Clinical evaluation of the (+) isomer of mepivacaine

Clinical evaluation of the (+) isomer of mepivacaine William M. Goebel, D.D.S., M.X.D.,” and David P. Mitchell, D.D.S., Ph.D.,+ Los Angeles, Calif., and Indianapolis, Ind. A human clinical study was undertaken to evaluate the effectiveness and safety of dexivacaine 2 per cent, mepivacaine 2 per cent, and mepivacaine 3 per cent. A doubleblind technique was used to evaluate time of onset, duration, depth of anesthesia, and side effects. Results indicated no significant differences among the three anesthetics, except that mepivacaine 3 per cent had a significantly longer duration of softtissue

minimal

symptoms

in

the

mandibular

and of no statistical

block

significance.

series.

The

few

The evaluation

side

effects

noted

were

of an anesthetic by the

several parameters employed and especially by the over-all opinion of the anesthesia was deemed a valuable research method when comparing the clinical effectiveness of local anesthetics.

S

ince its introduction in 1956, mepivacaine has been well accepted as an effective local anesthetic. Mepivacainc (dl-N-methyl pipecolic acid 2,6-xylidide) was synthesized in 1956 by af Ekenstam, Egner, and Petters0n.l It was introduced in the United States under the brand name Carbocaine HCl$ in the early 1960s.2 Its usefulness as a local anesthetic has been well documented over the last decade.2’ 3-22 Mepivacaine has gained acceptance because of its clinical safety and effectiveness, which are closely related to its inherent vasoconstricting properBeing a racemic compound, its optical isomers were tYZ3-28 and low toxicity.29-32 Agents used in this study were supplied by Sterling-Winthrop Research Institute. Supported by Cook-Waite Laboratories, Inc., and United States Public Health Service Training Grant TOl-DE-00228-05. Research was done as partial fulfillment of the requirements for the M.S.D. degree at Indiana University-Purdue University School of Dentistry, Indianapolis, Ind., and was presented in abstract form at the Atlanta meeting of the International Association for Dental Research in 1974. *Assistant Professor, Department of Oral Diagnosis/Medicine/Pathology, UCLA School of Dentistry, Los Angeles, Calif. ; Member Dental Research Institute, UCLA. tDeceased. $Carbocaine HCl (brand of mepivacaine), Cook-Waite Laboratories, Inc., New York, N. Y.

471

.\ninial stutlics haw slio~71 that tlw (+) isomtr of incpiva~ainr gives if longer I Iural ioli of infiltration illl(l n(arvt’ block ancstlicsia than (-) or raccmic nicpivawiiw. Slil)t~nt;llic,olls aii(l intravwious injwtions also illtlicalc that ill qua1 cow ctwtrations the i+) isomer is less toxic than tlic (-) or raccniic coniI)oui1cl.~~‘?-“; I Itman stntlit~s also have shown the (+) isomer to give equal or longer duration (If iIllC~StllCSi;l tllall (-) Illc‘pi\-;rtdilillc or the raccwiit. t~oI11~~01111tl.‘“. ST Oiitx possible t~splanatioli for tlic~l)irac.aiiic~‘s c+fct+ivcilrss may be rt~latcyl to its inherent, \,aso~olisti.it,tiiig propwt~-. This property has Iwcn showi to hc the great(‘St ill the (+) iso*ncy,L!~. ‘/Ii. :is. ii!) “Since the tsperinirntal data strongly suggests thal mcpiwc*ainc aloiic has sufficient vasoconstrictor action at the 3 per cent level lo protlut~~ satisfat+or?. dental anesthesia in a high percentage of patients, the clinical testing of (+ 1 mt~pivaeaillc Jvithout vasoconstrictor as a dental anesthetic, moulcl be jnstifietl on the basis that it may bc able to produce satisfactory ancsthcsia at a somewhat lo\~er coilcciitration.“:: MATERIALS

AND

METHODS

A total of 300 anesthetic injections for preparation ant1 restoration of masillary ~)reniolars ant1 c~usyids ant1 mandibular molars, prcmolars, and cuspids in human subjects \vere planned in order to evaluate desivacaine 2 per cent.* IEepirawiilc 2 pt’r writ and mcpivacaine 3 per cent were used as controls. Two hundvccl sevrwty-nilit> in jwtioils wcrc coniplctc~tl. Twcnt!;-one wcrc not completed ht?c+aus~ of positive aspiration, l~rok~~ntdartritlgcs, Icaking t,artridge-iieedle-syringe assembly, ant1 wax debris in the cartricigc. A total of 65 infiltration and 214 mandibular bltwk injwtions \\-erc evaluated. The stutly was conducted by the tloublc-blintt tcchniqne after thr mcthotl of Stibbs and Kern.” The senior author gave all in jc&ons, and all rcstorativt~ work was done by third- and fourth-yeal clcntal students. Thtt test solutions \verr containetl in cwtlctl, consecutively numbered, 1.8 CC. (lental cartridgw For cmcrgcncy purposes, the name of the individual drug used was sealctl on each csartriclgc hut was not ~?sihlc to tht> operator unless opened. Cartridges I\-err usetl in ~~umt~rit~alseyuerm from 101 to 400. A “i-gauge needle with an aspirating syringe was usctl to inject exactly 1.8 c.c. of test solution for each procedure. Of this, 1.5 (*.t*.was used to cflect anesthesia, with approximately, 0.3 t*.c. of each injection for long lnwwl infiltration or palatal infiltration. The rat,\ of iiljcction was 0.9 c’.c. per minute. Subjects were human beings of both scses and of differing ages, excepting the very old, very young, pregnant women, and other patients in whom anesthetics of the amide type arc contrai~ltli~atctl. Each patient received a topical application of NeoTopanolt for 15 seconds prior to llecdlc insertion. Informed consent was given by each particGpant. “Dexacaine 2 per cent, Drsacaine HCI (lnxnd of tlrsivacaiw (+) Cook-Waite Laboratories, Inc., New York, N. Y. tNeo’l’opano1, Cook-Waite Lalloratorirs, TM., Nrw York, N. T.

isomer

of mepivacaine),

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The following definitions were used : Grade of a?lesthesia. This observation was made by the patient and by the student doing the work. A. Complete elimination of any unpleasant sensation at the start of the operative procedure. Ten minutes was the maximum time allowed for onset of anesthesia. B. Injection not repeated but patient not completely comfortable at start of operative procedure. C. Reinjection necessary at start of operative procedures. Reinjection was with a commercial anesthetic chosen by the operative instructor. Time first symptoms of anesthesia developed. Onset of subjective symptoms noted by patient. Onset is measured from needle insertion until subjective symptoms occurred. Time numbness disappeared. Loss of operating anesthesia after Grade A or B anesthesia had been obtained or loss of soft-tissue subjective symptoms as reported by mail. On completion of the restorative procedure, if Grade A or B anesthesia had been maintained throughout, the patient was asked to complete a stamped, addressed postcard, to be returned by mail, stating “the numbness went away about . . . A.M., . . . P.M.” This was to evaluate the duration of soft tissue symptoms. Over-all opinion of the allesthesia. This was done on a basis comparable to that of a private practice situation. To be judged sufficient, anesthesia was obtained within 10 minutes and lasted approximately 30 minutes in the maxilla and 1 hour in the mandible. This evaluation was made by the author. Opinions were strictly subjective, formulated from patient response and student response. Poor-No anesthesia, Grade C ; Pair-Grade B; Good-Grade A of insufficient duration; Excellent-Grade A of sufficient duration. At the completion of all injections, the code was broken and the data were analyzed. Statistical analysis was performed by Sterling-Winthrop Research Institute, Rensselaer, New York. Onset time was analyzed by the Kruskal-Wallis One-Way Analysis of Variance. All other comparisons were analyzed by the Behren-Fisher t test. RESULTS

Table I concerns the characteristics of sex, age, weight, emotional state, and medical conditions of the 116 male and 163 female patients who participated. Sex distribution was similar and consistent except in the mcpivacaine 3 per cent mandibular block series, in which twenty male (29 per cent) and fifty female (71) patients participated. This difference was statistically significant (p < 0.05). Table II concerns systemic reactions and local reactions. The only local reactions were postoperative “blisters” on the gingivae and inner surface of the cheek, reported on the postcard after injection of dexivacaine 2 per cent in one patient. These reportedly appeared 8 hours postinjection and lasted for one day. Grade C anesthesia was obtained in this patient; therefore, an injection of

Oral October,

Surg. 1975

I. Sample characteristics regarding sex, age, weight, emotional state, and medical conditions, comparing dexivacaine 2 per cent with mepivacainc 2 per cent and 3 per cent Table

Dexivacaine 8 per cent

Infiltrntion

Manclibular block

Mepivacaine 2 per cent

Mepivacaine

Mandibular block i

In<mtion

3 per cent Mandibular block

infiltration

Srx Males Females Total (N) Median age (yrs.) (10.90 percentile) Median weight (lbs.) (10-90 percentile) Emotion& stnte Calm, cooperative Very Nervous difficult

13 11 (54%) (46%)

34 36

24

z-IO

(49%) (51%)

9 (50

%)

Is

44 30

(59%) (41%)

Yi

10 13 (43 (57

%) %)

23

20 (29%)a 50 (71%)h ?o

31

29

32

32

32

28

(21-47)

(2247)

(21-66)

(22-54)

(22-55)

(21-51)

158

150

158

159

150

140

(1X-206)

(123205)

20 (83%) 4 (17%) -

62 (89%) 8 (11%) -

(119-205) 16 (89 %) ; [ ;:;mj 0

(116-208) 59 (81%) 131 (18%) ( 1YO)d

Medical conditions Normal 18 (75%) 59 (84%) 16 (89 %) 58 Heart disease 3 i 33;; 1 ( 5.5%) 3 Diabetes 1 (-4%) 7 (10%) ( 5.5%) Other 5 (21%) 1 1: a-b Significant difference at 5 per cent level (p < 0.05). c Includes one patient for whom the medical condition fl One patient’s emotional state was not recorded.

(80%) ( 4%) ll:;;c was not

(109-203) 17 (74 6 (21-

(118-184) %) %)

56 (80%) 13 (19%) 1 ( 1%)

21 (90 %) 1 ! 4.5%)

53 (76%) 4 ( 6%)

1 ( 4.5%)

1:

II:;,’

recorded.

mepivacainc 2 per cent with 1:20,000 Neo-Cobefrin” was administered. Since this patient was not avail&h for sensitivity testing, it is not known whether an allergy existed to either anestheitc used. Postoperative vesicles on the tongue and bueeal mucosa after injection with mepivaeaine 2 per cent were also reported by another patient. These lasted 12 hours. Subsequent sensitivity testing by intradermal injection and mucosal appliaction was negative. One patient reported a “bruised” injection site for 3 to 4 days following administration of mepivacaine 3 per cent and reinjection with mepivacaine 2 per cent with 1:20,000 NeoCobefrin mepivacaine which resolved without treatment. Systemic reactions occurred with the administration of dcxivaeaine 2 per cent and mepivacaine 2 per cent. None occurred in the 3 per cent group. Four patients reported drowsiness or a tranquilizing effect after injection of dexivacaine 2 per cent. These effects disappeared as the anesthesia diminished. One case of immediate nausea and vomiting was reported, and in another instance urticaria of the fingers occurred 24 hours after injection of dexivacaine 2 per cent. The patient with urticaria was a dermatologist who later reported proving to his own satisfaction that the condition was coincidental and not related to the anesthetic agent. *Carbocaine of levo-nordefrin),

HCl

2 per cent (brand of mepivacaine) Cook- Waite Laboratories, Inc., New

with York,

Neo-Cobefrin N. Y.

1:20,000

(brand

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II. Systemic reactions and local reactions comparing dexivacaine 2 per cent with mepivacaine 2 per cent and 3 per cent Table

I Dexivacaine

a b c d e f s h

cent

I

Mepivacaine

d per

Menivacaine 3 per cent

cent

MandibzLlar block

t&ion

Mandibzllar block

Infiltration

3 (12%)abc 21

3 (40/,)-a 67

1:

5 (7%)b-f 67

0 23

0 70

0 24

1 (l%o)g 69

0 18

1 (l%)g 71

0 23

1 (l%)h 69

Infiltration Systemic reactions Number of reactions No reactions LocaE reactions Number of reactions No reactions

% per

InfiG

Mandibzllar block

Drowsiness. Nausea. Digital urticaria. Syncope. Dysphagia. Increased salivation. Postoperative vesicles on gingiva and buccal mucosa. Postoperative discomfort at the injection site.

With the administration of mepivacaine 2 per cent, there were two casesof immediate syncope, one of nausea and vomiting, one of increased salivation, and one of “difficulty in swallowing.” Sensitivity testing by mucosal application and intradermal injection for the dysphagia was conducted, and no reaction occurred. The symptom presumably was related to topical anesthesia of the oral pharynx. The patient could not feel herself swallow, but motor control (gag reflex) was intact. Indirect laryngoscopy was negative for edema. The sensation regressed in 45 minutes. Table III summarizes the clinical performance of the three test anesthetics. The onset time of all infiltrations averaged 2 minutes. This suggests that symptoms of anesthesia were apparent by the time the needle was withdrawn. All mandibular blocks averaged 3 minutes, which is within 1 minute of needle withdrawal. No significant differences were noted. The duration of soft-tissue symptoms was computed as a geometric mean. These values were taken from the times listed by patients on the postcards. (A high percentage [102 of 11’71of the cards were returned.) Statistical significance (p < 0.05) is noted with the values for mandibular blocks of mepivacaine 3 per cent, as compared to mepivacaine 2 per cent and dexivacaine 2 per cent. Geometric means were also computed for the duration of operating anesthesia. No significant differences were detected. In both duration values, a large standard error was noted as a result of the small sample size. Grade of anesthesia is expressed as percentages of Grades A, B, and C. No significant differences, again, were present. The over-all opinion of the anesthesia is possibly the most important evaluation, as it subjectively rates total performance as a combination of all the above factors. No significant differences were noted among the anesthetics.

Oral October,

Surg. 1975

Table Ill. Clinical perf’ormanc~~ (*omparing tlexivacaine 2 per pent with mepivacdainc2 per writ ant1 3 per cent IIexiuacaine 2 per cent

Infiltration Onwt time (minutes) Median (lo-90 percentile) Number of patients Duration of softtissue symptoms (minutes) Geometric mean Standard error (%I Number of patients Ihwation of operating anesthesia (minutes) Geometric mean Standard error (%*o‘, \.-, Number of patients a-c Significant c-b Significant

difference difference

Mandibular block

Mepiuacaine 8 per cent I?@Ztration

Mepivacaine 3 per cent

Mandibular block

In@ tration

Mandibular block

(2;;)

2 ( 2-3) 24

3 P-Z)

c;;,

cy+,

c;-;,

143.7

159.la

94.7

148.9b

141.4

186.1~

7.5 6

5.2 36

19.6 5

6.9 21

23.3 5

5.0 69.0

40.6

67.6

35.7

57.6

41.0

35

15.0 14

14.1 15

18.1 13

8.8 31

11.6 16

9.9 20

at 5 per cent level at 5 per cent level

(p < 0.05). (p < 0.05).

DISCUSSION

Over-all analysis of the results suggests that the mcpivacaine 3 per cent and dexivacaine 2 per cent arc comparable and perform similarly in most respects. Several local and systemic reactions did occur. The intraoral vesicular reactions could be considered allergic in nature, but in one patient this was disproven and in another patient cooperation was insufficient for definitive allergy test conclusions. Numerous other dental materials were used in the course of the operative procedure as well as rcinjection with an anesthetic containing a vasoconstrictor. Any of these could have accounted for the reactions. When the percentage of reaction-free injections (99 to 100 per cent) in this study is compared to those of other studies using mepivacaine 2 per cent and 3 per cent,*’ 5, lo. I43I8 values are comparable. The per cent of injections free of local reaction to dexivacaine 2 per cent also was 99 per cent or more. All the systemic effects in this study were probably related to psychogenic causes,“’ except for drowsiness, which occurred only with dexivacaine 2 per cent. Although the four casts are not statistically significant, they must be suspect because they did not occur in any other group. Since mepivacainc is a racemate and thus one half dexivacaine, it would seemthat the reaction, if there actually is a reaction, could occur in other groups, unless the 2 per cent concentration of dexivacaine represents a toxic threshold. The actual percentage of dexivacaine in mepivacaine 3 per cent is 1.5 per cent. Further human testing is necessary to resolve this question. To some operators, the tranquilizing effect may be a welcome side effect. The one caseof urticaria was proved by the patient, who is a dermatologist, to be coincidental and not related to the dexivacaine 2 per cent.

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Great variability in onset time of mepivacainc is reported by other authors.2, 5-12,lR, 20 The present study falls within the range of other studies. The 2to 3-minute onset time for dexivacaine 2 per cent was equal to that of mepivaCaine 2 per cent and 3 per cent. Likewise, the duration of soft-tissue subjectirc symptoms for mepivacaine 3 per cent is quite variable, as reported by others.“, ?-12,14 The present findings are within the highly variable range. Patient cooperation was very important in the tabulation of these results, as postcards completed by the patients had to be returned to us. Mumford and Gcddes’ reported a 92 per cent return rate. In the present study the return rate was 87.2 per cent. This is considered good, especially since the patients were not compensated or enticed in any way to cooperate. The method employed appeared to be effective but a slight imposition on the patient. The significant difference between the dexivacaine 2 per cent and mepivacaine 2 per cent in the mandibular block series, as compared to mepivacaine 3 per cent (Table III), may be quite valuable clinically. Patients appreciate being profoundly numb during the restorative procedure but not after leaving a dental office. The shorter duration of soft-tissue symptoms with still profound adequate operating anesthesia would be a welcome addition to the clinical properties of an anesthetic. When the operating duration of anesthesia with mcpivacaine 2 per cent and 3 per cent in the present study is compared with that reported by other authors,” 7-9, 11 it is again noted that a wide range of previously reported values exists. The results of present study are comparable to the findings of others. Although no significant difference is noted, it appears that dexivacaine 2 per cent compares favorably with mepivacainc 3 per cent and gives a longer duration of action than mepivacaine 2 per cent in the mandibular block. This would be consistent with animal studies which found the (+) isomer longer acting than the racemate at equal concentrations. The reduction of the (+) isomer’s concentration to 2 per cent should result in properties similar to those of the 3 per cent racemate. The results of this study indicate a slightly lower incidence of Grade A anesthesia with mepivacaine 2 per cent and 3 per cent when compared to other studies.2, 5, 6, IO-I?, 14,IX, 20 Th’ 1s may be related to the exact criteria placed on the definition of Grade A anesthesia as opposed to the definitions of other investigators. It may be further related to the experimental setting in the dental school with an open operatory which was not conducive to relaxation. Patients in this study were also required by Federal Food and 1)rug Administration regulations to sign an informed consent which stated that an experimental drug was being used. This might have increased their incentive to inform the operator of even a minimum of discomfort. Dexivacaine 2 per cent was found to be slightly inferior to mepivacaine 2 per cent and 3 per cent as to grade of anesthesia in the illfiltratio?L series, although this difference was not statistically significant. All drugs mere equal in their effectiveness in the mandibular block series. The difference noted probably is related to the small sample size: 65 infiltrations versus 214 mandibular blocks.

Oral October,

Surg. 1975

Over-all opinion of tlio anesthesia was the last and probably the most inJWrtant pnramrtcr to be cs\-aluatcd. Other authors have not reported this means of comparison. It s~~ciiictl to IW iin t+t%ctivc approach to an evaluation of anesthctic* pcrformaricc~ in this clinic setting. No significant differences are present although, as seen in Table III, dexivacaine 2 per cent performed equal to or better than nic~pivac~ainc 2 per cent or 3 per cent in both infiltration and mandibular block injections. Further study is necessary hcforc definite conclusions can be dra~vn. Inc*rcased sample sixc in future studies may substantiate this observation. In further (avaluations, mepivacaine 2 per cent should not be included as a caontrol, since it, is not a marketed anesthetic. The fact that one person gave all the injections presumably reduced variability in the study, but it severely limited the number of injections that could be given. The consistency lost by having more persons administrating the anesthetic would be counteracted by the increased number of injections possible. The role of a short-duration anesthetic in a teaching clinic is limited because of the increased time required for inexperienced students to complete a procedure. However, the discomfort of the restorative procedure after loss of operating anchsthcsia gives an exac*t indication of the operating duration of the ancsthctic. SUMMARY

AND

CONCLUSION

Animal studies have indicated that the effectiveness of mepivacaine is a function of its (+) isomer. A double-blind clinical study was undertaken to evaluate the effectiveness and safety of tlexi\acaine, ( t ) isomer of mepivacaine. The 2 per cent cdonccntration of th(> (+) isomer of mcpivacaine was clearly shown to possess anesthetic qualities comparable to those of mepivacaine 3 per cent. Dexivacainc 2 per cent had a significantly shorter duration of soft-tissue symptoms than did mcpiracaine 3 per cent, and the operating duration of anesthesia was similar. Iii clinic~al safety, tlexivac*ainc 2 per cent was comparable to mepivac+ainc2 per cent and 3 per cent. Further study to evaluate the occasional drowsinessreporttd might be in ortler. Of the reactions that did occur, none was serious. Evaluation of an anesthetic by the several parameters employed, and especially the over-all opinion of the anesthesia, is a valuable rcscarch method when the clinical cffecti~cncss of local anesthetics is being compared. REFERENCES

1. af Ekenstam, B., Egnet, B., and Petterson, G.: N-alkyl Pyrolidine and N-alkyl Piperidine Carboxylic Acid Amides, Acta Chem. &and. 11: 1183, 1957. 2. Hi&t, W.: Local Anesthesia: History; Potential Toxicity; Clinical Investigation of Mepivacaine, Dent. Clin. North Am., p 243, 1961. 3. Stibbs, G. I~., and Korn, J. H.: An Evaluation of the Local Anesthetic, Mepivacaine Hydrochloride, in Operative Dentis.try, J. Prosthet. Dent. 14: 355, 1964. 1. Sadove, M. S., Vernino, D., Lock, F., and Kolodny, S.: An Evalation of Mepivacaine Hydrochloride, J. Oral Surg. 20: 399, 1962. 5. Ross, N., and Dobbs, E. C.: A Preliminary Study on Carbocaine, J. Am. Dent. Sot. Anesthesth. 7: 4, 1960. fi. Lock, F., Vernino, I)., and Sadove, M.: Mepivacainc HCl (Carhocaine) : A Preliminary Clinical Study, J. Oral Surg. 19: 16, 1961. 7. Mumford, J. M., and Geddcs, I. C.: Trial of Carbocaine in Conservative Dentistry, Br. Dent. J. 110: 92, 1961.

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of a New Local Analgesic Hoe 40 045, 8. Winther, J. E., and Nathalang, B.: Effectivity Stand. J. Dent. Res. 80: 272, 1972. 9. Berling, C.: Carbocaine in Local Anesthesia in the Oral Cavity, Odontol. Revy 9: 254, 1958. 10. Wei!, C., Santangelo, C., Welham, F. S., and Yackel, R. F.: Clinical Evaluation of Mepivacaine Hydrochloride by a New Method, J. Am. Dent. Assoc. 63: 26, 1961. 11. Mumford, J. M., and Gray, T. C.: Dental Trial of Carbocaine, Br. J. Anaesth. 29: 210, 1957. 12. Bradley, D. J., and Martin, N. D.: Clinical Evaluation of Mepivacaine and Lidocaine, Aust. Dent. J. 14: 377, 1969. 13. D’Agostino, A., and Scata, F.: Considerations on the Use of Mepivacaine in Odontostomatologic Practice, Minerva Anestesiol. 32: 384, 1966. 14. ROSS, N. M., and Dobbs, E. C.: Mepivacaine HCl (Carbocaine) Without Vasoconstrictor, J. Oral Surg. 21: 215, 1963. 15. Albertson, G. L.: Mepivacaine HCl in Dental Surgery, Dent. Prog. 4: 52, 1963. 16. BjSorby, IL., and Osvald, 0.: Carbocain, ett nytt lokalanestetikum. Redogorelse for en klinisk undersokning, Odontol. Tidskr. 66: 365, 1958. 17. Dhuner, K. G., Oljelund, O., and Aagesen, G.: Carbocaine-d, l-N-methyl-pipecolic acid-2, 6-dimethylanilide; a New Local Anesthetic Agent, Acta Chir. Stand. 112: 350, 1956. 18. Dobbs, E. C., and Ross, N.: The New Local Anesthetic Carbocaine, N. Y. State Dent. J. 27: 453, 1961. 19. Feldman, G., and Nordenram, A.: Carbocainets och lidocainets anlstetiska effekt, Sven. Tandlak. Tidskr. 52: 531. 1959. 20. Sadove, M., and Wessinger, G. D.: Mepivacaine, a Potent New Local Anesthetic, J. Int. Coll. Burg. 34: 573, 1960. 21. Vitenberg, J.: Un nouvel anesthesique local la Carboeaine (ou mepivacaine), Inf. Dent. 45: 2209, 1963. (Translated by Robert Langlais D.D.S.) 22. Sadove, M. 8.: A Preliminary Report on Carboeaine, a New Local Anesthetic, New Phys. 9: 39. 1960. 23. Jorfkldt, L., Lofstrom, B., Pernov, B., and Wahren, J.: The Effect of Mepivacaine and Lidocaine on Forearm Resistance and Cauacitance Vessels in Man. Acta Anaesthesiol. * Seand. 14: 183, 1970. 24. du Mesnil de Rochemont, W., and Hensel, H.: Measurement of the Blood Supply of Human Skin Under the Influence of Various Local Anesthetics, Naunyn Schmiedebergs Arch. Exp. Pathol. 239: 464, 1960. (English summary in reference 14.) 25. Mumford, J., and Geddes, I.: Adrenaline : Its Role in Local Anesthetic Solutions for Dentistrv. Dent. Pratt. Dent. Rec. 10: 2. 1959. 26. Adler, R.; Adler, G., and Aberg, G.: Studies on Dental Blood Flow in Dogs, Sven. Tandlak. Tidskr. 62: 699, 1969. 27. Pohto, M., and Scheinin, T.: Microscopic Observations on Living Dental Pulp. I. Method for Intravital Study of Circulation in Rat Incisor Pulp, Acta Odontol. Seand. 16: 303, 1958. 28. Aberg, G., and Adler, R.: Thermographic Registrations of Some Vascular Effects of a Local Anaesthetic Compound, Sven. Tanklak. Tidskr. 63: 671, 1970. 29. Luduena, F. P., Hoppe, J. E., Coulston, F., and Drobeck, H. P.: The Pharmacology and Toxicology of Mepivacaine, a New Local Anesthetic, Toxicol. Appl. Pharmacol. 2: 295, 1960. 30. Gordon, R. A., Kerr, J. H., and Taylor, R.: A Laboratory and Clinical Evaluation of Mepivacaine (Carbocaine), Can. Anaesth. Sot. J. 7: 290, 1960. 31. Ulfendahl, R. R.: Some Pharmacological and Toxicological Properties of a New Local Anesthetic, Carbocaine, Acta Anaesthiol Stand 1: 81, 1957. 32. Henn, F.: Determination of the Toxicological and Pharmacological Properties of Carbocaine, Lidocaine, and Procaine by Means of Simultaneous Experiments, Acta Anaesthesiol. Stand. 4: 125, 1960. 33. Luduena, F. P.: Duration of Local Anesthesia, Ann. Rev. Pharmacol. 9: 503 1969. 34. Luduena, F. P., Bogado, E. F., and Tullar, B. F.: Optical Isomers of Mepifvaeaine and Bupivacaine, Arch. Int. Pharmacodyn. Ther. 200: 359, 1972. 35. ILberg, G. : Toxicological and Local Anaesthetic Effects of Optically Active Isomers of Two Local Anaesthetic Compounds, Acta Pharmacol. Toxicol. 31: 273,. 1972. 36. Dhuner, K. G., Lewis, D. H., Nygvist, A., Selander, D., and Stig, E.: Vascular Effects of the Isomers of Mepivaeaine, Acta Anaesthesiol. Stand. (Supp.) 48: 48, 1972. 37. Adler, R., Adler, G., and Aberg, G.: Effects of Optically Active Isomers and Racemate of Mepivacaine (Carbocaine R) in Dental Anesthesia, Sven. Tandlak. Tidskr. 62: 501, 1969. 38. ILberg, G., and Anderson, R.: Studies on Mechanical Actions of Mepivacaine (Carbocaine) and Its Optically Active Isomers on Isolated Smooth Muscle: Role of Cat+ and Cyclic AMP. Acta Pharmacol. Toxicol. 31: 321. 1972. 39. Aberg, CT., and WahlstrSm, B.: Vascular Effects of Mepivacaine, Acta Physiol. Stand. (Supp.) 330: 71, 1969.

Oral October, 40. E’ersron, G.: (::rtrcllolnxrlin~:s Rcanll.

Ecprint

General Side EfTwts as Vasoconstrivtors

, Rupp.)

53:

of 1,ocal Dental Anaesthesia :rnd to tlte Effect of Some

1, 1969.

requests to:

Dr. William hl. Goebel Department of Oral I)iagnosis/MrdicirIr/Patl~ology UCLA School of Dentistry Los Angeles, Calif. 90024

Wit11 Special Premedicants,

Sury. 1975

Reference to hcta Odontol.