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CYCLIC A.M.P. AND ACUTE ALLERGIC SKIN REACTIONS
1151 from these infants, which will suggest metallic concentrations in body stores. Other studies in the living child will surely shed further light on this interesting proposal. Southwestern Institute of
Forensic Sciences at Dallas, 5230 Medical Center Drive, Dallas, Texas 75235, U.S.A.
WILLIAM
Q. STURNER.
CYCLIC A.M.P. AND ACUTE ALLERGIC SKIN REACTIONS is some evidence that the adenyl cyclase/ Snz, There A.M.P. system may be involved in immediate (type 1) cyclic hypersensitivity reactions in the skin. Recent work in this laboratory 1.2 has shown that in sensitised rat or human skin the IgE-mediated release of histamine is markedly inhibited in vitro both by theophylline and P-adrenergic drugs, and a synergistic inhibition of histamine release is noted when the theophylline and adrenaline are combined. Since xanthines and P-adrenergic catecholamines enhance intracellular stores of cyclic A.M.P. by independent mechanisms these results suggest that the adenyl cyclase/cyclic A.M.P. system may inhibit IgE-mediated histamine release in the skin. This view is supported by the finding that dibutyryl-c.A.M.P. produces a dose-related inhibition of histamine release in vitro.1.2 We have therefore studied the effect of xanthines, P-adrenergic drugs, and cyclic A.M.P. in vivo in type-1 skin reactions under the following conditions. 7 atopic subjects who each produced a weal and flare after the intradermal injection of a Bencard antigen extract were studied to see whether isoprenaline or cyclic A.M.P. would modify the reaction produced by the antigen. All the injections were given on the flexor surface of the forearm and the size of the reaction was measured by the mean diameter of the weal ten minutes after injection. In 7 subjects the effect of 0-05 ml. of antigen extract mixed with saline was compared with the weal produced by 0-05 ml. of the same antigen mixed with 50 ng. isoprenaline. In 4 of these subjects the isoprenaline reduced the diameter of the weal by 10% to 50%, but in the other 3 subjects it had no effect. This experiment was repeated in 6 subjects using dibutyryl cyclic A.M.P. 10-4M instead of isoprenaline. This concentration of cyclic A.M.P. effectively inhibits IgE-mediated histamine release from human skin in vitro.1.22 In the present study cyclic A.M.P. failed to suppress the weal produced by the antigen in vivo. A negative result was similarly obtained with a concentration of 10-3M. If occluded skin was pre-injected with cyclic A.M.P. ten minutes before challenge of the injected site by antigen there was again no evidence of wealing. These results suggest that in vivo intradermal isoprenaline may suppress histamine release in some subjects whereas under similar conditions cyclic A.M.P. in a concentration of 10-3 or 10-4M does not. Assem and Richter3 reported a similar inconsistent inhibition of direct skin tests by intradermal isoprenaline in 2 allergic patients. The reason for our failure to demonstrate inhibition of the acute allergic reaction by local administration of cyclic A.M.P. is uncertain. Possibly injected cyclic A.M.P. does not achieve sufficiently high cellular concentration in inflamed skin, or alternatively intact skin may contain substances which are inhibitory to cyclic A.M.P. Chronic urticaria has some of the features of a type-1 hypersensitivity reaction, and so we have also tried to inhibit histamine release in this condition by stimulating 1. 2.
Yamamoto, S., Greaves, AL W. Int. Archs Allergy (in the press). Yamamoto, S., Greaves, M. W., Fairley, V. M. Immunology (in
the press). 3. Assem, E. S. K.,
Richter,
A. W. ibid.
1971, 21, 729.
cyclic-A.M.P. production. 9 patients with stable idiopathic chronic urticaria were included in a controlled clinical trial in which combined treatment with oral theophylline (’Englate’) 300 mg. three times daily and salbutamol sulphate (’Ventolin’) 2 mg. three times daily for four weeks was compared with placebo tablets for four weeks. The patients recorded the duration and severity of their urticarial eruption every day throughout the trial. 2 patients could not tolerate the active treatment because of nausea and vomiting, and in the remaining 7 patients the treatment was no more effective than the placebo in suppressing urticaria. Our present findings show that more work is required before the promising in-vitro results previously reported can be extrapolated to the clinical situation. University Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP.
J. L. BURTON M. W. GREAVES.
POTASSIUM BALANCE DURING TREATMENT OF DIABETIC ACIDOSIS the SiR,-In interesting paper by Dr. Soler and others 30, (Sept. p. 665) I was surprised to find no mention of the values of red-cell potassium. Twenty years ago I was working on this subject. The number of cases was necessarily small (this was before the days of flame photometers), but the results showed that intracellular potassium was much depleted in the early stages of ketoacidosis, and rose to normal before there was any rise in serum-potassium. It seems to me that using serum levels as a guide to treatment is like observing a pale reflection of what is actually happening in the tissues, and may delay correct electrolyte treatment by several days. Hanworth Clinic, Grove Crescent,
Hanworth, Feltham, Middlesex.
L. A. GELLATLY.
GRAFT-VERSUS-HOST REACTION AND TOXIC EPIDERMAL NECROLYSIS SiR,-Dr. Ammann and his colleagues (Sept. 2,p. 484) have suggested that graft-versus-host reaction (G.v.H.) is a cause of toxic epidermal necrolysis (T.E.N.). We have previously described and discussed the association of these two entities in detail.l Although it is tempting to conclude, as Ammann and his colleagues did, that the T.E.N. in each of their was a sequela of G.v.H., clinical and histological evidence for this is not presented in their report. No details of their first patient are given, except that he had received a bone-marrow transplant. G.v.H. in their second case was diagnosed by the presence of donor antigens on the patient’s lymphocytes. However, it has been found that nontransplanted immunodeficient children, such as Ammann’s second patient, may carry extra HL-A antigens.2 Therefore, the presence of extra antigens does not prove engraftment Did the authors find population of donor and G.V.H. HL-A antigens or a mixture of donor and recipient antigens in their patient ? The diagnosis of G.v.H.-induced T.E.N. is difficult because transplant patients usually receive a variety of treatments, such as total-body irradiation, antilymphocyte serum, cytostatic drugs, antibiotics, and other drugs such as allopurinol, many of which have been suggested as causes of
patients
1. 2.
Peck, G. L., Herzig, G. P., Elias, P. M. Archs Derm. 1972, 105, 561. Terasaki, P. I., Miyajima, T., Singar, D. P. S., Stiehm, E. R. Transplantation, 1972, 13, 250.
Forensic Sciences at Dallas, 5230 Medical Center Drive, Dallas, Texas 75235, U.S.A.
WILLIAM
Q. STURNER.
CYCLIC A.M.P. AND ACUTE ALLERGIC SKIN REACTIONS is some evidence that the adenyl cyclase/ Snz, There A.M.P. system may be involved in immediate (type 1) cyclic hypersensitivity reactions in the skin. Recent work in this laboratory 1.2 has shown that in sensitised rat or human skin the IgE-mediated release of histamine is markedly inhibited in vitro both by theophylline and P-adrenergic drugs, and a synergistic inhibition of histamine release is noted when the theophylline and adrenaline are combined. Since xanthines and P-adrenergic catecholamines enhance intracellular stores of cyclic A.M.P. by independent mechanisms these results suggest that the adenyl cyclase/cyclic A.M.P. system may inhibit IgE-mediated histamine release in the skin. This view is supported by the finding that dibutyryl-c.A.M.P. produces a dose-related inhibition of histamine release in vitro.1.2 We have therefore studied the effect of xanthines, P-adrenergic drugs, and cyclic A.M.P. in vivo in type-1 skin reactions under the following conditions. 7 atopic subjects who each produced a weal and flare after the intradermal injection of a Bencard antigen extract were studied to see whether isoprenaline or cyclic A.M.P. would modify the reaction produced by the antigen. All the injections were given on the flexor surface of the forearm and the size of the reaction was measured by the mean diameter of the weal ten minutes after injection. In 7 subjects the effect of 0-05 ml. of antigen extract mixed with saline was compared with the weal produced by 0-05 ml. of the same antigen mixed with 50 ng. isoprenaline. In 4 of these subjects the isoprenaline reduced the diameter of the weal by 10% to 50%, but in the other 3 subjects it had no effect. This experiment was repeated in 6 subjects using dibutyryl cyclic A.M.P. 10-4M instead of isoprenaline. This concentration of cyclic A.M.P. effectively inhibits IgE-mediated histamine release from human skin in vitro.1.22 In the present study cyclic A.M.P. failed to suppress the weal produced by the antigen in vivo. A negative result was similarly obtained with a concentration of 10-3M. If occluded skin was pre-injected with cyclic A.M.P. ten minutes before challenge of the injected site by antigen there was again no evidence of wealing. These results suggest that in vivo intradermal isoprenaline may suppress histamine release in some subjects whereas under similar conditions cyclic A.M.P. in a concentration of 10-3 or 10-4M does not. Assem and Richter3 reported a similar inconsistent inhibition of direct skin tests by intradermal isoprenaline in 2 allergic patients. The reason for our failure to demonstrate inhibition of the acute allergic reaction by local administration of cyclic A.M.P. is uncertain. Possibly injected cyclic A.M.P. does not achieve sufficiently high cellular concentration in inflamed skin, or alternatively intact skin may contain substances which are inhibitory to cyclic A.M.P. Chronic urticaria has some of the features of a type-1 hypersensitivity reaction, and so we have also tried to inhibit histamine release in this condition by stimulating 1. 2.
Yamamoto, S., Greaves, AL W. Int. Archs Allergy (in the press). Yamamoto, S., Greaves, M. W., Fairley, V. M. Immunology (in
the press). 3. Assem, E. S. K.,
Richter,
A. W. ibid.
1971, 21, 729.
cyclic-A.M.P. production. 9 patients with stable idiopathic chronic urticaria were included in a controlled clinical trial in which combined treatment with oral theophylline (’Englate’) 300 mg. three times daily and salbutamol sulphate (’Ventolin’) 2 mg. three times daily for four weeks was compared with placebo tablets for four weeks. The patients recorded the duration and severity of their urticarial eruption every day throughout the trial. 2 patients could not tolerate the active treatment because of nausea and vomiting, and in the remaining 7 patients the treatment was no more effective than the placebo in suppressing urticaria. Our present findings show that more work is required before the promising in-vitro results previously reported can be extrapolated to the clinical situation. University Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP.
J. L. BURTON M. W. GREAVES.
POTASSIUM BALANCE DURING TREATMENT OF DIABETIC ACIDOSIS the SiR,-In interesting paper by Dr. Soler and others 30, (Sept. p. 665) I was surprised to find no mention of the values of red-cell potassium. Twenty years ago I was working on this subject. The number of cases was necessarily small (this was before the days of flame photometers), but the results showed that intracellular potassium was much depleted in the early stages of ketoacidosis, and rose to normal before there was any rise in serum-potassium. It seems to me that using serum levels as a guide to treatment is like observing a pale reflection of what is actually happening in the tissues, and may delay correct electrolyte treatment by several days. Hanworth Clinic, Grove Crescent,
Hanworth, Feltham, Middlesex.
L. A. GELLATLY.
GRAFT-VERSUS-HOST REACTION AND TOXIC EPIDERMAL NECROLYSIS SiR,-Dr. Ammann and his colleagues (Sept. 2,p. 484) have suggested that graft-versus-host reaction (G.v.H.) is a cause of toxic epidermal necrolysis (T.E.N.). We have previously described and discussed the association of these two entities in detail.l Although it is tempting to conclude, as Ammann and his colleagues did, that the T.E.N. in each of their was a sequela of G.v.H., clinical and histological evidence for this is not presented in their report. No details of their first patient are given, except that he had received a bone-marrow transplant. G.v.H. in their second case was diagnosed by the presence of donor antigens on the patient’s lymphocytes. However, it has been found that nontransplanted immunodeficient children, such as Ammann’s second patient, may carry extra HL-A antigens.2 Therefore, the presence of extra antigens does not prove engraftment Did the authors find population of donor and G.V.H. HL-A antigens or a mixture of donor and recipient antigens in their patient ? The diagnosis of G.v.H.-induced T.E.N. is difficult because transplant patients usually receive a variety of treatments, such as total-body irradiation, antilymphocyte serum, cytostatic drugs, antibiotics, and other drugs such as allopurinol, many of which have been suggested as causes of
patients
1. 2.
Peck, G. L., Herzig, G. P., Elias, P. M. Archs Derm. 1972, 105, 561. Terasaki, P. I., Miyajima, T., Singar, D. P. S., Stiehm, E. R. Transplantation, 1972, 13, 250.