The effect of aminophylline on urticarial skin reactions

THE

EFFECT

OF AMINOPHYLLINE REACTIONS”

ON URTICARIAL

H. HAYWOOD TURNER, M.II.,

ATLANTA,

SKIN

GA.

ALE, in 1910,l noted the similarity between the action of histamine and anaphylactic shock. Staub and Bovet*’ 3 showed that various compounds, previously prepared in the laboratory of M. Fourneau for investigation of autonomic properties, were able in varying degrees to counteract histamine effects. Two preparations, 929 F and 1571 F, were more potently antihistaminic than the others. A common property of these was the possession of HH an amino-ethyl structure (-C-C-N=). 929 F and 1571 F were considered HH too toxic for clinical use, but from them evolved the currently used antihisHowever, pyridine tamine drugs containing the amino-ethyl structure. derivatives not possessing the amino-ethyl structure are also effectively antihistaminic. Aminophylline (theophylline-ethylenediamine) is used clinically for a variety of conditions. Although credit is generally given to Herrmann, Aynesworth, and Martin4 for drawing attention to its use in bronchial asthma, Mallen states that Rischawy and Diaz both had recommended it previously. In 1936, Tuft and Brodsky6 showed that intravenous injections of aminophylline reduced the sizes of allergic wheals produced by intradermal injections of antigenic substances. This effect was comparable to, but much less marked than, a similar effect by epinephrine. In 1941, Emmelin and associatesT reported definite antihistaminic properties of the xanthines, and Mallen described results, at times dramatic, in cases of chronic allergic skin reactions with urticaria and angioneurotic edema following repeated intravenous injections of aminophylline with calcium salts. In 1947, Epstein* described the relief of itching in dermatoses by intravenous aminophylline. From Fig. 1 it is seen that an amino-ethyl structure exists in histamine, ethylenediamine, the antihistamine drugs, and procaine (also used in allergic Also from Fig. 1 it is seen that histamine, theophylline, and reactions). Antistine each contain an imidazole ring. The theory of action of the antihistamine drugs is that they compete with histamine rather than destroy or neutralize it. Aminophylline (theophylline-ethylenediamine) might be effective in competition with histamine both by virtue of its theophylline content with the xanthine structure containing the imidazole ring and by virtue of the loosely attached ethylenediamine, with its amino-ethyl structure. In fact, the entire structure of histamine is contained in aminophylline. Because of the chemical similarity of aminophylline to histamine and the antihistamine

D

*From the Department of Medicine, Medical Service, Grady Hospital.

Enlory 307

University

School of Medicine,

and the

308

THE:

JOURNAL

OP ALLKRGY

drugs, and because of its accepted efficacy in the treatment asthma, it was decided to determine the effect of aminophylline lergic reactions. /*y HC

*N--C

0

HH - C-C-NH2 HH

*\

Histsmine

/2 ' 2 CJ C-*(C$kj)2 HH

0: (/

of t)t.otlchi;ll 011 other al-

H N-CH2 H'N-C-C: 1 H y2

1571 F

Antistine

HH H2N-C-O-NH2 HH Thenylene

oc\ 70

CH2 HH c? Q>N-;-;-N(CHJ)2

H3C,N--

H3m Theophylline

C C N(C214)2 HH

Q3

&N-;-;-N(Cb)2

Py-ribenzzmine

HC(CH312 Ii H 'O-

H3Q

929 F

HH

Neoantergan

/NH-CH HC1 (I N-CImidazola Fig.

Ring

Procaine

1.

Thirty-five patients with allergic reactions, mostly urticarial, were treated in the emergency clinics at Grady Hospital. Brief histories and physical examinations were done. Because of the large subjective element in response to treatment and because of the variation in severity of syrnptoms from minute to minute, varied approaches to individual patients were used. Some were given intravenous placebos prior to aminophylline, others were given aminophylline by injection into clysis tubing without their knowledge, some were led to scratch so as to aggravate the itching, and others were merely observed. In all with skin reactions, itching was present at the time of treatment. Aminophylline was given intravenously, the syringes being filled from 10 cc. ampules containing 0.375 gram. Doses varied from 1 C.C. in the case of a 5-yearold child to 30 C.C. in that of an adult, but most patients received 10 cubic centimeters. Results are shown in Table J. TABLE

I.

RESULTS

OF TREATMENT

DISEASE Serum sickness with urticaria Immediate urticarial reaction antitetanus horse serum Urticaria due to other causes with plants, insect stings, Serum sickness with arthritis

OF ALLERGIC AMINOPHYLLINE

REACTIONS

NUMBER OFCASES

COMPLETE RELIEF

INTRAVENOUS

MODERATE KELIEF

MINIMALOR NORELIEF

17

5

6

6

7

4

2

1

I) 2

2

1

Fl

1

1

to (contact etc.)

WITH

TURNER

:

EFFECT

OF

AMINOPHYLLINE

ON

URTICARIAL

SKIN

309

REACTIONS

One patient with severe pains in the leg muscles, nausea, and vomiting but no abdominal rigidity after a spider bite (probably a black widow) showed dramatic improvement immediately after receiving 10 cc. aminophylline. When complete relief was obtained, the response was dramatic, generally occurring before the injection was completed, and, at times, after only 2 or 3 C.C. had been given. When only moderate relief was obtained, the change one-half of the was usually apparent several minutes later. In approximately patients there was no change in the skin lesions. In the others, changes varied from slight blanching to complete disappearance. The relief afforded by Occasional nausea aminophylline generally lasted from four to six hours. and vomiting and transient dizziness were the only untoward effects noted. Orally administered aminophylline in doses up to 0.4 Gm. every four hours was tried in several cases without apparent benefit, either as initial or as continued treatment. Subcutaneously administered epinephrine was effective in some, but not all in the patients who obtained no relief from aminophylline. It is realized that suggestion may have played an appreciable part in the results. This was demonstrated by one patient who obtained complete relief after a placebo of intravenous nicotinic acid, and another, a child, who denied pruritis after an unsuccessful attempt at venepuncture. In the management of these patients, antihistamine drugs by mouth after initial relief of symptoms by aminophylline was found to be adequate. SUMMARY

1. Aminophylline with allergic reactions, 2. Complete relief eleven. 3. Aminophylline epinephrine in cases of

was administered intravenously to thirty-five mostly urticarial. was obtained in fifteen of these, and pftrtial appeared urticaria.

to have

an effect

comparable

patients relief

in

to that

of

REFERENCES

1. Dale, 2. 3. 4. 5. 6. 7.

H. H., and Laidlaw, P. P.: Physiological Action of b-iminazolylethylamine, J. Physiol. 41: 318, 1910. Staub. A. M.. and Bovet. D.: Action de la thvmoxvethvldiethvlamine (929 F1 et des ‘ethers phenoliques ‘sur le choc anaphylactique” du “cobaye, Compt.‘ rend. ‘Sot. de biol. 125: 818, 1937. Recherches SW quelques Bases Synthetiques antagonistes de l’histamine, Staub, A. M.: Ann. Inst. Pasteur 63: 400, 1939. Herrmann, G., Aynesworth, M. B., and Martin, J.: Successful Treatment of Persistent Extreme Dyspnea, “Status Asthmaticus,” J. Lab. & Clin. Med. 23: 135, 1937. Mallen, M. 5.: Uso de la Aminofilina con Calcio en Dermatologia, Rev. med. d. Hosp. gen. 3: 461, 1941. Tuft, L., and Brodsky, M. L.: Influence of Various Drugs Upon Allergic Reactions, J. ALLERGY 7: 238, 1936. Emmelin, N., Kahlson, G. S., and Lindstrem, K.: On the Antihistamine, Antianaphylactic. and Atrooine-Like Effects of Some Xanthine Derivatives. Acta Scandinav. 3: 39, 1941. Inhvsiol. Y

8. Epstein,

E.: & Syph.

Theophylline 53: 281, 1941;

Ethylenediamine 56: 373, 1947.

as an

Anti-Pruritic

Agent,

Arch.

Dermat.