247
Treatment of CMV retinitis SIR,-Your Dec 14 editorial details previously unpublished results of a randomised trial of ganciclovir versus foscamet therapy for cytomegalovirus (CMV)-associated retinitis in AIDS patients. The two drugs were apparently equally effective in producing an initial clinical response and in preventing recrudescence of disease, but patients treated with foscamet survived longer than those treated with ganciclovir. Interpretation of these results is difficult. There is no proof that either ganciclovir or foscamet are effective drugs in CMVassociated retinitis because no placebo-controlled trials have been done.12 Moreover, there is no epidemiological evidence proving that CMV causes retinitisand HIV may be the direct cause of retinitis in AIDS patients.4 The data accrued in the trial of ganciclovir versus foscamet therapy could therefore mean that both drugs are effective because of their anti-CMV activity or because they are active against another aetiological agent. However, an alternative conclusion is that neither drug is effective and that retinitis often resolves spontaneously. As you note, treatment of CMV-associated retinitis in AIDS patients is far from satisfactory. In addition to the recognised drawbacks of intravenous administration and toxicity of ganciclovir and foscamet, the need to withdraw systemic zidovudine treatment before systemic ganciclovir therapy is initiated means that a drug known to delay death from AIDS must be stopped in order to administer a possibly ineffective drug as treatment for CMVassociated retinitis. Simultaneous systemic ganciclovir and zidovudine therapy is precluded by severe bone-marrow toxicity.s Further progress in the treatment of CMV-associated retinitis may therefore be made only after the development of orally active anti-CMV agents of lower toxicity than ganciclovir and foscamet and/or anti-HIV agents of lower toxicity than zidovudine.6 Clinical trials will then need to establish whether an anti-CMV drug alone or ananti-CMV drug combined with an anti-HIV drug represents the best treatment for retinitis in AIDS patients.6 Division of Virology, Department of Pathological Sciences, University of Manchester Medical School, Manchester M13 9PT, UK
(children). Concerns about vasculitis, based
on
arteriopathy. Control of rejection by FK 506 is achieved with a striking reduction in steroid requirement (80% of children are off prednisone at 3 months) and antihypertensive therapy. Moreover, cholesterol values in both adults and children are lower than in cyclosporin controls. All transplanted organs are susceptible to chronic rejection, manifested in the heart as coronary arteriopathy. Indeed, the Stanford group has previously ascribed coronary disease in some cardiac allografts of FK 506-treated non-human primates to the overall rejection process.7 On the basis of our observations so far we are optimistic that one of the benefits of FK 506 in human cardiac transplantation may be a reduction in the long-term risk of GVD. Departments of Surgery and Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
ANGUS W. THOMSON JOHN M. ARMITAGE ANTHONY J. DEMETRIS
Billingham ME, Moms RE The effect of cyclosporine and the two new immunosuppressive macrolides, FK 506, and rapamycin on heart graft rejection and graft coronary atherosclerosis. J Heart Transplant 1990; 9: 55. 2. Wu GD, Cramer DV, Chapman FA, et al. FK 506 inhibits the development of transplant atherosclerosis. Transplant Proc 1991; 23: 3272-74. 3. Murase N, Demetris AJ, Matsuzaki T, et al. Long survival in rats after multivisceral versus isolated small-bowel allotransplantation under FK 506. Surgery 1991; 110: 87-98. 4. Armitage JM, Kormos RL, Fung J, et al. The clinical trial of FK 506 as primary and rescue immunosuppression in adult cardiac transplantation. Transplant Proc 1991; 23: 3056-57. 5 Armitage JM, Fricker FJ, Del Nido P, et al The clinical trial of FK 506 as primary and rescue immunosuppression in pediatric cardiac transplantation. Transplant Proc 1. Meiser BM,
1991; 23: 3058-60. Ochiai T, Sakamoto K, Gunji Y, et al. Effects of combination treatment with FK 506 and cyclosporine on survival time and vascular changes in renal-allograft-recipient dogs. Transplantation 1989, 48: 193-97. 7. Flavin T, Ivens K, Wang J, et al. Initial experience with FK 506 as an 6
immunosuppressant for nonhuman primate recipients Transplant Proc 1991; 23: 531-32.
FK 506, cardiac transplantation, and graft-vessel disease SIR,-We are aware of the published observations’ of Dr Meiser and colleagues (Nov 23, p 1297) about modulation of graft-vessel disease (GVD) by the immunosuppressants cyclosporin, FK 506, and rapamycin in rats given cardiac allografts. In their recent report more severe GVD is seen in rats treated with FK 506 (1 or 2 mg/kg daily) for 50 days than in those who received cyclosporin or rapamycin. Meiser et al predict that GVD might occur in heart transplant patients treated with FK 506. Wu et al, however, have described the inhibition of rat heart allograft arteriosclerosis by FK 5062 at a dose (1 mg/kg daily FK 506 for 90 days) that Meiser et al report enhances GVD. No vascular lesions appeared in FK 506-treated recipients of syngeneic grafts. We have also seen no graft-vessel arteriopathy in small bowel of liver allografts of rats treated with 0-64 mg/kg FK 506 for up to 200 days.3In the now rather large experience at this centre, very good cardiac allograft function and quality of life have been achieved in adults4 and children’ receiving lower doses of the drug (maintenance dose 02-04 mg/kg daily) as primary immunosuppressive therapymedian follow-up times being 260 days (adults) and 304 days
of cardiac
allografts.
Celiprolol
DAVID J. MORRIS
1 Moms DJ. Antiviral chemotherapy for cytomegalovirus disease, J Antimicrob Chemother 1988; 21: 519-22. 2. Morris DJ. Clinical trials of antiviral agents J Antimicrob Chemother (in press). 3. Morris DJ. Epidemiological evidence is crucial as proof of causation in cytomegalovirus disease. J Infect 1991; 23: 233-40 4. Moms DJ. Is human immunodeficiency virus (HIV) rather than cytomegalovirus the cause of retinitis and colitis in HIV-infected patients? Rev Infect Dis 1990; 12: 557-59 5 Millar AB, Miller RF, Patou G, Mindel A, Marsh R, Semple SJG Treatment of retinitis with zidovudine and ganciclovir in patients with AIDS: outcome and toxicity. Genitourin Med 1990; 66: 156-58. 6. Moms DJ. Antiviral chemotherapy for retinitis in HIV-infected patients. Genitourin Med 1991, 67: 72-73
observations of
coronary arteritis in FK 506-treated dogshave not been realised in either group, and angiography done at the first and second year follow-ups has revealed only a very low frequency of coronary
SiR,—Your Dec 7 editorial (p 1426) needs to be discussed with a clinical perspective. You state that celiprolol is manifestly not an agent of choice for treatment of hypertension in asthmatic patients. However, much of the discussion implies that the development of (3-blockers that may be safe for use in asthmatic patients is a worthwhile pursuit. You suggest that sufficient 02-agonist properties and relative 0,-selectivity may confer such therapeutic potential. However, the wide choice of available antihypertensive agents and the lack of any pre-eminent characteristic of p-blockers in the management of hypertension would seem to make this goal pointless at best and potentially hazardous at worst. Celiprolol does not seem to have any significant &bgr;2-mediated vasodilating action on acute administration to man. It seems likely, as suggested by Milne and Bucklesthat vasodilatation after longer term administration of celiprolol relates to some other mechanism. It is most important that a spurious assumption of &bgr;2-agonist activity is not equated with "broncho-sparing properties" and consequent safety for the asthmatic patient. Such properties have, sensibly, never been claimed for pindolol or acebutolol, which clearly do have significant &bgr;2-agonist activity. The real mechanisms of action of celiprolol need to be further investigated and clearly recognised by both the pharmaceutical industry and clinicians, otherwise incorrect assumptions may continue to fuel inappropriate objectives. Department of Clinical Pharmacology, St Mary’s Hospital Medical School, Imperial College of Science, Technology and Medicine, London W2 1NY, UK
SIMON THOM ALUN HUGHES MICHAEL SCHACHTER PETER SEVER
Hughes A, Martin G, Goldberg P, Thom S, Sever P. No evidence for a direct vasodilatory effect of captopril on human vasculature in vivo or in vitro. J Cardiovasc Pharmacol 1987; 10(5): 589-92. 2. Milne RJ, Buckley M. Celiprolol—an updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in cardiovascular disease. Drugs 1991, 41: 941-69 1.
Treatment of CMV retinitis SIR,-Your Dec 14 editorial details previously unpublished results of a randomised trial of ganciclovir versus foscamet therapy for cytomegalovirus (CMV)-associated retinitis in AIDS patients. The two drugs were apparently equally effective in producing an initial clinical response and in preventing recrudescence of disease, but patients treated with foscamet survived longer than those treated with ganciclovir. Interpretation of these results is difficult. There is no proof that either ganciclovir or foscamet are effective drugs in CMVassociated retinitis because no placebo-controlled trials have been done.12 Moreover, there is no epidemiological evidence proving that CMV causes retinitisand HIV may be the direct cause of retinitis in AIDS patients.4 The data accrued in the trial of ganciclovir versus foscamet therapy could therefore mean that both drugs are effective because of their anti-CMV activity or because they are active against another aetiological agent. However, an alternative conclusion is that neither drug is effective and that retinitis often resolves spontaneously. As you note, treatment of CMV-associated retinitis in AIDS patients is far from satisfactory. In addition to the recognised drawbacks of intravenous administration and toxicity of ganciclovir and foscamet, the need to withdraw systemic zidovudine treatment before systemic ganciclovir therapy is initiated means that a drug known to delay death from AIDS must be stopped in order to administer a possibly ineffective drug as treatment for CMVassociated retinitis. Simultaneous systemic ganciclovir and zidovudine therapy is precluded by severe bone-marrow toxicity.s Further progress in the treatment of CMV-associated retinitis may therefore be made only after the development of orally active anti-CMV agents of lower toxicity than ganciclovir and foscamet and/or anti-HIV agents of lower toxicity than zidovudine.6 Clinical trials will then need to establish whether an anti-CMV drug alone or ananti-CMV drug combined with an anti-HIV drug represents the best treatment for retinitis in AIDS patients.6 Division of Virology, Department of Pathological Sciences, University of Manchester Medical School, Manchester M13 9PT, UK
(children). Concerns about vasculitis, based
on
arteriopathy. Control of rejection by FK 506 is achieved with a striking reduction in steroid requirement (80% of children are off prednisone at 3 months) and antihypertensive therapy. Moreover, cholesterol values in both adults and children are lower than in cyclosporin controls. All transplanted organs are susceptible to chronic rejection, manifested in the heart as coronary arteriopathy. Indeed, the Stanford group has previously ascribed coronary disease in some cardiac allografts of FK 506-treated non-human primates to the overall rejection process.7 On the basis of our observations so far we are optimistic that one of the benefits of FK 506 in human cardiac transplantation may be a reduction in the long-term risk of GVD. Departments of Surgery and Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
ANGUS W. THOMSON JOHN M. ARMITAGE ANTHONY J. DEMETRIS
Billingham ME, Moms RE The effect of cyclosporine and the two new immunosuppressive macrolides, FK 506, and rapamycin on heart graft rejection and graft coronary atherosclerosis. J Heart Transplant 1990; 9: 55. 2. Wu GD, Cramer DV, Chapman FA, et al. FK 506 inhibits the development of transplant atherosclerosis. Transplant Proc 1991; 23: 3272-74. 3. Murase N, Demetris AJ, Matsuzaki T, et al. Long survival in rats after multivisceral versus isolated small-bowel allotransplantation under FK 506. Surgery 1991; 110: 87-98. 4. Armitage JM, Kormos RL, Fung J, et al. The clinical trial of FK 506 as primary and rescue immunosuppression in adult cardiac transplantation. Transplant Proc 1991; 23: 3056-57. 5 Armitage JM, Fricker FJ, Del Nido P, et al The clinical trial of FK 506 as primary and rescue immunosuppression in pediatric cardiac transplantation. Transplant Proc 1. Meiser BM,
1991; 23: 3058-60. Ochiai T, Sakamoto K, Gunji Y, et al. Effects of combination treatment with FK 506 and cyclosporine on survival time and vascular changes in renal-allograft-recipient dogs. Transplantation 1989, 48: 193-97. 7. Flavin T, Ivens K, Wang J, et al. Initial experience with FK 506 as an 6
immunosuppressant for nonhuman primate recipients Transplant Proc 1991; 23: 531-32.
FK 506, cardiac transplantation, and graft-vessel disease SIR,-We are aware of the published observations’ of Dr Meiser and colleagues (Nov 23, p 1297) about modulation of graft-vessel disease (GVD) by the immunosuppressants cyclosporin, FK 506, and rapamycin in rats given cardiac allografts. In their recent report more severe GVD is seen in rats treated with FK 506 (1 or 2 mg/kg daily) for 50 days than in those who received cyclosporin or rapamycin. Meiser et al predict that GVD might occur in heart transplant patients treated with FK 506. Wu et al, however, have described the inhibition of rat heart allograft arteriosclerosis by FK 5062 at a dose (1 mg/kg daily FK 506 for 90 days) that Meiser et al report enhances GVD. No vascular lesions appeared in FK 506-treated recipients of syngeneic grafts. We have also seen no graft-vessel arteriopathy in small bowel of liver allografts of rats treated with 0-64 mg/kg FK 506 for up to 200 days.3In the now rather large experience at this centre, very good cardiac allograft function and quality of life have been achieved in adults4 and children’ receiving lower doses of the drug (maintenance dose 02-04 mg/kg daily) as primary immunosuppressive therapymedian follow-up times being 260 days (adults) and 304 days
of cardiac
allografts.
Celiprolol
DAVID J. MORRIS
1 Moms DJ. Antiviral chemotherapy for cytomegalovirus disease, J Antimicrob Chemother 1988; 21: 519-22. 2. Morris DJ. Clinical trials of antiviral agents J Antimicrob Chemother (in press). 3. Morris DJ. Epidemiological evidence is crucial as proof of causation in cytomegalovirus disease. J Infect 1991; 23: 233-40 4. Moms DJ. Is human immunodeficiency virus (HIV) rather than cytomegalovirus the cause of retinitis and colitis in HIV-infected patients? Rev Infect Dis 1990; 12: 557-59 5 Millar AB, Miller RF, Patou G, Mindel A, Marsh R, Semple SJG Treatment of retinitis with zidovudine and ganciclovir in patients with AIDS: outcome and toxicity. Genitourin Med 1990; 66: 156-58. 6. Moms DJ. Antiviral chemotherapy for retinitis in HIV-infected patients. Genitourin Med 1991, 67: 72-73
observations of
coronary arteritis in FK 506-treated dogshave not been realised in either group, and angiography done at the first and second year follow-ups has revealed only a very low frequency of coronary
SiR,—Your Dec 7 editorial (p 1426) needs to be discussed with a clinical perspective. You state that celiprolol is manifestly not an agent of choice for treatment of hypertension in asthmatic patients. However, much of the discussion implies that the development of (3-blockers that may be safe for use in asthmatic patients is a worthwhile pursuit. You suggest that sufficient 02-agonist properties and relative 0,-selectivity may confer such therapeutic potential. However, the wide choice of available antihypertensive agents and the lack of any pre-eminent characteristic of p-blockers in the management of hypertension would seem to make this goal pointless at best and potentially hazardous at worst. Celiprolol does not seem to have any significant &bgr;2-mediated vasodilating action on acute administration to man. It seems likely, as suggested by Milne and Bucklesthat vasodilatation after longer term administration of celiprolol relates to some other mechanism. It is most important that a spurious assumption of &bgr;2-agonist activity is not equated with "broncho-sparing properties" and consequent safety for the asthmatic patient. Such properties have, sensibly, never been claimed for pindolol or acebutolol, which clearly do have significant &bgr;2-agonist activity. The real mechanisms of action of celiprolol need to be further investigated and clearly recognised by both the pharmaceutical industry and clinicians, otherwise incorrect assumptions may continue to fuel inappropriate objectives. Department of Clinical Pharmacology, St Mary’s Hospital Medical School, Imperial College of Science, Technology and Medicine, London W2 1NY, UK
SIMON THOM ALUN HUGHES MICHAEL SCHACHTER PETER SEVER
Hughes A, Martin G, Goldberg P, Thom S, Sever P. No evidence for a direct vasodilatory effect of captopril on human vasculature in vivo or in vitro. J Cardiovasc Pharmacol 1987; 10(5): 589-92. 2. Milne RJ, Buckley M. Celiprolol—an updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in cardiovascular disease. Drugs 1991, 41: 941-69 1.
