Abstract
The introduction of cyclosporin significantly improved solid organ transplantation outcomes. However, the costs associated with immunosuppressive therapy increased from approximately $US1000 to $US2000 per patient per year with azathioprine (AZA) and prednisone to $US5000 to $US8000 per patient per year with the addition of cyclosporin (1997 values).
Because of the financial demands placed on medical care in the current era, research has been directed towards developing drug combinations which potentiate the therapeutic effect of cyclosporin whereby reducing the amount of drug administered and consequently the costs of long term immunosuppressive therapy. To date, many drugs that interact with cyclosporin have been recognised. Included in this list are the azole antifungal drugs, ketoconazole, fluconazole and itraconazole; the calcium channel blockers, diltiazem, verapamil and nicardipine; and the macrolide antibacterials, erythromycin and related compounds. Although all of these drugs increase cyclosporin drug concentrations when used concomitantly, ketoconazole and diltiazem appear to be the best candidates on the basis of reducing financial pressures of chronic immunosuppressive therapy without sacrificing patients’ well-being.
Studies of various regimens involving the combined use of ketoconazole and cyclosporin have shown that cyclosporin dosages can be reduced by approximately 70 to 85% while maintaining therapeutic blood concentrations in renal, cardiac and liver transplant recipients. The calcium channel blocker, diltiazem, allows a decrease in cyclosporin dosage by approximately 30 to 50% in this same group of organ transplant patients. These reductions in cyclosporin dosage have been achieved with no reported severe adverse effects that would discourage the use of these agents concurrently in practice.
The combined use of cyclosporin and ketoconazole or diltiazem could reduce medication costs by approximately $US915 to $US3000 per year per patient. If all patients treated with cyclosporin are considered, these combinations could reduce medication costs by hundreds of millions of dollars per year in the US alone. While these are promising approaches, further characterisation of these drug interactions is necessary before this practice is adopted as standard protocol worldwide.
The objective of this paper is to review the clinical and economic potential of cyclosporin-sparing agents such as the azole antifungal drugs and calcium channel blockers in an attempt to decrease the costs associated with this expensive immunosuppressive agent
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Borel JF, Feuer C, Gubler HU, et al. Biological effects of cyclosporine A: a new antilymphocyte agent. Agents Actions 1976; 6 (4): 432–40
Borel JF. Comparative study of in vitro and in vivo drug effects on cell mediated cytotoxicity. Immunology 1976; 31: 631–41
Calne RY, Rolles K, White DJG, et al. Cyclosporine A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 33 kidneys, 2 pancreases and 2 livers. Lancet 1979; II: 1033–6
European Multicentre Trial Group. Cyclosporine in cadaveric renal transplantation: one-year follow-up of a multicenter trial. Lancet 1983; II: 986–9
Canadian Multicenter Transplant Study Group. A randomized clinical trial of cyclosporine in cadaveric renal transplantation: analysis at three years. N Engl J Med 1986; 314: 1219–25
Stiller CR, Dupre J, Gent M, et al. Sandimmune (cyclosporine) in insulin-dependent diabetes mellitus (type I) of recent onset. Science 1984; 223: 1362–7
Nussenblatt RB, Palestine AG, Rook AH, et al. Cyclosporine therapy for intraocular inflammatory disease. Lancet 1983; II: 235–8
Masuda K, Nakajima A. A double-masked study of cyclosporin treatment in Behcet’s disease. In: Schinder R, editor. Ciclosporine in autoimmune diseases. Berlin: Springer-Verlag, 1985: 162–4
Hunsicker LG. Impact of cyclosporine on cadaveric renal transplantation: a summary statement. Am J Kidney Dis 1985; 5: 335–41
Macoviak JA, Oyer PE, Stinson EB, et al. Four-year experience with cyclosporine for heart and heart-lung transplantation. Transplant Proc 1985; 17 Suppl. 2: 97–8
Morris PE. The immunology of rejection. In: Morris PJ, editor. Kidney transplantation: principles and practice. 3rd ed. Orlando (FL): Grune & Stratton, 1988: 15–32
European Multicentre Trial Group. Cyclosporine in cadaveric renal transplantation: 5-year follow-up of a multicentre trial. Transplant Proc 1988; 20 (3 Suppl. 3): 73–7
Kramer NC, Peters TG, Rohr MS, et al. Beneficial effect of cyclosporine on renal transplantation. Transplantation 1990; 49: 343–8
Starzl TE, Demetris AJ, Van Thiel D. Medical progress: liver transplantation. N Engl J Med 1989; 321: 1014–22
Hall BM, Tiller DJ, Hardic I, et al. Comparison of three immunosuppressive regimens in cadaveric renal transplantation: long-term cyclosporine, short-term cyclosporine followed by azathioprine and prednisolone, and azathioprine and prednisolone without cyclosporine. N Engl J Med 1988; 318: 1499–507
Viste A, Moudry-Mounns K, Sutherland DER. Prognostic risk factors for graft failure following pancreas transplantation: results of multivariate analysis of data from the International Pancreas Transplant Registry. Transpl Int 1990; 3: 98–102
Evans RW, Manninen DL. Economic impact of cyclosporine in transplantation. Transplant Proc 1988; 20 Suppl. 3: 49–62
Eggers PW. The effect of cyclosporine on the use of hospital resources for kidney transplantation. N Engl J Med 1990; 322: 1010–1
Barclay PG, Allen RDM, Stewart JH, et al. Costs of immunosuppressive therapies used in renal transplantation. Transplant Proc 1992; 24: 165–6
Areosty J, Rettig RA. The cost effects of improved kidney transplantation. Santa Monica (CA): RAND, 1984. Publication no.: R-3099-NIH/RC
Simon DG. A cost-effectiveness analysis of cyclosporine in cadaveric kidney transplantation. Med Decis Making 1986; 6: 199–207
Krakauer H. Assessment of alternative technologies for the treatment of end-stage renal disease. Isr J Med Sci 1986; 22: 245–59
Henry ML, Sommer BG, Ferguson RM. Beneficial effects of cyclosporine compared with azathioprine in cadaveric renal transplantation. Am J Surg 1985; 150: 533–6
Showstack J, Katz P, Amend W, et al. The effect of cyclosporine on the use of hospital resources for kidney transplantation. N Engl J Med 1989; 321: 1086–92
Showstack J, Katz P, Amend W, et al. The association of cyclosporine with the one-year costs of cadaver-donor kidney transplants. JAMA 1990; 264: 1818–23
Tilney NL, Strom TB, Kupiec-Weglinski JW. Pharmacologic and immunologic agonists and antagonists of cyclosporine. Transplant Proc 1988; 20 Suppl. 3: 13–22
Yee GC, Rosano T, Ptachinski R. Pharmacology: profiles, parameters, interpretations and drug interactions. Transplant Proc 1988; 20 Suppl. 2: 715–21
Como JA, Dismukes WE. Oral azoles drugs as systemic antifungal therapy. N Engl J Med 1994; 330: 263–8
Markin S, Stratta RJ, Woods GL. Infection after liver transplantation. Am J Surg Pathol 1990; 14 Suppl. 1: 64–71
First MR, Schroeder TJ, Weiskittel P, et al. Concomitant administration of cyclosporin and ketoconazole in renal transplant recipients. Lancet 1989; II: 1198–201
First MR, Schroeder TJ, Weiskittel P, et al. Cyclosporine-ketoconazole interaction. Transplantation 1993; 55: 1000–4
First MR, Schroeder TJ, Daoud J, et al. Ketoconzole is not associated with increased inpatient or outpatient resources while decreasing cyclosporine annual costs by approximately $3,300 per patient [abstract]. The 15th Annual Meeting, American Society of Transplant Physicians; 1997 May 11-14, Dallas
Odocha O, Kelly B, Trimble S, et al. Cost-containment strategies in transplantation: the utility of cyclosporine-ketoconazole combination therapy. Transplant Proc 1996; 28: 907–9
Sobh M, El-Agroudy A, Moustafa F, et al. Co-administration of ketoconazole to cyclosporin-treated kidney transplant recipients: a prospective randomized study. Am J Nephrol 1995; 15: 493–9
Patton PR, Brunson ME, Pfaff WW, et al. A preliminary report of diltiazem and ketoconazole: their cyclosporine-sparing effect and impact on transplant outcome. Transplantation 1994; 57: 889–92
Keogh A, Spratt P, McCosker C, et al. Ketoconazole to reduce the need for cyclosporine after cardiac transplantation. N Engl J Med 1995; 333: 628–33
Butman SM, Wild JC, Nolan PE, et al. Prospective study of the safety and financial benefit of ketoconazole as adjunctive therapy to cyclosporine after heart transplantation. J Heart Lung Transplant 1991; 10: 351–8
Sergent WK, Martin JE, Schroeder TJ, et al. Pharmacokinetics of the interaction between itraconazole oral solution and cyclosporine in stable post-liver transplant recipients [abstract]. The American Society of Health System Pharmacists Midyear Clinical Meeting; 1998 Dec, Las Vegas
Rossi SJ, Martin JE, Gelhot A, et al. A randomized prospective trial of fluconazole vs. clotrimazole for fungal prophylaxis in liver transplant recipients. The 14th Annual Meeting of the American Society of Transplant Physicians; 1995 May 14-17, Chicago
Loose DS, Kan PB, Hirst MA, et al. Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P-450 dependent enzymes. J Clin Invest 1983; 71: 1495–9
Meredith CG, Maldonado AL, Speeg KV. The effect of ketoconazole on hepatic oxidative drug metabolism in the rat in vivo and in vitro. Drug Metab Dispos 1985; 13: 156–62
Ferguson RM, Sutherland DER, Summons RL, et al. Ketoconazole, cyclosporine metabolism and renal transplantation. Lancet 1982; II: 882–3
Schroeder TJ, Melvin DB, Clardy CW, et al. The use of cyclosporine and ketoconazole without nephrotoxicity in two cardiac transplant recipients. J Heart Lung Transplant 1987; 6: 84–9
Gandhi BV, Kale S, Bhowmik DM, et al. Concomitant administration of cyclosporine and ketoconazole in renal transplant patients. Transplant Proc 1992; 24: 1715
Canafax DM, Graves NM, Hilligoss DM, et al. Interaction between cyclosporine and fluconazole in renal allograft recipients. Transplantation 1991; 51: 1014–8
Lopez-Gil JA. Fluconazole-cyclosporine interaction: a dosedependent effect? Ann Pharmacother 1993; 27: 427–30
Sugar AM, Saunders C, Idelson BA, et al. Interaction of fluconazole and cyclosporine [letter]. Ann Intern Med 1989; 110: 844
Pfizer, Inc. Fluconazole product information insert. Groton (CT): Pfizer, Inc., 1990
Kruger HU, Schuler U, Zimmermann R, et al. Absence of significant interaction of fluconazole with cyclosporin. J Antimicrob Chemother 1989; 24: 781–6
Canafax DM, Graves NM, Hilligoss DM, et al. Increased cyclosporine levels as a result of simultaneous fluconazole and cyclosporine therapy in renal transplant recipients: a double-blind, randomized pharmacokinetic and safety study. Transplant Proc 1991; 23: 1041–2
Jackson CA, Dismukes WE. Oral azole drugs as systemic antifungal therapy. N Engl J Med 1994; 330: 263–72
Novakova I, Donnelly P, De Witte T, et al. Itraconazole and cyclosporine nephrotoxicity. Lancet 1987; II: 920–1
Shaw MA, Gumbleton M, Nicholls PJ. Interaction of cyclosporine and itraconazole [letter]. Lancet 1987; II: 637
Lavrijsen K, Van Houdt J, Thijs D, et al. Interaction of miconazole, ketoconazole and itraconazole with rat-liver microsomes. Xenobiotica 1987; 17: 45–57
Kramer MR, Marshall SE, Denning DW, et al. Cyclosporine and itraconazole interaction in heart and lung transplant recipients. Ann Intern Med 1990; 113: 327–9
Kwan JT, Foxall PJ, Davidson DG, et al. Interaction of cyclosporine and itraconazole [letter]. Lancet 1987; II: 282
Trenk D, Brett W, Jahnchen E, et al. Time course of cyclosporine-itraconazole interaction. Lancet 1987; II: 1335–6
Luke RG. Pathophysiology and treatment of post-transplant hypertension. J Am Soc Nephrol 1991; 2 Suppl. 1: S37–44
Cheigh JS, Stenzel KHS, Wang J. Hypertension is associated with decreaed graft survival in long-term kidney transplant recipients. Transplant Proc 1985; 17: 174–5
Murray BM, Paller MS. Beneficial effects of renal denervation and prazosin on GFR and renal blood flow after cyclosporine in rats. Clin Nephrol 1986; 25: 537–9
Xue H, Bukoski RD, McCarron DA, et al. Induction of contraction in isolated rat aorta by cyclosporine. Transplantation 1987; 43: 715–8
Jao S, Waltzer W, Arbeit LA. Acute cyclosporine induced decrease in GFR is mediated by changes in renal blood flow and renal vascular resistance [abstract]. Kidney Int 1986; 29: 431
Kawaguchi A, Goldman MN, Shapiro R, et al. Increase in urinary thromboxane B2 in rats caused by cyclosporine. Transplantation 1985; 40: 214–8
Kon V, Sugiuza M, Inagami T, et al. Cyclosporine causes endothelin-dependent acute renal failure [abstract]. Kidney Int 1990; 37: 486
Landmann J, Mihatsch MJ, Ratschek M, et al. Cyclosporine A and intravascular coagulation. Transplant Proc 1987; 19: 1817–9
Smith C, Hampton EM, Pederson JA, et al. Clinical and medicoeconomic impact of the cyclosporine-diltiazem interaction in renal transplant recipients. Pharmacotherapy 1994; 14: 471–81
Valantine H, Keogh A, McIntosh N, et al. Cost containment: coadministration of diltiazem with cyclosporine after heart transplantation. J Heart Lung Transplant 1992; 11: 1–7
Pirsch JD, D’Alessandro AM, Roecker EB, et al. A controlled, double-blind, randomized trial of verapamil and cyclosporine in cadaver renal tranplant patients. Am J Kidney Dis 1993; 2: 189–95
Chan C, Maurer J, Cardella C, et al. A randomized controlled trial of verapamil on cyclosporine nephrotoxicity in heart and lung transplant recipients. Transplantation 1997; 63: 1435–40
McCauley J, Ptachcinski RJ, Shapiro R. The cyclosporine-sparing effects of diltiazem in renal transplantation. Transplant Proc 1989; 21: 3955–7
Chrysostomou A, Walker RG, Russ GR, et al. Diltiazem in renal allograft recipients receiving cyclosporine. Transplantation 1993; 55: 300–4
Al Edreesi M, Caille G, Dupuis C, et al. Safety, tolerability, and pharmacokinetic actions of diltiazem in pediatric liver transplant recipients on cyclosporine. Liver Transplant Surg 1995; 1: 383–8
MacDonald P, Keogh A, Connell J, et al. Diltiazem co-administration reduces cyclosporine toxicity after heart transplantation: A prospective randomized trial. Transplant Proc 1992; 24: 2259–62
Kiowski W, Linder L, Buhler FR. Arterial vasodilator and anti-hypertensive effects of diltiazem. J Cardiovasc Pharmacol 1990; 16 Suppl. 6: S7–10
Hung J, Hackett PL, Gordon SPF, et al. Pharmacokinetics of diltiazem in patients with unstable angina pectoris. Clin Pharmacol Ther 1988; 43: 466–70
Pochet JM, Pirson Y. Cyclosporin-diltiazem interaction [letter]. Lancet 1986; I: 979
Grino JM, Sabate I, Castelao AM, et al. Influence of diltiazem on cyclosporine clearance [letter]. Lancet 1986; I: 1387
Renton KW. Inhibition of hepatic microsomal drug metabolism by the calcium channel blockers diltiazem and verapamil. Biochem Pharmacol 1985; 34: 2549–53
Bourge RC, Kirklin JK, Naftel DC, et al. Diltiazem-cyclosporine interaction in cardiac transplant recipients; impact on cyclosporine dose and medication costs. Am J Med 1991; 90: 402–4
Kohlhaw K, Wonigeit K, Frei U, et al. Effect of the calcium channel blocker diltiazem on cyclosporine A blood levels and dose requirements. Transplant Proc 1988; 20: 572–4
Shennib H, Auger JL. Diltiazem improves cyclosporine dosage in cystic fibrosis lung transplant recipients. J Heart Lung Transplant 1994; 13: 292–6
Sketris IS, Methot ME, Nichol D, et al. Effect of calcium-channel blockers on cyclosporine clearance and use in renal transplant patients. Ann Pharmacother 1994; 28: 1227–31
Wagner K, Philipp TH, Heinemeyer G, et al. Interaction of cyclosporin and calcium antagonists. Transplant Proc 1989; 21: 1453–6
Jones TE, Morris RG, Mathew TH. Diltiazem-cyclosporin pharmacokinetic interaction: dose-response relationship. Br J Clin Pharmacol 1997; 44: 499–504
Jones TE, Morris RG. Diltizem does not always increase blood cyclosporin concentration. Br J Clin Pharmacol 1996; 42: 642–4
Schroeder J, Gao S-Z, Alderman E, et al. A preliminary study of diltiazem in the prevention of coronary artery disease. N Engl J Med 1993; 238: 164–70
McMillen MA, Lewis T, Jaffe BM, et al. Verapamil inhibition of lymphocyte proliferation and function in vitro. J Surg Res 1985; 39: 76–80
McMillen MA, Baumgarten WK, Schaefer HC, et al. Potentiation of cyclosporine by verapamil in vitro. Transplantation 1995; 40: 444–6
Angermann CE, Spes CH, Anthuber M, et al. Verapamil increases cyclosporin-A trough levels in cardiac transplant recipients [abstract]. J Am Coll Cardiol 1988; 11: 206A
Peterson JC, Brannigan J, Pickard T, et al. Cyclosporine-verapamil interaction. Kidney Int 1988; 33: 449–50
Dawidson I, Rooth P, Lu C, et al. Verapamil improves the outcome after cadaver renal transplantation. J Am Soc Nephrol 1991; 2: 983–90
Tjia JF, Back DJ, Breckenridge AM. Calcium channel antagonists and cyclosporine metabolism: in vitro studies with human liver microsomes. Br J Clin Pharmacol 1989; 28: 362–5
Bourbigot B, Guiserix J, Airiau J, et al. Nicardipine increases cyclosporin blood levels [letter]. Lancet 1986; I: 1447
Kessler M, Renoult E, Jonon B, et al. Influence of nicardipine on renal function and plasma cyclosporin in renal transplant patients [letter]. Eur J Clin Pharmacol 1989; 36: 637–8
Cantarovich M, Hiesse C, Lockiec F, et al. Confirmation of the interaction between cyclosporine and the calcium channel blocker nicardipine in renal transplant patients. Clin Nephrol 1987; 28: 190–3
Ludden TM. Pharmacokinetic interactions of the macrolide antibiotics. Clin Pharmacokinet 1985; 10: 63–79
Fabre I, Fabre G, Maurel P, et al. Metabolism of cyclosporin A. III: interaction of the macrolide antibiotic, erythromycin, using rabbit hepatocytes and microsomal fractions. Drug Metab Dispos 1988; 16: 296–301
Henricsson S, Lindholm A. Inhibition of cyclosporine metabolism by other drugs in vitro. Transplant Proc 1988; 20: 569–71
Kohan DE. Possible interaction between cyclosporine and erythromycin [letter]. N Engl J Med 1986; 314: 448
Ptachcinski RJ, Carpenter BJ, Burckart GJ, et al. Effect of erythromycin on cyclosporine levels [letter]. N Engl J Med 1985; 313: 1416–7
Gonwa TA, Nghiem DD, Schulak JA, et al. Erythromycin and cyclosporine. Transplantation 1986; 41: 797–9
Wadhwa NK, Schroeder TJ, O’Flaherty E, et al. Interaction between erythromycin and cyclosporine in a kidney and pancreas allograft recipient. Ther Drug Monit 1987; 9: 123–5
Jensen CWB, Flechner SM, Van Buren CT, et al. Exacerbation of cyclosporine toxicity by concomitant administration of erythromycin. Transplantation 1987; 43: 263–70
Kreft-Jais C, Billaud EM, Gaudry C, et al. Effect of josamycin on plasma cyclosporine levels. Eur J Clin Pharmacol 1987; 32: 327–8
Torregrosa JV, Campistol JM, Franco A, et al. Interaction of josamycin with cyclosporine A. Nephron 1993; 65: 476–7
Gersema LM, Porter CB, Russell EH. Suspected drug interaction between cyclosporine and clarithromycin. J Heart Lung Transplant 1994; 13: 343–5
Burke MD, Omar G, Thomson AW, et al. Inhibition of the metabolism of cyclosporine by human liver microsomes by FK506. Transplantation 1990; 50: 901–2
Pichard L, Fabre I, Fabre G, et al. Cyclosporine A drug interactions: screening for inducers and inhibitors of cytochrome P-450 (cyclosporine A oxidase) in primary cultures of human hepatocytes and in liver microsomes. Drug Metab Dispos 1990; 18: 595–606
Adrianus AMJ, Hollander MD, Jeroaen van Rooij MD, et al. The effect of grapefruit juice on cyclosporine and prednisone metabolism in transplant patients. Clin Pharmacol Ther 1995; 57: 318–24
Yee GC, Stanley DL, Pessa, et al. Effect of grapefruit juice on blood cyclosporine concentration. Lancet 1995; 345: 955–6
Brunner LJ, Munar MY, Vallian J, et al. Interaction between cyclosporine and grapefruit juice requires long-term ingestion in stable renal transplant recipients. Pharmacotherapy 1998; 18: 23–9
Ameer B, Weintraub RA. Drug interactions with grapefruit juice. Clin Pharmacokinet 1997; 33: 103–21
Rouseff RL, Martin SF, Youtsey O. Quantitative survey of narirutin, naringin, hesperiden and neohesperidin in citrus. J Agric Food Chem 1987; 35: 1027–30
Didlake RH, Dreyfus K, Kerman RH, et al. Patient non-compliance: a major cause of late graft failure in cyclosporinetreated renal patients. Transplant Proc 1988; 20: 63–9
Gaston R, Hudson S, Ward M, et al. The relationship between graft loss and noncompliance [abstract]. Presented at the XVII World Congress of The Transplantation Society; 1998 May 10-13, Chicago
Kiley DJ, Lam CS, Pollak R. A study of treatment compliance following kidney transplantation. Transplantation 1993; 55: 51–6
Murphy J, Coster G. Issues in patient compliance. Drugs 1997; 54: 797–800
Blum RA, D’Andrea DT, Florentino BM, et al. Increased gastric H and the bioavailability of fluconazole and ketoconazole. Ann Intern Med 1991; 114: 755–7
Karlix JL, Cheng MA, Brunson ME, et al. Decreased cyclosporine concentrations with the addition of an H2-receptor antagonist in a patient on ketoconazole. Transplantation 1994; 57 (6): 889–92
Michalets EL. Update: clinically significant cytochrome P-450 drug interactions. Pharmacotherapy 1998; 18: 84–112
Monahan BP, Ferguson CL, Killeavy ES, et al. Torsdes de pointes occurring in association with terfenadine use. JAMA 1990; 264: 2788–90
Oberg K, Bauman JL. QT interval prolongation and torsades de pointes due to erythromycin lactobionate. Pharmacotherapy 1995; 15: 687–92
Illingworth DR, Tobert JA. A review of clinical trials comparing HMG-CoA reductase inhibitors. Clin Ther 1994; 16: 366–85
Zurcher RM, Frey BM, Frey FJ. Impact of ketoconazole on the metabolism of prednisolone. Clin Pharmacol Ther 1989; 45: 366–72
Gillum JG, Isreal DS, Polk RE. Pharmacokinetic drug interactions with antimicrobial agents. Clin Pharmacokinet 1993; 25: 450–82
Cooke CE. Nontherapeutic cyclosporine levels: sustained-release diltiazem products are NOT the same. Transplantation 1994; 57: 1687–8
Jones TE, Morris RG, Mathew TH. Formulation of diltiazem affects cyclosporine-sparing activity. Eur J Clin Pharmacol 1997; 52: 55–8
Moore LW, Alloway RR, Acchiardo SR, et al. Clinical observations of metabolic changes occurring in renal transplant recipients receiving ketoconazole. Transplantation 1996; 61: 537–41
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Martin, J.E., Daoud, A.J., Schroeder, T.J. et al. The Clinical and Economic Potential of Cyclosporin Drug Interactions. Pharmacoeconomics 15, 317–337 (1999). https://doi.org/10.2165/00019053-199915040-00001
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DOI: https://doi.org/10.2165/00019053-199915040-00001