- Email: [email protected]
Mycophenolate mofetil for prevention of acute rejection
FeLV antigen was not detected in any of the samples; all but one were negative for FIV antibodies with ELISA. The one ELISA-reactive sample (an adult ANLL case) proved clearly negative in western blot, and therefore apparently represents a false-positive ELISA result. Similarly, no FeLV sequence was found in the PB-MNCs and bone marrow cells. To conclude, we have not found any evidence of infection with either FeLV or FIV in patients with different
haematological neoplasms. *N Nowotny, A Uthman, O A Haas, A Borkhardt, K Lechner, H F Egberink, K Möstl, M C Horzinek *Institute of Virology, Veterinary University of Vienna, A-1030 Vienna, Austria; Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases, University of Vienna Medical School, Vienna; Children’s Cancer Research Institute, St Anna Children’s Hospital, Vienna; Department of Paediatrics, Haematology and Oncology, University of Giessen, Giessen, Germany; Department of Medicine I, Division of Haematology and Haemostaseology, University of Vienna Medical School; Department of Infectious Diseases and Immunology, Division of Virology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands; Institute of Virology, Veterinary University of Vienna; and Department of Infectious Diseases and Immunology, Division of Virology, Faculty of Veterinary Medicine, Utrecht University
1 Donaldso LJ, Rankin J, Proctor S. Is it possible to catch leukaemia from a cat? Lancet 1994; 344: 971-72. 2 Uthman A. Detection of animal and human retroviral nucleic acid sequences in various tissues by using the polymerase chain reaction (dissertation). Vienna: Veterinary University of Vienna, 1995.
Mycophenolate mofetil for prevention of acute rejection SIR-The
European Mycophenolate Mofetil Cooperative Study Group (May 27, p 1321) reports the encouraging results of adding mycophenolate mofetil (mycophenolic acid) to prophylactic immunosuppression with cyclosporin and prednisolone for renal transplant recipients. The importance of these results for clinical practice, however, should be viewed with caution since the control immunosuppression regimen produces suboptimum results in terms of graft survival’ compared with the more standard induction regimen, such as triple therapy with cyclosporin, azathioprine, and steroids, as used in over 80% of renal transplant cases in Europe. Furthermore, the cyclosporin formulation used was the conventional form (Sandimmun), which has been superseded by a more readily absorbed formulation (Neoral). The two formulations cannot be regarded as interchangeable, especially since a recent trial has suggested that the rate of acute rejection seen with the Neoral formulation is lower than with the Sandimmun form. It would therefore be interesting to examine the adjunctive use of mycophenolate mofetil with a Neoral-based
immunosuppressive regimen. A recent case at Cardiff Royal Infirmary shows the clinical difference between the two formulations of cyclosporin. A 44-year-old man received a one haplotype-matched kidney from his mother and was given prophylactic immunosuppression with cyclosporin (Sandimmun), prednisolone, and azathioprine. At day 7 post transplant he had an episode of acute biopsy-proven rejection (figure). Treatment was initiated with methylprednisolone, but because of clinical severity and histological features indicating a vascular component, he was started on OKT3 (muromonab-CD3). After a period of dialysis dependence, his renal function improved, but then plateaued, and biopsy confirmed continuing grade II cellular rejection. Further pulses of methylprednisolone led to a transient response, but biopsy-confirmed rejection continued and anti-thymocyte globulin (ATG) was begun. During this period cyclosporin blood concentrations fluctuated widely. Thus, a cyclosporin pharmacokinetic profile after a single dose of 300 mg
Figure: Clinical course of transplant showing time of biopsies (Bx) and treatment with methylprednisolone (MP), OKT3, and ATG and time of transfer to cyclosporin Neoral (NEO) Sandimmun
done. The time to maximum absorption a maximum whole blood concentration (Tmax) of 1200 ng/mL. Graft function improved after ATG, (Cmax) but plateaued at an unacceptable level. Another biopsy showed no evidence of acute cellular rejection, but in view of the history of severe recurrent rejection and the slow absorption, which may have explained the patient’s complicated clinical course, he was transferred to Neoral. No further rejection took place, creatinine concentration fell, and cyclosporin blood concentrations stabilised. A repeat pharmacokinetic profile was performed on Neoral. After a single dose of 200 mg (33% reduction), the Tmax decreased to less than 2 h and the Cmax to 1600 ng/mL. Mycophenolate mofetil is undoubtedly a promising new drug and alongside tacrolimus and Neoral offers new hope for transplant recipients to prevent acute rejection and promote long-term graft survival. However, before widespread clinical use is advocated we need more data on its use as adjunctive therapy to the optimum immunosuppressive protocols; this is especially true in view of the probable extra cost that would be associated with the addition of mycophenolate mofetil and tacrolimus to lifelong post-transplant immunosuppression. In this context, cost-effectiveness analysis focuses on outcomes and, in particular, graft survival rather than acute rejection. From a provider perspective it is disappointing, therefore, that it may be some time before compelling clinical data are available to satisfy health commissioners that the use of these powerful new agents is of proven clinical and economic effectiveness. was
5
was
h, with
*Richard Moore, Peter Griffin, Adam Jurewicz, Rozanne Lord Cardiff
1 2
Christopher Darby,
Royal Infirmary, Cardiff CF2 1SZ, UK
Opelz G. Collaborative Transplant Study—10-year report. Transplant Proc 1992; 24: 2342-55. Niese D. A double blind randomized study of Sandimmun Neoral versus Sandimmun in new renal transplant recipients—results after twelve months. Transplant Proc 1995; 27: 1849-56.
SIR-The
European Mycophenolate Mofetil Cooperative Study Group quite appropriately draws only modest conclusions from the study of mycophenolate mofetil on the prevention of acute renal allograft rejection. The of combination and corticosteroids, cyclosporin, mofetil (three immunosuppressive agents) mycophenolate was more effective than cyclosporin, corticosteroids, and placebo (two immunosuppressive agents). So what? The important question is, does this triple therapy combination 253
provide improved immunosuppression or merely more immunosuppression? The higher incidence of opportunistic infections in the mycophenolate mofetil-treated patients suggests the latter. There are established methods of testing whether immunosuppressant drugs act synergistically or additively when used in combination but the design of this study precludes their use.’ I
C G Winearls Oxford Regional Renal Unit, Oxford Radcliffe Hospital Trust, Headington, Oxford OX3 7LI, UK
1
Berenbaum MC.
Synergy, additivism and antagonism in immunosuppression: a critical review. Clin Exp Immunol 1977;
28:
1-18.
High-dose frusemide for cardiac failure SiR-Many patients, especially elderly people, need further diuretic treatment in addition to angiotensin-convertingenzyme (ACE) inhibitors. Among elderly people with advanced disease, a lack of response to low-dose frusemide is common. The options are to use a larger dose of frusemide or to add another diuretic agent. High-dose frusemide therapy (250-400 mg per day), given by mouth, by intravenous bolus, or by continuous infusion is effective in refractory congestive cardiac failure.’ Many physicians are, however, reluctant to use high-dose frusemide, mainly because of concerns about renal function. The alternative approach is to use a combination of diuretics, usually frusemide with a thiazide or potassiumsparing agent. Although this approach can be effective, 2 severe electrolyte disturbances can occur. We reviewed 15 geriatric inpatients (eight male, six female; mean age 83 [65-93] years) admitted to a rehabilitation unit with left, congestive, or biventricular cardiac failure, who were treated with moderate to high doses of frusemide. All 15 patients were on clinically optimum doses of ACE inhibitors at discharge and 12 were being so treated on admission. 13 had atrial fibrillation and were receiving digoxin. The average daily frusemide dose was 193 mg (SD 136, maximum 500) on admission and 297 mg (181, 750) at Mean serum creatinine was 161 discharge (p<0006). ’
jjLmol/L (56-7, 325) on admission and 160 jjLmol/L (77-7, 392) at discharge (not significant). There was an average weight loss of 5-6 kg and an average rise in the Barthel score of 4 points. 11 patients returned to their previous home (six) or hostal (five), three were relocated to a hostel (one) or nursing home (two), and one patient had an acute myocardial infarction and died in hospital. There were no significant electrolyte disturbances apart from hypokalaemia that responded to potassium supplementation. In the setting of cardiac failure resistant to an optimum dose of an ACE inhibitor and low-dose frusemide, although the addition of a thiazide diuretic may be a useful adjunct, we conclude that the use of high-dose frusemide was an effective and safe approach to management of severe cardiac
Ibuprofen
versus
sumatriptan for high-altitude
headache SiR-Ibuprofen, a non-steroidal anti-inflammatory drug, has been shown to be superior for treatment of high-altitude headache than placebo.’ Bartsch and colleagues2 recently proposed that sumatriptan a 5-HTB receptor agonist, might be even more effective than ibuprofen.- To test this hypothesis, we compared oral ibuprofen and sumatriptan in a randomised, double-blind, within-patient crossover trial. 33 volunteers (18 men, 15 females, mean age 29, range 19-52) were transported from 200 m to an altitude of 3480 m (by bus and cable car) and stayed there for 18 h. Medical history and clinical examination of the subjects revealed no evidence of existing acute or chronic diseases. Nutrition and physical activity were standardised 12 h before and during the altitude sojourn. 5-15 h after arrival at altitude, 13 (9 males, 4 females, mean age 36, range 23-52) developed headache. Treatment was started when a headache score of 2 (0=none, l=mild, 2=moderate, 3=severe) and an acute mountain sickness score3 greater than 2 were reached. The patients were randomised to ibuprofen (600 mg) and sumatriptan (100 mg), respectively. Scoring was repeated 2 h after drug intake. If patients needed further medication, they were given the drug not initially administered. Heart rate, blood pressure, and oxygen saturation were measured in all subjects before and during the altitude sojourn. Score
changes within groups were analysed with Wilcoxon’s signed rank tests. To compare differences for continuous variables we used t tests. All statistical tests were 2-tailed. After intake of ibuprofen, nearly complete relief of the headache occurred in these patients (n=7) within 2 h. In contrast, no decrease of the headache score was found in patients (n=6) treated with sumatriptan. 5 of these patients needed further medication and achieved complete relief within 2 h of subsequent ibuprofen intake (figure). A significant reduction of the acute mountain sickness score was observed within the ibuprofen group (mean 4-3 [SD 049] vs 0-57 [0-98], p=0018). No such reduction occurred within the sumatriptan group. No assessments except headache score were made for the sumatriptan group after ibuprofen intake. The mean values of heart rate, blood pressure, and oxygen saturation did not differ between the group with headache and the group without headache throughout the investigation. However, heart rates tended to decrease 2 h after treatment with ibuprofen (88-7 [16.7] vs 75-0 [15-3], p=0.1) probably due to the decrease in painrelated sympathetic adrenergic stimulation. No heart rate changes occurred in the group treated with sumatriptan. No adverse effects were observed.
failure. *G Waterer, M Donaldson Departments of *Neurology and Geriatrics, Royal Perth Hospital, Perth, Western Australia 6001
1 2
Gerlag PG, van Meijel JJM. High-dose frusemide in the treatment of refractory congestive heart failure. Arch Intern Med 1988; 148: 286-91. Oster JR, Epstein M, Smoler S. Combined therapy with thiazide-type and loop diuretic agents for resistant sodium retention. Ann Intern Med
with
1983; 99: 405-06.
p values calculated with Wilcoxon’s
254
Figure: Changes sumatriptan sumatriptan
in
(SD) headache scores after treatment ibuprofen, or ibuprofen after previous
mean
or
signed rank
tests.
haematological neoplasms. *N Nowotny, A Uthman, O A Haas, A Borkhardt, K Lechner, H F Egberink, K Möstl, M C Horzinek *Institute of Virology, Veterinary University of Vienna, A-1030 Vienna, Austria; Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases, University of Vienna Medical School, Vienna; Children’s Cancer Research Institute, St Anna Children’s Hospital, Vienna; Department of Paediatrics, Haematology and Oncology, University of Giessen, Giessen, Germany; Department of Medicine I, Division of Haematology and Haemostaseology, University of Vienna Medical School; Department of Infectious Diseases and Immunology, Division of Virology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands; Institute of Virology, Veterinary University of Vienna; and Department of Infectious Diseases and Immunology, Division of Virology, Faculty of Veterinary Medicine, Utrecht University
1 Donaldso LJ, Rankin J, Proctor S. Is it possible to catch leukaemia from a cat? Lancet 1994; 344: 971-72. 2 Uthman A. Detection of animal and human retroviral nucleic acid sequences in various tissues by using the polymerase chain reaction (dissertation). Vienna: Veterinary University of Vienna, 1995.
Mycophenolate mofetil for prevention of acute rejection SIR-The
European Mycophenolate Mofetil Cooperative Study Group (May 27, p 1321) reports the encouraging results of adding mycophenolate mofetil (mycophenolic acid) to prophylactic immunosuppression with cyclosporin and prednisolone for renal transplant recipients. The importance of these results for clinical practice, however, should be viewed with caution since the control immunosuppression regimen produces suboptimum results in terms of graft survival’ compared with the more standard induction regimen, such as triple therapy with cyclosporin, azathioprine, and steroids, as used in over 80% of renal transplant cases in Europe. Furthermore, the cyclosporin formulation used was the conventional form (Sandimmun), which has been superseded by a more readily absorbed formulation (Neoral). The two formulations cannot be regarded as interchangeable, especially since a recent trial has suggested that the rate of acute rejection seen with the Neoral formulation is lower than with the Sandimmun form. It would therefore be interesting to examine the adjunctive use of mycophenolate mofetil with a Neoral-based
immunosuppressive regimen. A recent case at Cardiff Royal Infirmary shows the clinical difference between the two formulations of cyclosporin. A 44-year-old man received a one haplotype-matched kidney from his mother and was given prophylactic immunosuppression with cyclosporin (Sandimmun), prednisolone, and azathioprine. At day 7 post transplant he had an episode of acute biopsy-proven rejection (figure). Treatment was initiated with methylprednisolone, but because of clinical severity and histological features indicating a vascular component, he was started on OKT3 (muromonab-CD3). After a period of dialysis dependence, his renal function improved, but then plateaued, and biopsy confirmed continuing grade II cellular rejection. Further pulses of methylprednisolone led to a transient response, but biopsy-confirmed rejection continued and anti-thymocyte globulin (ATG) was begun. During this period cyclosporin blood concentrations fluctuated widely. Thus, a cyclosporin pharmacokinetic profile after a single dose of 300 mg
Figure: Clinical course of transplant showing time of biopsies (Bx) and treatment with methylprednisolone (MP), OKT3, and ATG and time of transfer to cyclosporin Neoral (NEO) Sandimmun
done. The time to maximum absorption a maximum whole blood concentration (Tmax) of 1200 ng/mL. Graft function improved after ATG, (Cmax) but plateaued at an unacceptable level. Another biopsy showed no evidence of acute cellular rejection, but in view of the history of severe recurrent rejection and the slow absorption, which may have explained the patient’s complicated clinical course, he was transferred to Neoral. No further rejection took place, creatinine concentration fell, and cyclosporin blood concentrations stabilised. A repeat pharmacokinetic profile was performed on Neoral. After a single dose of 200 mg (33% reduction), the Tmax decreased to less than 2 h and the Cmax to 1600 ng/mL. Mycophenolate mofetil is undoubtedly a promising new drug and alongside tacrolimus and Neoral offers new hope for transplant recipients to prevent acute rejection and promote long-term graft survival. However, before widespread clinical use is advocated we need more data on its use as adjunctive therapy to the optimum immunosuppressive protocols; this is especially true in view of the probable extra cost that would be associated with the addition of mycophenolate mofetil and tacrolimus to lifelong post-transplant immunosuppression. In this context, cost-effectiveness analysis focuses on outcomes and, in particular, graft survival rather than acute rejection. From a provider perspective it is disappointing, therefore, that it may be some time before compelling clinical data are available to satisfy health commissioners that the use of these powerful new agents is of proven clinical and economic effectiveness. was
5
was
h, with
*Richard Moore, Peter Griffin, Adam Jurewicz, Rozanne Lord Cardiff
1 2
Christopher Darby,
Royal Infirmary, Cardiff CF2 1SZ, UK
Opelz G. Collaborative Transplant Study—10-year report. Transplant Proc 1992; 24: 2342-55. Niese D. A double blind randomized study of Sandimmun Neoral versus Sandimmun in new renal transplant recipients—results after twelve months. Transplant Proc 1995; 27: 1849-56.
SIR-The
European Mycophenolate Mofetil Cooperative Study Group quite appropriately draws only modest conclusions from the study of mycophenolate mofetil on the prevention of acute renal allograft rejection. The of combination and corticosteroids, cyclosporin, mofetil (three immunosuppressive agents) mycophenolate was more effective than cyclosporin, corticosteroids, and placebo (two immunosuppressive agents). So what? The important question is, does this triple therapy combination 253
provide improved immunosuppression or merely more immunosuppression? The higher incidence of opportunistic infections in the mycophenolate mofetil-treated patients suggests the latter. There are established methods of testing whether immunosuppressant drugs act synergistically or additively when used in combination but the design of this study precludes their use.’ I
C G Winearls Oxford Regional Renal Unit, Oxford Radcliffe Hospital Trust, Headington, Oxford OX3 7LI, UK
1
Berenbaum MC.
Synergy, additivism and antagonism in immunosuppression: a critical review. Clin Exp Immunol 1977;
28:
1-18.
High-dose frusemide for cardiac failure SiR-Many patients, especially elderly people, need further diuretic treatment in addition to angiotensin-convertingenzyme (ACE) inhibitors. Among elderly people with advanced disease, a lack of response to low-dose frusemide is common. The options are to use a larger dose of frusemide or to add another diuretic agent. High-dose frusemide therapy (250-400 mg per day), given by mouth, by intravenous bolus, or by continuous infusion is effective in refractory congestive cardiac failure.’ Many physicians are, however, reluctant to use high-dose frusemide, mainly because of concerns about renal function. The alternative approach is to use a combination of diuretics, usually frusemide with a thiazide or potassiumsparing agent. Although this approach can be effective, 2 severe electrolyte disturbances can occur. We reviewed 15 geriatric inpatients (eight male, six female; mean age 83 [65-93] years) admitted to a rehabilitation unit with left, congestive, or biventricular cardiac failure, who were treated with moderate to high doses of frusemide. All 15 patients were on clinically optimum doses of ACE inhibitors at discharge and 12 were being so treated on admission. 13 had atrial fibrillation and were receiving digoxin. The average daily frusemide dose was 193 mg (SD 136, maximum 500) on admission and 297 mg (181, 750) at Mean serum creatinine was 161 discharge (p<0006). ’
jjLmol/L (56-7, 325) on admission and 160 jjLmol/L (77-7, 392) at discharge (not significant). There was an average weight loss of 5-6 kg and an average rise in the Barthel score of 4 points. 11 patients returned to their previous home (six) or hostal (five), three were relocated to a hostel (one) or nursing home (two), and one patient had an acute myocardial infarction and died in hospital. There were no significant electrolyte disturbances apart from hypokalaemia that responded to potassium supplementation. In the setting of cardiac failure resistant to an optimum dose of an ACE inhibitor and low-dose frusemide, although the addition of a thiazide diuretic may be a useful adjunct, we conclude that the use of high-dose frusemide was an effective and safe approach to management of severe cardiac
Ibuprofen
versus
sumatriptan for high-altitude
headache SiR-Ibuprofen, a non-steroidal anti-inflammatory drug, has been shown to be superior for treatment of high-altitude headache than placebo.’ Bartsch and colleagues2 recently proposed that sumatriptan a 5-HTB receptor agonist, might be even more effective than ibuprofen.- To test this hypothesis, we compared oral ibuprofen and sumatriptan in a randomised, double-blind, within-patient crossover trial. 33 volunteers (18 men, 15 females, mean age 29, range 19-52) were transported from 200 m to an altitude of 3480 m (by bus and cable car) and stayed there for 18 h. Medical history and clinical examination of the subjects revealed no evidence of existing acute or chronic diseases. Nutrition and physical activity were standardised 12 h before and during the altitude sojourn. 5-15 h after arrival at altitude, 13 (9 males, 4 females, mean age 36, range 23-52) developed headache. Treatment was started when a headache score of 2 (0=none, l=mild, 2=moderate, 3=severe) and an acute mountain sickness score3 greater than 2 were reached. The patients were randomised to ibuprofen (600 mg) and sumatriptan (100 mg), respectively. Scoring was repeated 2 h after drug intake. If patients needed further medication, they were given the drug not initially administered. Heart rate, blood pressure, and oxygen saturation were measured in all subjects before and during the altitude sojourn. Score
changes within groups were analysed with Wilcoxon’s signed rank tests. To compare differences for continuous variables we used t tests. All statistical tests were 2-tailed. After intake of ibuprofen, nearly complete relief of the headache occurred in these patients (n=7) within 2 h. In contrast, no decrease of the headache score was found in patients (n=6) treated with sumatriptan. 5 of these patients needed further medication and achieved complete relief within 2 h of subsequent ibuprofen intake (figure). A significant reduction of the acute mountain sickness score was observed within the ibuprofen group (mean 4-3 [SD 049] vs 0-57 [0-98], p=0018). No such reduction occurred within the sumatriptan group. No assessments except headache score were made for the sumatriptan group after ibuprofen intake. The mean values of heart rate, blood pressure, and oxygen saturation did not differ between the group with headache and the group without headache throughout the investigation. However, heart rates tended to decrease 2 h after treatment with ibuprofen (88-7 [16.7] vs 75-0 [15-3], p=0.1) probably due to the decrease in painrelated sympathetic adrenergic stimulation. No heart rate changes occurred in the group treated with sumatriptan. No adverse effects were observed.
failure. *G Waterer, M Donaldson Departments of *Neurology and Geriatrics, Royal Perth Hospital, Perth, Western Australia 6001
1 2
Gerlag PG, van Meijel JJM. High-dose frusemide in the treatment of refractory congestive heart failure. Arch Intern Med 1988; 148: 286-91. Oster JR, Epstein M, Smoler S. Combined therapy with thiazide-type and loop diuretic agents for resistant sodium retention. Ann Intern Med
with
1983; 99: 405-06.
p values calculated with Wilcoxon’s
254
Figure: Changes sumatriptan sumatriptan
in
(SD) headache scores after treatment ibuprofen, or ibuprofen after previous
mean
or
signed rank
tests.