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Diltiazem-cyclosporine interaction in cardiac transplant recipients: Impact on cyclosporine dose and medication costs
BRIEF CLINICAL
OBSERVATIONS
GANCICLOVIR
60
60
100
GANCICLOVIR
120
160
140
DAYS POST
ed to the regimen. On Day 146 after transplantation, he received rhGM-CSF 250 pg/m2 (Immunex Corporation, Seattle, Washington) subcutaneously twice a day. The neutropenia resolved promptly after the second day of treatment. Administration of rhGM-CSF was discontinued after 14 days according to the treatment protocol. The patient became progressively neutropenic with maintenance ganciclovir therapy (ANC 344/pL), and received a second 14-day course of rhGM-CSF on Day 207 after transplantation. This also led to an increase in neutrophils. He had no side effects attributable to GM-CSF in either course. Nine months after transplantation, ganciclovir treatment was stopped, BAL was negative for CMV infection, and a chest roentgenogram showed resolution of the infiltrate. The patient has chronic graft-versushost disease and occasional positive throat cultures for CMV, but remains free of pulmonary infection 18 months after transplantation. In summary, with the addition of rhGM-CSF to stimulate granulopoiesis, our patient was able to receive a prolonged course of gan402
March
1991
The American
Journal
160
200
220
240
260
260
TRANSPLANTATION
ciclovir using doses adequate to control CMV infection. Similar findings have been reported using a combination of GM-CSF and ganciclovir for the treatment of CMV retinitis in AIDS patients [6]. We conclude that the addition of GM-CSF may be of benefit in patients who require long-term therapy with this antiviral compound. MATTHEW SULECKI, M.D. CRAIG S. ROSENFELD,M.D. DONNA PRZEPIORKA,M.D., ph.0 ELANA J. BLOOM, M.D. Western Pennsylvania Hospital Pittsburgh, Pennsylvania WILLIAM BUHLES, Jr., D.v.M., Ph.D. Syntex Research Institute of Clinical Medicine Palo Alto, California RICHARDK. SHADDUCK,M.D. Western Pennsylvania Hospital Pittsburgh, Pennsylvania
1. Meyers JD, Flournoy N. Thomas ED. Risk factors for cytomegalovirus infection after human marrow transplant. J Infect Dis 1988; 153: 478-88. 2. Plotkin SA, Drew WL. Felstein D, Hirsch M. Sensitivity of clinical isolates from human cytomegalovirus to 9-(1,3-dihydroxy-2-propoxymethyl)guanine. J Infect Dis 1985; 152: 833-4. 3. Reed EC, Bowden RA, Dandliker PS, Lilleby KE, Meyers JD. Treatment of cytomegalovirus pneumonia with ganciclovir and intravenous cytomegalovirus immunoglobulin in patients with bone marrow transplants. Ann Intern Med 1988; 109: 783-8. 4. Emanuel D. Cunningham I, Jules-Elysee K. et a/. Cytomegalovirus pneumonia after bone marrow
of Medicine
Volume
90
Figure 1. White blood cell count (WBC) and absolute neutrophil count (ANC) during therapy with ganciclovir (top lines). The 2-week treatment intervals with granulocyte-macrophage colonystimulating factor (GM-CSF) are indicated by dotted lines.
transplant successfully treated with the combination of ganciclovir and high-dose intravenous immune globulin. Ann Intern Med 1988; 109: 772-82. S.Shepp DH, Dandliker PS, De Miranda P, et a/. Activity of 9-[2-hydroxy-l-(hydroxymethyl)ethoxymethyllguanine in the treatment of cytomegalovirus pneumonia. Ann Intern Med 1985; 103: 368-73. 6. Grossberg HS, Bonnem EM, Buhles WC. Granulocyte-macrophage colony-stimulating factor and ganciclovir for the treatment of CMV retinitis in AIDS. N Engl J Med 1989; 320: 1560. Submitted
May 7. 1990, and accepted
August 28, 1990
DILTIAZEM-CYCLOSi’ORINE INTERACTIONIN CARDIAC TRANSPLANT RECIPIENTS: IMPACT ON CYCLOSPORINE DOSEAND MEDlCAilON COSTS Cyclosporine, currently the basic component of immunosuppression for cardiac transplantation, is a significant cost burden for cardiac transplant recipients, insurance carriers, and Medicare. Drugs that influence the hepatic cytochrome P-450 microsomal enzyme system are known to alter cyclosporine metabolism and thus tissue and blood cyclosporine levels [1,2]. The use of cyclosporine is associated with significant systemic hypertension in more than 90% of cardiac trans-
1000 900
800 700 600
Cyclosporine
(nglml)
500 400
Figure 1. Time course of diltiazem interaction with cyclosporine in a single patient. Time 0 is 30 days prior to the initiation of diltiazem therapy. The open circles represent individual cyclosporine whole blood levels. The solid line indicates the daily cyclosporine dose. The dash/dot line indicates the daily diltiazem dose.
plant recipients [3,4]. Diltiazem, a benzothiazepine derivative, is a calcium antagonist (slow channel-blocking agent) used in the therapy of systemic hypertension [5,6] and is known to alter cyclosporine metabolism [7,8]. An analysis of our initial experience using diltiazem after cardiac transplantation was made to assess the effects of diltiazem therapy on cyclosporine blood levels and their variability, long-term cyclosporine dosage, and medication costs following cardiac transplantation.
300
60
80
100
120
Patients and Methods. Between September 1, 1986, and January 1, 1939, eight cardiac transplant patients at the University of Alabama at Birmingham began to receive diltiazem for the treatment of systemic hypertension and/or to allow a reduction in cyclosporine dose in patients requiring large daily doses to achieve therapeutic whole blood levels. Whole blood cyclosporine levels were obtained by a radioimmunoassay using a polyclonal antibody (INCSTAR Corporation, Stillwater, Minne-
140
160
180
200
220
240
260
sota). Cyclosporine was administered in a 12-hour dosing schedule with trough whole blood levels obtained prior to the morning dose. Diltiazem was given in an initial dose of 60 to 90 mg/day in divided doses, with a final dose of 60 to 180 mg/day. The cyclosporine dosage was adjusted as necessary to maintain appropriate therapeutic cyclosporine levels. The pre-diltiazem period was defined as the l-month period prior to the start of diltiazem therapy. The post-diltiazem period was defined as the l-month
TABLEI Diltkem and Cyclosporine:Doses,Bloodlevels, and Costs*
I
Patient Number
Cyclosporine Dose (mg/day)
Pre-Diltiazem Period (Cyclosporine Alone) Cyclosporine Level Mean f SD Number (ng/mL)
Post.Diltiazem Period (Cyclosporine plus Diltiazem) cost of Cyclosporine (dollars/day)
Diltiazem Dose (mg/day)
Cyclosporine Dose (mg/day)
Cyclosporine Level Mean f SD Number (ng/mL)
cost of Cyclosporine plus Diltiazem (dollars/day)
Annual Savings (dollars)
I
i
270 280
z
570*371 280f18
11.00 11.41
1%
2
1,210 430
z
770f237 480f94
49.31 17.52
9”:
;
460 420
;3
7OOk 108 460f252
17.12 18.75
180
200 230 320 180 290 720 370 410
Mean
509
7
560 f 183
20.78
135
340
:
400 600
29
780&226 440f155
16.30 24.86
180
z
380 f 41 460 125
9.48
2,044.OO 5,613.70
; 1: 4
380 430 f 57 22 820 770f f 168 128 860f 113
:E!8122 30.22 12.40 16.41
-916.15 1,014.70 1,868.80
2
720 f 158
18.04
259.15
4
603 f 102
14.92
2,138.90
“3;;:;;
L * Drug costs are average wholesale price from Drug Topics Redbook, Medical Economics Publishing Co., Oradell. New Jersey, 1989. p (cost of cyclosporine and diltiazem, pre- to post-diltiazem period) = 0.06. p (change of cyclosporine dose, pre- to post-diltiazem period) = 0.04. p (change of cyclosporine level, pre- to post-diltiazem period) = 0.6. p (change in variability of cyclosporine blood level) = 0.14.
March
1991
The American
Journal
of Medicine
Volume
90
403
period beginning 1 month after a stable diltiazem dose was achieved. It was selected to provide the most reasonable approximation of a long-term period of diltiazem therapy. Statistical analysis consisted of comparison of means using paired t-tests. Changes in variability of cyclosporine blood levels from the pre-diltiazem to post-stable-dose diltiazem period were examined using an F-test for comparison of variance. Results. No patient experienced side effects attributable to diltiazem that resulted in discontinuation of the medication (mean follow-up = 24.4 months). After initiation of diltiazem therapy, the cyclosporine dosage was gradually reduced to maintain desired whole blood cyclosporine levels (Figure 1). The mean cyclosporine dose in all patients decreased from 509 mg/ day in the pre-diltiazem period to 340 mg/day in the post-diltiazem period (p = 0.04) (Table I). There was no significant change in the pre- to post-diltiazem period cyclosporine level (p = 0.6). The average daily combined cost of cyclosporine and diltiazem was reduced from $20.78 to $14.92 after the addition of diltiazem therapy (p = 0.06) (Table I). The estimated predicted wholesale savings per year for one patient would be approximately $2,140. Comments. Several previous reports have described diltiazem’s interaction with cyclosporine to increase cyclosporine levels [7,8], but the exact mechanism is unknown. Our general experience as well as the present study indicates that cyclosporine levels begin to increase rapidly within a week of initiation of diltiazem therapy. In this study of cardiac transplant recipients, the interaction between cyclosporine and diltiazem resulted in a one-third reduction in average cyclosporine dose with diltiazem to achieve 404
March
1991
The American
Journal
the same cyclosporine level with possibly less variability in measured levels. The daily wholesale cost savings with cyclosporine and diltiazem was probably significant (p = 0.06) for this group of eight patients, resulting in a projected annual savings of greater than $2,000 per patient if diltiazem could be used routinely to reduce the cyclosporine dose. This early clinical evaluation supports the judicious use of diltiazem following cardiac transplantation, as an adjunctive agent to specifically allow a reduction in the dosage and therefore cost of cyclosporine therapy. Frequent cyclosporine level determinations are advisable to permit proper adjustment of the cyclosporine dosage until a stable blood level has been achieved. Further studies will be required to evaluate any possible beneficial or deleterious effect of diltiazem on the immunosuppressive effects of cyclosporine and its efficacy for the treatment of hypertension in patients undergoing cardiac transplantation. ROBERT C. BOURGE, M.D. JAMES K. KIRKLIN, M.D. DAVID C. NAFTEL, Ph.D. WILLIAM D. FIGG, R.Ph. CONNIE WHITE- WILLIAMS, R.N. CATHERYN KETCHUM, Ph.D. University of Alabama at Birmingham Birmingham, Alabama 1. Kahan BD. Drug therapy: cyclosporine. N Engl J Med 1989; 321: 1725-38. 2. Kahan BD. Individualization of cyclosporine therapy using pharmacokinetic and pharmacodynamic parameters. Transplantation 1985; 40: 457-76. 3. Olivari MT, Antolick A, Ring WS. Arterial hypertension in heart transplant recipients treated with triple-drug immunosuppressive therapy. J Heart Transplant 1989; 8: 34-9. 4. Starling RC. Cody RJ. Cardiac transplant hypertension. Am J Cardiol 1990; 65: 106-11. 5. Henry PD. Comparative pharmacology of calcium antagonists: nifedipine, verapamil, and diltiazem. Am J Cardiol 1980; 46: 1047-58. 6. Renton KW. Inhibition of hepatic microsomal drug metabolism by the calcium channel blockers diltiazem and verapamil. Biomedical Pharmacology 1985; 14: 2549-53. 7. Kohlwaw K, Wonigeit K, Frei U, Oldhafer K. Neumann K, Pichlmayr R. Effect of the calcium channel blocker diltiazem on cyclosporine A blood levels and
of Medicine
Volume
90
doserequirements. Transplant Proc 1988; 20: 5724. 8. Wagner K, Henkel M, Heinemeyer G, Neumayer HH. Interaction of calcium blockers and cyclosporine. Transplant Proc 1988; 20: 561-8. Submitted
February
7, 1990, and accepted in revised form August 28, 1990
RAPID-ONSETREVERSIBLE OCULARTOXICITY FROM ETHAMBUTOLTHERAPY Recently there has been an increased incidence of mycobacterial infections related to the increasing frequency of infection with the human immunodeficiency virus, and the occurrence of opportunistic mycobacterial infections in immunosuppressed hosts. To treat these infections, there has been a renewed interest in optimizing antimycobacterial therapy, including the use of ethambutol to treat “atypical” forms of mycobacterial disease. Ethambutol hydrochloride was introduced in 1961 as a synthetic bacteriostatic agent against Mycobacterium tuberculosis [l]. Although ethambutol is known to cause dose-related optic neuritis [2], adverse ocular effects after only a few days of therapy have rarely been documented [1,3]. We present this case to highlight the potential for the rapid onset of ocular toxicity following ethambutol administration, and report the first reversible case of this early side effect. A 46-year-old woman with a history of ischemic cardiomyopathy underwent orthotopic heart transplantation in May 1987. Past medical history included hypertension, hyperlipidemia, mild chronic renal failure, and chronic hyperbilirubinemia secondary to hepatic congestion. On August 12, 1989, she presented with multiple nodular skin lesions of 3 weeks’ duration. Her daily immunosuppressive regimen consisted of cyclosporine
OBSERVATIONS
GANCICLOVIR
60
60
100
GANCICLOVIR
120
160
140
DAYS POST
ed to the regimen. On Day 146 after transplantation, he received rhGM-CSF 250 pg/m2 (Immunex Corporation, Seattle, Washington) subcutaneously twice a day. The neutropenia resolved promptly after the second day of treatment. Administration of rhGM-CSF was discontinued after 14 days according to the treatment protocol. The patient became progressively neutropenic with maintenance ganciclovir therapy (ANC 344/pL), and received a second 14-day course of rhGM-CSF on Day 207 after transplantation. This also led to an increase in neutrophils. He had no side effects attributable to GM-CSF in either course. Nine months after transplantation, ganciclovir treatment was stopped, BAL was negative for CMV infection, and a chest roentgenogram showed resolution of the infiltrate. The patient has chronic graft-versushost disease and occasional positive throat cultures for CMV, but remains free of pulmonary infection 18 months after transplantation. In summary, with the addition of rhGM-CSF to stimulate granulopoiesis, our patient was able to receive a prolonged course of gan402
March
1991
The American
Journal
160
200
220
240
260
260
TRANSPLANTATION
ciclovir using doses adequate to control CMV infection. Similar findings have been reported using a combination of GM-CSF and ganciclovir for the treatment of CMV retinitis in AIDS patients [6]. We conclude that the addition of GM-CSF may be of benefit in patients who require long-term therapy with this antiviral compound. MATTHEW SULECKI, M.D. CRAIG S. ROSENFELD,M.D. DONNA PRZEPIORKA,M.D., ph.0 ELANA J. BLOOM, M.D. Western Pennsylvania Hospital Pittsburgh, Pennsylvania WILLIAM BUHLES, Jr., D.v.M., Ph.D. Syntex Research Institute of Clinical Medicine Palo Alto, California RICHARDK. SHADDUCK,M.D. Western Pennsylvania Hospital Pittsburgh, Pennsylvania
1. Meyers JD, Flournoy N. Thomas ED. Risk factors for cytomegalovirus infection after human marrow transplant. J Infect Dis 1988; 153: 478-88. 2. Plotkin SA, Drew WL. Felstein D, Hirsch M. Sensitivity of clinical isolates from human cytomegalovirus to 9-(1,3-dihydroxy-2-propoxymethyl)guanine. J Infect Dis 1985; 152: 833-4. 3. Reed EC, Bowden RA, Dandliker PS, Lilleby KE, Meyers JD. Treatment of cytomegalovirus pneumonia with ganciclovir and intravenous cytomegalovirus immunoglobulin in patients with bone marrow transplants. Ann Intern Med 1988; 109: 783-8. 4. Emanuel D. Cunningham I, Jules-Elysee K. et a/. Cytomegalovirus pneumonia after bone marrow
of Medicine
Volume
90
Figure 1. White blood cell count (WBC) and absolute neutrophil count (ANC) during therapy with ganciclovir (top lines). The 2-week treatment intervals with granulocyte-macrophage colonystimulating factor (GM-CSF) are indicated by dotted lines.
transplant successfully treated with the combination of ganciclovir and high-dose intravenous immune globulin. Ann Intern Med 1988; 109: 772-82. S.Shepp DH, Dandliker PS, De Miranda P, et a/. Activity of 9-[2-hydroxy-l-(hydroxymethyl)ethoxymethyllguanine in the treatment of cytomegalovirus pneumonia. Ann Intern Med 1985; 103: 368-73. 6. Grossberg HS, Bonnem EM, Buhles WC. Granulocyte-macrophage colony-stimulating factor and ganciclovir for the treatment of CMV retinitis in AIDS. N Engl J Med 1989; 320: 1560. Submitted
May 7. 1990, and accepted
August 28, 1990
DILTIAZEM-CYCLOSi’ORINE INTERACTIONIN CARDIAC TRANSPLANT RECIPIENTS: IMPACT ON CYCLOSPORINE DOSEAND MEDlCAilON COSTS Cyclosporine, currently the basic component of immunosuppression for cardiac transplantation, is a significant cost burden for cardiac transplant recipients, insurance carriers, and Medicare. Drugs that influence the hepatic cytochrome P-450 microsomal enzyme system are known to alter cyclosporine metabolism and thus tissue and blood cyclosporine levels [1,2]. The use of cyclosporine is associated with significant systemic hypertension in more than 90% of cardiac trans-
1000 900
800 700 600
Cyclosporine
(nglml)
500 400
Figure 1. Time course of diltiazem interaction with cyclosporine in a single patient. Time 0 is 30 days prior to the initiation of diltiazem therapy. The open circles represent individual cyclosporine whole blood levels. The solid line indicates the daily cyclosporine dose. The dash/dot line indicates the daily diltiazem dose.
plant recipients [3,4]. Diltiazem, a benzothiazepine derivative, is a calcium antagonist (slow channel-blocking agent) used in the therapy of systemic hypertension [5,6] and is known to alter cyclosporine metabolism [7,8]. An analysis of our initial experience using diltiazem after cardiac transplantation was made to assess the effects of diltiazem therapy on cyclosporine blood levels and their variability, long-term cyclosporine dosage, and medication costs following cardiac transplantation.
300
60
80
100
120
Patients and Methods. Between September 1, 1986, and January 1, 1939, eight cardiac transplant patients at the University of Alabama at Birmingham began to receive diltiazem for the treatment of systemic hypertension and/or to allow a reduction in cyclosporine dose in patients requiring large daily doses to achieve therapeutic whole blood levels. Whole blood cyclosporine levels were obtained by a radioimmunoassay using a polyclonal antibody (INCSTAR Corporation, Stillwater, Minne-
140
160
180
200
220
240
260
sota). Cyclosporine was administered in a 12-hour dosing schedule with trough whole blood levels obtained prior to the morning dose. Diltiazem was given in an initial dose of 60 to 90 mg/day in divided doses, with a final dose of 60 to 180 mg/day. The cyclosporine dosage was adjusted as necessary to maintain appropriate therapeutic cyclosporine levels. The pre-diltiazem period was defined as the l-month period prior to the start of diltiazem therapy. The post-diltiazem period was defined as the l-month
TABLEI Diltkem and Cyclosporine:Doses,Bloodlevels, and Costs*
I
Patient Number
Cyclosporine Dose (mg/day)
Pre-Diltiazem Period (Cyclosporine Alone) Cyclosporine Level Mean f SD Number (ng/mL)
Post.Diltiazem Period (Cyclosporine plus Diltiazem) cost of Cyclosporine (dollars/day)
Diltiazem Dose (mg/day)
Cyclosporine Dose (mg/day)
Cyclosporine Level Mean f SD Number (ng/mL)
cost of Cyclosporine plus Diltiazem (dollars/day)
Annual Savings (dollars)
I
i
270 280
z
570*371 280f18
11.00 11.41
1%
2
1,210 430
z
770f237 480f94
49.31 17.52
9”:
;
460 420
;3
7OOk 108 460f252
17.12 18.75
180
200 230 320 180 290 720 370 410
Mean
509
7
560 f 183
20.78
135
340
:
400 600
29
780&226 440f155
16.30 24.86
180
z
380 f 41 460 125
9.48
2,044.OO 5,613.70
; 1: 4
380 430 f 57 22 820 770f f 168 128 860f 113
:E!8122 30.22 12.40 16.41
-916.15 1,014.70 1,868.80
2
720 f 158
18.04
259.15
4
603 f 102
14.92
2,138.90
“3;;:;;
L * Drug costs are average wholesale price from Drug Topics Redbook, Medical Economics Publishing Co., Oradell. New Jersey, 1989. p (cost of cyclosporine and diltiazem, pre- to post-diltiazem period) = 0.06. p (change of cyclosporine dose, pre- to post-diltiazem period) = 0.04. p (change of cyclosporine level, pre- to post-diltiazem period) = 0.6. p (change in variability of cyclosporine blood level) = 0.14.
March
1991
The American
Journal
of Medicine
Volume
90
403
period beginning 1 month after a stable diltiazem dose was achieved. It was selected to provide the most reasonable approximation of a long-term period of diltiazem therapy. Statistical analysis consisted of comparison of means using paired t-tests. Changes in variability of cyclosporine blood levels from the pre-diltiazem to post-stable-dose diltiazem period were examined using an F-test for comparison of variance. Results. No patient experienced side effects attributable to diltiazem that resulted in discontinuation of the medication (mean follow-up = 24.4 months). After initiation of diltiazem therapy, the cyclosporine dosage was gradually reduced to maintain desired whole blood cyclosporine levels (Figure 1). The mean cyclosporine dose in all patients decreased from 509 mg/ day in the pre-diltiazem period to 340 mg/day in the post-diltiazem period (p = 0.04) (Table I). There was no significant change in the pre- to post-diltiazem period cyclosporine level (p = 0.6). The average daily combined cost of cyclosporine and diltiazem was reduced from $20.78 to $14.92 after the addition of diltiazem therapy (p = 0.06) (Table I). The estimated predicted wholesale savings per year for one patient would be approximately $2,140. Comments. Several previous reports have described diltiazem’s interaction with cyclosporine to increase cyclosporine levels [7,8], but the exact mechanism is unknown. Our general experience as well as the present study indicates that cyclosporine levels begin to increase rapidly within a week of initiation of diltiazem therapy. In this study of cardiac transplant recipients, the interaction between cyclosporine and diltiazem resulted in a one-third reduction in average cyclosporine dose with diltiazem to achieve 404
March
1991
The American
Journal
the same cyclosporine level with possibly less variability in measured levels. The daily wholesale cost savings with cyclosporine and diltiazem was probably significant (p = 0.06) for this group of eight patients, resulting in a projected annual savings of greater than $2,000 per patient if diltiazem could be used routinely to reduce the cyclosporine dose. This early clinical evaluation supports the judicious use of diltiazem following cardiac transplantation, as an adjunctive agent to specifically allow a reduction in the dosage and therefore cost of cyclosporine therapy. Frequent cyclosporine level determinations are advisable to permit proper adjustment of the cyclosporine dosage until a stable blood level has been achieved. Further studies will be required to evaluate any possible beneficial or deleterious effect of diltiazem on the immunosuppressive effects of cyclosporine and its efficacy for the treatment of hypertension in patients undergoing cardiac transplantation. ROBERT C. BOURGE, M.D. JAMES K. KIRKLIN, M.D. DAVID C. NAFTEL, Ph.D. WILLIAM D. FIGG, R.Ph. CONNIE WHITE- WILLIAMS, R.N. CATHERYN KETCHUM, Ph.D. University of Alabama at Birmingham Birmingham, Alabama 1. Kahan BD. Drug therapy: cyclosporine. N Engl J Med 1989; 321: 1725-38. 2. Kahan BD. Individualization of cyclosporine therapy using pharmacokinetic and pharmacodynamic parameters. Transplantation 1985; 40: 457-76. 3. Olivari MT, Antolick A, Ring WS. Arterial hypertension in heart transplant recipients treated with triple-drug immunosuppressive therapy. J Heart Transplant 1989; 8: 34-9. 4. Starling RC. Cody RJ. Cardiac transplant hypertension. Am J Cardiol 1990; 65: 106-11. 5. Henry PD. Comparative pharmacology of calcium antagonists: nifedipine, verapamil, and diltiazem. Am J Cardiol 1980; 46: 1047-58. 6. Renton KW. Inhibition of hepatic microsomal drug metabolism by the calcium channel blockers diltiazem and verapamil. Biomedical Pharmacology 1985; 14: 2549-53. 7. Kohlwaw K, Wonigeit K, Frei U, Oldhafer K. Neumann K, Pichlmayr R. Effect of the calcium channel blocker diltiazem on cyclosporine A blood levels and
of Medicine
Volume
90
doserequirements. Transplant Proc 1988; 20: 5724. 8. Wagner K, Henkel M, Heinemeyer G, Neumayer HH. Interaction of calcium blockers and cyclosporine. Transplant Proc 1988; 20: 561-8. Submitted
February
7, 1990, and accepted in revised form August 28, 1990
RAPID-ONSETREVERSIBLE OCULARTOXICITY FROM ETHAMBUTOLTHERAPY Recently there has been an increased incidence of mycobacterial infections related to the increasing frequency of infection with the human immunodeficiency virus, and the occurrence of opportunistic mycobacterial infections in immunosuppressed hosts. To treat these infections, there has been a renewed interest in optimizing antimycobacterial therapy, including the use of ethambutol to treat “atypical” forms of mycobacterial disease. Ethambutol hydrochloride was introduced in 1961 as a synthetic bacteriostatic agent against Mycobacterium tuberculosis [l]. Although ethambutol is known to cause dose-related optic neuritis [2], adverse ocular effects after only a few days of therapy have rarely been documented [1,3]. We present this case to highlight the potential for the rapid onset of ocular toxicity following ethambutol administration, and report the first reversible case of this early side effect. A 46-year-old woman with a history of ischemic cardiomyopathy underwent orthotopic heart transplantation in May 1987. Past medical history included hypertension, hyperlipidemia, mild chronic renal failure, and chronic hyperbilirubinemia secondary to hepatic congestion. On August 12, 1989, she presented with multiple nodular skin lesions of 3 weeks’ duration. Her daily immunosuppressive regimen consisted of cyclosporine