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Studies on Local Anesthetics XXI*
Studies on Local Anesthetics XXI* Some Derivatives of w-Diethylaminoacetanilide By ALOIS BOROVANSKY, ALES SEKERA,t and CENiK VRBA: The preparation, surface, and infiltration activities and the toxicity of diethylaminoacetanilide and seven of its derivatives are described.
We studied Ibamicchieflyacids.the Bybasicappropriate esters of substituted carstructural modiN
OUR
EARLIER
PUBLICATIONS
fications we succeeded in preparing several very active, often slightly toxic compounds (1, 2). Several of these, in spite of their very favorable therapeutic index, proved themselves unsuitable for clinical trials because of their poor local tolerance (irritation). From the supposition that this undesirable property results chiefly from the formation of aromatic amine by the metabolism of the active carbanilate, we began studies of the substances, structures of which allowed us to suppose that the formation of aromatic amine would be decreased and, eventually, completely excluded. In the choice of new structural types, in order to be able even in these new series to apply our knowledge of relations between the structures, the physicochemical properties, and the anesthetic activity of the basic carbanilates, we have knowingly directed our attention to the compounds having structures similar to the substances previously studied. Our first work in that area was the preparation of basic alkoxy-propiophenones of the Falicaine series (3,4) and of basic carbanilates ( 5 , 6) of which the stability was augmented by (group -NH.COO-) the methylation of the benzene nucleus. Continuing these studies, we decided to direct our attention to a closely related series-the basic anilides, on the supposition that the group A r N H C 0 . R would be more slowly metabolized in the alkaline medium of human tissue than the Ar.NH.CO0.R group. For the fundamental orientation in this new series, we prepared eight derivatives of type 11; the description of the preparation and the results of the pharmacological experiments make the subject o f this com*Received October 8 , 1958, from The Department of Pharmaceutical Chemistry, Masaryk University. Brno, Czechoslovakia. Paper XX of this series: Chem. listy. 51 2339(1937). t Inquiries on this paper should be direkted to A. Sekera. Present address: Service de Chimie, Laboratoire de Pharmacologie. 21 rue de I'Ecole de Medecine. Paris V I P , France. $ Department of Pharmacology, Schoo! of X'eterinary N e d cine, B m o . Czechoslovakia.
TABLE I .-SUBSTITUTED CHLOROACETANILIDBS
Yield, No.
RI
Rz
1 2 3
H CH: CH, CHI H C4H90 H H
H H CHI CH3 H
4
5 6 7 8
H H H
Ra
R1
H H H H H H 4-CH3 H H C6H5 H H 3-CgHeOH 4-ChHeOH
%
M. P . .
'c.
79 78 79 74
135" 108-109' 142c 172J 90 119-121" 96 54' 8% 94-99 96 1 2 3 ~ 1 2 5 ~
munication. Some substances have already been described in the literature (7-9) but nevertheless we have included them in our series in order to be able to study all together, utilizing the same pharmacological technique. The structure of the substances studied can be seen in Table 11. For their preparation we have utilized the method (8) starting from the corresponding aromatic amines which, passing through the chloroacetanilides (I), have supplied, in the reaction with diethylamine, the final basic anilides. EXPERIMENTAL'
Mesidine.-This was prepared (5) by the catalytic hydrogenation of nitromesitylene over Raney nickel (initial pressure 30 Atm.). Butoxyanilines.-A similar mode of reduction w a s 1 All melting points were determined on a Kofler block and are corrected. Microanalyses were carried out by Mrs. Kleinovi-Parolkova.
SCIENTIFIC EDITION
July 1959
403
TABLE II.-SUHSTITUTED DIETHYLAMINOACETANILIDES
__
- ~ _ _
~
NO.
s 201
s 202 S 203 s 210 s 220 s 221 s 222
Ri H CH3 CHI CHI H CiHsO
H H
R? H H CH 3 CH3 H H H H
R3
H
R*
Yield,
H H H H CsHa
H H 4-CHa H H H 3-CiH90 H 4-CiH00 H
72 59 61 66 88 56 45 53
b. p..
"C./mm. 140-141/1.5a 141 5 / 0 . e b l59/ld 154-155/0.G' 175/lh 182-183/@.7 18fi-187/0.5 185/0.5i
HvdrochlorideN c1 Found, Calcd., Found,
7-
__
Base--
s 200
--
~
~
m. P . , OC. ,
... 70d
...
...
... 43-45
m . p.. Calcd., 70 OC. 108-109 11.54 120-122c 10.91 11G-1186 9.70 140" 9.84 145-14Bi 8.79 118-120 8.90 123-125 8.90 152-15qk 8.90
%
%
"?o
11.38 10.99 9.62 9.94 8.49
14.61 13.81 12.28 12.45 11.12 11.26 11.26 11.26
14.39 13.77 12.24 12.47 11.36 11.14 11.14 11.10
8.80 9.10 8.78
Literature (7) b. p. 116-117"/0.15 mm. b Literature (7) b. P. 159-1GOo/0.1 mm. C From acetone. d Literature (8) b. p 159-16O0/2 mm.. m. p. 87'. Sample for analjtsis dried over PzOs by 110°/0.2 mm. Anal.-Calcd. for C14HzaONzCl.H20 (288.8): C, 58.22; H , 8.02. Found: C , 58.51, H , 8.39. Even after prolonged drying under these conditions we were not able to prepare the anhydrous hydrochloride, described by Lofgren. I Literature (8) b. p. 155-156O/0.6 mm. 0 From acetone. Sample for analysis dried over PzOs by 110°/0.2 mm. Literature (8) m. p. 136-13i". h Literature (8) b. p. 194"/3 mm. i And-Cal for C1sHza0NzCl(318.9): C. 67.80; H, 7.27. Found: C, 67.70; H, 7.31. i Literature (9) b. p. 186"/0.5 mm. k Literature m. p. 153'.
8
used in the preparation of these substances from the aromatic nitro-derivatives n hich were synthetized using the method described in one of our previous communications (1). Chloroacetanilides (I).-In a solution of 0.3 mole of aromatic amine in 180 cc. anhydrous acetone 60 Gin. (excess ca. 80y0) of the acid chloride of monochloroacetic acid was introduced in small portions. The reaction conipleted, the mixture was, after one hour of settling, poured into 300 cc. of hydrochloric acid (8%). The crystals of the chloroacetanilide were separated after twenty-four hours and washed free of acid. The N-chloroacetyldiphenylamine was prepared from the diphenylamine and the chloride of the monochloroacetic acid in boiling toluene (8). The samples for analysis were recrystallized from diluted alcohol. The yields and constants of the prepared products are reported in Table I. Diethylaminoacetanilides (I1 ; S 200-5 222).0.2 Mole of chloroacetanilides v. as refluxed for six hours with 37 Gm. (0.5 mole) of diethylamine in 100 cc. of anhydrous benzene. The hydrochloride cf diethylamine formed in the reaction was filtered off and the benzene solution washed twice with two 50-cc. portions of water. The solvent was removed by distillation. The residue was dissolved in 100 cc. of hydrochloric acid (lo%), and the solution extracted twice by 70 cc. of ether. The acid solution was made alkaline by treatment with ammonia solution in order to liberate the base. This was extracted by ether (four times, 50 cc.) and the ethereal solution, dried on sodium carbonate, was fractionated. The substance S 210 was prepared in anhydrous ether by heating for four hours (8). The hydrochlorides were prepared in anhydrous ether. In the case of substance S 202 the isolation of a better defined crystalline base proved advantageous. The yields, constants, and analyses of t h e prepared substances are collected in Table 11.
PHARMACOLOGY The relative activity of the compounds in surface anesthesia (rabbit cornea, M/100 cocaine as standard) and infiltration anesthesia (intradermal application t o guinea pigs, M/50 procaine as standard) was calculated from the molar concentration, experimentally found t o give the same effect as the standard. The method has been described in detail by Vrba and Sekera (10) and Roth (11). The toxicity was studied according to the method of Karber (12) by determining the LDw in white mice (strain H) by subcutaneous injection. The units are presented in Table 111.
DISCUSSION AND SUMMARY The preparation and the results of the tests of surface and infiltration anesthesia and t h e toxicTABLE III.-PHARMACOLOGY OF SUBSTITUTED DIETHYLAMINOACETANILIDES ----Relative Substance
s 200 s 201 s 202
(Sylocaine) S 203 (Mesokain) 210 s-~220 s 221 s 222 Cocaine Procaine
s
Surface .4nesthesia
.4ctivity-~ InfiltraLDra tion s. c . Anesthesia mg./Kg.
0.12
890
0.24 1.4
450 365
1
2.5
295
0.03 0.58 7.5 3 1 0.15
7.4 0.2 9 5.5 3.6 1
290 1 ,930 170 550 125 630
Incomplete anesthesiaB
After application of M/3 solution. bAfter application of 64/3 solution complete anesthesia of .4.5 =t2 minutes. 2 We are obliged to Miss M. Pernikovd and I. RBtickovl for technical assistance with the pharmacological tests.
JOURNAL OF THE AMERICANPHARMACEUTICAL ASSOCIATION Vol. XLVIII, No. 7
404
ity of eight basic anilides of the Xylocaine series have been described. The compounds have been shown to be effective in both surface and infiltration anesthesia; some of these have been found to be more active than the standards, namely, cocaine and procaine. The following correlation between molecular structure and pharmacodynamic action (Table 111) can be made: 1. The methylation of the benzene nucleus of diethylaminoacetanilide in the ortho position increases the surface and infiltration anesthetic activities. This augmentation of anesthetic effect can perhaps be explained, in addition to the influence of the physicochemical properties, by the increased stability of the anilidic group (Ar .NH’CO’R), which we have already mentioned in a previous communication (6). 2. As a result of the comparison of the effectuated tests of the activity and toxicity, it would seem that Mesokain (S 203) is more advantageous than Xylocaine (S 202). 3. Interesting also is the derivative S 210 which is seven times more active than procaine in surface anesthesia and is only twice more toxic. Surprising is its slight activity in surface anesthesia. 4. Butoxylation of the benzene nucleus of
diethylaminoacetanilide increased surface and infiltration anesthetic activity in the series ortho < para < metu. Parallel to this can be noticed an increase in the toxicity. The most advantageous therapeutic index is that of substance S 222 which is three times more active than cocaine in surface anesthesia, five and one-half times more active than procaine in infiltration anesthesia, and only slightly more toxic than procaine. REFERENCES (1) Sekera, A,, Borovanskf, A,. Jakubec, I., PalBt, K., and Vrba, C‘eskosloo. farm., 5 , 388(1956). (2) Pallt, K., Sekera, A,, and Vrba, Chem. listy, 51, 563( 1957). (3) Eeladnlk. M.,Pallt, K., Sekera, A,, and Vrba, E., Arch. Pharm.. 290. 194(1957). (4) celadkk, M., Pal&K.. Sekera, A,, and Vrba, E.. ibid., 291, 3(1958). (5) Sekera. A,, and Vrba. ibid., 291, 122(1958). (6) Sekera, A,, Sova, J., and Vrba, E., Exgerientia, 11, 275( 1955). (7) Erdtman, H., and Ldfgren, N., Suensk Kem. Tidskr., 49, 163(1937). ( 8 ) Lafgren. N., Arkio Kemi, Mineral. Geol., 22A, 1 (1946). (9) Biichi J. Lauener G. Ragaz L. Bdniger. H., and Lieberherr, R:, H c l u . Chim: Acia. 34. 2?8(i951). (10) Vrba, E . , and Sekera, A,, Arch. intern. gharmacodynamie, 118, 155,1959) (11) Roth, Z.,h i d . , 118, 289(1959). (12) Kiirber G. in Burn J. H. Biologische Auswertungsmethoden,” Sdringer, Berlih, 193?, p. 27. (13) Dimroth 0. Ber. dcut. chem. Gcs. 35 4052(1902). ~. (14) MotylewLki,’2..Bull. intern. acab. &on. sci., 1926,
c..
c.,
c.,
Y3.
(15) Ldfgren, N., “Xylocaine, A New Synthetic Drug,” Ivar HoeggstrBms Boktryckeri A. B., Stockholm, 1948. (16) Frerichs, H., Arch. Pharm., 241, 220(1903).
A Comparison of the Hypotensive Effects of the Monophosphoric Acid Ester of Thiamine and Thiamine Hvdrochloride* J
By NATHAN WATZMANt, JOHN J. DeFEO$, and JOSEPH P. BUCKLEY The hypotensive‘ effects of the monophosphoric acid ester of thiamine (RO 1-4788) and thiamine hydrochloride were investigated in anesthetized rats and dogs. The depressor effect of thiamine h drochloride was 40.8% greater than that o r R O 1-4788 in the rat and 42.8% greater than RO 1-4788 in the dog.
thiamine hydrochloride has Ician.created a new problem for the practicing physiClinicians (1-3) have reported that paN RECENT YEARS
renterafly administered thiamine hydrochloride has produced peripheral circulatory collapse and a shock syndrome similar to that produced by vasodepressors and allergenic agents. Reingold and
* Received December 11, 1958, from the University of Pittsburgh. Schoo! of Pharmacy, Pittsburgh, Pa. This mvesbgation was supported in part by a research grant from Hoffmann-LaRoche, Iuc.. Nutley, N. J. t George A. Kelly, Sr.. Fellow. Present address: School of Pharmacy, University of Rhode Island. Kingston.
Webb (4) reported a death following an intravenous administration of 100 mg. of thiamine hydrochloride. Laboratory investigators have corroborated these findings in many species of animals ( 5 6 ) . Mazzella (7) reported that 50 mg./Kg., i. v., of thiamine hydrochloride produced arterial hypotension and bradycardia in the sympathectomized dog. These effects were still evident even after ganglionic blockade with tetraethylammonium chloride or adrenergic blockade with dibenamine indicating the possibility of a direct vascular depressant action. Smith, et al. (5), demonstrated, through perfusion of the mesenteric and femoral arteries of the dog and the isolated ear vein of the rabbit, that the vasodilatory property of thiamine hydrochloride was not necessarily a direct peripheral action but possibly central, involving depression of the vaso-
We studied Ibamicchieflyacids.the Bybasicappropriate esters of substituted carstructural modiN
OUR
EARLIER
PUBLICATIONS
fications we succeeded in preparing several very active, often slightly toxic compounds (1, 2). Several of these, in spite of their very favorable therapeutic index, proved themselves unsuitable for clinical trials because of their poor local tolerance (irritation). From the supposition that this undesirable property results chiefly from the formation of aromatic amine by the metabolism of the active carbanilate, we began studies of the substances, structures of which allowed us to suppose that the formation of aromatic amine would be decreased and, eventually, completely excluded. In the choice of new structural types, in order to be able even in these new series to apply our knowledge of relations between the structures, the physicochemical properties, and the anesthetic activity of the basic carbanilates, we have knowingly directed our attention to the compounds having structures similar to the substances previously studied. Our first work in that area was the preparation of basic alkoxy-propiophenones of the Falicaine series (3,4) and of basic carbanilates ( 5 , 6) of which the stability was augmented by (group -NH.COO-) the methylation of the benzene nucleus. Continuing these studies, we decided to direct our attention to a closely related series-the basic anilides, on the supposition that the group A r N H C 0 . R would be more slowly metabolized in the alkaline medium of human tissue than the Ar.NH.CO0.R group. For the fundamental orientation in this new series, we prepared eight derivatives of type 11; the description of the preparation and the results of the pharmacological experiments make the subject o f this com*Received October 8 , 1958, from The Department of Pharmaceutical Chemistry, Masaryk University. Brno, Czechoslovakia. Paper XX of this series: Chem. listy. 51 2339(1937). t Inquiries on this paper should be direkted to A. Sekera. Present address: Service de Chimie, Laboratoire de Pharmacologie. 21 rue de I'Ecole de Medecine. Paris V I P , France. $ Department of Pharmacology, Schoo! of X'eterinary N e d cine, B m o . Czechoslovakia.
TABLE I .-SUBSTITUTED CHLOROACETANILIDBS
Yield, No.
RI
Rz
1 2 3
H CH: CH, CHI H C4H90 H H
H H CHI CH3 H
4
5 6 7 8
H H H
Ra
R1
H H H H H H 4-CH3 H H C6H5 H H 3-CgHeOH 4-ChHeOH
%
M. P . .
'c.
79 78 79 74
135" 108-109' 142c 172J 90 119-121" 96 54' 8% 94-99 96 1 2 3 ~ 1 2 5 ~
munication. Some substances have already been described in the literature (7-9) but nevertheless we have included them in our series in order to be able to study all together, utilizing the same pharmacological technique. The structure of the substances studied can be seen in Table 11. For their preparation we have utilized the method (8) starting from the corresponding aromatic amines which, passing through the chloroacetanilides (I), have supplied, in the reaction with diethylamine, the final basic anilides. EXPERIMENTAL'
Mesidine.-This was prepared (5) by the catalytic hydrogenation of nitromesitylene over Raney nickel (initial pressure 30 Atm.). Butoxyanilines.-A similar mode of reduction w a s 1 All melting points were determined on a Kofler block and are corrected. Microanalyses were carried out by Mrs. Kleinovi-Parolkova.
SCIENTIFIC EDITION
July 1959
403
TABLE II.-SUHSTITUTED DIETHYLAMINOACETANILIDES
__
- ~ _ _
~
NO.
s 201
s 202 S 203 s 210 s 220 s 221 s 222
Ri H CH3 CHI CHI H CiHsO
H H
R? H H CH 3 CH3 H H H H
R3
H
R*
Yield,
H H H H CsHa
H H 4-CHa H H H 3-CiH90 H 4-CiH00 H
72 59 61 66 88 56 45 53
b. p..
"C./mm. 140-141/1.5a 141 5 / 0 . e b l59/ld 154-155/0.G' 175/lh 182-183/@.7 18fi-187/0.5 185/0.5i
HvdrochlorideN c1 Found, Calcd., Found,
7-
__
Base--
s 200
--
~
~
m. P . , OC. ,
... 70d
...
...
... 43-45
m . p.. Calcd., 70 OC. 108-109 11.54 120-122c 10.91 11G-1186 9.70 140" 9.84 145-14Bi 8.79 118-120 8.90 123-125 8.90 152-15qk 8.90
%
%
"?o
11.38 10.99 9.62 9.94 8.49
14.61 13.81 12.28 12.45 11.12 11.26 11.26 11.26
14.39 13.77 12.24 12.47 11.36 11.14 11.14 11.10
8.80 9.10 8.78
Literature (7) b. p. 116-117"/0.15 mm. b Literature (7) b. P. 159-1GOo/0.1 mm. C From acetone. d Literature (8) b. p 159-16O0/2 mm.. m. p. 87'. Sample for analjtsis dried over PzOs by 110°/0.2 mm. Anal.-Calcd. for C14HzaONzCl.H20 (288.8): C, 58.22; H , 8.02. Found: C , 58.51, H , 8.39. Even after prolonged drying under these conditions we were not able to prepare the anhydrous hydrochloride, described by Lofgren. I Literature (8) b. p. 155-156O/0.6 mm. 0 From acetone. Sample for analysis dried over PzOs by 110°/0.2 mm. Literature (8) m. p. 136-13i". h Literature (8) b. p. 194"/3 mm. i And-Cal for C1sHza0NzCl(318.9): C. 67.80; H, 7.27. Found: C, 67.70; H, 7.31. i Literature (9) b. p. 186"/0.5 mm. k Literature m. p. 153'.
8
used in the preparation of these substances from the aromatic nitro-derivatives n hich were synthetized using the method described in one of our previous communications (1). Chloroacetanilides (I).-In a solution of 0.3 mole of aromatic amine in 180 cc. anhydrous acetone 60 Gin. (excess ca. 80y0) of the acid chloride of monochloroacetic acid was introduced in small portions. The reaction conipleted, the mixture was, after one hour of settling, poured into 300 cc. of hydrochloric acid (8%). The crystals of the chloroacetanilide were separated after twenty-four hours and washed free of acid. The N-chloroacetyldiphenylamine was prepared from the diphenylamine and the chloride of the monochloroacetic acid in boiling toluene (8). The samples for analysis were recrystallized from diluted alcohol. The yields and constants of the prepared products are reported in Table I. Diethylaminoacetanilides (I1 ; S 200-5 222).0.2 Mole of chloroacetanilides v. as refluxed for six hours with 37 Gm. (0.5 mole) of diethylamine in 100 cc. of anhydrous benzene. The hydrochloride cf diethylamine formed in the reaction was filtered off and the benzene solution washed twice with two 50-cc. portions of water. The solvent was removed by distillation. The residue was dissolved in 100 cc. of hydrochloric acid (lo%), and the solution extracted twice by 70 cc. of ether. The acid solution was made alkaline by treatment with ammonia solution in order to liberate the base. This was extracted by ether (four times, 50 cc.) and the ethereal solution, dried on sodium carbonate, was fractionated. The substance S 210 was prepared in anhydrous ether by heating for four hours (8). The hydrochlorides were prepared in anhydrous ether. In the case of substance S 202 the isolation of a better defined crystalline base proved advantageous. The yields, constants, and analyses of t h e prepared substances are collected in Table 11.
PHARMACOLOGY The relative activity of the compounds in surface anesthesia (rabbit cornea, M/100 cocaine as standard) and infiltration anesthesia (intradermal application t o guinea pigs, M/50 procaine as standard) was calculated from the molar concentration, experimentally found t o give the same effect as the standard. The method has been described in detail by Vrba and Sekera (10) and Roth (11). The toxicity was studied according to the method of Karber (12) by determining the LDw in white mice (strain H) by subcutaneous injection. The units are presented in Table 111.
DISCUSSION AND SUMMARY The preparation and the results of the tests of surface and infiltration anesthesia and t h e toxicTABLE III.-PHARMACOLOGY OF SUBSTITUTED DIETHYLAMINOACETANILIDES ----Relative Substance
s 200 s 201 s 202
(Sylocaine) S 203 (Mesokain) 210 s-~220 s 221 s 222 Cocaine Procaine
s
Surface .4nesthesia
.4ctivity-~ InfiltraLDra tion s. c . Anesthesia mg./Kg.
0.12
890
0.24 1.4
450 365
1
2.5
295
0.03 0.58 7.5 3 1 0.15
7.4 0.2 9 5.5 3.6 1
290 1 ,930 170 550 125 630
Incomplete anesthesiaB
After application of M/3 solution. bAfter application of 64/3 solution complete anesthesia of .4.5 =t2 minutes. 2 We are obliged to Miss M. Pernikovd and I. RBtickovl for technical assistance with the pharmacological tests.
JOURNAL OF THE AMERICANPHARMACEUTICAL ASSOCIATION Vol. XLVIII, No. 7
404
ity of eight basic anilides of the Xylocaine series have been described. The compounds have been shown to be effective in both surface and infiltration anesthesia; some of these have been found to be more active than the standards, namely, cocaine and procaine. The following correlation between molecular structure and pharmacodynamic action (Table 111) can be made: 1. The methylation of the benzene nucleus of diethylaminoacetanilide in the ortho position increases the surface and infiltration anesthetic activities. This augmentation of anesthetic effect can perhaps be explained, in addition to the influence of the physicochemical properties, by the increased stability of the anilidic group (Ar .NH’CO’R), which we have already mentioned in a previous communication (6). 2. As a result of the comparison of the effectuated tests of the activity and toxicity, it would seem that Mesokain (S 203) is more advantageous than Xylocaine (S 202). 3. Interesting also is the derivative S 210 which is seven times more active than procaine in surface anesthesia and is only twice more toxic. Surprising is its slight activity in surface anesthesia. 4. Butoxylation of the benzene nucleus of
diethylaminoacetanilide increased surface and infiltration anesthetic activity in the series ortho < para < metu. Parallel to this can be noticed an increase in the toxicity. The most advantageous therapeutic index is that of substance S 222 which is three times more active than cocaine in surface anesthesia, five and one-half times more active than procaine in infiltration anesthesia, and only slightly more toxic than procaine. REFERENCES (1) Sekera, A,, Borovanskf, A,. Jakubec, I., PalBt, K., and Vrba, C‘eskosloo. farm., 5 , 388(1956). (2) Pallt, K., Sekera, A,, and Vrba, Chem. listy, 51, 563( 1957). (3) Eeladnlk. M.,Pallt, K., Sekera, A,, and Vrba, E., Arch. Pharm.. 290. 194(1957). (4) celadkk, M., Pal&K.. Sekera, A,, and Vrba, E.. ibid., 291, 3(1958). (5) Sekera. A,, and Vrba. ibid., 291, 122(1958). (6) Sekera, A,, Sova, J., and Vrba, E., Exgerientia, 11, 275( 1955). (7) Erdtman, H., and Ldfgren, N., Suensk Kem. Tidskr., 49, 163(1937). ( 8 ) Lafgren. N., Arkio Kemi, Mineral. Geol., 22A, 1 (1946). (9) Biichi J. Lauener G. Ragaz L. Bdniger. H., and Lieberherr, R:, H c l u . Chim: Acia. 34. 2?8(i951). (10) Vrba, E . , and Sekera, A,, Arch. intern. gharmacodynamie, 118, 155,1959) (11) Roth, Z.,h i d . , 118, 289(1959). (12) Kiirber G. in Burn J. H. Biologische Auswertungsmethoden,” Sdringer, Berlih, 193?, p. 27. (13) Dimroth 0. Ber. dcut. chem. Gcs. 35 4052(1902). ~. (14) MotylewLki,’2..Bull. intern. acab. &on. sci., 1926,
c..
c.,
c.,
Y3.
(15) Ldfgren, N., “Xylocaine, A New Synthetic Drug,” Ivar HoeggstrBms Boktryckeri A. B., Stockholm, 1948. (16) Frerichs, H., Arch. Pharm., 241, 220(1903).
A Comparison of the Hypotensive Effects of the Monophosphoric Acid Ester of Thiamine and Thiamine Hvdrochloride* J
By NATHAN WATZMANt, JOHN J. DeFEO$, and JOSEPH P. BUCKLEY The hypotensive‘ effects of the monophosphoric acid ester of thiamine (RO 1-4788) and thiamine hydrochloride were investigated in anesthetized rats and dogs. The depressor effect of thiamine h drochloride was 40.8% greater than that o r R O 1-4788 in the rat and 42.8% greater than RO 1-4788 in the dog.
thiamine hydrochloride has Ician.created a new problem for the practicing physiClinicians (1-3) have reported that paN RECENT YEARS
renterafly administered thiamine hydrochloride has produced peripheral circulatory collapse and a shock syndrome similar to that produced by vasodepressors and allergenic agents. Reingold and
* Received December 11, 1958, from the University of Pittsburgh. Schoo! of Pharmacy, Pittsburgh, Pa. This mvesbgation was supported in part by a research grant from Hoffmann-LaRoche, Iuc.. Nutley, N. J. t George A. Kelly, Sr.. Fellow. Present address: School of Pharmacy, University of Rhode Island. Kingston.
Webb (4) reported a death following an intravenous administration of 100 mg. of thiamine hydrochloride. Laboratory investigators have corroborated these findings in many species of animals ( 5 6 ) . Mazzella (7) reported that 50 mg./Kg., i. v., of thiamine hydrochloride produced arterial hypotension and bradycardia in the sympathectomized dog. These effects were still evident even after ganglionic blockade with tetraethylammonium chloride or adrenergic blockade with dibenamine indicating the possibility of a direct vascular depressant action. Smith, et al. (5), demonstrated, through perfusion of the mesenteric and femoral arteries of the dog and the isolated ear vein of the rabbit, that the vasodilatory property of thiamine hydrochloride was not necessarily a direct peripheral action but possibly central, involving depression of the vaso-