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Observations on the mode of action of metrazol in convulsive doses*
Observations on the Moc e of Action of Metrazol in Convuls ive Doses* By MAYNARD MURRAY, C. ROWELL HOFFMANN, and FRED R. SCROGGINS in the guanidine content of t h e blood of epileptics has been reported b y Ellis (1). In a recent communication (2), it was shown that there was not only a slight increase in the basal level of guanidine-like substances in the blood of patients with epilepsy, b u t that there was a synchronous rise in t h e quantity of these substances in the blood with the convulsion (Fig. 1). We were interested t o determine whether this rise in blood guanidine levels occurred in artificially induced fits as well as in spontaneous ones, i.e., whether the guanidine rise
A
N INCREASE
studied. The same method for the determination of guanidine-like substances in the blood was employed as that used in the previous study on idiopathic epileptics. The normal blood guanidine level, and the levels a t periods of one, fifteen, and sixty minutes after injection of metrazol in convulsive doses were ascertained in each case. The results of these determinations are given in Table I. A comparison of the alteration in blood guanidine levels in spontaneous and in metrazol fits is represented graphically in Fig. 1. It will be seen that in this series of metrazol convulsions on ten patients hl1 the values fill within the normal range, as reported by Andes and Myers (3). and that there was no rise in the blood guanidine levels in these fits comparable t o that seen in spontaneous convulsions in idiopathic epileptics. T h e Effect of Metrazol Shock on the Gonads Investigators are generally agreed that many patients with involutional melancholia are improved markedly by metrazol shock therapy. This disorder is commonly considered to be due to a gonadal hormone insufficiency. Since it has been demonstrated by Marshall & Verney (4) that ovulation of
TABLE I.-GUANIDINE VALUE I N MG. % METRAZOL CONVULSIONS
0 .
Patient's No.
Normal Level
One Minute After Metrazol
Fifteen Minutes After Metrazol
Sixty Minutes After Metrazol
16 17 18
0.23 0.27 0.24
0.23 0.25 0.29
19 -_
0.31
0.33 .
20 21 22 23 24 25
0.23 0.26 0.25 0.26 0.28 0.19
0.24 0.25 0.25 0.26 0.27 0.20
0.14 0.26 0.31 0.34 0.24 0.25 0.24 0.27 0.27 0.21
0.21 0.26 0.28 0.32 0.24 0.25 0.23 0.25 0.27 0.20
EPILEPTIC
.= METRAZQL
was a result of the convulsion per se, or whether there was a difference in this biochemical reaction i n the t w o types of fits. T h e Effect of Metrazol Shock on Blood Guanidine' Levels A group of ten patients a t Longview State Hospital who were receiving metrazol shock therapy was
*
Received Nov. 13 1948 from the Physiology Laboratory University of Ci&inna&. This work was done in 1940 but 'interrupted by the authors' service with the Armed Forces. 1 Throughout this article the term guanidine is used in lieu of guanidine-like substances.
IN
~~
central origin through the anterior pituitary may be induced in the rabbit by electrical stimulation of either the cerebrum or the lumbosacral cord, and by convulsions produced by the intravenous injections of picrotoxin (5), the following question occurred: Does metrazol shock exert its beneficial therapeutic effect in these cases by acting directly upon the gonads, or upon gonadotropic secretions of the anterior pituitary gland? An attempt t o answer this question was made. Because of their peculiarly prompt response to estrogens and to gonadotropic anterior pituitary fractions, female rabbits of twelve to fourteen weeks of age were chosen as test animals, since any anterior pituitary gonadotropic principle would in all likelihood cause ovulation (6), while follicular activity would cause endometrial hyperplasia (7).
300
SCIENTIFIC EDITION Twelve female rabbits weighing between 2400 Gm., and 2800 Gm., were given intravenous injections of 0.20 Gm. of metrazol. Immediately the animals were thrown into violent convulsions, lasting between ten and fifteen minutes. With the exception of one animal, which broke several teeth as a result of spasm of the muscles of mastication, no injuries or fractures were observed. Following this, laparotomies were performed on the animals, in groups of three at twenty-four, forty-eight, seventytwo, and ninety-six hours, respectively. The ovaries, tubes, and uteri were removed. In no case did examination show changes in the ovaries such as congestion, enlargement, developing follicles or corpora hemorrhagica or leutes. A study of sections of the uterine mucosa showed no evidence of endometrial hypertrophy. Another group of twelve female rabbits of the same age and weight range were given metrazol convulsions on successive days for seven days, and then forty-eight hours after the last convulsion, laparotomies were performed. In no case were ovarian changes noted, nor were any changes noted in the uterine mucosa when sections of this organ were studied.
301 CONCLUSION
Metrazol fits are not attended by a rise in the level of blood guanidine as are spontaneous convulsions in idiopathic epileptics, indicating a different chemical reaction in the two types. Metrazol convulsions cause no changes in the ovaries or the endometrium of female rabbits indicating that this therapy, although effective in involutional melancholia, does not act in any demonstrable fashion on the anterior pituitary gland or the gonads. REFERENCES (1) Ellis M. M Biochem. J . 22 930(1928). (2) Muriay, M.:’and Hoffmadn, 6. R., J . Lab. Clin. Mcd.,
25, 1072(1940).
3) Andes J E. and Myers V. C ibid. 22 1147(1937). 14) Marsdali P’ H. A,, anh Veriey, E. J . Physiol. (London) 86 $27(1936). (5) An’des,’J. E.,and Emerson, G. A,, Arch. Infern. phormocodynomie 60, 30(1938). ( 6 ) Fried6an. M. H., Am. J. Physiol., 90, 617(1929). (7) Loem, O., PYOC.Roy. SOC. (London), B., 118, 299 (1935).
6,
Qualitative and Quantitative Determination of Peroxides in Petrolatum* By MILTON J. GOLDEN A simple and accurate qualitative and quantitative Peroxide Test method is proposed for the determination of peroxides in peuolatums. The amount of peroxides in a petrolatum can be determined chemically by the oxidation of the ferrous ion to the ferric ion by the peroxides, utilizing the corresponding development of a pink or red color. Samples of etrolatum have been tested accordingly, a n 8 a table is given which compares the quantitative Peroxide Values of the petrolatums with their respective Peroxide Tests. A Peroxide Test of at least two hours is suggested as one of the minimum standards for petrolatums used in the manufacture of pharmaceuticals and cosmetics.
ETROLATUM, a substance closely related to pWhite Mineral Oil, has become, in recent years, an important constituent of pharmaceutical and cosmetic preparations. I n contrast to mineral oil, which is a liquid under normal conditions, petrolatum is semisolid at ordinary temperatures, consisting of a mixture of solid and liquid hydrocarbons. It is amorphous and microcrystalline and may be regarded as a colloidal system in which two phases are present,
*
Received Nov. 8, 1948, from the Research Laboratories, McKesson & Robbins, Inc., Bridgeport, Conn.
an external phase of solid wax and an oily internal phase. I n the selection of the proper type of petrolatum for a specific purpose, several important properties must be considered, namely fiber characteristic, melting point, and consistency. It seems that for most pharmaceutical and cosmetic preparations, a medium fiber is generally used. A short fiber petrolatum, characteristic of synthetic petrolatums and those refined by chemical treatment, is undesirable since i t tends to produce a thin body and lacks the smooth consistency usually found with medium fiber. A long fiber petrolatum, on the other hand, produces a sticky and stringy finished product. In addition to the fiber characteristic, the melting point demands consideration and should be sufficiently high so that the finished preparation will not liquefy at slightly elevated temperatures. Furthermore, correct and uniform consistency is by far one of the most important factors in determining the suitability of a petrolatum. The Pharmacopceia of the United States has recognized the importance of the purity of petrolatum and has, therefore, included tests for ash content, organic and mineral acids, alkali
A
N INCREASE
studied. The same method for the determination of guanidine-like substances in the blood was employed as that used in the previous study on idiopathic epileptics. The normal blood guanidine level, and the levels a t periods of one, fifteen, and sixty minutes after injection of metrazol in convulsive doses were ascertained in each case. The results of these determinations are given in Table I. A comparison of the alteration in blood guanidine levels in spontaneous and in metrazol fits is represented graphically in Fig. 1. It will be seen that in this series of metrazol convulsions on ten patients hl1 the values fill within the normal range, as reported by Andes and Myers (3). and that there was no rise in the blood guanidine levels in these fits comparable t o that seen in spontaneous convulsions in idiopathic epileptics. T h e Effect of Metrazol Shock on the Gonads Investigators are generally agreed that many patients with involutional melancholia are improved markedly by metrazol shock therapy. This disorder is commonly considered to be due to a gonadal hormone insufficiency. Since it has been demonstrated by Marshall & Verney (4) that ovulation of
TABLE I.-GUANIDINE VALUE I N MG. % METRAZOL CONVULSIONS
0 .
Patient's No.
Normal Level
One Minute After Metrazol
Fifteen Minutes After Metrazol
Sixty Minutes After Metrazol
16 17 18
0.23 0.27 0.24
0.23 0.25 0.29
19 -_
0.31
0.33 .
20 21 22 23 24 25
0.23 0.26 0.25 0.26 0.28 0.19
0.24 0.25 0.25 0.26 0.27 0.20
0.14 0.26 0.31 0.34 0.24 0.25 0.24 0.27 0.27 0.21
0.21 0.26 0.28 0.32 0.24 0.25 0.23 0.25 0.27 0.20
EPILEPTIC
.= METRAZQL
was a result of the convulsion per se, or whether there was a difference in this biochemical reaction i n the t w o types of fits. T h e Effect of Metrazol Shock on Blood Guanidine' Levels A group of ten patients a t Longview State Hospital who were receiving metrazol shock therapy was
*
Received Nov. 13 1948 from the Physiology Laboratory University of Ci&inna&. This work was done in 1940 but 'interrupted by the authors' service with the Armed Forces. 1 Throughout this article the term guanidine is used in lieu of guanidine-like substances.
IN
~~
central origin through the anterior pituitary may be induced in the rabbit by electrical stimulation of either the cerebrum or the lumbosacral cord, and by convulsions produced by the intravenous injections of picrotoxin (5), the following question occurred: Does metrazol shock exert its beneficial therapeutic effect in these cases by acting directly upon the gonads, or upon gonadotropic secretions of the anterior pituitary gland? An attempt t o answer this question was made. Because of their peculiarly prompt response to estrogens and to gonadotropic anterior pituitary fractions, female rabbits of twelve to fourteen weeks of age were chosen as test animals, since any anterior pituitary gonadotropic principle would in all likelihood cause ovulation (6), while follicular activity would cause endometrial hyperplasia (7).
300
SCIENTIFIC EDITION Twelve female rabbits weighing between 2400 Gm., and 2800 Gm., were given intravenous injections of 0.20 Gm. of metrazol. Immediately the animals were thrown into violent convulsions, lasting between ten and fifteen minutes. With the exception of one animal, which broke several teeth as a result of spasm of the muscles of mastication, no injuries or fractures were observed. Following this, laparotomies were performed on the animals, in groups of three at twenty-four, forty-eight, seventytwo, and ninety-six hours, respectively. The ovaries, tubes, and uteri were removed. In no case did examination show changes in the ovaries such as congestion, enlargement, developing follicles or corpora hemorrhagica or leutes. A study of sections of the uterine mucosa showed no evidence of endometrial hypertrophy. Another group of twelve female rabbits of the same age and weight range were given metrazol convulsions on successive days for seven days, and then forty-eight hours after the last convulsion, laparotomies were performed. In no case were ovarian changes noted, nor were any changes noted in the uterine mucosa when sections of this organ were studied.
301 CONCLUSION
Metrazol fits are not attended by a rise in the level of blood guanidine as are spontaneous convulsions in idiopathic epileptics, indicating a different chemical reaction in the two types. Metrazol convulsions cause no changes in the ovaries or the endometrium of female rabbits indicating that this therapy, although effective in involutional melancholia, does not act in any demonstrable fashion on the anterior pituitary gland or the gonads. REFERENCES (1) Ellis M. M Biochem. J . 22 930(1928). (2) Muriay, M.:’and Hoffmadn, 6. R., J . Lab. Clin. Mcd.,
25, 1072(1940).
3) Andes J E. and Myers V. C ibid. 22 1147(1937). 14) Marsdali P’ H. A,, anh Veriey, E. J . Physiol. (London) 86 $27(1936). (5) An’des,’J. E.,and Emerson, G. A,, Arch. Infern. phormocodynomie 60, 30(1938). ( 6 ) Fried6an. M. H., Am. J. Physiol., 90, 617(1929). (7) Loem, O., PYOC.Roy. SOC. (London), B., 118, 299 (1935).
6,
Qualitative and Quantitative Determination of Peroxides in Petrolatum* By MILTON J. GOLDEN A simple and accurate qualitative and quantitative Peroxide Test method is proposed for the determination of peroxides in peuolatums. The amount of peroxides in a petrolatum can be determined chemically by the oxidation of the ferrous ion to the ferric ion by the peroxides, utilizing the corresponding development of a pink or red color. Samples of etrolatum have been tested accordingly, a n 8 a table is given which compares the quantitative Peroxide Values of the petrolatums with their respective Peroxide Tests. A Peroxide Test of at least two hours is suggested as one of the minimum standards for petrolatums used in the manufacture of pharmaceuticals and cosmetics.
ETROLATUM, a substance closely related to pWhite Mineral Oil, has become, in recent years, an important constituent of pharmaceutical and cosmetic preparations. I n contrast to mineral oil, which is a liquid under normal conditions, petrolatum is semisolid at ordinary temperatures, consisting of a mixture of solid and liquid hydrocarbons. It is amorphous and microcrystalline and may be regarded as a colloidal system in which two phases are present,
*
Received Nov. 8, 1948, from the Research Laboratories, McKesson & Robbins, Inc., Bridgeport, Conn.
an external phase of solid wax and an oily internal phase. I n the selection of the proper type of petrolatum for a specific purpose, several important properties must be considered, namely fiber characteristic, melting point, and consistency. It seems that for most pharmaceutical and cosmetic preparations, a medium fiber is generally used. A short fiber petrolatum, characteristic of synthetic petrolatums and those refined by chemical treatment, is undesirable since i t tends to produce a thin body and lacks the smooth consistency usually found with medium fiber. A long fiber petrolatum, on the other hand, produces a sticky and stringy finished product. In addition to the fiber characteristic, the melting point demands consideration and should be sufficiently high so that the finished preparation will not liquefy at slightly elevated temperatures. Furthermore, correct and uniform consistency is by far one of the most important factors in determining the suitability of a petrolatum. The Pharmacopceia of the United States has recognized the importance of the purity of petrolatum and has, therefore, included tests for ash content, organic and mineral acids, alkali