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EFFECT OF LEVAMISOLE ON CHRONIC LYMPHOCYTIC LEUKÆMIC LYMPHOCYTES
932 The spatially averaged ultrasonic intensity tolerated at 0.75 MHz was 0-34-0.5W/cm2. Mild superficial reddening of the. skin frequently occurred, occasionally persisting for several days. The area irradiated by the transducer was calculated
from beam
profiles obtained by scanning a piezoelectric probe hydrophone through the centre of the beam, parallel to the transducer face. The total ultrasonic power emitted by the transducer was measured by a radiation-float technique.9 The table shows the mean plasma 13-T.G. in the three blood samples. Although a butterfly cannula is not the recommended method of collecting blood samples for p-T.G. measurement, the concentration of &bgr;-T.G. in our first control samples (20-60
ng/ml,
mean
38-7±s.D. 13.6
ng/ml)
compares well with that
samples obtained through clean standard venepuncture by experienced clinician (20-40 ng/ml). LJltrasonic intensities of up to 0.5W/cm2 at 0-7$MHz (the most damaging frequency in vitro3) did not induce detectable p-T.G. release from normal human platelets in vivo. It should be pointed out, however, that therapeutic -intensities of up to 3-0 W/cm2 are routinely administered to soft-tissue sites where there is no adja-
in
an
bone. Our results thus cannot be taken as evidence that higher intensities of therapeutic ultrasound do not have thrombogenic effects in vivo, particularly in patients with an increased risk of clot formation. cent
Medical
Biophysics Department, University of Manchester, Manchester M13 9PT
A. R. WILLIAMS
Central Toxicology Laboratory, I.C.I. Ltd., Alderley Park, Cheshire
B. V. CHATER J. H. SANDERSON
Hæmatology Department, Withington Hospital,
D. A. TABERNER
Manchester
S. J. MAY
Radiochemical Centre, Amersham
K. A. ALLEN M. R. SHERWOOD
LEVAMISOLE-INDUCED HYPERSENSITIVITY et al.1 described two patients with levamisole. A patient who had, in addition, thrombocytopenia and leucopenia with evidence of circulating immune complexes, has also been described.2 Dr Yust and his colleagues (Aug. 27, p. 457) found reaginic hypersensitivity to levamisole in a patient who had become febrile. We describe here a patient with evidence of reaginic hypersensitivity to levamisole in whom skin biopsy revealed deposits of immunoglobulin and complement. A 73-year-old woman with rheumatoid arthritis was treated with levamisole (150 mg daily, 2 days a week). Her arthritis improved but she had a severely itching rash and the drug was stopped after 6 months treatment. Penicillamine was subsequently given and tolerated without rashes. 15 months after regular levamisole was stopped, she was given a single dose of 150 mg which provoked a fever of 400C and a generalised rash. These disappeared within 24 h. 13 punch-biopsy specimens were examined by direct immunofluorescence microscopy. In the first, obtained 18 months before levamisole was started, no deposits were found. In 3, during the 6 months of levamisole treatment, granular deposits of IgG and complement (C3) were found at the dermal-epidermal junction. 8 obtained during the penicillamine treatment showed that the deposits disappeared gradually, the last 3 being completely negative. However, in a specimen obtained 1 day after levamisole challenge, there were again granular deposits of IgG in the dermal-epidermal junction. 3 days after the febrile episode, the patient’s leucocytes were
SIR,-Christiansen
febrile reactions
to
9. Oberst, H., Riechmann, P. Physikalisol Bundesonstalt. 1953, 2, s35. 1. Christiansen, F. T., Ng, K. C., Zilko, P. J., Dawkins, R. L. Lancet,
1977, i, 1111. 2. Parkinson, D. R., Cano, P. O., Jerry, L. M., Capek, A., Shibata, H. R., Mansell, P. W., Lewis, M. G., Marquis, G. ibid. p. 1129.
in vitro to levamisole (10 flg/ml). 36% histamine release occurred. The release from normal, unsensitised leuco2 months later, prick tests with cytes in this test is < 12%.3 levamisole (500 g/ml) showed weal-and-flare reactions in this patient of the same size as the histamine controls, and no reactipn in 3 control persons. Our results provide further evidence that levamisole can cause immediate-type as well as Arthus-type hypersensitivity reactions.
exposed
Department of Dermatology, Municipal Hospital, Copenhagen, Denmark University Clinic for Infectious Diseases, Rigshospital, Copenhagen
LENA SECHER
HENRIK PERMIN PER STAHL SKOV
Department of Dermatology, Rigshospital, Copenhagen
SUSANNE ULLMANN
Department of Medicine, Hvidovre Hospital, Copenhagen
POUL HALBERG
FATAL BENIGN PHENYTOIN HYPERSENSITIVITY
SIR,-A 71-year-old alcoholic was admitted to hospital with weakness, tremulousness, and inability to walk. He subse-
quently had status epilepticus and was treated with phenytoin. No eosinophilia was detectable at first, but 1 month after admission an absolute eosinophilia, generalised lymphadenopathy, and a widespread erythematous rash developed. The lymphadenopathy plus a severe weight-loss and an electromyelogram compatible with the Eaton-Lambert syndrome (paracarcinomatous syndrome), suggested the presence of tumour. An axillary lymph-node biopsy showed massive eosinophil infiltration and the eosinophilia reached a peak of 17 280/p on the day before the patient died. He had a diffuse erythematous rash throughout, progressive oliguria, and, finally, anuria. Necropsy revealed anasarca. No neoplasm was present and no lymph-node greater than 1 cm in diameter was found. Both kidneys had extensive interstitial infiltrates composed of eosinophils and scattered neutrophils. Portal areas of the liver were also extensively infiltrated by eosinophils. It appears, therefore, that patients who become hypersensitive to phenytoin may develop interstitial nephritis4 in this case; although the lymphadenopathy was benign, the hypersensitivity was fatal. Deptartment of Clinical Pathology, Wishard Memorial Hospital, Indiana University Medical Center Indianapolis, Indiana 46202, U.S.A.
LEO J. MCCARTHY J. C. AGUILAR
EFFECT OF LEVAMISOLE ON CHRONIC LYMPHOCYTIC LEUKÆMIC LYMPHOCYTES
SIR,-Levamisole apparently had an in-vivo lympholytic effect in a patient with chronic lymphocytic leukxmia (c.t.L.)’ We investigated the in-vitro effect of levamisole in cultured lymphocytes from normal individuals and C.L.L. patients. Lymphocytes from 3 controls and 3 patients with C.L.L. were obtained by separation on a ’Ficoll’-’Hypaque’ gradient and cultured in growth medium (RPM 11640 with 10% fetal calf serum) with levamisole at different concentrations. The results are shown in the accompanying table. To exclude the possibility of complete lysis having taken place, cell-counts were done at the end of culture. These showed no significant loss of cells. The in-vivo lymphopenia which was reported in a levamisole-treated C.L.L. patient may have an immunological basis, since leucocytopenia has been reported in patients with other diseases treated with this drug6-8 and leucoagglutinating antibodies have been found. 3. Stahl Skov, P., Norn, S. Acta allergol. 1977, 32, 17. 4. Hepinstall, R. H. Pathology of the Kidney; p. 826. Boston, 1974. 5. Sancherz, G., Mira, A. G. New Engl. J. Med. 1977, 296, 1412. 6. Rosenthal, M., Trabert, U., Müller, W. Lancet, 1976, i, 369. 7. Ruuskanen, O., Remes, M., Mäkelä, A. H. L., Isomaki, H., Toivanen, A. ibid. 1976, ii, 958. 8. Graber, H., Takacs, L., Vedrödy, K. ibid. p. 1248.
933 EFFECT OF LEVAMISOLE ON VIABILITY OF LYMPHOCYTES IN
CULTURE
However, myeloid cells have usually been involved. Our
stu-
dies indicate that levamisole has
lym-
no
direct action
on c.L.L.
phocytes in-vitro. Department of Pathology, University of Saskatchewan, Saskatoon, Saskatchewan S7N 0W0, Canada
L. F. SKINNIDER M. RIEDER
MASSIVE FACTOR-VIII INFUSION IN HÆMOPHILIAC WITH FACTOR-VIII INHIBITOR, HIGH RESPONDER
SIR,-Bleeding in hsemophiliacs with factor-vm inhibitors of low-responder type is generally overcome by massive factorVIII infusions. The addition of immunosuppressive therapy may be successful in high responders, delaying and possibly weakening the anamnestic response.2.3 "Activated" factor-ix concentrates may also be usefu1.4 These regimens, however, are unsuitable when prolonged substitution therapy is necessary in a high responder. Our patient is a 20-year-old hxmophiliac with factor-vm inhibitor. His elder brother, also a haemophiliac with inhibitor, died aged 18 from a retroperitoneal haemorrhage. Our patient has had bleeding episodes since birth and has been given many infusions of whole blood, plasma, cryoprecipitate, and factorvm concentrates in more than thirty hospital admissions, without much success. Inhibitor was detected when he was 12 years old. Three times he has received concentrates in combination with immunosuppressive therapy, the last (1973) being with cyclophosphamide (15 mg/kg intravenously followed by 2 mg/kg body-weight orally for 10 days) when the inhibitor concentration increased after 4-5 days from 0.5units/ml to a peak of 30-40 units/ml after 2 weeks. The preinfusion level was regained after 2 months. In 1976 at the age of 18 he passed his final school examination, brilliantly, but he was confined to a wheelchair or bed and he wanted to be more independent. This would need prolonged physiotherapy, which could be achieved only if covered by factor-vm after elimination of inhibitor. We decided to use the treatment given by the haemophilic centre in Bonn5-a combination of daily massive infusions of factor vin and activated factor ix until the increase in inhibitor, which follows infusions, has been eliminated, after which daily doses should keep the inhibitor level low and permit physiotherapy. Our patient was treated in Bonn. His factor-viii level was 1% and his inhibitor level was 0.5 Bethesda units/ml on admission. The dosages and inhibi1 Allain, I P., Frommel. D Blood, 1976, 47, 937. Dormandy, K., Hawkey, C., Churchill, W G. L., Cowley, J. Thromb. Diath.
2
hœmorth 971, 43, 355. 3 Nielsson, I. M., Hedner, U Scand.
J
Hœmat
1976, 16, 364
Manucci, P. M., Bader, R , Ruggeri, Z. M. Lancet, 1976, i, 41. 5 Brackmann, H. H., Etzel, F., Hofmann, P., Egli, H. Thromb Hœmostas. 1977, 38, 369 abstr.
4
Fig.-Factor
VIII inhibitor
during treatment.
levels are shown in the figure. At first he received 3000 units of factor vm and 2500 units of concentrated factor ix daily. His inhibitor level increased during the first week to about 1100 units/ml and did not fall significantly until he had received 12 000 units of factor vm per day for 10 days. The dose could then be reduced, and after 3 months with daily injections an inhibitor level of 1 unit/ml was obtained. The inhibitor concentration rose 3 weeks later, the daily dosage of factor viii having been reduced too far, but the inhibitor concentration fell again when the dose was increased. After 7 months he has no demonstrable inhibitor while on 3000 units of factor vm and 1000 units of factor ix concentrate (’Feiba’) daily. He received, due to shortage of feiba, other factor-ix concentrates in between. There have been a few bleeding episodes, mostly in one bad elbow but sometimes more general. In more general bleeds we often found a positive ethanol test, increased amounts of fibrinogen-related antigens, shortened euglobulin-lysis time, a low platelet-count, and a defect in A.D.P., adrenaline, and collagen-induced platelet aggregation in vitro. He has biochemically no hepatic or renal damage. Platelet or leucocyte antibodies and hepatitis B antigen or antibody have not been found. He has been able to do progressively more active physiotherapy, and is making great progress. Furthermore he has passed another examination, and is able to use his typewriter again. Except for the first days in Bonn he has administered the injector
tions himself. A feature of this case is the very the very large doses of factor vm.
high
level of inhibitor and
Institute of Experimental Hæmatolgy and Blood Transfusion, University of Bonn, H. H. BRACKMANN Bonn, West Germany
Coagulation Laboratory, Municipal Hospital, 1399 Copenhagen K, Denmark
J. GORMSEN
from beam
profiles obtained by scanning a piezoelectric probe hydrophone through the centre of the beam, parallel to the transducer face. The total ultrasonic power emitted by the transducer was measured by a radiation-float technique.9 The table shows the mean plasma 13-T.G. in the three blood samples. Although a butterfly cannula is not the recommended method of collecting blood samples for p-T.G. measurement, the concentration of &bgr;-T.G. in our first control samples (20-60
ng/ml,
mean
38-7±s.D. 13.6
ng/ml)
compares well with that
samples obtained through clean standard venepuncture by experienced clinician (20-40 ng/ml). LJltrasonic intensities of up to 0.5W/cm2 at 0-7$MHz (the most damaging frequency in vitro3) did not induce detectable p-T.G. release from normal human platelets in vivo. It should be pointed out, however, that therapeutic -intensities of up to 3-0 W/cm2 are routinely administered to soft-tissue sites where there is no adja-
in
an
bone. Our results thus cannot be taken as evidence that higher intensities of therapeutic ultrasound do not have thrombogenic effects in vivo, particularly in patients with an increased risk of clot formation. cent
Medical
Biophysics Department, University of Manchester, Manchester M13 9PT
A. R. WILLIAMS
Central Toxicology Laboratory, I.C.I. Ltd., Alderley Park, Cheshire
B. V. CHATER J. H. SANDERSON
Hæmatology Department, Withington Hospital,
D. A. TABERNER
Manchester
S. J. MAY
Radiochemical Centre, Amersham
K. A. ALLEN M. R. SHERWOOD
LEVAMISOLE-INDUCED HYPERSENSITIVITY et al.1 described two patients with levamisole. A patient who had, in addition, thrombocytopenia and leucopenia with evidence of circulating immune complexes, has also been described.2 Dr Yust and his colleagues (Aug. 27, p. 457) found reaginic hypersensitivity to levamisole in a patient who had become febrile. We describe here a patient with evidence of reaginic hypersensitivity to levamisole in whom skin biopsy revealed deposits of immunoglobulin and complement. A 73-year-old woman with rheumatoid arthritis was treated with levamisole (150 mg daily, 2 days a week). Her arthritis improved but she had a severely itching rash and the drug was stopped after 6 months treatment. Penicillamine was subsequently given and tolerated without rashes. 15 months after regular levamisole was stopped, she was given a single dose of 150 mg which provoked a fever of 400C and a generalised rash. These disappeared within 24 h. 13 punch-biopsy specimens were examined by direct immunofluorescence microscopy. In the first, obtained 18 months before levamisole was started, no deposits were found. In 3, during the 6 months of levamisole treatment, granular deposits of IgG and complement (C3) were found at the dermal-epidermal junction. 8 obtained during the penicillamine treatment showed that the deposits disappeared gradually, the last 3 being completely negative. However, in a specimen obtained 1 day after levamisole challenge, there were again granular deposits of IgG in the dermal-epidermal junction. 3 days after the febrile episode, the patient’s leucocytes were
SIR,-Christiansen
febrile reactions
to
9. Oberst, H., Riechmann, P. Physikalisol Bundesonstalt. 1953, 2, s35. 1. Christiansen, F. T., Ng, K. C., Zilko, P. J., Dawkins, R. L. Lancet,
1977, i, 1111. 2. Parkinson, D. R., Cano, P. O., Jerry, L. M., Capek, A., Shibata, H. R., Mansell, P. W., Lewis, M. G., Marquis, G. ibid. p. 1129.
in vitro to levamisole (10 flg/ml). 36% histamine release occurred. The release from normal, unsensitised leuco2 months later, prick tests with cytes in this test is < 12%.3 levamisole (500 g/ml) showed weal-and-flare reactions in this patient of the same size as the histamine controls, and no reactipn in 3 control persons. Our results provide further evidence that levamisole can cause immediate-type as well as Arthus-type hypersensitivity reactions.
exposed
Department of Dermatology, Municipal Hospital, Copenhagen, Denmark University Clinic for Infectious Diseases, Rigshospital, Copenhagen
LENA SECHER
HENRIK PERMIN PER STAHL SKOV
Department of Dermatology, Rigshospital, Copenhagen
SUSANNE ULLMANN
Department of Medicine, Hvidovre Hospital, Copenhagen
POUL HALBERG
FATAL BENIGN PHENYTOIN HYPERSENSITIVITY
SIR,-A 71-year-old alcoholic was admitted to hospital with weakness, tremulousness, and inability to walk. He subse-
quently had status epilepticus and was treated with phenytoin. No eosinophilia was detectable at first, but 1 month after admission an absolute eosinophilia, generalised lymphadenopathy, and a widespread erythematous rash developed. The lymphadenopathy plus a severe weight-loss and an electromyelogram compatible with the Eaton-Lambert syndrome (paracarcinomatous syndrome), suggested the presence of tumour. An axillary lymph-node biopsy showed massive eosinophil infiltration and the eosinophilia reached a peak of 17 280/p on the day before the patient died. He had a diffuse erythematous rash throughout, progressive oliguria, and, finally, anuria. Necropsy revealed anasarca. No neoplasm was present and no lymph-node greater than 1 cm in diameter was found. Both kidneys had extensive interstitial infiltrates composed of eosinophils and scattered neutrophils. Portal areas of the liver were also extensively infiltrated by eosinophils. It appears, therefore, that patients who become hypersensitive to phenytoin may develop interstitial nephritis4 in this case; although the lymphadenopathy was benign, the hypersensitivity was fatal. Deptartment of Clinical Pathology, Wishard Memorial Hospital, Indiana University Medical Center Indianapolis, Indiana 46202, U.S.A.
LEO J. MCCARTHY J. C. AGUILAR
EFFECT OF LEVAMISOLE ON CHRONIC LYMPHOCYTIC LEUKÆMIC LYMPHOCYTES
SIR,-Levamisole apparently had an in-vivo lympholytic effect in a patient with chronic lymphocytic leukxmia (c.t.L.)’ We investigated the in-vitro effect of levamisole in cultured lymphocytes from normal individuals and C.L.L. patients. Lymphocytes from 3 controls and 3 patients with C.L.L. were obtained by separation on a ’Ficoll’-’Hypaque’ gradient and cultured in growth medium (RPM 11640 with 10% fetal calf serum) with levamisole at different concentrations. The results are shown in the accompanying table. To exclude the possibility of complete lysis having taken place, cell-counts were done at the end of culture. These showed no significant loss of cells. The in-vivo lymphopenia which was reported in a levamisole-treated C.L.L. patient may have an immunological basis, since leucocytopenia has been reported in patients with other diseases treated with this drug6-8 and leucoagglutinating antibodies have been found. 3. Stahl Skov, P., Norn, S. Acta allergol. 1977, 32, 17. 4. Hepinstall, R. H. Pathology of the Kidney; p. 826. Boston, 1974. 5. Sancherz, G., Mira, A. G. New Engl. J. Med. 1977, 296, 1412. 6. Rosenthal, M., Trabert, U., Müller, W. Lancet, 1976, i, 369. 7. Ruuskanen, O., Remes, M., Mäkelä, A. H. L., Isomaki, H., Toivanen, A. ibid. 1976, ii, 958. 8. Graber, H., Takacs, L., Vedrödy, K. ibid. p. 1248.
933 EFFECT OF LEVAMISOLE ON VIABILITY OF LYMPHOCYTES IN
CULTURE
However, myeloid cells have usually been involved. Our
stu-
dies indicate that levamisole has
lym-
no
direct action
on c.L.L.
phocytes in-vitro. Department of Pathology, University of Saskatchewan, Saskatoon, Saskatchewan S7N 0W0, Canada
L. F. SKINNIDER M. RIEDER
MASSIVE FACTOR-VIII INFUSION IN HÆMOPHILIAC WITH FACTOR-VIII INHIBITOR, HIGH RESPONDER
SIR,-Bleeding in hsemophiliacs with factor-vm inhibitors of low-responder type is generally overcome by massive factorVIII infusions. The addition of immunosuppressive therapy may be successful in high responders, delaying and possibly weakening the anamnestic response.2.3 "Activated" factor-ix concentrates may also be usefu1.4 These regimens, however, are unsuitable when prolonged substitution therapy is necessary in a high responder. Our patient is a 20-year-old hxmophiliac with factor-vm inhibitor. His elder brother, also a haemophiliac with inhibitor, died aged 18 from a retroperitoneal haemorrhage. Our patient has had bleeding episodes since birth and has been given many infusions of whole blood, plasma, cryoprecipitate, and factorvm concentrates in more than thirty hospital admissions, without much success. Inhibitor was detected when he was 12 years old. Three times he has received concentrates in combination with immunosuppressive therapy, the last (1973) being with cyclophosphamide (15 mg/kg intravenously followed by 2 mg/kg body-weight orally for 10 days) when the inhibitor concentration increased after 4-5 days from 0.5units/ml to a peak of 30-40 units/ml after 2 weeks. The preinfusion level was regained after 2 months. In 1976 at the age of 18 he passed his final school examination, brilliantly, but he was confined to a wheelchair or bed and he wanted to be more independent. This would need prolonged physiotherapy, which could be achieved only if covered by factor-vm after elimination of inhibitor. We decided to use the treatment given by the haemophilic centre in Bonn5-a combination of daily massive infusions of factor vin and activated factor ix until the increase in inhibitor, which follows infusions, has been eliminated, after which daily doses should keep the inhibitor level low and permit physiotherapy. Our patient was treated in Bonn. His factor-viii level was 1% and his inhibitor level was 0.5 Bethesda units/ml on admission. The dosages and inhibi1 Allain, I P., Frommel. D Blood, 1976, 47, 937. Dormandy, K., Hawkey, C., Churchill, W G. L., Cowley, J. Thromb. Diath.
2
hœmorth 971, 43, 355. 3 Nielsson, I. M., Hedner, U Scand.
J
Hœmat
1976, 16, 364
Manucci, P. M., Bader, R , Ruggeri, Z. M. Lancet, 1976, i, 41. 5 Brackmann, H. H., Etzel, F., Hofmann, P., Egli, H. Thromb Hœmostas. 1977, 38, 369 abstr.
4
Fig.-Factor
VIII inhibitor
during treatment.
levels are shown in the figure. At first he received 3000 units of factor vm and 2500 units of concentrated factor ix daily. His inhibitor level increased during the first week to about 1100 units/ml and did not fall significantly until he had received 12 000 units of factor vm per day for 10 days. The dose could then be reduced, and after 3 months with daily injections an inhibitor level of 1 unit/ml was obtained. The inhibitor concentration rose 3 weeks later, the daily dosage of factor viii having been reduced too far, but the inhibitor concentration fell again when the dose was increased. After 7 months he has no demonstrable inhibitor while on 3000 units of factor vm and 1000 units of factor ix concentrate (’Feiba’) daily. He received, due to shortage of feiba, other factor-ix concentrates in between. There have been a few bleeding episodes, mostly in one bad elbow but sometimes more general. In more general bleeds we often found a positive ethanol test, increased amounts of fibrinogen-related antigens, shortened euglobulin-lysis time, a low platelet-count, and a defect in A.D.P., adrenaline, and collagen-induced platelet aggregation in vitro. He has biochemically no hepatic or renal damage. Platelet or leucocyte antibodies and hepatitis B antigen or antibody have not been found. He has been able to do progressively more active physiotherapy, and is making great progress. Furthermore he has passed another examination, and is able to use his typewriter again. Except for the first days in Bonn he has administered the injector
tions himself. A feature of this case is the very the very large doses of factor vm.
high
level of inhibitor and
Institute of Experimental Hæmatolgy and Blood Transfusion, University of Bonn, H. H. BRACKMANN Bonn, West Germany
Coagulation Laboratory, Municipal Hospital, 1399 Copenhagen K, Denmark
J. GORMSEN