Oral Erythromycin and the Risk of Sudden Death
http://www.100md.com
《新英格兰医药杂志》
To the Editor: Ray and colleagues (Sept. 9 issue)1 seem to have overlooked several important issues when describing the association of erythromycin with the risk of sudden death from cardiac causes. First, was there a higher risk associated with any specific erythromycin preparations? The most recent edition of The Use of Antibiotics, edited by Kucers et al., lists six available erythromycin preparations (base, stearate, estolate, ethylsuccinate, ascitrate, and parenteral erythromycin).2 Can the authors differentiate the risks associated with these preparations?
Second, the authors mention clarithromycin as "a strong CYP3A inhibitor," yet they consider this antibiotic separately and do not offer conclusions about the risk it poses. There are other macrolides and related antibiotics available. Spiramycin, josamycin, rosaramicin, roxithromycin, and azithromycin (a subclass of macrolides referred to as azalides) are also members of this class.2 Azithromycin is widely used in patients with human immunodeficiency virus (HIV) infection or AIDS, a disease that may affect the myocardium. To guide clinicians, could the authors provide data or speculation as to whether the same risks exist with these drugs?
Finally, is there any age-related difference in risk? The report included only patients 15 to 84 years of age. Is there reason for similar concern on the part of those of us who care for children?
Edward L. Kaplan, M.D.
University of Minnesota Medical School
Minneapolis, MN 55455
References
Ray WA, Murray KT, Meredith S, Narasimhulu SS, Hall K, Stein CM. Oral erythromycin and the risk of sudden death from cardiac causes. N Engl J Med 2004;351:1089-1096.
Kucers A, Crowe SM, Grayson ML, Hoy JF, eds. The use of antibiotics: a clinical review of antibacterial, antifungal, and antiviral drugs. 5th ed. Boston: Butterworth-Heinemann, 1997.
To the Editor: The article by Ray et al. and the accompanying Perspective article by Liu and Juurlink1 draw attention to the important risk of prolongation of the QT interval in patients taking erythromycin and other antibiotics. One group that is at particular risk is patients with anorexia nervosa. The prevalence of QT-interval prolongation is increased in this group,2 and a long QT interval is recognized as a risk factor for sudden death.3
QT-interval prolongation may develop in patients with anorexia nervosa for a number of reasons. First, starvation itself appears to cause QT-interval prolongation.4 Second, patients with anorexia often have electrolyte abnormalities such as hypokalemia, which can precipitate QT-interval prolongation. Third, drugs that can prolong the QT interval, such as antipsychotic agents and tricyclic antidepressants, are often prescribed to patients in this group. Finally, selective serotonin-reuptake inhibitors, which inhibit cytochrome P-450 enzymes, are often used to treat anorexia nervosa or associated depression.
The risks posed by the prescription of erythromycin, other macrolides, and quinolones to patients with anorexia nervosa are substantial but probably underrecognized.
Anthony P. Winston, M.R.C.Psych.
Warwick Hospital
Warwick CV34 5BW, United Kingdom
anthony.winston@swarkpct.nhs.uk
References
Liu BA, Juurlink DN. Drugs and the QT interval -- caveat doctor. N Engl J Med 2004;351:1053-1056.
Cooke RA, Chambers JB, Singh R, et al. QT interval in anorexia nervosa. Br Heart J 1994;72:69-73.
Isner JM, Roberts WC, Heymsfield SB, Yager J. Anorexia nervosa and sudden death. Ann Intern Med 1985;102:49-52.
Swenne I, Larsson PT. Heart risk associated with weight loss in anorexia nervosa and eating disorders: risk factors for QTc interval prolongation and dispersion. Acta Paediatr 1999;88:304-309.
To the Editor: As a caveat to doctors, Liu and Juurlink make suggestions about drugs that "are particularly important" because of the large numbers of patients who use them or because, in combination with other drugs, they can prolong the QT interval and induce tachyarrhythmias and torsades de pointes. However, the table in their Perspective article, showing "common drugs that in combination may prolong the QT interval," unfortunately leaves out all of the newer "atypical" antipsychotic drugs and includes only two older "typical" drugs. The first, thioridazine, which has the longest QT-interval prolongation of all antipsychotic drugs, is now largely off the shelves, and the other, haloperidol, has been found by the Food and Drug Administration to be associated with the lowest mean increase in the corrected QT interval (QTc) and the lowest risk of an increase of more than 60 msec when compared with the newer antipsychotic drugs.1
Between thioridazine and haloperidol are the "atypical" drugs, which are far more potent blockers of cytochrome P-450 inhibitors than haloperidol. Although haloperidol was found to increase the QT interval by 4.7 msec, ziprasidone increased it by 20.6 msec, followed by quetiapine (14.5 msec), risperidone (10.0 msec), and olanzapine (6.4 msec).2
Jack C. Schoenholtz, M.D.
Rye Hospital Center
Rye, NY 10580
kcajcp@aol.com
References
Center for Drug Evaluation and Research. Psychopharmacological Drugs Advisory Committee, July 19, 2000. Zeldox (ziprasidone hydrochloride capsules) NDA 20-825. (Accessed December 30, 2004, at http://www.fda.gov/OHRMS/DOCKETS/AC/00/backgrd/3619b1.htm.)
Huffman JC, Stern TA. QTc prolongation and the use of antipsychotics: a case discussion. Prim Care Companion J Clin Psychiatry 2003;5:278-81.
To the Editor: In response to the article by Liu and Juurlink, we note that methadone has also been associated with QTc prolongation. Both Kornick et al.1 and Krantz et al.2 concluded that there is a linear relationship between the dose of methadone and the QTc interval, suggesting that patients receiving higher doses of methadone are especially at risk. Since methadone is often administered concurrently with tricyclic antidepressants for pain management, there may even be a greater risk of QTc-interval prolongation and torsades de pointes in patients receiving this combination.
As a safety precaution, we perform baseline electrocardiographic studies in patients taking doses of methadone greater than 120 mg per day, then repeat the studies in four weeks and again every three months thereafter. If there is any evidence of QTc-interval prolongation, we discontinue the medication.
Juan-Diego Harris, M.D.
Oscar A. de Leon-Casasola, M.D.
Roswell Park Cancer Institute
Buffalo, NY 14263
juan-diego.harris@roswellpark.org
References
Kornick CA, Kilborn MJ, Santiago-Palma J, et al. QTc interval prolongation associated with intravenous methadone. Pain 2003;105:499-506.
Krantz MJ, Kutinsky IB, Robertson AD, Mehler PS. Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes. Pharmacotherapy 2003;23:802-805.
To the Editor: In addition to the medications listed by Liu and Juurlink, grapefruit juice is also known to be a potent inhibitor of cytochrome P-450 isoenzyme 3A4 (CYP3A4), the main enzyme responsible for the metabolism of erythromycin.1 In humans, administration of grapefruit juice with erythromycin significantly increases the resulting maximal plasma concentration of erythromycin (by 52 percent) and the area under the curve (by 49 percent).2 More prolonged administration results in even greater inhibition of CYP3A4, increasing plasma levels of erythromycin further3 and potentially increasing the risk of sudden death from QT-interval prolongation.
It has been proposed that a psoralen compound, 6'7'-dihydroxybergamottin, which is found in grapefruit juice but not in orange juice, is responsible for this inhibition.4 Recovery from inhibition is largely complete within three days, a period consistent with an enzyme-regeneration mechanism.5 Given the large numbers of people who drink grapefruit juice, this drug interaction may be one of the most commonly encountered in clinical practice; however, it may easily be overlooked if the appropriate history is not obtained. Fortunately, many pharmacists are well aware of this drug interaction and counsel patients accordingly.
John K. Amory, M.D.
David W. Amory, Sr., M.D., Ph.D.
University of Washington
Seattle, WA 98195
jamory@u.washington.edu
References
Fuhr U. Drug interactions with grapefruit juice: extent, probable mechanism and clinical relevance. Drug Saf 1998;18:251-272.
Kanazawa S, Ohkubo T, Sugawara K. The effects of grapefruit juice on the pharmacokinetics of erythromycin. Eur J Clin Pharmacol 2001;56:799-803.
Veronese ML, Gillen LP, Burke JP, et al. Exposure-dependent inhibition of intestinal and hepatic CYP3A4 in vivo by grapefruit juice. J Clin Pharmacol 2003;43:831-839.
Edwards DJ, Bellevue FH III, Woster PM. Identification of 6',7'-dihydroxybergamottin, a cytochrome P450 inhibitor, in grapefruit juice. Drug Metab Dispos 1996;24:1287-1290.
Greenblatt DJ, von Moltke LL, Harmatz JS, et al. Time course of recovery of cytochrome p450 3A function after single doses of grapefruit juice. Clin Pharmacol Ther 2003;74:121-129.
Dr. Ray and colleagues reply: In response to Dr. Kaplan: esters of erythromycin base (stearate, estolate, and ethylsuccinate) have been formulated to improve acid stability and enhance absorption, but they result in the same active product — erythromycin base. For this reason, we had no a priori hypothesis regarding the different formulations of erythromycin and thus did not conduct any analyses of this factor. During the study period, other macrolides were prescribed infrequently and thus could not be studied separately. We concur that such research is very important and must take into account the potentially different electrophysiological effects of individual drugs. Although our study did not include children, we believe on theoretical grounds that one should avoid prescribing erythromycin with strong CYP3A inhibitors to all patients.
Both Dr. Kaplan and Dr. Winston raise the interesting issue of the use of drugs with potentially adverse electrophysiological effects in high-risk patients (those with HIV infection or AIDS, or with anorexia nervosa), who may have an increased risk of arrhythmias because of the disease, its sequelae, or medications used in its treatment. Although caution is prudent, further study is needed to define risks better in these populations.
Wayne A. Ray, Ph.D.
Katherine T. Murray, M.D.
C. Michael Stein, M.B., Ch.B.
Vanderbilt University School of Medicine
Nashville, TN 37232
Drs. Liu and Juurlink reply: The goal of our Perspective article was to provide a general overview of the complex and poorly studied clinical problem of drug interactions, with an emphasis on those that can prolong the QT interval. A detailed consideration of special populations was beyond the scope of our discussion, but we agree with Winston that patients who have eating disorders often have multiple coexisting reasons for QT-interval prolongation. Physicians should be mindful of this issue when making prescribing decisions.
As Harris and de Leon-Casasola point out, methadone is among the scores of drugs capable of prolonging the QT interval. To have listed all of these drugs would have rendered our commentary redundant1 and precluded a focus on drug interactions. From a drug-safety perspective, the primary advantage of methadone over other narcotic analgesics is its long elimination half-life and the potential for once-daily dosing. Given the commercial availability of extended-release formulations of other high-potency opiates that are relatively free of effects on the QT interval, we believe that the use of methadone with other QT-interval–prolonging drugs such as cyclic antidepressants poses an unnecessary risk and should be avoided whenever possible.
The table to which Schoenholtz refers was explicitly intended to highlight key pharmacokinetic drug interactions involving cytochrome P-450 isoenzymes. His assertion that, as a class, atypical antipsychotics are potent inhibitors of drug-metabolizing enzymes is supported by no data; this is why they do not appear on the lefthand side of our table. With the exception of ziprasidone, newer antipsychotic agents are generally less likely than traditional agents to prolong the QT interval.2,3 We agree, however, that clinicians should exercise caution when using any of these drugs, particularly in treating high-risk patients.
Amory and Amory correctly note that grapefruit juice inhibits CYP3A4. Indeed, the same phenomenon may be seen with intact grapefruit segments.4 This effect is confined to intestinal rather than hepatic CYP3A4, and significant increases in drug levels are most likely with CYP3A4 substrates that normally undergo a high degree of presystemic metabolism.5 With the exception of cisapride (which is no longer in widespread use), this is not the case for most of the CYP3A4 substrates implicated in the genesis of torsades de pointes. Nevertheless, a recognition of the potential effects of grapefruit on drug bioavailability is essential, given the multitude of drugs metabolized by CYP3A4.
Barbara A. Liu, M.D.
David N. Juurlink, M.D., Ph.D.
Sunnybrook and Women's College Health Sciences Centre
Toronto, ON M4N 3M5, Canada
References
Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004;350:1013-1022.
Czekalla J, Beasley CM Jr, Dellva MA, Berg PH, Grundy S. Analysis of the QTc interval during olanzapine treatment of patients with schizophrenia and related psychosis. J Clin Psychiatry 2001;62:191-198.
Harrigan EP, Miceli JJ, Anziano R, et al. A randomized evaluation of the effects of six antipsychotic agents on QTc, in the absence and presence of metabolic inhibition. J Clin Psychopharmacol 2004;24:62-69.
Dreier JP, Endres M. Statin-associated rhabdomyolysis triggered by grapefruit consumption. Neurology 2004;62:670-670.
Bailey DG, Dresser GK. Interactions between grapefruit juice and cardiovascular drugs. Am J Cardiovasc Drugs 2004;4:281-97.
Second, the authors mention clarithromycin as "a strong CYP3A inhibitor," yet they consider this antibiotic separately and do not offer conclusions about the risk it poses. There are other macrolides and related antibiotics available. Spiramycin, josamycin, rosaramicin, roxithromycin, and azithromycin (a subclass of macrolides referred to as azalides) are also members of this class.2 Azithromycin is widely used in patients with human immunodeficiency virus (HIV) infection or AIDS, a disease that may affect the myocardium. To guide clinicians, could the authors provide data or speculation as to whether the same risks exist with these drugs?
Finally, is there any age-related difference in risk? The report included only patients 15 to 84 years of age. Is there reason for similar concern on the part of those of us who care for children?
Edward L. Kaplan, M.D.
University of Minnesota Medical School
Minneapolis, MN 55455
References
Ray WA, Murray KT, Meredith S, Narasimhulu SS, Hall K, Stein CM. Oral erythromycin and the risk of sudden death from cardiac causes. N Engl J Med 2004;351:1089-1096.
Kucers A, Crowe SM, Grayson ML, Hoy JF, eds. The use of antibiotics: a clinical review of antibacterial, antifungal, and antiviral drugs. 5th ed. Boston: Butterworth-Heinemann, 1997.
To the Editor: The article by Ray et al. and the accompanying Perspective article by Liu and Juurlink1 draw attention to the important risk of prolongation of the QT interval in patients taking erythromycin and other antibiotics. One group that is at particular risk is patients with anorexia nervosa. The prevalence of QT-interval prolongation is increased in this group,2 and a long QT interval is recognized as a risk factor for sudden death.3
QT-interval prolongation may develop in patients with anorexia nervosa for a number of reasons. First, starvation itself appears to cause QT-interval prolongation.4 Second, patients with anorexia often have electrolyte abnormalities such as hypokalemia, which can precipitate QT-interval prolongation. Third, drugs that can prolong the QT interval, such as antipsychotic agents and tricyclic antidepressants, are often prescribed to patients in this group. Finally, selective serotonin-reuptake inhibitors, which inhibit cytochrome P-450 enzymes, are often used to treat anorexia nervosa or associated depression.
The risks posed by the prescription of erythromycin, other macrolides, and quinolones to patients with anorexia nervosa are substantial but probably underrecognized.
Anthony P. Winston, M.R.C.Psych.
Warwick Hospital
Warwick CV34 5BW, United Kingdom
anthony.winston@swarkpct.nhs.uk
References
Liu BA, Juurlink DN. Drugs and the QT interval -- caveat doctor. N Engl J Med 2004;351:1053-1056.
Cooke RA, Chambers JB, Singh R, et al. QT interval in anorexia nervosa. Br Heart J 1994;72:69-73.
Isner JM, Roberts WC, Heymsfield SB, Yager J. Anorexia nervosa and sudden death. Ann Intern Med 1985;102:49-52.
Swenne I, Larsson PT. Heart risk associated with weight loss in anorexia nervosa and eating disorders: risk factors for QTc interval prolongation and dispersion. Acta Paediatr 1999;88:304-309.
To the Editor: As a caveat to doctors, Liu and Juurlink make suggestions about drugs that "are particularly important" because of the large numbers of patients who use them or because, in combination with other drugs, they can prolong the QT interval and induce tachyarrhythmias and torsades de pointes. However, the table in their Perspective article, showing "common drugs that in combination may prolong the QT interval," unfortunately leaves out all of the newer "atypical" antipsychotic drugs and includes only two older "typical" drugs. The first, thioridazine, which has the longest QT-interval prolongation of all antipsychotic drugs, is now largely off the shelves, and the other, haloperidol, has been found by the Food and Drug Administration to be associated with the lowest mean increase in the corrected QT interval (QTc) and the lowest risk of an increase of more than 60 msec when compared with the newer antipsychotic drugs.1
Between thioridazine and haloperidol are the "atypical" drugs, which are far more potent blockers of cytochrome P-450 inhibitors than haloperidol. Although haloperidol was found to increase the QT interval by 4.7 msec, ziprasidone increased it by 20.6 msec, followed by quetiapine (14.5 msec), risperidone (10.0 msec), and olanzapine (6.4 msec).2
Jack C. Schoenholtz, M.D.
Rye Hospital Center
Rye, NY 10580
kcajcp@aol.com
References
Center for Drug Evaluation and Research. Psychopharmacological Drugs Advisory Committee, July 19, 2000. Zeldox (ziprasidone hydrochloride capsules) NDA 20-825. (Accessed December 30, 2004, at http://www.fda.gov/OHRMS/DOCKETS/AC/00/backgrd/3619b1.htm.)
Huffman JC, Stern TA. QTc prolongation and the use of antipsychotics: a case discussion. Prim Care Companion J Clin Psychiatry 2003;5:278-81.
To the Editor: In response to the article by Liu and Juurlink, we note that methadone has also been associated with QTc prolongation. Both Kornick et al.1 and Krantz et al.2 concluded that there is a linear relationship between the dose of methadone and the QTc interval, suggesting that patients receiving higher doses of methadone are especially at risk. Since methadone is often administered concurrently with tricyclic antidepressants for pain management, there may even be a greater risk of QTc-interval prolongation and torsades de pointes in patients receiving this combination.
As a safety precaution, we perform baseline electrocardiographic studies in patients taking doses of methadone greater than 120 mg per day, then repeat the studies in four weeks and again every three months thereafter. If there is any evidence of QTc-interval prolongation, we discontinue the medication.
Juan-Diego Harris, M.D.
Oscar A. de Leon-Casasola, M.D.
Roswell Park Cancer Institute
Buffalo, NY 14263
juan-diego.harris@roswellpark.org
References
Kornick CA, Kilborn MJ, Santiago-Palma J, et al. QTc interval prolongation associated with intravenous methadone. Pain 2003;105:499-506.
Krantz MJ, Kutinsky IB, Robertson AD, Mehler PS. Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes. Pharmacotherapy 2003;23:802-805.
To the Editor: In addition to the medications listed by Liu and Juurlink, grapefruit juice is also known to be a potent inhibitor of cytochrome P-450 isoenzyme 3A4 (CYP3A4), the main enzyme responsible for the metabolism of erythromycin.1 In humans, administration of grapefruit juice with erythromycin significantly increases the resulting maximal plasma concentration of erythromycin (by 52 percent) and the area under the curve (by 49 percent).2 More prolonged administration results in even greater inhibition of CYP3A4, increasing plasma levels of erythromycin further3 and potentially increasing the risk of sudden death from QT-interval prolongation.
It has been proposed that a psoralen compound, 6'7'-dihydroxybergamottin, which is found in grapefruit juice but not in orange juice, is responsible for this inhibition.4 Recovery from inhibition is largely complete within three days, a period consistent with an enzyme-regeneration mechanism.5 Given the large numbers of people who drink grapefruit juice, this drug interaction may be one of the most commonly encountered in clinical practice; however, it may easily be overlooked if the appropriate history is not obtained. Fortunately, many pharmacists are well aware of this drug interaction and counsel patients accordingly.
John K. Amory, M.D.
David W. Amory, Sr., M.D., Ph.D.
University of Washington
Seattle, WA 98195
jamory@u.washington.edu
References
Fuhr U. Drug interactions with grapefruit juice: extent, probable mechanism and clinical relevance. Drug Saf 1998;18:251-272.
Kanazawa S, Ohkubo T, Sugawara K. The effects of grapefruit juice on the pharmacokinetics of erythromycin. Eur J Clin Pharmacol 2001;56:799-803.
Veronese ML, Gillen LP, Burke JP, et al. Exposure-dependent inhibition of intestinal and hepatic CYP3A4 in vivo by grapefruit juice. J Clin Pharmacol 2003;43:831-839.
Edwards DJ, Bellevue FH III, Woster PM. Identification of 6',7'-dihydroxybergamottin, a cytochrome P450 inhibitor, in grapefruit juice. Drug Metab Dispos 1996;24:1287-1290.
Greenblatt DJ, von Moltke LL, Harmatz JS, et al. Time course of recovery of cytochrome p450 3A function after single doses of grapefruit juice. Clin Pharmacol Ther 2003;74:121-129.
Dr. Ray and colleagues reply: In response to Dr. Kaplan: esters of erythromycin base (stearate, estolate, and ethylsuccinate) have been formulated to improve acid stability and enhance absorption, but they result in the same active product — erythromycin base. For this reason, we had no a priori hypothesis regarding the different formulations of erythromycin and thus did not conduct any analyses of this factor. During the study period, other macrolides were prescribed infrequently and thus could not be studied separately. We concur that such research is very important and must take into account the potentially different electrophysiological effects of individual drugs. Although our study did not include children, we believe on theoretical grounds that one should avoid prescribing erythromycin with strong CYP3A inhibitors to all patients.
Both Dr. Kaplan and Dr. Winston raise the interesting issue of the use of drugs with potentially adverse electrophysiological effects in high-risk patients (those with HIV infection or AIDS, or with anorexia nervosa), who may have an increased risk of arrhythmias because of the disease, its sequelae, or medications used in its treatment. Although caution is prudent, further study is needed to define risks better in these populations.
Wayne A. Ray, Ph.D.
Katherine T. Murray, M.D.
C. Michael Stein, M.B., Ch.B.
Vanderbilt University School of Medicine
Nashville, TN 37232
Drs. Liu and Juurlink reply: The goal of our Perspective article was to provide a general overview of the complex and poorly studied clinical problem of drug interactions, with an emphasis on those that can prolong the QT interval. A detailed consideration of special populations was beyond the scope of our discussion, but we agree with Winston that patients who have eating disorders often have multiple coexisting reasons for QT-interval prolongation. Physicians should be mindful of this issue when making prescribing decisions.
As Harris and de Leon-Casasola point out, methadone is among the scores of drugs capable of prolonging the QT interval. To have listed all of these drugs would have rendered our commentary redundant1 and precluded a focus on drug interactions. From a drug-safety perspective, the primary advantage of methadone over other narcotic analgesics is its long elimination half-life and the potential for once-daily dosing. Given the commercial availability of extended-release formulations of other high-potency opiates that are relatively free of effects on the QT interval, we believe that the use of methadone with other QT-interval–prolonging drugs such as cyclic antidepressants poses an unnecessary risk and should be avoided whenever possible.
The table to which Schoenholtz refers was explicitly intended to highlight key pharmacokinetic drug interactions involving cytochrome P-450 isoenzymes. His assertion that, as a class, atypical antipsychotics are potent inhibitors of drug-metabolizing enzymes is supported by no data; this is why they do not appear on the lefthand side of our table. With the exception of ziprasidone, newer antipsychotic agents are generally less likely than traditional agents to prolong the QT interval.2,3 We agree, however, that clinicians should exercise caution when using any of these drugs, particularly in treating high-risk patients.
Amory and Amory correctly note that grapefruit juice inhibits CYP3A4. Indeed, the same phenomenon may be seen with intact grapefruit segments.4 This effect is confined to intestinal rather than hepatic CYP3A4, and significant increases in drug levels are most likely with CYP3A4 substrates that normally undergo a high degree of presystemic metabolism.5 With the exception of cisapride (which is no longer in widespread use), this is not the case for most of the CYP3A4 substrates implicated in the genesis of torsades de pointes. Nevertheless, a recognition of the potential effects of grapefruit on drug bioavailability is essential, given the multitude of drugs metabolized by CYP3A4.
Barbara A. Liu, M.D.
David N. Juurlink, M.D., Ph.D.
Sunnybrook and Women's College Health Sciences Centre
Toronto, ON M4N 3M5, Canada
References
Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004;350:1013-1022.
Czekalla J, Beasley CM Jr, Dellva MA, Berg PH, Grundy S. Analysis of the QTc interval during olanzapine treatment of patients with schizophrenia and related psychosis. J Clin Psychiatry 2001;62:191-198.
Harrigan EP, Miceli JJ, Anziano R, et al. A randomized evaluation of the effects of six antipsychotic agents on QTc, in the absence and presence of metabolic inhibition. J Clin Psychopharmacol 2004;24:62-69.
Dreier JP, Endres M. Statin-associated rhabdomyolysis triggered by grapefruit consumption. Neurology 2004;62:670-670.
Bailey DG, Dresser GK. Interactions between grapefruit juice and cardiovascular drugs. Am J Cardiovasc Drugs 2004;4:281-97.