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Pharmacologic and Clinical Study of Bbenzoyloxy-B-Phenyl-Ethyl-Dimethylamine-Hydrochloride: A New Local Anesthetic*
788
The Journal of the American Dental Association
T h e technic o f application is fu lly de earliest possible time evidence o f the e f scribed elsewhere .1 fectiveness o f this m ethod, and in such I am reportin g m y o w n experience in form that it cannot be questioned. By the use o f this solution over a period o f this, I mean that a plan should be set up years and have here given a report on 405 by w hich thousands o f cases w ill be very carefu lly observed cases that have been carefu lly recorded and tabulated under recently rechecked. It is o f the utm ost the direction o f experienced research im portance that w e accum ulate at the w orkers, in order that the w eigh t o f evi 1. Prime, J. M .: D. Cosmos, 77:1046 (N ov.) dence w ill be such that every practitioner w ill be com pelled to accept it. 1935.
PHARMACOLOGIC AND CLINICAL STUDY OF BBENZOYLOXY-B-PHENYL-ETHYL'DIMETHYLAMINE-HYDROCHLORIDE: A NEW LOCAL ANESTHETIC* B y E R W IN W IL L I A M FER BER, D .D .S ., M .S ., San Francisco, Calif.
N an effort to prepare local anesthetic com pounds that exhibit both local an esthetic and vasoconstrictor activity, several investigators 1 have prepared and studied derivatives o f arylam inoalcohols related in chem ical constitution and physiologic action to epinephrine. Such com pounds are desirable particularly from tw o points o f v ie w : ( 1 ) theoreti cally, to advance know ledge o f the pos sible relationships betw een constitution and physiologic action and ( 2 ) prac tically, to offer a com pound that does not
I
*Read before the Research Section o f the California State Dental Association, April, 1935. 1. Takeda, J .: Rearrangement o f 2-Benzamido-l-Phenylethanal into Am ino-Aphenylethyl Benzoate, J. Pharm. Soc. Japan, 1917, pp. 691-709; Chem. Abs., 11:3241, 1917. M arvel, C. S., and Du Vigneaud, V .: Pres sor Anesthetics, J. Am . Chem. Soc., 66:2093, 1924. Ailes, G . A., and Knoefel, P. K . : Local Anesthetics with Vasopressor Activity, Arch, internat, de pharmacodyn. et de thérap., 47: 96 (Jan.) 1934. Jour. A .D .A ., Vol. 23, M ay, 1936
require the use o f epinephrine to secure desirable local effects and thus to avoid u n tow ard systemic reactions resulting from such addition to local anesthetic solutions. A generation ago, B rau n 2 p ro posed the addition o f epinephrine as a satisfactory ad ju nct in local anesthetic solutions to produce local vasoconstric tion, thereby reducing the rate o f ab sorption o f the local anesthetic, p rolon g ing the latter’s effect and dim inishing its systemic absorption and the attendant toxicity. It has been show n also 3 that the epinephrine so added m ay produce undesirable side effects and actually cause an increased toxicity due to the 2. Braun, H einrich: (Trans, and ed. by Harris, M . L . ) : Effect o f Suprarenin (A dren alin) on Local and General Poisoning, in Lo cal Anesthesia, Philadelphia: Lea and Febiger, 1924, p. 32. 3. Spagnol, G .: Pharmacology o f Solutions of Novocaine-Vasopressin and NovocaineAdrenaline in Local Anesthesia, Rev. SudAmericana Endocrinal Immunol., 14:569, 1931; Chem. Abs., 26:773, 1932.
Fer ber— A N e w Local Anesthetic
com pou nd w as synthesized by D r . A lles and its ph arm acologic activities w ere in vestigated by D rs. A lles and K n oefel. A com parison w as made o f the anes thetic activity o f “ locaine,” cocaine and procaine on the cornea o f the rabbit and on the sensory fibers o f the fr o g ’s sciatic nerve. D a ta fo r their relative intravenous toxicity in rabbits and subcutaneous to x icity in m ice w ere obtained also. T h ese data as reported 4 are as given in T a b le 1. I t appears that “ locaine” is alm ost as effective as cocaine in its anesthetic action on m ucous membranes, w here procaine is quite ineffective. O n the f r o g ’s sciatic
presence o f the local anesthetic, w h ich is absorbed systemically. T h e benzoate o f phenylethanoldim ethylam ine, or m ore exactly 5 -b en z oy lox y B - phenyl-ethyl-dim ethylam ine h ydroch lo ride, called fo r convenience “ locaine,” is a com pou n d o f the type described. T h e similarities in com bined structure and properties o f procaine, a local anesthetic; epinephrine, a vasoconstrictor, and the n ew loca l anesthetic “ locaine” are illus trated in F igure 1. A n earlier study o f the pharm acologic properties 4 indicated that it possesses both anesthetic and vasoconstrictor activity o f T
able
1 .— D
ata
on
R
elated
gents
Toxicity
Rabbit Cornea Du ration in Minutes
Minimum Lethal Dose Millimols per Kilogram
Z?-hydroxy-5-phenylethylamine
0 .1 M
5-benzoyloxy-B-phenylethylamine ß-hydroxy-B-phenylethyl dimethylamine
26 0 .1 M
S-benzoyloxy-5-phenylethyl dimethylamine Cocaine Procaine
17 20 —
4. Footnote 1, third reference.
A
Anesthesia
0.04M
an interesting degree. I t seemed w orth w hile, therefore, to determine w hether this n ew drug cou ld be applied clin ically fo r various operations in the field o f oral surgery. T h e results have been, in som e respects, highly satisfactory, but, in others, it proved to be inferior to p ro caine. T h is substance was selected by G . A . A lles and P . K . K n oefel from a consid erable grou p o f com pounds, used fo r their com parative pharm acologic studies o f esters o f arylethanolamines, as being the m ost suitable o f those investigated. T h e
789
0.02M No Anesthesia 18 No Anesthesia 12 16 —
I ntravenous Subcutaneous 0.17
5.0
0.10 0.80
0 .4 i.O
0.07 0.04 0.13
2.7 0.45 3 .0
nerve, “ locaine” w as fou nd to be m uch less tox ic than cocaine, and about as tox ic as procaine by subcutaneous injection, though m ore tox ic than procaine by the intravenous m ethod o f administration. T h ese laboratory findings indicate that “ locaine” m ay have real clinical pos sibilities as a useful anesthetic agent, par ticu larly in dentistry. C ertain further prelim inary laboratory w o rk w as carried ou t before the drug w as studied clin ically w ith regard to its local anesthetic activity in the ora l cavity and to determ ine m ore precisely its toxicity by various routes o f administration.
790
The Journal of the American Dental Association
T h is w ork on “ locaine” included a study o f : ( 1 ) some chem ical properties o f its solution s; ( 2 ) infiltration and block anesthesia in the oral cavity o f the d o g ; ( 3 ) toxicity by subcutaneous in jec tion, and ( 4 ) toxicity by intravenous in jection, w ith studies o n : (a) the phe nom ena o f acute intoxication, (b ) to x icity from rapid intravenous injections, ( c ) toxicity from slo w intravenous in jections and ( d ) fixation, elim ination or destruction by the liver. P art o f the prelim inary w o rk w as done by A llés and K n oefel, w h o com pared the relative toxicities o f “ locaine” in jec tions in rabbits and m ice. C om parisons T
a b le
2 .— D
ata
I
n d ic a t in g
A
c id it y
of
pH
L o c a in e
1 .0 g m . o f “ l o c a i n e ” a d d e d t o 9 9 . 0 c . c . o f c o ld d is tille d
w a t e r ..........................................................4 . 7
1 .0 g m . o f “ l o c a i n e ” a d d e d t o 9 9 . 0 c . c . o f n o r m a l s a l i n e s o l u t i o n .......................................................4 . 6 1 .0 g m . o f “ l o c a i n e ” a d d e d t o 9 9 . 0 c . c . o f b o ilin g
d is tille d
ten s e c o n d s
w a ter
and
b o ile d
a fte r th e a d d it io n
fo r
o f “ lo
c a i n e ” ............................................................................................. 4 . 4 1 .0 g m . o f “ l o c a i n e ”
a d d e d t o 9 9 .0 c .c . o f
b o ilin g
d is t ille d
w a ter
tw e n ty
m in u te s
a fte r
and th e
b o ile d a d d it io n
fo r of
“ l o c a i n e ” ..................................................................................... 3 . 7
w ere also made o f m ucous mem brane an esthesia, by observing the corneal re flexes .4 F rom Figure 1, it is evident that “ locaine” is m uch less tox ic than c o caine and that its anesthetic action on mucous membranes is almost as satisfac tory. T h ese laboratory findings, convincing as they are, om it any reference to clinical experiments and it therefore seemed d e sirable to determine the clinical possibil ities o f “ locaine,” especially fo r dentis try. T h e w o rk undertaken included a study o f “ locaine” in com parison w ith such w ell-k n ow n agents as cocaine and pro-
caine, using suitable experimental ani mals, as to ( 1 ) its relative toxicity, ( 2 ) its relative efficiency as a loca l anesthetic and ( 3 ) its relative efficiency as a topical anesthetic. PHYSICAL AND CHEMICAL PROPERTIES OF “
l o c a in e ”
“ L ocain e” possesses the em piric fo rm ula C 17H 19O 2N -H C l, and a m olecular w eight o f 30 5.6. Its structural form ula is given in Figure 1. It is a w hite crys talline substance, soluble in w ater to the extent o f 4.2 36 gm . in 100 c.c. solution o f distilled w ater at 2 0 C . I t melts at 211-2 12 C . “ L ocain e” is capable o f acting on nerve tissue in a circum scribed area, either by topical application or by injection into the tissues. It produces a paralysis which tem porarily inhibits the conductivity w ith ou t causing permanent tissue injury. A n aqueous solution o f “ locaine” is defi nitely acid. T a b le 2 illustrates this fact. I t is w ell know n that irritability and toxicity o f anesthetic solutions increase in direct relation to low erin g o f the pH, and also, up to a certain point, any addi tion o f alkali tends to th ro w d ow n a precipitate. Attem pts to raise the pn o f the solution meet w ith success up to a certain lim it. T h e addition o f 60 m g. o f dibasic sodium phosphate to 50 c.c. o f a 1 per cent solution o f “ locaine” raised the pu from 4.7 to 5.0, at w hich point there appeared a very finely divided sus pended precipitate. T oxicity .— T h e toxicity was deter m ined by tw o modes o f administration, namely subcutaneous and intravenous. T h u s, presumptive evidence w as obtained on absorption from subcutaneous tissues and rate o f detoxification, and on the possible dangers o f clinical application. F o r subcutaneous injection, albino mice w eighing from 15 to 30 gm. w ere used,
791
Ferber— A N e w Local Anesthetic
been show n by E ggleston and H atch er5 that cats react essentially as dogs do to administration o f local anesthetics. A l l o f the operative procedures on the cats w ere carried out w ith a general an esthetic (ch lora lose), 75 m g ./k g . by body w eight, given intraperitoneally, w ith w a rm w ater as a vehicle. T h e basal an esthetic chloralose maintained a constant level o f anesthesia, adequate fo r all sur gical purposes, fo r m any hours, no pre-
receiving the solution under the skin o f the back, near the root o f the tail. T h e resulting phenom ena w ere chiefly con vulsive in .nature. T h e average m inim um lethal dose o f a 2 per cent “ locaine” solution w as 825 m g ./k g . T h is com pares favorably w ith D r . A lle s and K n o e fe l’s findings. (F ig . 1.) T h e ir observations w ere based on in jections m ade w ith m olal amounts in equim olecular concentrations. T h e data
OH
NHo
H C
y n
0
c
- 0
❖
N0
.
.
- C
- C
H
H
H - C 'H
0 ::
\ H
c H
P R O C A I
.H -
C
- N V
H
- c H
\
H C H
H - C H
/
H
- N N
OH
H
- H
E P I N E P H R I N E .
NE .
0c
H C -H
- H
- o
-
❖0
0c H
H C
-
.
- H
/«
c
H
\
h
C H
- H
" L 0 C A I N E V
Fig. 1.— Structural formulae of procaine, epinephrine and “ locaine.”
concern in g the toxicity by the intravenous m ode o f adm inistration in cats f o l low .
M eth o d .— Cats w ere used, since they m ore closely resemble man in their re sponses to m any drugs than do rodents. D o g s w ere n ot used because, o w in g to their larger size and consequent need fo r larger dosage, there w ou ld have been an insufficient supply o f the drug. It has
lim inary etherization being necessary. In all o f the experiments on cats, the local anesthetic w as dissolved in 0.85 per cent sodium chloride solution. A ll o f the 5. Eggleston, C., and Hatcher, R. A . : x Pharmacology of Local Anesthetics, J. Phar macol. & Exper. Therap., 13:433 (A ug.) 1919. Eggleston, C., and Hatcher, R. A .: Pharma cology o f Novocaine, J. Pharmacol. & Exper. Therap., 8:385, 1916.
The Journal of the American Dental Association
792
solutions w ere freshly prepared o n the day on w hich they w ere used. In fact, m ost o f the solutions w ere used w ithin one h ou r o f their preparation. W h e n an intact animal, anesthetized w ith chloralose or a barbiturate, is in
cord in g to E ggleston and H atcher, but the elim ination o f these drugs occurs at different rates. T h e experiments can be repeated several times on the same animal even though every in jection has been tox ic enough to produce tem porary fail
jected w ith a local anesthetic, such as procaine, the prim ary effect is paralysis o f the respiration, the circu latory failure
ure o f respiration. F orty-five minutes after the adm inistration o f the chloralose anesthetic, the animal is ready for opera-
T a b l e 3 .— I n f il t r a t io n A n e s t h e s ia
Patient
1
Type of Injection Infiltration
Amount Injected
Time o f Onset o f Anesthesia
C.c.
Minutes
2 .0
Teeth Ex tracted
3 .0
5!
Degree of Anesthesia
Remarks
Complete
Satisfactory Anesthesia incomplete after fifteen minutes Anesthesia incomplete after fifteen minutes Inflamed soft tissue af ter forty-eight hours Incomplete
1
2
Infiltration
2 .0
3 .0
|4
Complete
3
Infiltration
2.0
2.5
I5
Complete
4
Infiltration
2.0
3 .0
¡4
Incomplete
5
Infiltration
2.0
1.5
4
Incomplete 1
6
Zygomatic
2.5
2.5
|678
Complete
7
Infiltration
2.0
3 .0
'
Incomplete
Incomplete
8
Infiltration
3 .0
1.5
Complete
Satisfactory
9
Zygomatic
2.5
3 .0
Incomplete
Incomplete
10
Zygomatic
2.5
3 .0
Incomplete
Incomplete
Complete
13
18 6
Incomplete anesthesia
1
11
Infiltration
2.0
2.0
12
Zygomatic
3.0
4 .0
13
Infiltration
2 .0
3 .0
4! 8
Incomplete
Anesthesia incomplete after five minutes Incomplete
5
Complete
Satisfactory
i
being secondary. I f the injection is dis continued as soon as respiration fails, and artificial respiration is instituted, the cir culation is apparently unim paired. T h e respiratory center quickly recovers and artificial respiration can then be discon tinued. P rocaine and cocaine are either fixed, elim inated or destroyed by the liver, ac
tion. I t is placed on its back and tied to a board, and the fu r is trim m ed away from the areas to be operated on. A rubber bag partially filled w ith air is adjusted over the chest o f the animal and maintained by means o f a suitable jacket. A rubber tube leads fro m the rubber bag and is attached to a rubber diaphragm w ith a recordin g arm, adjusted to a m ov
793
Ferber— A N e w Local Anesthetic ing kym ograph drum fo r the purpose o f recording depth and rate o f respiration. B lood pressure and heart rate are also registered on the kym ograph by the us ual m ethod. T h e anesthetic solution is injected into the exposed fem oral vein by a 22-gage needle in a 2 c.c. L u er syringe. In the rapid intravenous injection method, the local anesthetic to be used is injected into the vein as rapidly as the capacity o f the vein w ill permit. In the slow intravenous injection method, the local anesthetic is delivered at the rate o f 1 c.c. per minute and is kept as nearly as possible at a constant rate o f flow . T h e apparatus consisted
m ination o f the effects o f individual sublethal doses, bu t also makes possible du plicate estimations o f such effects. By this m ethod, the rather w ide variation in the average effects o f specific dosages shown by different animals o f the same species is elim inated. T h is agrees w ith the statements m ade by M a c D o n a ld and Israels.6 A severely toxic, but not fatal, dose o f procaine or “ locaine” rapidly injected into the fem oral vein produces the same general symptoms. W ith in a few sec onds, there is a cessation o f respiration and an abrupt fall o f blood pressure. T h e heart rate varies th roughou t the period.
Respiration
SnjecbuL75n "CtjtuwnA?
C at i - v . / ha. Rapid Intravenous Injection of "Locaine"
^Jjocavna." 3 .5 6 « .
SOmy.
...........
Fig. 2.— Effect on blood pressure and respiration o f rapid injection o f “ locaine” into femoral vein of cat.
o f a buret fitted w ith a M a riotte tube, and connected by a cannula to the fe m oral vein. A very accurate delivery was maintained by coun tin g the num ber o f air bubbles passing through the solution from the M a riotte tube fixed in the buret. T h e rate o f delivery w as so adjusted that during the passage o f eight bubbles through the solution, 1 c.c. o f solution w ou ld be delivered by w ay o f the tubing and cannula to the receiving vein. I f death occurs during the injection, the lethal dose can be estimated. T h e m ethod not on ly provides fo r the deter-
A t first, im m ediately after the fall in blood pressure, the rate is usually slowed, and there is an increased intensity of con traction o f the heart. T h e respiration usually stops fo r about thirty seconds, or may continue to show stim ulation, in both rate and am plitude. L ater, the heart beat begins to im prove and the b lood pressure rises to norm al, or even above norm al fo r a short period o f time. A t about the same time, there are usually several brief 6. M acD onald, A . D., and Israels, M . G .: Local Anesthetics, J. Pharmacol. & Exper. Therap., 44:359 (M arch) 1932.
794
T h e Journal of the American Dental Association
but severe clon ic convulsions, but, w ithin five minutes, the animal returns to n o r mal. T h e length o f time required for the onset o f symptoms does not differ m aterially fo r procaine or “ locaine” or fo r doses o f different size, as lon g as the dose is toxic. T h e effects on the heart and b lood pressure and on the respiration and time o f recovery are illustrated in the kym o graph recordin g show n in Figure 2, nearly a fatal vein dose having been ad ministered in the first injection. W it h the n ew local anesthetic, it has
Respiration
b*
(rt .carotid) E lim in atio n o f "L o c a tin e “ fro m B lo o d c ir c u la tio n b y L i v e r
JìocatsM '" ¿n to 6>oJita £ . Time = 5'iec.^ i
id u m ili Im m mimmi iiiisiim iimunn ummm irnimnn iiimm
10-1513: «
Fig. 3.— Effect on blood pressure and res piration o f rapid injection o f “ locaine” into portal vein o f cat.
been fou n d that the average m inim al lethal dose fo r “ locaine” injected rapidly intravenously w as fou n d to be about 20 m g ./k g . It has been found to be tw ice as tox ic as procaine, but not nearly so toxic as cocaine w hen injected intraven ously. ELIMINATION OF “ LOCAINE” FROM THE BODY TISSUES AFTER INJECTION
I t has been dem onstrated experim ent
ally b y H atch er and E ggleston that the liver actually w ill fix, destroy o r elim inate procaine rapidly if a solution o f it is perfused through the liver a num ber o f times. T h e fo llo w in g w o rk w ill dem onstrate that the action o f “ locaine” is likewise affected by the action o f the liver. T h e experim ental procedure was simplified in the fo llo w in g w ork on “ locaine.” In the w o rk perform ed by H atch er and E ggles ton, the liver w as w ashed nearly free fro m blood by passing L o c k e ’s solution through the portal vein. T h e liv er w as then rem oved from the b od y and perfused at a constant tem perature fo r one hour and tw en ty m inutes w ith a solution o f procaine and defibrinated blood, prev iously rem oved from the anim al. T h e perfused fluid w as oxygenated constantly and later tested biologica lly by injection. In the fo llo w in g w ork, a laporotom y w as perform ed, and the liver w as allow ed to remain intact in the anim al. T h e solu tion w as injected into the liver b y w ay o f the portal vein. T w e n ty minutes after injection, a solution w as introduced into the ju g u la r vein so that com parisons cou ld be made on the effect on respira tion and blood pressure. T h e effects are recorded on the kym ograph recordings in Figures 3 and 4. I t w ill be noted that in jection o f 20 m g. o f “ locaine” into the ju g u la r vein w as attended by a fa ll in b lood pressure, and subsequent injection o f 80 m g. o f “ locaine” into the portal vein had no m arked apparent effect. INFILTRATION AND BLOCK ANESTHESIA DEMONSTRATED IN THE ORAL CAVITY OF A DOG
In the effort to ascertain the possible dental application o f “ locaine,” the f o l lo w in g experiments on dogs w ere under taken.
Infiltration Anesthesia.— O n e-year-old
Ferber— A N e w Local Anesthetic dogs in good health, and w ith teeth in good condition, w ere used in the fo llo w ing experiments. T h e animal to be w orked on was placed in a box , the legs being tied to the sides o f the b ox and the head so fixed that it w as a llow ed slight m ovem ent. A section o f rubber hose w as adjusted in the anim al’s m outh in the region o f the posterior teeth, betw een the upper and low er arches to prevent closure o f the jaw s. A rubber dam w as then placed from cuspid to cuspid, thus isolat in g the eight anterior teeth. T h e pulp vitality o f these teeth w as tested by means o f the C am eron electric pulp
795
solution containing 1 :2 5 ,0 0 0 epinephrine. A pp roxim ately 4.5 c.c. w as used on the labial and 0.5 c.c. on the palatal surface. T h e injected m ucosa blanched im m e diately. T h e rubber dam w as again fixed in place. W it h in a period o f from fou r to five minutes, a sensitivity test was made o f the upper le ft incisors (u sin g the C a m eron pulp tester). T h e con trol was grad ually advanced to resistance 12 on the pulp tester w ith ou t any response from the animal. T h e reaction to the pulp tester w as checked periodically against the unanesthetized cuspid on the same side.
Chloralose 75mgl£q,
amz/dAe/UcL
"Jjaxxune " -¿rtitr
^/rjj& cbeeL QQmg.o£ 'X
Time^SA&c,.
60nw<& 'in tc
+ is9
--------------------------------------- iiiyriniiiKimrinTrrmn
Fig. 4.— Effect on blood pressure and respiration of rapid injection o f “ locaine” alternately into jugular and portal veins.
tester. T h is m ethod, although open to several objections, w as accurate enough fo r this experiment. T h e d og responded to the electric stimulus betw een re sistance 8 and 9 w hen the con trol o f the rheostat w as advanced to that degree. T h e rubber dam w as then reflected so as to expose the labial and palatal m ucous membrane. T h e tissue overlyin g the roots o f the upper left central and first and second lateral incisors w as infiltrated w ith a 2 per cent proeaine-hydrochloride
T h e rubber dam w as again reflected from the anterior teeth, the upper right central and first and second lateral in cisors being used fo r the injection. T h e same procedure w as fo llo w e d as in the first part o f the experiment, the same quantities o f solution being used, bu t a 2 per cent “ locaine” in place o f the procaine-hydrochloride solution. T h e re w as some blanching im m ediately on injection o f the solution, but not so m uch as in the case o f the procaine-epinephrine solution.
796
The Journal of the American Dental Association
T h e rubber dam was replaced and, after the same interval o f time, the pulp tester was again applied. T h e con trol w as ad vanced to resistance 12 w ith ou t any re sponse from the animal. T h e upper right cuspid reacted prom ptly to the electrical
injected fo r the three anterior teeth in the upper le ft arch, 0.5 c.c. on the labial aspect and 0.25 c.c. on the lingual. A n esthesia w as obtained in between fo u r and five minutes. T h e duration o f anesthesia w as approxim ately forty m inutes fo r the
stimulus. F ifteen hours later, the tissue appeared to be slightly inflamed in the region anesthetized by the procaine solu tion and, thirty-six hours later, sloughing was noticed. T h e tissue appeared to be
le ft central and sixty-five minutes fo r the first and second left lateral incisors. A 2 per cent procaine-hydrochloride solu tion, w ith ou t epinephrine, w as used fo r the three anterior teeth in the upper right
T
Patient
Type of Injection
Amount Injected C.c.
able
4 .— -B l o c k A
Time o f Onset of Anesthesia
n e s t h e s ia
Teeth Ex tracted
Degree of Anesthesia
1 15 ! 321, ! [ 123 I 6
Complete
Satisfactory
Complete
Anesthesia incomplete after fifteen minutes Satisfactory
Complete
Remarks
Minutes 1
Mandibular
3 .0
7 .0
2
Mandibular
3 .0
4.5
3
Mandibular
3 .0
8.0
4
Mandibular
3 .0
5.0
5
Mandibular
3. S
4.0
6
Mandibular
3. S
3.5
i 874321| 1
4.5
51 1
7
Mandibular
3.5
8
Mandibular
3.5
7.0
9
Mandibular
3.5
7.5
4| 1 6311 !
5.0
6| 1
10
Mandibular
3.5
Complete
Complete
Anesthesia incomplete after five minutes Anesthesia present for fifty-five minutes Satisfactory
Complete
Satisfactory
Complete Complete
Anesthesia incomplete after twenty minutes Satisfactory
Complete
Satisfactory
Complete
18
norm al in the region injected by the “ locaine” solution. A ft e r seventy-tw o hours, the tissue appeared to be norm al in both regions injected by the anesthetic solu tions. T w o weeks later, the foregoin g ex perim ent w as repeated w ith the same animal and the same procedure except as to the am ount o f solution. In this ex periment, procaine-hydrochloride contain ing 1 :2 5 ,0 0 0 epinephrine solution was
arch. T h e duration o f anesthesia was approxim ately forty-five m inutes fo r the three teeth. Block Anesthesia .— B lock anesthesia w as dem onstrated in the d og by giving injections o f anesthetic solutions at the base o f the tongue in the region o f the lingual nerve and on the medial surface o f the ramus opposite the m andibular foram en. In the region o f the in ferior dental nerve, 2 c.c. o f a 2 per cent p ro
F erber— A N ew Local Anesthetic caine-hydrochloride solution containing 1 :2 5 ,0 0 0 epinephrine w as injected. P a r tial anesthesia o f the tongue resulted. T h e r e w as com plete anesthesia o f the b order o f the ton gue and partial anes thesia over the greater portion o f the dorsal surface o f the tongue. N o anes thesia w as noticed on the posterior part o f the tongue, this probably being due to the various nerve supplies to the tongue. T h e degree o f anesthesia w as determined by inserting a sharp needle in o r pricking the tongue. T h e results fo r onset o f an esthesia fo llo w : T h e average time o f onset o f anesthesia using procaine-hydrochloride w as eleven minutes. T h e average time o f onset o f anesthesia using “ locaine” w as thirteen minutes. CLINICAL STUDY OF “ LOCAINE” (TABULAR RESULTS IN DENTAL CLINIC)
M a n d ib u la r “ block ” anesthesia was dem onstrated by in jectin g a 1 per cent “ locaine” solution in the vicinity o f the m andibular nerve, opposite the m andibu lar foram en. T h e onset o f anesthesia w as determ ined by testing the sensitivity o f the term inal nerve fibers on the low er lip, on the injected side, by pinching w ith a pair o f tw eezers and com paring the sensitivity w ith that o f the unanesthe tized side o f the lip. In filtration anesthesia w as dem on strated by in jectin g a 1 per cent “ locaine” solution in the soft tissue immediately adjacent to the tooth to be extracted. T h e onset o f anesthesia w as determ ined by inserting a chisel, at thirty-second inter vals, betw een the soft tissue and the tooth to be anesthetized. T h e foregoin g in jec tion technics are those used at the U n i versity o f C a liforn ia D en ta l C ollege, as described by C . D . G w in n . T h e results observed on patients in the dental clin ic are tabulated in T ab les 2 and 3. T h e average time o f onset o f block
797
anesthesia using a 1 per cent solution o f “ locain e” w as five and six-tenths m in utes. T h e average tim e fo r the onset o f in filtration anesthesia using a 1 per cent solution o f “ locaine” w as tw o and seventenths minutes. T h e foreg oin g average times may be com pared w ith a series o f injections made at the U n iversity o f C a liforn ia C ollege o f D en tistry E xtraction C lin ic using an alkalinized procaine-hydrochloride solu tion. T h e times given, being repeated fro m the results given in a paper “ T h e E ffect o f H y d rog en Ion Concentration in L o c a l Anesthetic Solutions,” by G w in n and F erber,7 w ere three and seven-tenths minutes fo r the onset o f b lock anesthesia using a 2 per cent p ro caine solution as com pared to five and six-tenths m inutes fo r “ locaine” ; and one and one-tenth minutes fo r the onset o f infiltration anesthesia using a 2 per cent procaine solution as com pared to tw o and seven-tenths m inutes fo r “ locaine.” I t w ill be necessary to point ou t the fact that the foregoin g determinations w ere m ade w ith a 1 per cent solution o f “ lo caine” in com parison to a 2 per cent al kalinized procaine solution. T h e reason fo r this is that it w as previously deter m ined that “ locaine” has approxim ately tw ice the toxicity o f procaine. T h e topical effect o f “ locaine” on the oral m ucosa w as next determined by placing the dry pow der on the mucosa o f the lip. T h e sensitivity was tested w ith a pointed pencil. C ocaine was used as a standard o f com parison. T h e onset o f anesthesia produced by “ locaine” was betw een fou r and five minutes, approx im ately tw o minutes slow er than the time fo r onset w ith cocaine. T h e duration o f anesthesia produced by “ locaine” was be 7. Gw inn, C. D., and Ferber, E. W .: Effect o f Hydrogen Ion Concentration in Local Anes thetic Solutions, J.A .D .A ., to be published.
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The Journal of the American Dental Association
tw een tw elv e and fifteen minutes, ap proxim ately ten minutes slow er than the duration o f anesthesia produced w ith c o caine. T h e topical anesthetic effect pro duced b y the use o f “ locaine” appeared to be as p rofou n d as that produced by the use o f cocaine. Prelim inary experiments are being car ried out on the use o f “ locaine” as a de sensitizer o f the dentinal fibrils. Present results are highly satisfactory, poin ting to the possibility o f using “ lo caine” as a topical anesthetic during cav ity preparation in hypersensitive teeth. SUMMARY
1. “ L ocain e” is capable o f acting on nerve tissue in a circum scribed area, either by topical application or by in jec tion into the tissues, and produces a pa ralysis w h ich tem porarily inhibits the nerve con du ctivity w ith ou t causing per manent tissue in ju ry. 2. Anesthesia produced by use o f an alkalinized “ locaine” solution is slow er than that produced by use o f an alkalin ized procaine solution. 3. Anesthesia produced by use o f “ lo caine,” w hen injected in the tissues, is
n ot so p rofou n d as that produced by use o f procaine. W h e n “ locaine” is ap plied directly as a topical anesthetic to ora l m ucous mem brane, it compares very fav orably w ith cocaine, and o f course is greatly superior to procaine. 4. T h e duration o f anesthesia is shorter than that produced by the use o f procaine. 5. T h e re w ere no noticeable general tox ic symptoms fo llo w in g the use o f “ lo caine.” T h e r e w as a slight degree o f loca l inflam m ation im mediately in the v i cinity o f the needle puncture, in prac tically all o f the infiltration injections, due probably to the relatively lo w hydrogen -ion concentration o f the solu tion. 6. T h e vasom otor activity o f “ lo caine” is not so pronounced as that pro duced by use o f a procaine solution con taining 1 :5 0 ,0 0 0 epinephrine. T h e proper dental application o f “ lo caine” in the clin ic requires the avoidance o f to o rapid injection into the tissues. I f it is administered in quantities equivalent to on e-half the strength and am ount o f procaine generally used, there is no neces sity fo r any greater precaution.
PRACTICABILITY OF CHROME NICKEL ALLOYS FOR ORTHODONTIC USE B y H O W A R D Y O S T , D .D .S ., G rand Island, N eb r.
H E title chrom e nickel alloys is chosen fo r base metal alloys o f chrom ium , nickel and steel because it m ore nearly describes the character o f alloys h aving the highest resistance to g al vanic action o r electrolysis.
T
F o r the past three years, I have used these base m etal a llo y s; first, stainless Jour. A .D .A ., Vol. 23, M ay, 1936
steel, and later the U . S. S. 18-8 (n o n m agn etic) alloys. A tten tion w as first at tracted to these alloys because o f the high resilience and flexibility o f the w ire form used in the construction o f orth odontic arch w ire s ; and also to the band material in its annealed (dead ben d ) state, because o f its pliability and the inherent quality o f
The Journal of the American Dental Association
T h e technic o f application is fu lly de earliest possible time evidence o f the e f scribed elsewhere .1 fectiveness o f this m ethod, and in such I am reportin g m y o w n experience in form that it cannot be questioned. By the use o f this solution over a period o f this, I mean that a plan should be set up years and have here given a report on 405 by w hich thousands o f cases w ill be very carefu lly observed cases that have been carefu lly recorded and tabulated under recently rechecked. It is o f the utm ost the direction o f experienced research im portance that w e accum ulate at the w orkers, in order that the w eigh t o f evi 1. Prime, J. M .: D. Cosmos, 77:1046 (N ov.) dence w ill be such that every practitioner w ill be com pelled to accept it. 1935.
PHARMACOLOGIC AND CLINICAL STUDY OF BBENZOYLOXY-B-PHENYL-ETHYL'DIMETHYLAMINE-HYDROCHLORIDE: A NEW LOCAL ANESTHETIC* B y E R W IN W IL L I A M FER BER, D .D .S ., M .S ., San Francisco, Calif.
N an effort to prepare local anesthetic com pounds that exhibit both local an esthetic and vasoconstrictor activity, several investigators 1 have prepared and studied derivatives o f arylam inoalcohols related in chem ical constitution and physiologic action to epinephrine. Such com pounds are desirable particularly from tw o points o f v ie w : ( 1 ) theoreti cally, to advance know ledge o f the pos sible relationships betw een constitution and physiologic action and ( 2 ) prac tically, to offer a com pound that does not
I
*Read before the Research Section o f the California State Dental Association, April, 1935. 1. Takeda, J .: Rearrangement o f 2-Benzamido-l-Phenylethanal into Am ino-Aphenylethyl Benzoate, J. Pharm. Soc. Japan, 1917, pp. 691-709; Chem. Abs., 11:3241, 1917. M arvel, C. S., and Du Vigneaud, V .: Pres sor Anesthetics, J. Am . Chem. Soc., 66:2093, 1924. Ailes, G . A., and Knoefel, P. K . : Local Anesthetics with Vasopressor Activity, Arch, internat, de pharmacodyn. et de thérap., 47: 96 (Jan.) 1934. Jour. A .D .A ., Vol. 23, M ay, 1936
require the use o f epinephrine to secure desirable local effects and thus to avoid u n tow ard systemic reactions resulting from such addition to local anesthetic solutions. A generation ago, B rau n 2 p ro posed the addition o f epinephrine as a satisfactory ad ju nct in local anesthetic solutions to produce local vasoconstric tion, thereby reducing the rate o f ab sorption o f the local anesthetic, p rolon g ing the latter’s effect and dim inishing its systemic absorption and the attendant toxicity. It has been show n also 3 that the epinephrine so added m ay produce undesirable side effects and actually cause an increased toxicity due to the 2. Braun, H einrich: (Trans, and ed. by Harris, M . L . ) : Effect o f Suprarenin (A dren alin) on Local and General Poisoning, in Lo cal Anesthesia, Philadelphia: Lea and Febiger, 1924, p. 32. 3. Spagnol, G .: Pharmacology o f Solutions of Novocaine-Vasopressin and NovocaineAdrenaline in Local Anesthesia, Rev. SudAmericana Endocrinal Immunol., 14:569, 1931; Chem. Abs., 26:773, 1932.
Fer ber— A N e w Local Anesthetic
com pou nd w as synthesized by D r . A lles and its ph arm acologic activities w ere in vestigated by D rs. A lles and K n oefel. A com parison w as made o f the anes thetic activity o f “ locaine,” cocaine and procaine on the cornea o f the rabbit and on the sensory fibers o f the fr o g ’s sciatic nerve. D a ta fo r their relative intravenous toxicity in rabbits and subcutaneous to x icity in m ice w ere obtained also. T h ese data as reported 4 are as given in T a b le 1. I t appears that “ locaine” is alm ost as effective as cocaine in its anesthetic action on m ucous membranes, w here procaine is quite ineffective. O n the f r o g ’s sciatic
presence o f the local anesthetic, w h ich is absorbed systemically. T h e benzoate o f phenylethanoldim ethylam ine, or m ore exactly 5 -b en z oy lox y B - phenyl-ethyl-dim ethylam ine h ydroch lo ride, called fo r convenience “ locaine,” is a com pou n d o f the type described. T h e similarities in com bined structure and properties o f procaine, a local anesthetic; epinephrine, a vasoconstrictor, and the n ew loca l anesthetic “ locaine” are illus trated in F igure 1. A n earlier study o f the pharm acologic properties 4 indicated that it possesses both anesthetic and vasoconstrictor activity o f T
able
1 .— D
ata
on
R
elated
gents
Toxicity
Rabbit Cornea Du ration in Minutes
Minimum Lethal Dose Millimols per Kilogram
Z?-hydroxy-5-phenylethylamine
0 .1 M
5-benzoyloxy-B-phenylethylamine ß-hydroxy-B-phenylethyl dimethylamine
26 0 .1 M
S-benzoyloxy-5-phenylethyl dimethylamine Cocaine Procaine
17 20 —
4. Footnote 1, third reference.
A
Anesthesia
0.04M
an interesting degree. I t seemed w orth w hile, therefore, to determine w hether this n ew drug cou ld be applied clin ically fo r various operations in the field o f oral surgery. T h e results have been, in som e respects, highly satisfactory, but, in others, it proved to be inferior to p ro caine. T h is substance was selected by G . A . A lles and P . K . K n oefel from a consid erable grou p o f com pounds, used fo r their com parative pharm acologic studies o f esters o f arylethanolamines, as being the m ost suitable o f those investigated. T h e
789
0.02M No Anesthesia 18 No Anesthesia 12 16 —
I ntravenous Subcutaneous 0.17
5.0
0.10 0.80
0 .4 i.O
0.07 0.04 0.13
2.7 0.45 3 .0
nerve, “ locaine” w as fou nd to be m uch less tox ic than cocaine, and about as tox ic as procaine by subcutaneous injection, though m ore tox ic than procaine by the intravenous m ethod o f administration. T h ese laboratory findings indicate that “ locaine” m ay have real clinical pos sibilities as a useful anesthetic agent, par ticu larly in dentistry. C ertain further prelim inary laboratory w o rk w as carried ou t before the drug w as studied clin ically w ith regard to its local anesthetic activity in the ora l cavity and to determ ine m ore precisely its toxicity by various routes o f administration.
790
The Journal of the American Dental Association
T h is w ork on “ locaine” included a study o f : ( 1 ) some chem ical properties o f its solution s; ( 2 ) infiltration and block anesthesia in the oral cavity o f the d o g ; ( 3 ) toxicity by subcutaneous in jec tion, and ( 4 ) toxicity by intravenous in jection, w ith studies o n : (a) the phe nom ena o f acute intoxication, (b ) to x icity from rapid intravenous injections, ( c ) toxicity from slo w intravenous in jections and ( d ) fixation, elim ination or destruction by the liver. P art o f the prelim inary w o rk w as done by A llés and K n oefel, w h o com pared the relative toxicities o f “ locaine” in jec tions in rabbits and m ice. C om parisons T
a b le
2 .— D
ata
I
n d ic a t in g
A
c id it y
of
pH
L o c a in e
1 .0 g m . o f “ l o c a i n e ” a d d e d t o 9 9 . 0 c . c . o f c o ld d is tille d
w a t e r ..........................................................4 . 7
1 .0 g m . o f “ l o c a i n e ” a d d e d t o 9 9 . 0 c . c . o f n o r m a l s a l i n e s o l u t i o n .......................................................4 . 6 1 .0 g m . o f “ l o c a i n e ” a d d e d t o 9 9 . 0 c . c . o f b o ilin g
d is tille d
ten s e c o n d s
w a ter
and
b o ile d
a fte r th e a d d it io n
fo r
o f “ lo
c a i n e ” ............................................................................................. 4 . 4 1 .0 g m . o f “ l o c a i n e ”
a d d e d t o 9 9 .0 c .c . o f
b o ilin g
d is t ille d
w a ter
tw e n ty
m in u te s
a fte r
and th e
b o ile d a d d it io n
fo r of
“ l o c a i n e ” ..................................................................................... 3 . 7
w ere also made o f m ucous mem brane an esthesia, by observing the corneal re flexes .4 F rom Figure 1, it is evident that “ locaine” is m uch less tox ic than c o caine and that its anesthetic action on mucous membranes is almost as satisfac tory. T h ese laboratory findings, convincing as they are, om it any reference to clinical experiments and it therefore seemed d e sirable to determine the clinical possibil ities o f “ locaine,” especially fo r dentis try. T h e w o rk undertaken included a study o f “ locaine” in com parison w ith such w ell-k n ow n agents as cocaine and pro-
caine, using suitable experimental ani mals, as to ( 1 ) its relative toxicity, ( 2 ) its relative efficiency as a loca l anesthetic and ( 3 ) its relative efficiency as a topical anesthetic. PHYSICAL AND CHEMICAL PROPERTIES OF “
l o c a in e ”
“ L ocain e” possesses the em piric fo rm ula C 17H 19O 2N -H C l, and a m olecular w eight o f 30 5.6. Its structural form ula is given in Figure 1. It is a w hite crys talline substance, soluble in w ater to the extent o f 4.2 36 gm . in 100 c.c. solution o f distilled w ater at 2 0 C . I t melts at 211-2 12 C . “ L ocain e” is capable o f acting on nerve tissue in a circum scribed area, either by topical application or by injection into the tissues. It produces a paralysis which tem porarily inhibits the conductivity w ith ou t causing permanent tissue injury. A n aqueous solution o f “ locaine” is defi nitely acid. T a b le 2 illustrates this fact. I t is w ell know n that irritability and toxicity o f anesthetic solutions increase in direct relation to low erin g o f the pH, and also, up to a certain point, any addi tion o f alkali tends to th ro w d ow n a precipitate. Attem pts to raise the pn o f the solution meet w ith success up to a certain lim it. T h e addition o f 60 m g. o f dibasic sodium phosphate to 50 c.c. o f a 1 per cent solution o f “ locaine” raised the pu from 4.7 to 5.0, at w hich point there appeared a very finely divided sus pended precipitate. T oxicity .— T h e toxicity was deter m ined by tw o modes o f administration, namely subcutaneous and intravenous. T h u s, presumptive evidence w as obtained on absorption from subcutaneous tissues and rate o f detoxification, and on the possible dangers o f clinical application. F o r subcutaneous injection, albino mice w eighing from 15 to 30 gm. w ere used,
791
Ferber— A N e w Local Anesthetic
been show n by E ggleston and H atch er5 that cats react essentially as dogs do to administration o f local anesthetics. A l l o f the operative procedures on the cats w ere carried out w ith a general an esthetic (ch lora lose), 75 m g ./k g . by body w eight, given intraperitoneally, w ith w a rm w ater as a vehicle. T h e basal an esthetic chloralose maintained a constant level o f anesthesia, adequate fo r all sur gical purposes, fo r m any hours, no pre-
receiving the solution under the skin o f the back, near the root o f the tail. T h e resulting phenom ena w ere chiefly con vulsive in .nature. T h e average m inim um lethal dose o f a 2 per cent “ locaine” solution w as 825 m g ./k g . T h is com pares favorably w ith D r . A lle s and K n o e fe l’s findings. (F ig . 1.) T h e ir observations w ere based on in jections m ade w ith m olal amounts in equim olecular concentrations. T h e data
OH
NHo
H C
y n
0
c
- 0
❖
N0
.
.
- C
- C
H
H
H - C 'H
0 ::
\ H
c H
P R O C A I
.H -
C
- N V
H
- c H
\
H C H
H - C H
/
H
- N N
OH
H
- H
E P I N E P H R I N E .
NE .
0c
H C -H
- H
- o
-
❖0
0c H
H C
-
.
- H
/«
c
H
\
h
C H
- H
" L 0 C A I N E V
Fig. 1.— Structural formulae of procaine, epinephrine and “ locaine.”
concern in g the toxicity by the intravenous m ode o f adm inistration in cats f o l low .
M eth o d .— Cats w ere used, since they m ore closely resemble man in their re sponses to m any drugs than do rodents. D o g s w ere n ot used because, o w in g to their larger size and consequent need fo r larger dosage, there w ou ld have been an insufficient supply o f the drug. It has
lim inary etherization being necessary. In all o f the experiments on cats, the local anesthetic w as dissolved in 0.85 per cent sodium chloride solution. A ll o f the 5. Eggleston, C., and Hatcher, R. A . : x Pharmacology of Local Anesthetics, J. Phar macol. & Exper. Therap., 13:433 (A ug.) 1919. Eggleston, C., and Hatcher, R. A .: Pharma cology o f Novocaine, J. Pharmacol. & Exper. Therap., 8:385, 1916.
The Journal of the American Dental Association
792
solutions w ere freshly prepared o n the day on w hich they w ere used. In fact, m ost o f the solutions w ere used w ithin one h ou r o f their preparation. W h e n an intact animal, anesthetized w ith chloralose or a barbiturate, is in
cord in g to E ggleston and H atcher, but the elim ination o f these drugs occurs at different rates. T h e experiments can be repeated several times on the same animal even though every in jection has been tox ic enough to produce tem porary fail
jected w ith a local anesthetic, such as procaine, the prim ary effect is paralysis o f the respiration, the circu latory failure
ure o f respiration. F orty-five minutes after the adm inistration o f the chloralose anesthetic, the animal is ready for opera-
T a b l e 3 .— I n f il t r a t io n A n e s t h e s ia
Patient
1
Type of Injection Infiltration
Amount Injected
Time o f Onset o f Anesthesia
C.c.
Minutes
2 .0
Teeth Ex tracted
3 .0
5!
Degree of Anesthesia
Remarks
Complete
Satisfactory Anesthesia incomplete after fifteen minutes Anesthesia incomplete after fifteen minutes Inflamed soft tissue af ter forty-eight hours Incomplete
1
2
Infiltration
2 .0
3 .0
|4
Complete
3
Infiltration
2.0
2.5
I5
Complete
4
Infiltration
2.0
3 .0
¡4
Incomplete
5
Infiltration
2.0
1.5
4
Incomplete 1
6
Zygomatic
2.5
2.5
|678
Complete
7
Infiltration
2.0
3 .0
'
Incomplete
Incomplete
8
Infiltration
3 .0
1.5
Complete
Satisfactory
9
Zygomatic
2.5
3 .0
Incomplete
Incomplete
10
Zygomatic
2.5
3 .0
Incomplete
Incomplete
Complete
13
18 6
Incomplete anesthesia
1
11
Infiltration
2.0
2.0
12
Zygomatic
3.0
4 .0
13
Infiltration
2 .0
3 .0
4! 8
Incomplete
Anesthesia incomplete after five minutes Incomplete
5
Complete
Satisfactory
i
being secondary. I f the injection is dis continued as soon as respiration fails, and artificial respiration is instituted, the cir culation is apparently unim paired. T h e respiratory center quickly recovers and artificial respiration can then be discon tinued. P rocaine and cocaine are either fixed, elim inated or destroyed by the liver, ac
tion. I t is placed on its back and tied to a board, and the fu r is trim m ed away from the areas to be operated on. A rubber bag partially filled w ith air is adjusted over the chest o f the animal and maintained by means o f a suitable jacket. A rubber tube leads fro m the rubber bag and is attached to a rubber diaphragm w ith a recordin g arm, adjusted to a m ov
793
Ferber— A N e w Local Anesthetic ing kym ograph drum fo r the purpose o f recording depth and rate o f respiration. B lood pressure and heart rate are also registered on the kym ograph by the us ual m ethod. T h e anesthetic solution is injected into the exposed fem oral vein by a 22-gage needle in a 2 c.c. L u er syringe. In the rapid intravenous injection method, the local anesthetic to be used is injected into the vein as rapidly as the capacity o f the vein w ill permit. In the slow intravenous injection method, the local anesthetic is delivered at the rate o f 1 c.c. per minute and is kept as nearly as possible at a constant rate o f flow . T h e apparatus consisted
m ination o f the effects o f individual sublethal doses, bu t also makes possible du plicate estimations o f such effects. By this m ethod, the rather w ide variation in the average effects o f specific dosages shown by different animals o f the same species is elim inated. T h is agrees w ith the statements m ade by M a c D o n a ld and Israels.6 A severely toxic, but not fatal, dose o f procaine or “ locaine” rapidly injected into the fem oral vein produces the same general symptoms. W ith in a few sec onds, there is a cessation o f respiration and an abrupt fall o f blood pressure. T h e heart rate varies th roughou t the period.
Respiration
SnjecbuL75n "CtjtuwnA?
C at i - v . / ha. Rapid Intravenous Injection of "Locaine"
^Jjocavna." 3 .5 6 « .
SOmy.
...........
Fig. 2.— Effect on blood pressure and respiration o f rapid injection o f “ locaine” into femoral vein of cat.
o f a buret fitted w ith a M a riotte tube, and connected by a cannula to the fe m oral vein. A very accurate delivery was maintained by coun tin g the num ber o f air bubbles passing through the solution from the M a riotte tube fixed in the buret. T h e rate o f delivery w as so adjusted that during the passage o f eight bubbles through the solution, 1 c.c. o f solution w ou ld be delivered by w ay o f the tubing and cannula to the receiving vein. I f death occurs during the injection, the lethal dose can be estimated. T h e m ethod not on ly provides fo r the deter-
A t first, im m ediately after the fall in blood pressure, the rate is usually slowed, and there is an increased intensity of con traction o f the heart. T h e respiration usually stops fo r about thirty seconds, or may continue to show stim ulation, in both rate and am plitude. L ater, the heart beat begins to im prove and the b lood pressure rises to norm al, or even above norm al fo r a short period o f time. A t about the same time, there are usually several brief 6. M acD onald, A . D., and Israels, M . G .: Local Anesthetics, J. Pharmacol. & Exper. Therap., 44:359 (M arch) 1932.
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T h e Journal of the American Dental Association
but severe clon ic convulsions, but, w ithin five minutes, the animal returns to n o r mal. T h e length o f time required for the onset o f symptoms does not differ m aterially fo r procaine or “ locaine” or fo r doses o f different size, as lon g as the dose is toxic. T h e effects on the heart and b lood pressure and on the respiration and time o f recovery are illustrated in the kym o graph recordin g show n in Figure 2, nearly a fatal vein dose having been ad ministered in the first injection. W it h the n ew local anesthetic, it has
Respiration
b*
(rt .carotid) E lim in atio n o f "L o c a tin e “ fro m B lo o d c ir c u la tio n b y L i v e r
JìocatsM '" ¿n to 6>oJita £ . Time = 5'iec.^ i
id u m ili Im m mimmi iiiisiim iimunn ummm irnimnn iiimm
10-1513: «
Fig. 3.— Effect on blood pressure and res piration o f rapid injection o f “ locaine” into portal vein o f cat.
been fou n d that the average m inim al lethal dose fo r “ locaine” injected rapidly intravenously w as fou n d to be about 20 m g ./k g . It has been found to be tw ice as tox ic as procaine, but not nearly so toxic as cocaine w hen injected intraven ously. ELIMINATION OF “ LOCAINE” FROM THE BODY TISSUES AFTER INJECTION
I t has been dem onstrated experim ent
ally b y H atch er and E ggleston that the liver actually w ill fix, destroy o r elim inate procaine rapidly if a solution o f it is perfused through the liver a num ber o f times. T h e fo llo w in g w o rk w ill dem onstrate that the action o f “ locaine” is likewise affected by the action o f the liver. T h e experim ental procedure was simplified in the fo llo w in g w ork on “ locaine.” In the w o rk perform ed by H atch er and E ggles ton, the liver w as w ashed nearly free fro m blood by passing L o c k e ’s solution through the portal vein. T h e liv er w as then rem oved from the b od y and perfused at a constant tem perature fo r one hour and tw en ty m inutes w ith a solution o f procaine and defibrinated blood, prev iously rem oved from the anim al. T h e perfused fluid w as oxygenated constantly and later tested biologica lly by injection. In the fo llo w in g w ork, a laporotom y w as perform ed, and the liver w as allow ed to remain intact in the anim al. T h e solu tion w as injected into the liver b y w ay o f the portal vein. T w e n ty minutes after injection, a solution w as introduced into the ju g u la r vein so that com parisons cou ld be made on the effect on respira tion and blood pressure. T h e effects are recorded on the kym ograph recordings in Figures 3 and 4. I t w ill be noted that in jection o f 20 m g. o f “ locaine” into the ju g u la r vein w as attended by a fa ll in b lood pressure, and subsequent injection o f 80 m g. o f “ locaine” into the portal vein had no m arked apparent effect. INFILTRATION AND BLOCK ANESTHESIA DEMONSTRATED IN THE ORAL CAVITY OF A DOG
In the effort to ascertain the possible dental application o f “ locaine,” the f o l lo w in g experiments on dogs w ere under taken.
Infiltration Anesthesia.— O n e-year-old
Ferber— A N e w Local Anesthetic dogs in good health, and w ith teeth in good condition, w ere used in the fo llo w ing experiments. T h e animal to be w orked on was placed in a box , the legs being tied to the sides o f the b ox and the head so fixed that it w as a llow ed slight m ovem ent. A section o f rubber hose w as adjusted in the anim al’s m outh in the region o f the posterior teeth, betw een the upper and low er arches to prevent closure o f the jaw s. A rubber dam w as then placed from cuspid to cuspid, thus isolat in g the eight anterior teeth. T h e pulp vitality o f these teeth w as tested by means o f the C am eron electric pulp
795
solution containing 1 :2 5 ,0 0 0 epinephrine. A pp roxim ately 4.5 c.c. w as used on the labial and 0.5 c.c. on the palatal surface. T h e injected m ucosa blanched im m e diately. T h e rubber dam w as again fixed in place. W it h in a period o f from fou r to five minutes, a sensitivity test was made o f the upper le ft incisors (u sin g the C a m eron pulp tester). T h e con trol was grad ually advanced to resistance 12 on the pulp tester w ith ou t any response from the animal. T h e reaction to the pulp tester w as checked periodically against the unanesthetized cuspid on the same side.
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Fig. 4.— Effect on blood pressure and respiration of rapid injection o f “ locaine” alternately into jugular and portal veins.
tester. T h is m ethod, although open to several objections, w as accurate enough fo r this experiment. T h e d og responded to the electric stimulus betw een re sistance 8 and 9 w hen the con trol o f the rheostat w as advanced to that degree. T h e rubber dam w as then reflected so as to expose the labial and palatal m ucous membrane. T h e tissue overlyin g the roots o f the upper left central and first and second lateral incisors w as infiltrated w ith a 2 per cent proeaine-hydrochloride
T h e rubber dam w as again reflected from the anterior teeth, the upper right central and first and second lateral in cisors being used fo r the injection. T h e same procedure w as fo llo w e d as in the first part o f the experiment, the same quantities o f solution being used, bu t a 2 per cent “ locaine” in place o f the procaine-hydrochloride solution. T h e re w as some blanching im m ediately on injection o f the solution, but not so m uch as in the case o f the procaine-epinephrine solution.
796
The Journal of the American Dental Association
T h e rubber dam was replaced and, after the same interval o f time, the pulp tester was again applied. T h e con trol w as ad vanced to resistance 12 w ith ou t any re sponse from the animal. T h e upper right cuspid reacted prom ptly to the electrical
injected fo r the three anterior teeth in the upper le ft arch, 0.5 c.c. on the labial aspect and 0.25 c.c. on the lingual. A n esthesia w as obtained in between fo u r and five minutes. T h e duration o f anesthesia w as approxim ately forty m inutes fo r the
stimulus. F ifteen hours later, the tissue appeared to be slightly inflamed in the region anesthetized by the procaine solu tion and, thirty-six hours later, sloughing was noticed. T h e tissue appeared to be
le ft central and sixty-five minutes fo r the first and second left lateral incisors. A 2 per cent procaine-hydrochloride solu tion, w ith ou t epinephrine, w as used fo r the three anterior teeth in the upper right
T
Patient
Type of Injection
Amount Injected C.c.
able
4 .— -B l o c k A
Time o f Onset of Anesthesia
n e s t h e s ia
Teeth Ex tracted
Degree of Anesthesia
1 15 ! 321, ! [ 123 I 6
Complete
Satisfactory
Complete
Anesthesia incomplete after fifteen minutes Satisfactory
Complete
Remarks
Minutes 1
Mandibular
3 .0
7 .0
2
Mandibular
3 .0
4.5
3
Mandibular
3 .0
8.0
4
Mandibular
3 .0
5.0
5
Mandibular
3. S
4.0
6
Mandibular
3. S
3.5
i 874321| 1
4.5
51 1
7
Mandibular
3.5
8
Mandibular
3.5
7.0
9
Mandibular
3.5
7.5
4| 1 6311 !
5.0
6| 1
10
Mandibular
3.5
Complete
Complete
Anesthesia incomplete after five minutes Anesthesia present for fifty-five minutes Satisfactory
Complete
Satisfactory
Complete Complete
Anesthesia incomplete after twenty minutes Satisfactory
Complete
Satisfactory
Complete
18
norm al in the region injected by the “ locaine” solution. A ft e r seventy-tw o hours, the tissue appeared to be norm al in both regions injected by the anesthetic solu tions. T w o weeks later, the foregoin g ex perim ent w as repeated w ith the same animal and the same procedure except as to the am ount o f solution. In this ex periment, procaine-hydrochloride contain ing 1 :2 5 ,0 0 0 epinephrine solution was
arch. T h e duration o f anesthesia was approxim ately forty-five m inutes fo r the three teeth. Block Anesthesia .— B lock anesthesia w as dem onstrated in the d og by giving injections o f anesthetic solutions at the base o f the tongue in the region o f the lingual nerve and on the medial surface o f the ramus opposite the m andibular foram en. In the region o f the in ferior dental nerve, 2 c.c. o f a 2 per cent p ro
F erber— A N ew Local Anesthetic caine-hydrochloride solution containing 1 :2 5 ,0 0 0 epinephrine w as injected. P a r tial anesthesia o f the tongue resulted. T h e r e w as com plete anesthesia o f the b order o f the ton gue and partial anes thesia over the greater portion o f the dorsal surface o f the tongue. N o anes thesia w as noticed on the posterior part o f the tongue, this probably being due to the various nerve supplies to the tongue. T h e degree o f anesthesia w as determined by inserting a sharp needle in o r pricking the tongue. T h e results fo r onset o f an esthesia fo llo w : T h e average time o f onset o f anesthesia using procaine-hydrochloride w as eleven minutes. T h e average time o f onset o f anesthesia using “ locaine” w as thirteen minutes. CLINICAL STUDY OF “ LOCAINE” (TABULAR RESULTS IN DENTAL CLINIC)
M a n d ib u la r “ block ” anesthesia was dem onstrated by in jectin g a 1 per cent “ locaine” solution in the vicinity o f the m andibular nerve, opposite the m andibu lar foram en. T h e onset o f anesthesia w as determ ined by testing the sensitivity o f the term inal nerve fibers on the low er lip, on the injected side, by pinching w ith a pair o f tw eezers and com paring the sensitivity w ith that o f the unanesthe tized side o f the lip. In filtration anesthesia w as dem on strated by in jectin g a 1 per cent “ locaine” solution in the soft tissue immediately adjacent to the tooth to be extracted. T h e onset o f anesthesia w as determ ined by inserting a chisel, at thirty-second inter vals, betw een the soft tissue and the tooth to be anesthetized. T h e foregoin g in jec tion technics are those used at the U n i versity o f C a liforn ia D en ta l C ollege, as described by C . D . G w in n . T h e results observed on patients in the dental clin ic are tabulated in T ab les 2 and 3. T h e average time o f onset o f block
797
anesthesia using a 1 per cent solution o f “ locain e” w as five and six-tenths m in utes. T h e average tim e fo r the onset o f in filtration anesthesia using a 1 per cent solution o f “ locaine” w as tw o and seventenths minutes. T h e foreg oin g average times may be com pared w ith a series o f injections made at the U n iversity o f C a liforn ia C ollege o f D en tistry E xtraction C lin ic using an alkalinized procaine-hydrochloride solu tion. T h e times given, being repeated fro m the results given in a paper “ T h e E ffect o f H y d rog en Ion Concentration in L o c a l Anesthetic Solutions,” by G w in n and F erber,7 w ere three and seven-tenths minutes fo r the onset o f b lock anesthesia using a 2 per cent p ro caine solution as com pared to five and six-tenths m inutes fo r “ locaine” ; and one and one-tenth minutes fo r the onset o f infiltration anesthesia using a 2 per cent procaine solution as com pared to tw o and seven-tenths m inutes fo r “ locaine.” I t w ill be necessary to point ou t the fact that the foregoin g determinations w ere m ade w ith a 1 per cent solution o f “ lo caine” in com parison to a 2 per cent al kalinized procaine solution. T h e reason fo r this is that it w as previously deter m ined that “ locaine” has approxim ately tw ice the toxicity o f procaine. T h e topical effect o f “ locaine” on the oral m ucosa w as next determined by placing the dry pow der on the mucosa o f the lip. T h e sensitivity was tested w ith a pointed pencil. C ocaine was used as a standard o f com parison. T h e onset o f anesthesia produced by “ locaine” was betw een fou r and five minutes, approx im ately tw o minutes slow er than the time fo r onset w ith cocaine. T h e duration o f anesthesia produced by “ locaine” was be 7. Gw inn, C. D., and Ferber, E. W .: Effect o f Hydrogen Ion Concentration in Local Anes thetic Solutions, J.A .D .A ., to be published.
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The Journal of the American Dental Association
tw een tw elv e and fifteen minutes, ap proxim ately ten minutes slow er than the duration o f anesthesia produced w ith c o caine. T h e topical anesthetic effect pro duced b y the use o f “ locaine” appeared to be as p rofou n d as that produced by the use o f cocaine. Prelim inary experiments are being car ried out on the use o f “ locaine” as a de sensitizer o f the dentinal fibrils. Present results are highly satisfactory, poin ting to the possibility o f using “ lo caine” as a topical anesthetic during cav ity preparation in hypersensitive teeth. SUMMARY
1. “ L ocain e” is capable o f acting on nerve tissue in a circum scribed area, either by topical application or by in jec tion into the tissues, and produces a pa ralysis w h ich tem porarily inhibits the nerve con du ctivity w ith ou t causing per manent tissue in ju ry. 2. Anesthesia produced by use o f an alkalinized “ locaine” solution is slow er than that produced by use o f an alkalin ized procaine solution. 3. Anesthesia produced by use o f “ lo caine,” w hen injected in the tissues, is
n ot so p rofou n d as that produced by use o f procaine. W h e n “ locaine” is ap plied directly as a topical anesthetic to ora l m ucous mem brane, it compares very fav orably w ith cocaine, and o f course is greatly superior to procaine. 4. T h e duration o f anesthesia is shorter than that produced by the use o f procaine. 5. T h e re w ere no noticeable general tox ic symptoms fo llo w in g the use o f “ lo caine.” T h e r e w as a slight degree o f loca l inflam m ation im mediately in the v i cinity o f the needle puncture, in prac tically all o f the infiltration injections, due probably to the relatively lo w hydrogen -ion concentration o f the solu tion. 6. T h e vasom otor activity o f “ lo caine” is not so pronounced as that pro duced by use o f a procaine solution con taining 1 :5 0 ,0 0 0 epinephrine. T h e proper dental application o f “ lo caine” in the clin ic requires the avoidance o f to o rapid injection into the tissues. I f it is administered in quantities equivalent to on e-half the strength and am ount o f procaine generally used, there is no neces sity fo r any greater precaution.
PRACTICABILITY OF CHROME NICKEL ALLOYS FOR ORTHODONTIC USE B y H O W A R D Y O S T , D .D .S ., G rand Island, N eb r.
H E title chrom e nickel alloys is chosen fo r base metal alloys o f chrom ium , nickel and steel because it m ore nearly describes the character o f alloys h aving the highest resistance to g al vanic action o r electrolysis.
T
F o r the past three years, I have used these base m etal a llo y s; first, stainless Jour. A .D .A ., Vol. 23, M ay, 1936
steel, and later the U . S. S. 18-8 (n o n m agn etic) alloys. A tten tion w as first at tracted to these alloys because o f the high resilience and flexibility o f the w ire form used in the construction o f orth odontic arch w ire s ; and also to the band material in its annealed (dead ben d ) state, because o f its pliability and the inherent quality o f