- Email: [email protected]
Cyclosporin analogues
195
These patients receive large quantities of IVIG over a long period, and provide important information on the safety of IVIGs. Our data confirm the general impression that sandoglobulin has enjoyed a long record of safety,s although we need to exclude the possibility that small rises in liver enzymes are due to transient sub-clinical hepatitis C virus infection, with perhaps the occasional patient acquiring chronic HCV hepatitis. Tolerance to infusions is a less important issue, but there may be differences between preparations. It will be useful to compare our data with that from surveys of other IVIGs in the future. Immune Deficiency Research Group, MRC Clinical Research Centre, Harrow HA1 3UJ, UK
M. HANY A. RYAN A. D. B. WEBSTER
1. Imbach P, ed. Immunotherapy with intravenous immunoglobulins. London: Academic Press, 1991. 2. Intravenous gammaglobulin for immunodeficiency; report from the European Group of Immunodeficiencies (EGID). Clin Exp Immunol 1986; 65: 683-90. 3. Williams PE, Yap P-L, Gillon J, et al. Transmission of non-A, non-B hepatitis by pH4-treated intravenous gammaglobulin. Vox Sang 1989; 57: 15-18. 4 Quinti K, Guerra E, Scala E, et al. Anti-HCV antibodies in gammaglobulin for intravenous use. In: Chapel HM, Levinsky RJ, Webster ADB, eds. Progress in immunodeficiency III. London: Royal Society of Medicine Services, 1991: 150. 5. Cunningham-Rundles C. Immunoglobulin replacement therapy. In. Webster ADB, ed. Immunodeficiency and disease. London: Kluwer Academic, 1988: 43-60.
other symptoms of acute serum sickness. The rate of infection was comparable in controls and BT 563 treated patients; there were five episodes in 3 controls and nine episodes in 7 patients on BT 563. Episodes of complete and incomplete rejection among controls and patients who received BT 563 are shown in the table. All but two episodes were easily controlled with methylprednisolone 3 x 0-5 g; the two steroid-resistant episodes were controlled with OKT3. Even when conventional immunosuppression was much reduced (C) the rate of rejection remained remarkably low among patients who received BT 563. In 15 of the 56 protocol biopsies, histological signs of rejection were noted but they were not accompanied by clinical signs or laboratory abnormalities.
6900
Chirurgische Universitatsklinik Heidelberg, Heidelberg, Germany
GERD OTTO JOCHEN THIES THOMAS KRAUS MARTIN MANNER CHRISTIAN HERFARTH
Pathological Institute, University of Heidelberg
WALTER J. HOFMANN
Biotest-Pharma GmbH, Dreieich
HELMUT SCHLAG
Department of Immunology, Deutsches Krebsforschungszentrum Heidelberg
STEFAN MEUER
1. Herve
Monoclonal anti-CD25 for acute rejection after liver transplantation SIR,-Antibodies to interleukin-2 receptors (CD25) represent a novel approach to the prevention of acute allograft rejection.l-4 Last year we reported a pilot study with the monoclonal CD25 antibody BT 563 (Biotest-Pharma) in liver transplantation.s This study has now been extended to 19 consecutive transplantations, with modification of both dose of antibody and the basic
immunosuppressive regimen. historical
control group (n = 6, mean age 51) consisted of methylprednisolone 1 ’5 mg/kg immunosuppression tapered down to 01 mg, cyclosporin (blood concentration 300-400 ng/ml [monoclonal] for 2 weeks, thereafter 100-200 ng/ml), and azathioprine 1 ’5 mg/kg for 2 months. Three regimens with BT 563 have been used: (A) n 6, mean age 43, 10 mg BT 563 per 24 h for 10 days by continuous infusion and 10 mg by intravenous bolus every other day until day 20, plus additional immunosuppressive drugs as in controls; (B) n 3, mean age 40, 5 mg BT 563 per 24 h for 10 days and 5 mg every other day until day 20, plus additional immunosuppression as in controls; and (C) n = 10, mean age 44, 10 mg BT 563 per 24 h for 12 days, plus additional immunosuppressive treatment reduced to 50% of that in controls. The primary diagnoses, which were comparable in the four groups, were hepatoma 7, chronic hepatitis 8, primary biliary cirrhosis 4, alcoholic cirrhosis 4, fulminant liver failure 1, and echinococcosis 1. The controls had had a biopsy if clinically indicated whereas the patients on BT 563 had planned biopsies on days 7,14, and 21. For histological grading we used the Hannover c1assification.6 An increase in bilirubin and a concomitant rise in aminotransferase activity with histopathological proof of rejection was defmed as "complete" rejection. However, even though this triad was incomplete some patients were treated for rejection. Of the 25 patients, 22 are alive and well 4-13 months postoperatively; 3 died from recurrent tumour 4-5 months after the transplant. BT 563 did not cause side-effects such as fever, rash, or In
a
=
=
NUMBER OF REJECTIONS DURING AND AFTER PROPHYLACTIC TREATMENT WITH BT 563
P, Wijdenes J, Bergerat JP, et al. Treatment of acute graft-versus-host disease with monoclonal antibody to IL-2 receptor. Lancet 1988; ii: 1072-73. 2. Cantarovich D, Le Mauff B, Hourmant M, et al. Anti-IL2 receptor monoclonal antibody (33B3.1) in prophylaxis of early kidney rejection in humans: a randomized trial versus rabbit antithymocyte globulin Transpl Proc 1989; 21: 1769-71. 3. Soulillou JP, Cantarovich D, Le Mauff B, et al. Randomized controlled trial of a monoclonal antibody against the interleukin-2 receptor (33B3.1) as compared with rabbit antithymocyte globulin for prophylaxis against rejection of renal allografts. N Engl J Med 1990; 322: 1175-82. 4. Carpenter CB, Kirkman RL, Shapiro ME, et al. Prophylactic use of monoclonal anti-IL-2-receptor antibody m cadavenc renal transplantation. Am J Kidney Dis 1989; 14: 54-57. 5. Otto G, Thies J, Manner M, et al. Monoclonal antibody to interleukin-2 receptor in liver graft rejection. Lancet 1990; 335: 1596-97. 6. Kemnitz J, Ringe B, Cohnert T, et al. Bile duct injury as a part of diagnostic criteria for liver allograft rejection. Hum Pathol 1989; 20: 132-43.
Cyclosporin analogues SIR,-In considering candidate immunosuppressive drugs which might replace cyclosporin in clinical practice, Professor Bach (July 6, p 59) is incorrect in describing rapamycin and mycophenolic acid as cyclosporin analogues. Neither rapamycin (like FK 506, a macrolide) nor mycophenolic acid (like azathioprine, a purine synthesis inhibitor) is related structurally to cyclosporin, a cyclic endecapeptide.Moreover, the three drugs have quite distinct modes of action.2,3 Despite considerable effort, no cyclosporin analogue, derivative, or metabolite has yet emerged with a higher therapeutic index than cyclosporin. Division of Transplantation, Department of Surgery, University of Pittsburgh,
Pittsburgh, Pennsylvania 15261,
USA
A. W. THOMSON
1. Wood
RP, Katz SM, Kahan BD. New immunosuppressive agents. Transplant Sci 1991, 1: 34-46. 2. Sigal NH, Lin CS, Siekierka JJ. Inhibition of human T-cell activation by FK 506, rapamycin and cyclosporine A. Transplant Proc 1991; 23 (suppl 2): 1-5. 3. Allison AC, Almquist SJ, Muller CD, Eugui EM. In vitro immunosuppressive effects of mycophenolic acid and an ester prodrug, RS-61443. Transplant Proc 1991; 23
(suppl 2):
10-14.
Foodborne intoxication associated with seaweed SIR,-We report preliminary information on a common-source outbreak offoodbome intoxication associated with seaweed. Over a 24 h period five people presented with vomiting, diarrhoea, stomach cramps, respiratory distress, muscle spasms, and numbness of the extremities and were admitted to hospital with a provisional diagnosis of ciguatera fish poisoning. Two patients with similar symptoms but who were less seriously affected were briefly held for observation; two additional patients were treated by private physicians as outpatients. These patients were from five households
These patients receive large quantities of IVIG over a long period, and provide important information on the safety of IVIGs. Our data confirm the general impression that sandoglobulin has enjoyed a long record of safety,s although we need to exclude the possibility that small rises in liver enzymes are due to transient sub-clinical hepatitis C virus infection, with perhaps the occasional patient acquiring chronic HCV hepatitis. Tolerance to infusions is a less important issue, but there may be differences between preparations. It will be useful to compare our data with that from surveys of other IVIGs in the future. Immune Deficiency Research Group, MRC Clinical Research Centre, Harrow HA1 3UJ, UK
M. HANY A. RYAN A. D. B. WEBSTER
1. Imbach P, ed. Immunotherapy with intravenous immunoglobulins. London: Academic Press, 1991. 2. Intravenous gammaglobulin for immunodeficiency; report from the European Group of Immunodeficiencies (EGID). Clin Exp Immunol 1986; 65: 683-90. 3. Williams PE, Yap P-L, Gillon J, et al. Transmission of non-A, non-B hepatitis by pH4-treated intravenous gammaglobulin. Vox Sang 1989; 57: 15-18. 4 Quinti K, Guerra E, Scala E, et al. Anti-HCV antibodies in gammaglobulin for intravenous use. In: Chapel HM, Levinsky RJ, Webster ADB, eds. Progress in immunodeficiency III. London: Royal Society of Medicine Services, 1991: 150. 5. Cunningham-Rundles C. Immunoglobulin replacement therapy. In. Webster ADB, ed. Immunodeficiency and disease. London: Kluwer Academic, 1988: 43-60.
other symptoms of acute serum sickness. The rate of infection was comparable in controls and BT 563 treated patients; there were five episodes in 3 controls and nine episodes in 7 patients on BT 563. Episodes of complete and incomplete rejection among controls and patients who received BT 563 are shown in the table. All but two episodes were easily controlled with methylprednisolone 3 x 0-5 g; the two steroid-resistant episodes were controlled with OKT3. Even when conventional immunosuppression was much reduced (C) the rate of rejection remained remarkably low among patients who received BT 563. In 15 of the 56 protocol biopsies, histological signs of rejection were noted but they were not accompanied by clinical signs or laboratory abnormalities.
6900
Chirurgische Universitatsklinik Heidelberg, Heidelberg, Germany
GERD OTTO JOCHEN THIES THOMAS KRAUS MARTIN MANNER CHRISTIAN HERFARTH
Pathological Institute, University of Heidelberg
WALTER J. HOFMANN
Biotest-Pharma GmbH, Dreieich
HELMUT SCHLAG
Department of Immunology, Deutsches Krebsforschungszentrum Heidelberg
STEFAN MEUER
1. Herve
Monoclonal anti-CD25 for acute rejection after liver transplantation SIR,-Antibodies to interleukin-2 receptors (CD25) represent a novel approach to the prevention of acute allograft rejection.l-4 Last year we reported a pilot study with the monoclonal CD25 antibody BT 563 (Biotest-Pharma) in liver transplantation.s This study has now been extended to 19 consecutive transplantations, with modification of both dose of antibody and the basic
immunosuppressive regimen. historical
control group (n = 6, mean age 51) consisted of methylprednisolone 1 ’5 mg/kg immunosuppression tapered down to 01 mg, cyclosporin (blood concentration 300-400 ng/ml [monoclonal] for 2 weeks, thereafter 100-200 ng/ml), and azathioprine 1 ’5 mg/kg for 2 months. Three regimens with BT 563 have been used: (A) n 6, mean age 43, 10 mg BT 563 per 24 h for 10 days by continuous infusion and 10 mg by intravenous bolus every other day until day 20, plus additional immunosuppressive drugs as in controls; (B) n 3, mean age 40, 5 mg BT 563 per 24 h for 10 days and 5 mg every other day until day 20, plus additional immunosuppression as in controls; and (C) n = 10, mean age 44, 10 mg BT 563 per 24 h for 12 days, plus additional immunosuppressive treatment reduced to 50% of that in controls. The primary diagnoses, which were comparable in the four groups, were hepatoma 7, chronic hepatitis 8, primary biliary cirrhosis 4, alcoholic cirrhosis 4, fulminant liver failure 1, and echinococcosis 1. The controls had had a biopsy if clinically indicated whereas the patients on BT 563 had planned biopsies on days 7,14, and 21. For histological grading we used the Hannover c1assification.6 An increase in bilirubin and a concomitant rise in aminotransferase activity with histopathological proof of rejection was defmed as "complete" rejection. However, even though this triad was incomplete some patients were treated for rejection. Of the 25 patients, 22 are alive and well 4-13 months postoperatively; 3 died from recurrent tumour 4-5 months after the transplant. BT 563 did not cause side-effects such as fever, rash, or In
a
=
=
NUMBER OF REJECTIONS DURING AND AFTER PROPHYLACTIC TREATMENT WITH BT 563
P, Wijdenes J, Bergerat JP, et al. Treatment of acute graft-versus-host disease with monoclonal antibody to IL-2 receptor. Lancet 1988; ii: 1072-73. 2. Cantarovich D, Le Mauff B, Hourmant M, et al. Anti-IL2 receptor monoclonal antibody (33B3.1) in prophylaxis of early kidney rejection in humans: a randomized trial versus rabbit antithymocyte globulin Transpl Proc 1989; 21: 1769-71. 3. Soulillou JP, Cantarovich D, Le Mauff B, et al. Randomized controlled trial of a monoclonal antibody against the interleukin-2 receptor (33B3.1) as compared with rabbit antithymocyte globulin for prophylaxis against rejection of renal allografts. N Engl J Med 1990; 322: 1175-82. 4. Carpenter CB, Kirkman RL, Shapiro ME, et al. Prophylactic use of monoclonal anti-IL-2-receptor antibody m cadavenc renal transplantation. Am J Kidney Dis 1989; 14: 54-57. 5. Otto G, Thies J, Manner M, et al. Monoclonal antibody to interleukin-2 receptor in liver graft rejection. Lancet 1990; 335: 1596-97. 6. Kemnitz J, Ringe B, Cohnert T, et al. Bile duct injury as a part of diagnostic criteria for liver allograft rejection. Hum Pathol 1989; 20: 132-43.
Cyclosporin analogues SIR,-In considering candidate immunosuppressive drugs which might replace cyclosporin in clinical practice, Professor Bach (July 6, p 59) is incorrect in describing rapamycin and mycophenolic acid as cyclosporin analogues. Neither rapamycin (like FK 506, a macrolide) nor mycophenolic acid (like azathioprine, a purine synthesis inhibitor) is related structurally to cyclosporin, a cyclic endecapeptide.Moreover, the three drugs have quite distinct modes of action.2,3 Despite considerable effort, no cyclosporin analogue, derivative, or metabolite has yet emerged with a higher therapeutic index than cyclosporin. Division of Transplantation, Department of Surgery, University of Pittsburgh,
Pittsburgh, Pennsylvania 15261,
USA
A. W. THOMSON
1. Wood
RP, Katz SM, Kahan BD. New immunosuppressive agents. Transplant Sci 1991, 1: 34-46. 2. Sigal NH, Lin CS, Siekierka JJ. Inhibition of human T-cell activation by FK 506, rapamycin and cyclosporine A. Transplant Proc 1991; 23 (suppl 2): 1-5. 3. Allison AC, Almquist SJ, Muller CD, Eugui EM. In vitro immunosuppressive effects of mycophenolic acid and an ester prodrug, RS-61443. Transplant Proc 1991; 23
(suppl 2):
10-14.
Foodborne intoxication associated with seaweed SIR,-We report preliminary information on a common-source outbreak offoodbome intoxication associated with seaweed. Over a 24 h period five people presented with vomiting, diarrhoea, stomach cramps, respiratory distress, muscle spasms, and numbness of the extremities and were admitted to hospital with a provisional diagnosis of ciguatera fish poisoning. Two patients with similar symptoms but who were less seriously affected were briefly held for observation; two additional patients were treated by private physicians as outpatients. These patients were from five households