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Hypersensitivity to thiamin chloride, with a note on sensitivity to pyridoxine hydrochloride
HYPERSENSITIVITY ON SENSITIVITY
TO THIAMIN CHLORIDE, WITH A NOTE TO PYRIDOXINE HYDROCHLORIDE MERRITT
H. STILES, M.D.
PHILADELPHIA,
PA.
\IWHILE it is generally believed that thiamin chloride may be administered without the risk of harmful effects,l a few writers have warned against possible dangers. Ochsner and Smith2 and Stern3 mentioned the lethal effects produced in animals by large experimental doses. Steinberg4 reported two patients in whom symptoms developed after long-continued use of thiamin chloride. He felt that the reactiions encountered in these cases might be due either to a sensitivity developing toward vitamin B, or to supersaturation of the tissues of the body with it. The following two cases are reported to emphasize the possibility that prolonged thiamin chloride administration may result in the development of hypersensitivity. CASE I-Mrs. A. B. was 59 years old. Thiamin chloride was first administered in August, 1937, and was taken intermittently by mouth throughout the next two years. Beginning in December, 1939, thiamin chloride was given by hypodermic injection, fairly regularly and usually twice weekly, in doses ranging from 8 to 90 mg. Liver extract was usually given in conjunction with the thiamin, and at times An oral polyvitamin other factors of the B complex were included in the injection. preparation was also taken throughout this period. On May 17, 1940, a few minutes after the injection of 30 mg. of thiamin chloride commbined with liver extract and a crude B complex preparation, transient sensations of weakness and faintness developed. On May 21, 1940, following a similar injection the patient complained of excessive nervousness. The pulse rate rose from 70 to 120, and the face and hands The symptoms subsided in less than one-half hour. The possibility were flushed. of a nicotinic acid reaction was considered, and no further injections were given for a week. On May 28 an injection
of liver
extract
was followed
by no reaction.
On June I injection of liver extract combined with 30 mg. of thiamin chloride was followed by a reaction similar to, although more severe than, that encountered on May 21, suggesting that thiamin, rather than nicotinic acid, was the responsible agent. During the following two weeks the patient several times attempted to take polyvitamin capsules and capsules containing liver extract, iron, and thiamin In each instance nervousness, associated with some flushing and tachy chloride. cardia, developed within an hour following ingestion of the capsules. On June 25 an intracutaneous injection of 3 mg. of thiamin chloride lowed by the development of a wheal approximately 2.5 cm. in diameter. 507
was folAt the
508
THE
JOURNAL
OB ALLERGY
the pulse rose to 140; and the face same time the patient became very nervous; was flushed. Later there was profuse perspiration. The symptoms subsided in about thirty minutes. Subsequently the intracutaneous injection of 0.15 mg. of thiamin in 0.03 C.C. of salt solution produced an irregular wheal measuring 2.0 by 1.9 cm., with a surrounding zone of erythema measuring 5 by 5 cm. in its greatest diameters. Similar injections in five control subjects produced no local or general reaction although the intraeutaneous injection of larger quantities of thiamin, 2.5 mg. in 0.5 C.C. of fluid, did result in wheal formation. An intracutaneous injection of chlorbutanol, the preservative used in the thiamin chloride solution, gave no local or general reaction. The administration of nicotinic acid by mouth, in doses up to 150 mg. daily, produced no reaction. Several months later the oral administration of thiamin was begun, the initial dose being 0.015 mg. The size of the dose was gradually increased, until, at the time of writing, 0.3 mg. was being taken three times daily, with no apparent reaction. CASE 2.-Mrs. C. D., aged 56 years, for several years took thiamin chloride During the summer of 1940 sevintermittently, both by mouth and by injection. eral injections were given at intervals of three or four days in doses of 20 to 50 mg. An hour or more after each of the last few of these injections a sensation of heat developed, followed rather quickly by profuse perspiration and by marked tinnitus. As these symptoms subsided feelings of agitation and panic developed, of thiamin chloride produced lasting up to twenty-four hours. Oral administration similar, but milder, symptoms. An intracutaneous test dose of 3 mg. of thiamin chloride produced a wheal about 2.0 cm. in diameter, although the usual sequence of general symptoms did An intraeutaneous injection of chlorbutanol produced no reaction. not follow. After discontinuing the use of thiamin, the patient was given a series of semiweekly injections of pyridoxine hydrochloride in doses up to 25 mg. While the response at first was entirely favorable, after about two months symptoms began to develop similar to those which had followed the thiamin chloride injections. Intracutaneous injection of 2.5 mg. of pyridoxine at this time produced a wheal A similar injection in patient A. B,. produced no about 3.5 cm. in diameter. Similar injections in three control subjects produced local or general reaction. small wheals, in no case greater than 1.1 cm. in diameter. SUMMARY
1. Two eases are reported in which the prolonged administration of thiamin chloride resulted in the production of severe symptoms, apparently due to the development of hypersensitivity. 2. Intracutaneous injection of 0.15 mg. of thiamin resulted in definite wheal formation, although similar injections produced no reaction in control subjects. 3. Subsequently small quantities of thiamin were safely administered by mouth to one patient. 4. The repeated injection of pyridoxine hydrochloride in the second patient was followed after about two months by the development of symptoms similar to those which had followed thiamin injection. 5. Intracutaneous injection of pyridoxine resulted in definite wheal formation in this patient, although it produced no reaction in the first patient, and only questionable wheal formation in three control subjects.
STILES
:
HYPERSENSITIVITY
TO
THIAMIN
CHLORIDE
509
ADDENDUM
Since the preparation of this paper a communication from Mills5 has Cases were appeared stressing possible toxic reactions to thiamin. cited in which the administration of thiamin was followed by symptoms similar to those encountered in the cases reported here. In Mills’ cases apparently the symptoms developed gradually following prolonged oral administration, rather than immediately following injection. REFERENCES
I. (a)
Moore, M. T.: Treatment of Multiple Sclerosis With Nicotinic Acid and Vitamin B,. Preliminary Report, Arch. Int. Med. 65: 1, 1940. (b) Metildi, P. F. : The Treatment of Tabetic Lightning Pains With Thiamin Chloride, .Am. J. Syph., Gonor., & Ven. Dis. 23: 1, 1939. (c) Meiklejohn, A. P.: The Water-Soluble Vitamins, New England J. Med. 22’0: 518, 1939. 2. Ochsner, A., and Smith, M. C.: The Use of Vitamin B, for the Relief of Pain in Varicose Ulcers. J. A. M. A. 114: 947. 1940. Injection of’ Vitamin B, for the Relief of In13. Stern, E. L.:.~ The I&aspinal tractable Pain and for Inflammatory and Degenerative Diseases of the Central Nervous System, Am. J. Surg. “39: 495, 1938. 4. Steinberg, C. L.: Untoward Effects Resulting From the Use of Large Doses of Vitamin B,, Am. J, Digest. Dis. 5: 680, 1938. 5. Mills, C. A.: Correspondence, J. A. M. A. 116: 2101, 1941.
TO THIAMIN CHLORIDE, WITH A NOTE TO PYRIDOXINE HYDROCHLORIDE MERRITT
H. STILES, M.D.
PHILADELPHIA,
PA.
\IWHILE it is generally believed that thiamin chloride may be administered without the risk of harmful effects,l a few writers have warned against possible dangers. Ochsner and Smith2 and Stern3 mentioned the lethal effects produced in animals by large experimental doses. Steinberg4 reported two patients in whom symptoms developed after long-continued use of thiamin chloride. He felt that the reactiions encountered in these cases might be due either to a sensitivity developing toward vitamin B, or to supersaturation of the tissues of the body with it. The following two cases are reported to emphasize the possibility that prolonged thiamin chloride administration may result in the development of hypersensitivity. CASE I-Mrs. A. B. was 59 years old. Thiamin chloride was first administered in August, 1937, and was taken intermittently by mouth throughout the next two years. Beginning in December, 1939, thiamin chloride was given by hypodermic injection, fairly regularly and usually twice weekly, in doses ranging from 8 to 90 mg. Liver extract was usually given in conjunction with the thiamin, and at times An oral polyvitamin other factors of the B complex were included in the injection. preparation was also taken throughout this period. On May 17, 1940, a few minutes after the injection of 30 mg. of thiamin chloride commbined with liver extract and a crude B complex preparation, transient sensations of weakness and faintness developed. On May 21, 1940, following a similar injection the patient complained of excessive nervousness. The pulse rate rose from 70 to 120, and the face and hands The symptoms subsided in less than one-half hour. The possibility were flushed. of a nicotinic acid reaction was considered, and no further injections were given for a week. On May 28 an injection
of liver
extract
was followed
by no reaction.
On June I injection of liver extract combined with 30 mg. of thiamin chloride was followed by a reaction similar to, although more severe than, that encountered on May 21, suggesting that thiamin, rather than nicotinic acid, was the responsible agent. During the following two weeks the patient several times attempted to take polyvitamin capsules and capsules containing liver extract, iron, and thiamin In each instance nervousness, associated with some flushing and tachy chloride. cardia, developed within an hour following ingestion of the capsules. On June 25 an intracutaneous injection of 3 mg. of thiamin chloride lowed by the development of a wheal approximately 2.5 cm. in diameter. 507
was folAt the
508
THE
JOURNAL
OB ALLERGY
the pulse rose to 140; and the face same time the patient became very nervous; was flushed. Later there was profuse perspiration. The symptoms subsided in about thirty minutes. Subsequently the intracutaneous injection of 0.15 mg. of thiamin in 0.03 C.C. of salt solution produced an irregular wheal measuring 2.0 by 1.9 cm., with a surrounding zone of erythema measuring 5 by 5 cm. in its greatest diameters. Similar injections in five control subjects produced no local or general reaction although the intraeutaneous injection of larger quantities of thiamin, 2.5 mg. in 0.5 C.C. of fluid, did result in wheal formation. An intracutaneous injection of chlorbutanol, the preservative used in the thiamin chloride solution, gave no local or general reaction. The administration of nicotinic acid by mouth, in doses up to 150 mg. daily, produced no reaction. Several months later the oral administration of thiamin was begun, the initial dose being 0.015 mg. The size of the dose was gradually increased, until, at the time of writing, 0.3 mg. was being taken three times daily, with no apparent reaction. CASE 2.-Mrs. C. D., aged 56 years, for several years took thiamin chloride During the summer of 1940 sevintermittently, both by mouth and by injection. eral injections were given at intervals of three or four days in doses of 20 to 50 mg. An hour or more after each of the last few of these injections a sensation of heat developed, followed rather quickly by profuse perspiration and by marked tinnitus. As these symptoms subsided feelings of agitation and panic developed, of thiamin chloride produced lasting up to twenty-four hours. Oral administration similar, but milder, symptoms. An intracutaneous test dose of 3 mg. of thiamin chloride produced a wheal about 2.0 cm. in diameter, although the usual sequence of general symptoms did An intraeutaneous injection of chlorbutanol produced no reaction. not follow. After discontinuing the use of thiamin, the patient was given a series of semiweekly injections of pyridoxine hydrochloride in doses up to 25 mg. While the response at first was entirely favorable, after about two months symptoms began to develop similar to those which had followed the thiamin chloride injections. Intracutaneous injection of 2.5 mg. of pyridoxine at this time produced a wheal A similar injection in patient A. B,. produced no about 3.5 cm. in diameter. Similar injections in three control subjects produced local or general reaction. small wheals, in no case greater than 1.1 cm. in diameter. SUMMARY
1. Two eases are reported in which the prolonged administration of thiamin chloride resulted in the production of severe symptoms, apparently due to the development of hypersensitivity. 2. Intracutaneous injection of 0.15 mg. of thiamin resulted in definite wheal formation, although similar injections produced no reaction in control subjects. 3. Subsequently small quantities of thiamin were safely administered by mouth to one patient. 4. The repeated injection of pyridoxine hydrochloride in the second patient was followed after about two months by the development of symptoms similar to those which had followed thiamin injection. 5. Intracutaneous injection of pyridoxine resulted in definite wheal formation in this patient, although it produced no reaction in the first patient, and only questionable wheal formation in three control subjects.
STILES
:
HYPERSENSITIVITY
TO
THIAMIN
CHLORIDE
509
ADDENDUM
Since the preparation of this paper a communication from Mills5 has Cases were appeared stressing possible toxic reactions to thiamin. cited in which the administration of thiamin was followed by symptoms similar to those encountered in the cases reported here. In Mills’ cases apparently the symptoms developed gradually following prolonged oral administration, rather than immediately following injection. REFERENCES
I. (a)
Moore, M. T.: Treatment of Multiple Sclerosis With Nicotinic Acid and Vitamin B,. Preliminary Report, Arch. Int. Med. 65: 1, 1940. (b) Metildi, P. F. : The Treatment of Tabetic Lightning Pains With Thiamin Chloride, .Am. J. Syph., Gonor., & Ven. Dis. 23: 1, 1939. (c) Meiklejohn, A. P.: The Water-Soluble Vitamins, New England J. Med. 22’0: 518, 1939. 2. Ochsner, A., and Smith, M. C.: The Use of Vitamin B, for the Relief of Pain in Varicose Ulcers. J. A. M. A. 114: 947. 1940. Injection of’ Vitamin B, for the Relief of In13. Stern, E. L.:.~ The I&aspinal tractable Pain and for Inflammatory and Degenerative Diseases of the Central Nervous System, Am. J. Surg. “39: 495, 1938. 4. Steinberg, C. L.: Untoward Effects Resulting From the Use of Large Doses of Vitamin B,, Am. J, Digest. Dis. 5: 680, 1938. 5. Mills, C. A.: Correspondence, J. A. M. A. 116: 2101, 1941.