphur oc cupies its characteristic position below oxygen in the periodic table and hence in many respects is sim ilar to oxygen, w e 2 thought it would be interesting to pre pare and study compounds analogous to the procaine series w ith the ester oxygen replaced by a sulphur. As expected, these compounds all have marked anesthetic properties, both for topical anesthesia and for injection when soluble.
S
*Read at the Seventy-Fifth Annual Session of the American Dental Association in con junction with the Chicago Centennial Dental Congress, Aug. 11, 1933. 1. Einhorn and U hlfelder: Ann., 371: 131, 1909. 2. Hansen, H. L., and Fosdick, L. S.: J. Am. Chem. Soc., 55:2872, 1933. Jour. A .D .A .,O cto b er, 1934
As in the case of the procaine series, all of the esters prepared, with the excep tion of the salts of the alkamine ester, were insoluble in w ater and could not be conveniently studied. T h e following work is an investigation of the anesthetic efficiency and toxicity of thiocaine hydro chloride (diethylaminoethyl p-amino thiobenzoate hydrochloride), a salt of the only alkamine ester as yet prepared. E X P E R IM E N T A L P R O C E D U R E
T h e anesthetic efficiency was deter mined by the gold fish method ,3 the “wheal test” and the rabbit’s cornea method. F or the gold fish method, fish of the common variety, weighing from 2 to 4 gm., were used. T hey were kept in tanks at about 20 C. with no sudden change in temperature, and, when ready for use, were transferred by means of a cloth net to the anesthetic solution, which was of the same temperature. T h e fish were used only once to eliminate the possibility of their developing tolerance for the drug. T h ree gold fish were transferred to a 600 c.c. beaker containing about 250 c.c. of the solution to be used, and the time required to anesthetize them was noted by the usual method of pressure applied to the tail by means of a glass stirring rod. W hen the fish did not respond to pressure, it was considered that anesthesia 3. 1926.
1777
Adams et al.: J. Am. Chem. Soc., 48:6,
1778
T h e Journal of the American D en ta l Association
was complete and the time was noted with a stop watch. T h e solutions used were procaine hy drochloride 1 :500 and thiocaine hydro chloride 1 :500 and 1 :1000. T h e time of anesthesia for procaine hydrochloride as obtained by Dailey and co-workers 4 and by us was checked and found to be four teen minutes. T h e procedure of the “wheal test” is as follows : A sterile procaine solution in iso tonic salt was made up to a 2 per cent strength. Sterile thiocaine hydrochloride
H ealthy rabbits were procured and a few drops of anesthetic solution was dropped in the conjunctival sac in each eye. T h e solutions used were 1 per cent cocaine hydrochloride and 1 per cent thio caine hydrochloride. Cocaine hydrochlo ride solution was placed in one eye of the T
able
2.— R
P a tie n t 1 2
T
able
1.— R
w it h
Goldfish 1 2 3 4 5 6 7 8 9 10 11
G o l d F is h E x p e r i m e n t T h i o c a i n e H y d r o c h l o r id e esults of
T im e fo r Anesthesia M in . Sec. 2 10 2 10 2 2
10
2 2 2 2 2
21 21 21
3 3
5
12
3
13 14
3 4
15
5
5 5 5
Procaine 2 1 P e r Cent P er Cent M in . M in . 28 33 23* 33
3 4 5
C once n tra tio n
Ph
1 :5 0 0 1 :5 0 0
6.5 6.5 6.5
1 :5 0 0 1 :5 0 0 1 :5 0 0 1 :5 0 0 1 :5 0 0 1 :5 0 0 1 :5 0 0 1 :1 ,0 0 0 1 :1 ,0 0 0
6.5 6.5 6.5 6.5 6.5 6.5
1 :1 ,0 0 0
6.4 6.4 6.4
1 :1,000 1 :1 ,0 0 0
6.4 6.4
1 :1 ,0 0 0
6.4
Average for thiocaine hydrochloride, 1 :500, 2 minutes 10 seconds. Average for thiocaine hydrochloride, 1:1,000, 3 minutes 48 seconds. Average for procaine hydrochloride, 1:500, 14 minutes.
solutions were made up in isotonic salt of the concentrations of 1, 0.5 and 0.2 per cent. A wheal was produced on the arm by injecting 0.3 c.c. of each solution subcutaneously. T h e wheal was then pricked from time to time w ith a sharp probe and when pain could be detected, it was considered th at the anesthesia was over.
esults o f W h e a l T t i o n o f A n e s t h e s ia
6
able
D
ura
T hiocaine O.S 0.2 P er Cent P er Cent M in . Sec. M in . — 5 31 — 30
38
43
37
25 37
37 43
25 31
34 38
42 30 32
29 21
34
28
Average *Poor wheal. T
est;
3.— T
e sts w i t h
R
31 32
a b b i t ’s
C o rnea
T h io c a in e 1 P e r C ent Cocaine 1 Per Cent D u ra tio n O nset ' D u ra tio n Onset R abbit M in . Sec. M in . M in . Sec. M in . 1 1 20 1 30 14 2
55 40
3 4
45 52
25 23
1
5
Average T
18 28 26
able
4.—
T
o x ic it y
H Ï--K g . 640 400 320 275 225 200 175
T
1 2
11 25
2
40 20 15
22
1
55
18
ests w it h
T
h io c a in e
y d r o c h l o r id e
N o. M ic e Used 5
6 10 10 10 10 10
Dead 5 5 8 5 3 3 0
M o rta lity P er Cent 100 83 80 50 30 30 0
rabbit, while thiocaine hydrochloride so lution was placed in the other eye. Tim e for th e onset of anesthesia as well as the duration was determined by brushing the eye w ith a stiff bristle and noting the presence or absence of the winking reflex. T h e toxicity was determined by the 4. Dailey, H. T ., and Benedict, H. C .: D. use of white mice according to the Cosmos, 71:704 (July) 1929.
Fosdick and Hansen— Efficiency of N e w Local Anesthetic method of Schmitz and Loevenhart ,5 w ith the modification of Dailey .4 Sterile technic was employed as much as such animal w ork permits. T h e work of Dailey was first checked in respect to procaine and was found to be satisfactory. Fresh solutions of thiocaine hydrochlo ride were made up and the concentra tions varied by dilution w ith distilled w ater. T h e concentrations were adjusted so th at each mouse received approxi mately the same volume of fluid, not more than 1 c.c. being injected in any mouse.
1779
T h e mice were weighed and the cal culated amount of drug was injected, the results being shown in T able 4.
never such a wide variation th at it would be impossible to tell the relative efficiency. I t follows from the foregoing that the anesthetic efficiency of thiocaine hydro chloride is from four to six times that of procaine hydrochloride when used for injection and approximately twice as powerful as that of cocaine when used as a topical anesthetic. T h e toxicity is be tween two and three times as great as that of procaine, depending on whether it is classified on the basis of minimum lethal doses or per cent m ortality and is approximately one half as toxic as cocaine on either basis. T h e results th at we have obtained were checked in the clinic on various types of injections w ith satisfactory re sults. In all clinical cases, a 0.5 per cent solution was used. T h e anesthesia was obtained in tw o minutes and had a dura tion of about th at of procaine. T h e topi cal effect has been observed in the eye clinic w ith favorable results. Borate of thiocaine is now being stud ied and other alkamine esters of the same type are now being prepared.
COM M ENT
C O N C L U S IO N
RESU LTS
T h e results of the gold fish experi ments are summarized in T able I. T h e results for the wheal test are sum marized in T able 2 . T h e results obtained by the rabbit’s cornea are shown in T ab le 3. T O X IC IT Y
1. T h e toxicity and anesthetic effi ciency of thiocaine hydrochloride has been determined. 2. T h e substitution of sulphur for oxygen in an ester linkage produced a 5. Schmitz, H. L., and Loevenhart, A. S.: J. Pharm. Exper. Ther., 24:159, 167 (Sept) compound more toxic and w ith more an esthetic efficiency. 1924. T h e foregoing results show clearly th at the actual anesthetic efficiency of the drug varies somewhat w ith the method used for its determination. T h ere is