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Some by-effects of procaine
Pharmacology
and
SOME BY-EFFECTS
Therapeutics OF PROCAINE
P
ROCAINE is the most frequently used local anesthetic; its mode of act,ion is, nevertheless, not yet clarified definitely. Being aimed to add to the solution of this problem, pharmacological effects of disintegrat,ed (discolored) procaine solutions were examined by w.~ Of our results in this connection one deserves being mentioned: discolored procaine solutions have a decreased capacity to produce anesthesia, and in addition their toxicity becomes increased. For this reason the use of discolored procaine solutions (yellowish tint) is objectionable. In order to avoid mistakes, uncolored glass should be used for the ampoules made to contain preparations of procaine for the trade. In these examinations, for comparison’s sake, freshly prepared procaine In these solution was injected intravenously into our experimental animals. experiments we observed some effects not reported elsewhere in the literature. These seem to us worthy of publication. Experiments were carried out on cats of 2-3 kilogram weight, under narHood cosis by means of chloralose (0.10 g./kg.), with art,ificial respiration. pressure in the carotid artery was directly measured by a mercury manometer, and intestinal movements were regist,rated by the balloon method. In some animals epinephrcctomy, in ot,hers decapitation, using Elliot’s method, was carried out. Drugs to be examined were injected intravenously. Dosage of procaine was lower than the minimal toxic one to the respirat,ory and vasomotor center, according to data of Schmutzigcr and Wolfner. * The maximal dosage applied amounted to 0.5 ml. of a 4 per cent solution, but in most instances 0.5 ml. of a 2 per cent This solution was used, containing 20 respectively 10 mg. per cent procaine. dosage is surely atoxic since by procaine-esterase 30 mg. are decomposed” in the living organism within five minutes. Between repeated injections there was a 1)ause of minimally ten minutes in OUI’ csperiments. In order to procure chanping conditions suprarcnin (0.5-5.0 y), acetylcholine (0.05-10.0 y), and atropine snlfat,c (10 mg./kg.) were gircn. :\I1 drugs were dissolvcd in! and diluted by isotonic salt solution. Wc were surprised to find that if procaine is injected just before the injcct,ion of snprarenin, the suprarenin causes a more marked rise in blood pressure than if given without preinjecting procaine. It seems that by procaine, the t+xn the Pharmacological Institute and from the Stomatolosical (:linic of the TJniversity. Ik~brecen, Hungary. Keceiocd Cor publication Oct. 5. 1948. Specialist in Stomatology. *zAssistant of the Phnrnxwological Institute, **Assistant professor of Orthodontics, Head of the Stomntr)lwical Clinic.
201
This is in an apparent contradiction to suprarenin effects become sensitized. even modern textbooks of pharmacology; for this reason experiments wwc rcpcatedly carried out on ten cats. First of all, normal reactions to suprarcnin were checked; tllrn an qua1 dose of suprarenin was given after injecting procaine preriously. In all experiments a marke(l rise of the Mood pressure OCbudged. In Fig. 1, II the rise of the hIooc~ J)rcSSLll’(: caused h)- 0.5 y SLlpJ~arellill But. if this cpinephrine dosage is given after is shown. Tt amounts to ?.‘, ni~n. a previous inject,ion of 10 trig. procaine. the rise of the l~lood prcssurr amounts to 35 mm. as shown in Fig. 1, 71. Tn order to ohtain this effect, suprarenin has to he injected while the blood pressure lowering cffcct, of the procaine is present K?- increasing the dosage of procaine and/or cI)inephrine, the a fore descrihetl effect becomes mow marked, TnjectioJl , of 20 ~llg. Jwocxille Causes riot OJllp ii snore niarked rise of the blood ~)ressuw hut is also maintaining this higher level for a longer time. ‘1’1~ sensitization to snprarenin ly procaine is to he seen in animals after atropine premcdicat ion. a ftcr clew pitation, and after epinephrccAtropine prcmedication decrcascs the sensitizing effrct, while after epitolrl~~. rirphrectom~ the effect is considerably mow ~tmk.2l. In the l~loocl pressure vlll’v(~ the JlIiJSiIJJlllJl inCWilsc~ is maintained for sonic t,ime in most animals. By thcsc experiments it is proved that procaine, similarly to some othr tlrugs and 1)iologic agents such as cocaine. calcium ions, aI!-ceroJ,hosphatc. lecithin, albumin, peptones, some amino acids. tll.woxin, and under wrtain cow ditions cve~i awl)-lcliolines is capable of sensitizin g t lie organisril to suprarenin dfCdS.4 Tllis contradicts SOJJIC statements in the literature whic>h den>- the sensitizing of atlrinciyic cffwtors lgr J)KW’iliIlC being diffcJwt fro111 wwainc.5~ 6* ’ (‘ont,radicltoi,~ rwults were ohtninccl in cspcrimc~iitation with isolated organs. which is I’C’~iil*tl(‘tl t 0 he an unsuitahlc mctliod 01’st iltlying I)rocaine effects. Sonic ideas ma\- h gined h>- incrrasiJlg the SlJpl’~lJ’WiIl c~ffwls with proraiJJe.“2 ‘. “I The findings which confirm the reslllts ot’ Rtwr7rnil nntl collaborators.” of NoZlc~ ;lJlti ~~fPff~?LSSO)t.‘”Of .l/C/C[/W{]O/-,I” who 1ia1.c demonstrated a g~aratf.7 rise of 111~ blood sugar lIJV injecting 20 Jlig. pJ*ocainc before 1 II(I Sll~~l’ilrc~J~iIJ, Swnle~~ not Suficicnl. t 0 stress cmphatic;ill\- that l)rocainc is cal);ll)lc of itlcrcasinp the susceptiI)ility of adrinrrgic wlls, whrrehy reactions to srlprarcnin lwwnc nlorc Inarkcd. .Iccordinp to Our’ ~~SJK’l~iJllf3lts illltf eOJltl’aJ*)~ to I’OJ.JJJPV b?Iit’l’. ii is to 1~ slrcssed that t4fectors arc sensitized to suprarrnin 1)~ ~)l’W;lilJC. LI se~~md ohsrrration worth ment,ionin g is i-lie irritative action of procaine whicdll is 11loJ*c Jnil &cd than the action ohtaincd 111)or1intrstinal morcw~eJltS,” with acet~lcholint. Tn Fig. 2 the action of 10 mu. procaine is shown to effect an increasctil tonicit~ and :I storJrr;\JWriStakiS. Tn the same animal 0.05 7 acetylcholine hacl l~a.dly any t~ff’wt. T’rocaillc action upon the intestines is most Inarked iI1 wmhination wit 11 iI longer-lasting lowering of the blood pressure by aftn. t11c drug. The pi’ncainc cffwt on the intestines is prrsent also in allilllah Aficr irtllllitiistr~ilion 01’ ;I high al ropin(l tlosage premrtlication wilh atrol)inc. ilO mg./kg.), ac,c~l!-lclloliiic~ is 1101 ca1)al)lc ol’ wusing intestinal niovement if ziV(JJl iJ1 1 llt?l~il~)(LLlt iv tlOS:lp(~ : it (~:lllS~~s sli~llt nlovc~l~cnts ill cstrcrlJely high dosage only 110 71. Tn thr same animals, 10 mg. procaine caused an increased t,onieity of the intcstincs. and 20 mg. procaine caused peristalsis to start again (Fig. 3,
This observation may have some 1)rac.ticnl inrlwrt anc(x. The intestinal byeffects of procaine were present if int txvcnous injections wwc itratle unintciitionally. Care should he taken about this Iry-cffcct if l)rocainc is administered intentionally l)y the intravenous method to cause analgesia or to stop cardiac arrhythmia. I~‘urthermore, the eventual therapeutic use of procaine to check intestinal paralysis has also to be taken into considcrat,ion. This possible use of procaine is supported lg- csperimental ohservat,ions of Goi7l~7yi~” : when injccting a sublethal procaine dose to dogs, among other synlptonls, intensive dcf’eration takes place. It might he possible to product, 1)~.some strnc~tural change 01 procaine molecules, a new ehcmieal comlmnnd, l)cthal)s Tyitll diminished anesthetic quality hlxt with all ill~UWWt1 avtivit)up011 illt(~Stillill nlox-etllfwts.
WC observed, furthermore, that it’ procaine was administered after application of snprarenin, it did not cause-contrary to the usual reaction-a lowering of I)lood pressure, but had cithcr no effect, whatever upon it or cawed a, slight rise. Twent,y mg. procaine injected during the duration of thr action of 0.5 7 suprarenin caused further rise of blood pressure while in SC it caused a drop (Fig. 4). Similar effects mere observed in dogs by l\7iewwnv~.16 This cffcct may be called “ imitation effect. ” If administered after constant tlosagcs of suprawnin, the effect is proportional to the procaine dosage ; it is only to be obscrvetl if procaine is admiiiistcrcd while suprawnin effects aw prcscnt. TlltJ 1110s!
Fig. 3.-intestinal ication. a, Action
motility, upper of acetylcholine
curve, and blood presmre, lower curve. after atropine preme(l: b, action of 10 mg. procaine : c, action of 20 mg. wocaine.
marked procaine effect is to be observed if the drug is given when suprarenin effects begin to fade away. After suprarenin effects have subsided, procaine causes a slight decrease of the blood pressure again. The imitation effect is best seen in cats during spring; from this fact we conclude that the state of’ the autonomous nervous system has a considerable influence upon it. Besides supraIf given renin, procaine imitates acetylcholine too, though not so regularly. after previous acetylcholine application, in several animals, hut not in all, pro-
206
.I.
IJlU
\SD
I’.
\DLF:t:
action it is resorbed. ivhat by-effect of procaine incomes manifest depends on the state of the autonomous nervous sptrtii ol’ the I)atientz whether he is in it sympathicotonic or in a paras-lrtpatliicotolti(~ state al the time when procaine is resorbed and acts. This explanation seems supporf.cvl b!- the facl that these ill by-effects arc observed mainly in vcgetativeI,v stigmat~ized persons, by-ctffect which may be responsible for the ill effects not rarely met with in dental practice.
Summary I’lxperiments carried out in cats, narcotized by chloralose, under artificial respiration, registrating blood pressure and intestinal movements, while administcring nontoxic procaine dosages intravenously under different conditions are reported. Procaine causes sensitization of the cffector organs t>o suprarenin, similarly to cocaine and to some other agents. This sensitizing effect of procaine is not present in isolated organs. Kcsides lowering the blood pressure slightly, procaine increases intestinal nlot i lit?- in a c~onsiderablc degree. RclativelJ- slight procaine dosage causes Iwrist alsis to start after paralyzin, Q intestinal movements by at,ropine. This cffcct of procaine may have therapeutic usefulness. Procaine imitates, or esceptionnlly lengthens? the effect of suprarenin or awt~lcholine given previously. This imit,at,ion effect is proportional to the procainc desagc used. RJ- this imitation effect, individual variations of ill effects ai’tw l)rocainc inject,ions which OCCLII’ in dental practice are explained.
References 1. 2. ::. 4. is. 6. i.
s. 9. IO. Il. 1”. 1:;. II. I .r. Ifi.
Uri, .J., and A~ller, P.: Current, Researches in hnesth. & Analg., l!i-LS, in press. Rchweiz. I\lon:ttschr. Zahnh. 57: 1, 1947. Hchmutziger, B., and Wolfner, I’.: Burgen, A. S. V., and Keele, C. A.: d. Pharnmcol. 3: 128, l!M. T’ri, J., and Adler, P.: Ztschr. f. \~itaminforsrh., in press. Mae&, T.: Nagasaki Igakwai Zassi 12: 591, l!)U. Uorssuck, P.: Diss. Tiihingen, p. 27, 1!1:1.5. Xoller, K. 0.: Arch. Internat. de pharmacodyn. et (le thfiY>Lp. 57: 51, 1X:7. 8: 384, 19lfi. Hatcher, R. A., and Eggleston, C.: d. Pharmacol. Sternberg, H.: Arch. exp. Phxrnr. Thc.r. 100: 112, 1923. I,angecker, H.: Sehmiedebergs Arch. 129: !NZ, 19%. Sendrail, II., Katuruz, K., and ‘J’amulet. T,. I.: C’ompt. rend. Sot. de biol. 139: 198, 1939. Arch. Internat. de pharmxcod,vn. et de thbrap. 75: 31011~1, I<. O., and Stefansson, K.: 25. 19::i. I\r:~cgregor. 1). 1.: .I. Ph:umwol. 66: :\O:; I!)::!,. press. T-ri. J., :tn~l Adler, f’.: Klin. Wchnwhr.,‘in (;oilr;trtl, P.: (‘ompt. rend. Sot. tie Hiol. 118: 689, 1!):{.5. \Vic~nr:lllrl, 0.: Ztscllr. f. (1. ges. c’sl”I’. 1Ietl. 40: :ifi!b, l!lL!1.
and
SOME BY-EFFECTS
Therapeutics OF PROCAINE
P
ROCAINE is the most frequently used local anesthetic; its mode of act,ion is, nevertheless, not yet clarified definitely. Being aimed to add to the solution of this problem, pharmacological effects of disintegrat,ed (discolored) procaine solutions were examined by w.~ Of our results in this connection one deserves being mentioned: discolored procaine solutions have a decreased capacity to produce anesthesia, and in addition their toxicity becomes increased. For this reason the use of discolored procaine solutions (yellowish tint) is objectionable. In order to avoid mistakes, uncolored glass should be used for the ampoules made to contain preparations of procaine for the trade. In these examinations, for comparison’s sake, freshly prepared procaine In these solution was injected intravenously into our experimental animals. experiments we observed some effects not reported elsewhere in the literature. These seem to us worthy of publication. Experiments were carried out on cats of 2-3 kilogram weight, under narHood cosis by means of chloralose (0.10 g./kg.), with art,ificial respiration. pressure in the carotid artery was directly measured by a mercury manometer, and intestinal movements were regist,rated by the balloon method. In some animals epinephrcctomy, in ot,hers decapitation, using Elliot’s method, was carried out. Drugs to be examined were injected intravenously. Dosage of procaine was lower than the minimal toxic one to the respirat,ory and vasomotor center, according to data of Schmutzigcr and Wolfner. * The maximal dosage applied amounted to 0.5 ml. of a 4 per cent solution, but in most instances 0.5 ml. of a 2 per cent This solution was used, containing 20 respectively 10 mg. per cent procaine. dosage is surely atoxic since by procaine-esterase 30 mg. are decomposed” in the living organism within five minutes. Between repeated injections there was a 1)ause of minimally ten minutes in OUI’ csperiments. In order to procure chanping conditions suprarcnin (0.5-5.0 y), acetylcholine (0.05-10.0 y), and atropine snlfat,c (10 mg./kg.) were gircn. :\I1 drugs were dissolvcd in! and diluted by isotonic salt solution. Wc were surprised to find that if procaine is injected just before the injcct,ion of snprarenin, the suprarenin causes a more marked rise in blood pressure than if given without preinjecting procaine. It seems that by procaine, the t+xn the Pharmacological Institute and from the Stomatolosical (:linic of the TJniversity. Ik~brecen, Hungary. Keceiocd Cor publication Oct. 5. 1948. Specialist in Stomatology. *zAssistant of the Phnrnxwological Institute, **Assistant professor of Orthodontics, Head of the Stomntr)lwical Clinic.
201
This is in an apparent contradiction to suprarenin effects become sensitized. even modern textbooks of pharmacology; for this reason experiments wwc rcpcatedly carried out on ten cats. First of all, normal reactions to suprarcnin were checked; tllrn an qua1 dose of suprarenin was given after injecting procaine preriously. In all experiments a marke(l rise of the Mood pressure OCbudged. In Fig. 1, II the rise of the hIooc~ J)rcSSLll’(: caused h)- 0.5 y SLlpJ~arellill But. if this cpinephrine dosage is given after is shown. Tt amounts to ?.‘, ni~n. a previous inject,ion of 10 trig. procaine. the rise of the l~lood prcssurr amounts to 35 mm. as shown in Fig. 1, 71. Tn order to ohtain this effect, suprarenin has to he injected while the blood pressure lowering cffcct, of the procaine is present K?- increasing the dosage of procaine and/or cI)inephrine, the a fore descrihetl effect becomes mow marked, TnjectioJl , of 20 ~llg. Jwocxille Causes riot OJllp ii snore niarked rise of the blood ~)ressuw hut is also maintaining this higher level for a longer time. ‘1’1~ sensitization to snprarenin ly procaine is to he seen in animals after atropine premcdicat ion. a ftcr clew pitation, and after epinephrccAtropine prcmedication decrcascs the sensitizing effrct, while after epitolrl~~. rirphrectom~ the effect is considerably mow ~tmk.2l. In the l~loocl pressure vlll’v(~ the JlIiJSiIJJlllJl inCWilsc~ is maintained for sonic t,ime in most animals. By thcsc experiments it is proved that procaine, similarly to some othr tlrugs and 1)iologic agents such as cocaine. calcium ions, aI!-ceroJ,hosphatc. lecithin, albumin, peptones, some amino acids. tll.woxin, and under wrtain cow ditions cve~i awl)-lcliolines is capable of sensitizin g t lie organisril to suprarenin dfCdS.4 Tllis contradicts SOJJIC statements in the literature whic>h den>- the sensitizing of atlrinciyic cffwtors lgr J)KW’iliIlC being diffcJwt fro111 wwainc.5~ 6* ’ (‘ont,radicltoi,~ rwults were ohtninccl in cspcrimc~iitation with isolated organs. which is I’C’~iil*tl(‘tl t 0 he an unsuitahlc mctliod 01’st iltlying I)rocaine effects. Sonic ideas ma\- h gined h>- incrrasiJlg the SlJpl’~lJ’WiIl c~ffwls with proraiJJe.“2 ‘. “I The findings which confirm the reslllts ot’ Rtwr7rnil nntl collaborators.” of NoZlc~ ;lJlti ~~fPff~?LSSO)t.‘”Of .l/C/C[/W{]O/-,I” who 1ia1.c demonstrated a g~aratf.7 rise of 111~ blood sugar lIJV injecting 20 Jlig. pJ*ocainc before 1 II(I Sll~~l’ilrc~J~iIJ, Swnle~~ not Suficicnl. t 0 stress cmphatic;ill\- that l)rocainc is cal);ll)lc of itlcrcasinp the susceptiI)ility of adrinrrgic wlls, whrrehy reactions to srlprarcnin lwwnc nlorc Inarkcd. .Iccordinp to Our’ ~~SJK’l~iJllf3lts illltf eOJltl’aJ*)~ to I’OJ.JJJPV b?Iit’l’. ii is to 1~ slrcssed that t4fectors arc sensitized to suprarrnin 1)~ ~)l’W;lilJC. LI se~~md ohsrrration worth ment,ionin g is i-lie irritative action of procaine whicdll is 11loJ*c Jnil &cd than the action ohtaincd 111)or1intrstinal morcw~eJltS,” with acet~lcholint. Tn Fig. 2 the action of 10 mu. procaine is shown to effect an increasctil tonicit~ and :I storJrr;\JWriStakiS. Tn the same animal 0.05 7 acetylcholine hacl l~a.dly any t~ff’wt. T’rocaillc action upon the intestines is most Inarked iI1 wmhination wit 11 iI longer-lasting lowering of the blood pressure by aftn. t11c drug. The pi’ncainc cffwt on the intestines is prrsent also in allilllah Aficr irtllllitiistr~ilion 01’ ;I high al ropin(l tlosage premrtlication wilh atrol)inc. ilO mg./kg.), ac,c~l!-lclloliiic~ is 1101 ca1)al)lc ol’ wusing intestinal niovement if ziV(JJl iJ1 1 llt?l~il~)(LLlt iv tlOS:lp(~ : it (~:lllS~~s sli~llt nlovc~l~cnts ill cstrcrlJely high dosage only 110 71. Tn thr same animals, 10 mg. procaine caused an increased t,onieity of the intcstincs. and 20 mg. procaine caused peristalsis to start again (Fig. 3,
This observation may have some 1)rac.ticnl inrlwrt anc(x. The intestinal byeffects of procaine were present if int txvcnous injections wwc itratle unintciitionally. Care should he taken about this Iry-cffcct if l)rocainc is administered intentionally l)y the intravenous method to cause analgesia or to stop cardiac arrhythmia. I~‘urthermore, the eventual therapeutic use of procaine to check intestinal paralysis has also to be taken into considcrat,ion. This possible use of procaine is supported lg- csperimental ohservat,ions of Goi7l~7yi~” : when injccting a sublethal procaine dose to dogs, among other synlptonls, intensive dcf’eration takes place. It might he possible to product, 1)~.some strnc~tural change 01 procaine molecules, a new ehcmieal comlmnnd, l)cthal)s Tyitll diminished anesthetic quality hlxt with all ill~UWWt1 avtivit)up011 illt(~Stillill nlox-etllfwts.
WC observed, furthermore, that it’ procaine was administered after application of snprarenin, it did not cause-contrary to the usual reaction-a lowering of I)lood pressure, but had cithcr no effect, whatever upon it or cawed a, slight rise. Twent,y mg. procaine injected during the duration of thr action of 0.5 7 suprarenin caused further rise of blood pressure while in SC it caused a drop (Fig. 4). Similar effects mere observed in dogs by l\7iewwnv~.16 This cffcct may be called “ imitation effect. ” If administered after constant tlosagcs of suprawnin, the effect is proportional to the procaine dosage ; it is only to be obscrvetl if procaine is admiiiistcrcd while suprawnin effects aw prcscnt. TlltJ 1110s!
Fig. 3.-intestinal ication. a, Action
motility, upper of acetylcholine
curve, and blood presmre, lower curve. after atropine preme(l: b, action of 10 mg. procaine : c, action of 20 mg. wocaine.
marked procaine effect is to be observed if the drug is given when suprarenin effects begin to fade away. After suprarenin effects have subsided, procaine causes a slight decrease of the blood pressure again. The imitation effect is best seen in cats during spring; from this fact we conclude that the state of’ the autonomous nervous system has a considerable influence upon it. Besides supraIf given renin, procaine imitates acetylcholine too, though not so regularly. after previous acetylcholine application, in several animals, hut not in all, pro-
206
.I.
IJlU
\SD
I’.
\DLF:t:
action it is resorbed. ivhat by-effect of procaine incomes manifest depends on the state of the autonomous nervous sptrtii ol’ the I)atientz whether he is in it sympathicotonic or in a paras-lrtpatliicotolti(~ state al the time when procaine is resorbed and acts. This explanation seems supporf.cvl b!- the facl that these ill by-effects arc observed mainly in vcgetativeI,v stigmat~ized persons, by-ctffect which may be responsible for the ill effects not rarely met with in dental practice.
Summary I’lxperiments carried out in cats, narcotized by chloralose, under artificial respiration, registrating blood pressure and intestinal movements, while administcring nontoxic procaine dosages intravenously under different conditions are reported. Procaine causes sensitization of the cffector organs t>o suprarenin, similarly to cocaine and to some other agents. This sensitizing effect of procaine is not present in isolated organs. Kcsides lowering the blood pressure slightly, procaine increases intestinal nlot i lit?- in a c~onsiderablc degree. RclativelJ- slight procaine dosage causes Iwrist alsis to start after paralyzin, Q intestinal movements by at,ropine. This cffcct of procaine may have therapeutic usefulness. Procaine imitates, or esceptionnlly lengthens? the effect of suprarenin or awt~lcholine given previously. This imit,at,ion effect is proportional to the procainc desagc used. RJ- this imitation effect, individual variations of ill effects ai’tw l)rocainc inject,ions which OCCLII’ in dental practice are explained.
References 1. 2. ::. 4. is. 6. i.
s. 9. IO. Il. 1”. 1:;. II. I .r. Ifi.
Uri, .J., and A~ller, P.: Current, Researches in hnesth. & Analg., l!i-LS, in press. Rchweiz. I\lon:ttschr. Zahnh. 57: 1, 1947. Hchmutziger, B., and Wolfner, I’.: Burgen, A. S. V., and Keele, C. A.: d. Pharnmcol. 3: 128, l!M. T’ri, J., and Adler, P.: Ztschr. f. \~itaminforsrh., in press. Mae&, T.: Nagasaki Igakwai Zassi 12: 591, l!)U. Uorssuck, P.: Diss. Tiihingen, p. 27, 1!1:1.5. Xoller, K. 0.: Arch. Internat. de pharmacodyn. et (le thfiY>Lp. 57: 51, 1X:7. 8: 384, 19lfi. Hatcher, R. A., and Eggleston, C.: d. Pharmacol. Sternberg, H.: Arch. exp. Phxrnr. Thc.r. 100: 112, 1923. I,angecker, H.: Sehmiedebergs Arch. 129: !NZ, 19%. Sendrail, II., Katuruz, K., and ‘J’amulet. T,. I.: C’ompt. rend. Sot. de biol. 139: 198, 1939. Arch. Internat. de pharmxcod,vn. et de thbrap. 75: 31011~1, I<. O., and Stefansson, K.: 25. 19::i. I\r:~cgregor. 1). 1.: .I. Ph:umwol. 66: :\O:; I!)::!,. press. T-ri. J., :tn~l Adler, f’.: Klin. Wchnwhr.,‘in (;oilr;trtl, P.: (‘ompt. rend. Sot. tie Hiol. 118: 689, 1!):{.5. \Vic~nr:lllrl, 0.: Ztscllr. f. (1. ges. c’sl”I’. 1Ietl. 40: :ifi!b, l!lL!1.