et al. Synthesis and anti-inflammatory and analgesic activity of 5aroyl-I ,2, dihydro-3H-pyrrolo (I ,2-a) pyrrole-I-carboxylic acids and related compounds, J Med Chem 1985;28:1037-49. 6. Rooks WH II, Tomolonis AJ, Maloney PJ, Wallach MB, Schuler ME. The analgesic and anti-inflammatory profile of (±)-5 benwyl-I ,2dihydro-3H-pyrrolo (l,2-a) pyrrole-l-carboxylic acid (RS37619). Agents Actions 1982;12:684-90. 7. Atkinson DC, Collier HOJ. Salicylates: molecular mechanism of therapeutic action. Adv Pharmacol Chemother 1980;17:233-88. 8. Ferreira SH, Lorezetti BB, Correa FMA. Central and peripheral analgesic, action of aspirin-like drugs. Eur J PharmacoI1978;53:39-48. 9. Yee JP, Koshiver JE, Allbon C, Brown CR. Comparison of intra-muscular ketorolac tromethamine and morphine sulfate for analgesia of pain after major surgery. Pharmacotherapy 1986;6:253-61. 10. O'Hara DA, Fragen RJ, Kinzer M, Pemberton D. Ketorolac tromethamine as compared with morphine sulfate for treatment of postoperative pain. Clin Pharmacol Ther 1987;41:556-61. 11. Oosterlinck W, Philp NH, Charig C, Gillies G, Hetherington JW, Lloyd J. A double-blind single dose comparison of intramuscular ketorolac tromethamine and pertidine in the treatment of renal colic. J Clin Pharmacoll990;30:336-41. 12. Estenne B, Julien M, Charleux H, Arsac M, Arvis G, Loygue J. Comparison of ketorolac. pentazocine, and placebo in treating postoperative pain. Curr Ther Res 1988;43:1173-82.
13. MacDonald FC, Gough KJ, Nicoll RAG, Dow RJ. Psychomotor effects of ketorolac in comparison with bupremorphine and diclofenac. Br J Clin PharmacoI1989;27:453-9. 14. Conard KA, Fagan TC, Mackie MJ, Mayshar PV. Effects of ketorolac tromethamine on hemostasis in volunteers. Clin Pharmacol Ther 1988;43:542-6. 15. Roe RL, Bruno JJ, Ellis OJ. Effects of a new nonsteroidal anti-inflammatory agent on platelet function in male and female subjects (abstract). Clin Pharmacol Ther 1981;29:197. 16. Brandon-Bravo LJC, Mattie H, Spierdijk J, Bovill JG, Burm AGL. The effects on ventilation of ketorolac in comparison to morphine. Eur J Clin PharmacoI1988;35:49l-4. 17. Murray AW, Brockway MS, Kenny GNC. Comparison of the cardiorespiratory effects of ketorolac and alfentaril during propofol anaesthesia. Br J Anaesth 1989;63:601-3. 18. Alderman EL, Barry WH, Graham AF, Harrison DC. Hemodynamic effects of morphine and pentazocine differ in cardiac patients. N EnglJ Med 1972;287:623-7. 19. Yeh KC, Kwan KC. Comparison of numerical integrating algorithms by trapezoidal, lagrange and spline approximation. J Pharmacokinet Biopharm 1978;6:79-98. 20. Segal RS, Jarvis OJ, Duncan SR, White PF, Mate M. Clinical efficacy of oral-transderrnal clonidine combinations during the preoperative period. Anesthesiology 1991;74:220-5.
HYPERSENSITIVITY IMMUNE REACTION AS A MECHANISM FOR DILEVALOL·ASSOCIATED HEPATITIS Vasco A.J. Maria and Rui M.M. Victorino
To assess lymphocyte reactivity to dilevalol and to serum containing putative ex vivo dilevalol antigens or metabolites in a case of dilevalol-induced liver injury.
OBJECTIVE:
PATIENT: A 58-year-old woman with a clinical diagnosis of dilevalol-induced liver injury. METHODS: Peripheral blood mononuclear cells collected from the patient were cultured in the presence of a solution of dilevalol and also with sera collected from a volunteer before and after dilevalol intake. A similar protocol was performed with lymphocytes from a healthy subject. RESULTS: No lymphocyte proliferation was observed either in the patient or in the healthy volunteer in the presence of dilevalol solutions. A significant proliferative response to serum collected after dilevalol intake was observed in the case of the patient compared with the proliferative response to the serum collected before the drug intake. No reactivity was found when lymphocytes
VASCO AJ. MARIA, M.D.. is a Research Fellow in Clinical Immunology; and RUI M.M. VICTORINO, M.D., Ph.D., is an Associate Professor and Consultant Physician in Internal Medicine and Clinical Immunology, Medicine 2/Clinical Immunology, Faculty of Medicine of Lisbon, Lisbon, Portugal. Reprints: Rui M.M. Victorino, M.D., Ph.D.. Department of Medicine 2/Clinical Immunology, Av. Prof. Egas Moniz. 1600 Lisbon, Portugal. The work was supported by grants from Junta Nacional de Investigacao Cientffica e Tecnol6gica and Instituto Nacional de lnvestigacao Cientffica.
924 •
The Annals of Pharmacotherapy
•
from the healthy subject were tested under similar conditions. The methodology used allowed the detection of lymphocyte sensitization to sera containing ex vivo-prepared dilevalol antigens, suggesting the involvement of an immunologic mechanism in dilevalol-induced liver injury.
CONCLUSIONS:
Ann Pharmacother 1992;26:924-6,
of labetalol, with a combination of beta-adrenergic blocking effects and selective beta.-agonist activity. Dilevalol was introduced in the 1980s as an antihypertensive and was licensed in Portugal and Japan in 1990. Several cases of dilevalol-induced liver injury have been reported.l" which led to withdrawal of the drug from the market in August 1990. However, no studies of the possible mechanisms for such adverse reactions have been published. The detection of lymphocyte sensitization to a drug in vitro is considered as evidence favoring a hypersensitivity mechanisrrr-' and can provide additional support to the involvement of the drug in hepatitis. We report immunologic studies performed in a patient with a clinical diagnosis of dilevalol-induced liver injury. DILEV ALOL IS A STEREOISOMER
1992 July/August, Volume 26
Short Reports
The studies were done to assess lymphocyte reactivity to the native drug as well as to serum-containing putative ex vivo drug antigens or metabolites, using an experimental protocol," Lymphocyte sensitization to ex vivo drug antigens or metabolites, rather than to the native drug, was detected.
4
CJ)
w
3
X
W
Methods
Cl
A 58-year-old woman started treatment with dilevalol 200 mg/d po for moderate essential hypertension. Routine blood tests done two weeks later disclosed elevations of aminotransferases (about ten times the normal values) and of gamma-glutamyl transpeptidase (five times the normal value). Alternative causes for liver injury were excluded by means of serology for hepatitis viruses, ultrasound examination of the upper abdomen, and a liver biopsy. The patient was then referred to our laboratory for immunologic investigation. Peripheral blood mononuclear cells (PBMC) collected from the patient were stimulated in vitro for six days with five different concentrations of dilevalol using a previously described method.' Briefly, 100 ul. of PBMC were distributed in each well of a microtitre plate. Twenty ul, of each concentration of dilevalol were added to the wells. Cells were cultured for six days in a humidified COrenriched atmosphere, and 12 hours before the end of the cultures 20 ul, of tritiated thymidine were added to each well. Cells were harvested to filter discs and counted in a cintillation counter. Results were expressed in counts per minute (cpm) and in stimulation indices (SI = cpm of cultures with drug/cpm of cultures without drug). Lymphocyte responses were considered significant when SI was ~2. Simultaneously, the patient's lymphocytes were cultured in the presence of sera collected from a healthy volunteer (one of the authors) before and one hour after the ingestion of a therapeutic dose of dilevalol, under the assumption that serum collected after drug intake could contain ex vivo drug antigens or metabolites. No lymphocyte proliferation was observed when lymphocytes were cultured in the presence of the different concentrations of the native drug. However, in the experiments with sera, there was a significant proliferative response to the serum collected after drug intake, compared with serum collected before drug ingestion (Figure I). In the healthy volunteer simultaneously studied, no proliferative responses were observed either in cultures with the parental drug or in cultures with sen! (Figure I).
Although there are cases of drug-induced liver injury with beta-blockers, its frequency is very low."" However, several cases of dilevalol-induced liver injury have been reported with a frequency well above that reported for other beta-blockers.':' In July 1990, Schering-Plough submitted a report to the Food and Drug Administration containing data on 15 patients with possible dilevalol-associated hepatotoxicity. The relationship between liver injury and dilevalol was classified as probable in 7 patients and possible in 4 by means of clinical criteria. Additional cases have been reported subsequently in Portugal and Japan, the two countries where dilevalol was marketed. The worldwide dilevalol hepatotoxicity incidence rate was calculated to be I in 1015 for cases with a period of exposure longer than three months and classified as probable or possible.' The diagnosis of drug-induced hepatitis usually is based on the temporal relationship between drug intake and the occurrence of the liver injury with exclusion of alternative causes for the hepatitis." These criteria were used for the diagnosis of the cases of dilevalol-associated hepatitis previously reported, but no studies of possible mechanisms were done. The lymphocyte transformation test has been used in cases in which an immunologic mechanism probably was involved, in an attempt to demonstrate lymphocyte sensitization to the suspected drug. However, negative
Z
z 2
o
~
::>
~
1
CJ)
0"'----........__ CONTROL
PATIENT
Figure I. Lymphocyte responses to serum with dilevalol antigens. 0 = cultures with serum collected before dilevalol intake; • = cultures with serum collected after dilevalol oral intake.
results have often been reported in cases with clinical evidence, suggesting a hypersensitivity drug reaction; thus, the test usually is considered to have a low sensitivity," We have previously analyzed the possibility of detecting lymphocyte reactivity not only to the native drug but also to serum collected from healthy volunteers after ingestion of the drug. We assumed that such serum could contain ex vivo drug antigens or drug metabolites and thus increase the sensitivity of the test,6,14 This methodology, although complex, may be helpful in cases in which confirmation of the clinical diagnosis appears to be important, particularly in cases in which several drugs may be involved. It is possible to speculate that the native drug or its metabolites present in the sera could act as haptens that, after binding to plasma proteins, would form stable compounds with antigenic properties and thus be capable of inducing lymphocyte responses in vitro. This methodology was applied in our patient and evidence for lymphocyte sensitization to sera containing ex vivo dilevalol antigens or metabolites was detected. These results suggest that dilevalol-induced hepatitis can occur by an immunologic mechanism and they represent further evidence in favor of the association of dilevalol with liver injury. ~ We are grateful to Professor Carneiro de Moura, director of the Department of Medicine 2, for the support given to our work and to Dr. Julio Veloso for referring the patient for immunologic studies.
References I, Chrisp P, Goa KL. Dilevalol: a review of its pharmacodynamic and pharrnacokinetic properties and therapeutic potential in hypertension, Drugs 1990;39:234-63.
2, Arvengt C. Labetalol hepatotoxicity (letter), Ann Intern Med 1991;114: 341.
3, Report on the analysis of cases of drug induced liver injury associated to dilevaloL Kenilworth. NJ: Schering-Plough, 1990. 4, Sherlock S. The spectrum of hepatotoxicitydue to drugs, Lancet 1986;2: 440-4,
5, Kaplowitz N, Aw TY, Simon FR, Stolz A. Drug-inducedhepatotoxicity, Ann Intern Med 1986;104:826-39,
The Annals ofPharmacotherapy
•
1992 July/August, Volume 26
•
925
6. Victorino RMM, Maria VA, Correia AP, de Moura Me. Floxacillininduced cholestatic hepatitis with evidence of lymphocyte sensitization.
Arch Intern Med 1987;147:987-9. 7. Victorino RMM, Hodgson HJR. Relationship between T cell subpopulations and the mitogen responsiveness and suppressor cell function of peripheral blood mononuclear cells in normal individuals. Clin Exp lm-
munoI1980;42:571-8. 8. Larrey D, Henrion J, Heller F, Babany G, Degott C, Pessayre D, et al. Metoprolol-induced hepatitis: rechallenge and drug oxidation phenotyping. Ann Intern Med 1988;108:67-8. 9. Tanner LA, Bosco LA, Zimmerman HJ. Hepatic toxicity after acebutolol therapy. Ann Intern Med 1989;111:533-4. 10. Schwartz MS, Frank MS, Yanoff A, Morecki R. Atenolol-associated cholestasis. Am J Gastroenterol 1989;84:1084-6.
II. Clark JA, Zimmerman HJ, Tanner LA. Labetalol hepatotoxicity. Ann
Intern Med 1990;113:210-3. 12. Shearman DJC, Finlayson NDe. Drugs, toxins and the liver. In: Diseases of the gastrointestinal tract and liver. London: Churchill Livingstone, 1982:527-54. 13. Rotmensch HH, Leiser A, Dan M, Klejman A, Livni E, I\lie B, et al. Evaluation of prajrnalium-induced cholestasis by immunological tests.
Arch Intern Med 1981;141:1797-801. 14. Victorino RMM, Maria V AJ. Modifications of the lymphocyte transformation test in a case of drug-induced cholestatic hepatitis. Diagn Immunol 1985;3:177-81.
PROPAFENONE-INDUCED LIVER INJURY Sarah A. Spinler, Cheryl A. Elder, and K. Elizabeth Kindwall
OBJECTIVE: DFSIGN:
To describe propafenone-induced liver injury.
Retrospective case report.
Referred care in a large tertiary care center. Laboratory tests were performed at the auxiliary site and the tertiary care center.
SETIlNG:
PATIENT: A 71-year-old woman with atrial fibrillation developed elevations of greater than two times the upper limit of normal in alkaline phosphatase (ALK), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyltransferase (GOT) after initiation ofpropafenone therapy.
INTERVENTIONS:
Studies included serial measurements of ALK, ALT,
AST, and GOT.
this case, the pattern demonstrated by elevations in liver enzymes may be classified as acute cholestatic liver injury. Because the reported incidence is 0.1-0.2 percent and there are no known fatalities secondary to propafenone liver injury, routine monitoring of liver function tests in all patients receiving propafenone cannot be recommended at this time. Baseline liver function tests prior to initiating propafenone therapy with follow-up laboratory studies one month later are recommended in patients with known liver dysfunction. If elevations are noted, a reduction in dose may result in lower liver enzyme concentrations, although discontinuation of therapy may be required in some cases.
Ann Pharmacother 1992;26:926-8.
The patient developed elevations of greater than two times the upper limit of normal in ALK, ALT, and AST, one month after initiating propafenone therapy. The propafenone dose was decreased from 900 to 675 mg/d and, ten days later, the ALK, AL T, and AST were decreased slightly, but still above the upper limit of normal. One month later, serum transaminases had returned to baseline, but propafenone therapy was discontinued because of recurrent atrial fibrillation, persistent elevation in ALK, and elevation in GOT. Two months after discontinuing propafenone, serum arninotransaminase and ALK concentrations had normalized and GOT had decreased and remained only slightly elevated. RFSULTS:
The occurrence of liver injury secondary to propafenone therapy is rare. Reported cases appear to be secondary to hepatocellular injury, cholestasis, or a combination of the two. In
CONCLUSIONS:
SARAH A. SPINLER, Pharm.D., is an Assistant Professor of Clinical Pharmacy, Philadelphia College of Pharmacy and Science, and an Adjunct Assistant Professor of Pharmacy in Medicine, University of Pennsylvania, Cardiovascular Section, Hospital of the University of Pennsylvania: CHERYL A. ELDER, B.S.Pharm.• is a Pharm.D. Student, Philadelphia College of Pharmacy and Science; and K. ELIZA· BETH KINDW ALL, M.D.. is an Assistant Professor of Medicine, University of Pennsylvania, Cardiovascular Section. Hospital of the University of Pennsylvania. Reprints: Sarah A. Spinier, Pharm.D .• Philadelphia College of Pharmacy and Science, 600 S. 43rd St., Philadelphia. PA 19104.
926
•
The Annals ofPharmacotherapy
•
PROPAFENONE HYDROCHLORIDE is a class IC antiarrhythmic agent indicated for the treatment of life-threatening ventricular arrhythmias. t Although not labeled for use in the treatment of supraventricular arrhythmias, propafenone has also been found to be effective in atrial flutter, atrial fibrillation, and re-entrant arrhythmias associated with the WolffParkinson-White syndrome.' By blocking the fast inward sodium channel, propafenone causes a reduction in upstroke velocity of phase 0 of the action potential (Vrnax ) and decreases conduction velocity in the atria, ventricles, and Purkinje fibers. Propafenone lengthens AH and HV conduction time and thereby prolongs the PR interval and QRS duration on the electrocardiogram. The drug reduces spontaneous automaticity and prolongs the Vma. duration and effective refractory period. In addition, propafenone has weak beta-adrenergic blocking (only 1/40 of the activity of propranolol) and some calcium-antagonist activity,' Propafenone is generally well tolerated but may cause both cardiovascular and noncardiovascular adverse effects. Cardiovascular adverse effects include proarrhytlunia, wors-
1992 July/August, Volume 26
13. MacDonald FC, Gough KJ, Nicoll RAG, Dow RJ. Psychomotor effects of ketorolac in comparison with bupremorphine and diclofenac. Br J Clin PharmacoI1989;27:453-9. 14. Conard KA, Fagan TC, Mackie MJ, Mayshar PV. Effects of ketorolac tromethamine on hemostasis in volunteers. Clin Pharmacol Ther 1988;43:542-6. 15. Roe RL, Bruno JJ, Ellis OJ. Effects of a new nonsteroidal anti-inflammatory agent on platelet function in male and female subjects (abstract). Clin Pharmacol Ther 1981;29:197. 16. Brandon-Bravo LJC, Mattie H, Spierdijk J, Bovill JG, Burm AGL. The effects on ventilation of ketorolac in comparison to morphine. Eur J Clin PharmacoI1988;35:49l-4. 17. Murray AW, Brockway MS, Kenny GNC. Comparison of the cardiorespiratory effects of ketorolac and alfentaril during propofol anaesthesia. Br J Anaesth 1989;63:601-3. 18. Alderman EL, Barry WH, Graham AF, Harrison DC. Hemodynamic effects of morphine and pentazocine differ in cardiac patients. N EnglJ Med 1972;287:623-7. 19. Yeh KC, Kwan KC. Comparison of numerical integrating algorithms by trapezoidal, lagrange and spline approximation. J Pharmacokinet Biopharm 1978;6:79-98. 20. Segal RS, Jarvis OJ, Duncan SR, White PF, Mate M. Clinical efficacy of oral-transderrnal clonidine combinations during the preoperative period. Anesthesiology 1991;74:220-5.
HYPERSENSITIVITY IMMUNE REACTION AS A MECHANISM FOR DILEVALOL·ASSOCIATED HEPATITIS Vasco A.J. Maria and Rui M.M. Victorino
To assess lymphocyte reactivity to dilevalol and to serum containing putative ex vivo dilevalol antigens or metabolites in a case of dilevalol-induced liver injury.
OBJECTIVE:
PATIENT: A 58-year-old woman with a clinical diagnosis of dilevalol-induced liver injury. METHODS: Peripheral blood mononuclear cells collected from the patient were cultured in the presence of a solution of dilevalol and also with sera collected from a volunteer before and after dilevalol intake. A similar protocol was performed with lymphocytes from a healthy subject. RESULTS: No lymphocyte proliferation was observed either in the patient or in the healthy volunteer in the presence of dilevalol solutions. A significant proliferative response to serum collected after dilevalol intake was observed in the case of the patient compared with the proliferative response to the serum collected before the drug intake. No reactivity was found when lymphocytes
VASCO AJ. MARIA, M.D.. is a Research Fellow in Clinical Immunology; and RUI M.M. VICTORINO, M.D., Ph.D., is an Associate Professor and Consultant Physician in Internal Medicine and Clinical Immunology, Medicine 2/Clinical Immunology, Faculty of Medicine of Lisbon, Lisbon, Portugal. Reprints: Rui M.M. Victorino, M.D., Ph.D.. Department of Medicine 2/Clinical Immunology, Av. Prof. Egas Moniz. 1600 Lisbon, Portugal. The work was supported by grants from Junta Nacional de Investigacao Cientffica e Tecnol6gica and Instituto Nacional de lnvestigacao Cientffica.
924 •
The Annals of Pharmacotherapy
•
from the healthy subject were tested under similar conditions. The methodology used allowed the detection of lymphocyte sensitization to sera containing ex vivo-prepared dilevalol antigens, suggesting the involvement of an immunologic mechanism in dilevalol-induced liver injury.
CONCLUSIONS:
Ann Pharmacother 1992;26:924-6,
of labetalol, with a combination of beta-adrenergic blocking effects and selective beta.-agonist activity. Dilevalol was introduced in the 1980s as an antihypertensive and was licensed in Portugal and Japan in 1990. Several cases of dilevalol-induced liver injury have been reported.l" which led to withdrawal of the drug from the market in August 1990. However, no studies of the possible mechanisms for such adverse reactions have been published. The detection of lymphocyte sensitization to a drug in vitro is considered as evidence favoring a hypersensitivity mechanisrrr-' and can provide additional support to the involvement of the drug in hepatitis. We report immunologic studies performed in a patient with a clinical diagnosis of dilevalol-induced liver injury. DILEV ALOL IS A STEREOISOMER
1992 July/August, Volume 26
Short Reports
The studies were done to assess lymphocyte reactivity to the native drug as well as to serum-containing putative ex vivo drug antigens or metabolites, using an experimental protocol," Lymphocyte sensitization to ex vivo drug antigens or metabolites, rather than to the native drug, was detected.
4
CJ)
w
3
X
W
Methods
Cl
A 58-year-old woman started treatment with dilevalol 200 mg/d po for moderate essential hypertension. Routine blood tests done two weeks later disclosed elevations of aminotransferases (about ten times the normal values) and of gamma-glutamyl transpeptidase (five times the normal value). Alternative causes for liver injury were excluded by means of serology for hepatitis viruses, ultrasound examination of the upper abdomen, and a liver biopsy. The patient was then referred to our laboratory for immunologic investigation. Peripheral blood mononuclear cells (PBMC) collected from the patient were stimulated in vitro for six days with five different concentrations of dilevalol using a previously described method.' Briefly, 100 ul. of PBMC were distributed in each well of a microtitre plate. Twenty ul, of each concentration of dilevalol were added to the wells. Cells were cultured for six days in a humidified COrenriched atmosphere, and 12 hours before the end of the cultures 20 ul, of tritiated thymidine were added to each well. Cells were harvested to filter discs and counted in a cintillation counter. Results were expressed in counts per minute (cpm) and in stimulation indices (SI = cpm of cultures with drug/cpm of cultures without drug). Lymphocyte responses were considered significant when SI was ~2. Simultaneously, the patient's lymphocytes were cultured in the presence of sera collected from a healthy volunteer (one of the authors) before and one hour after the ingestion of a therapeutic dose of dilevalol, under the assumption that serum collected after drug intake could contain ex vivo drug antigens or metabolites. No lymphocyte proliferation was observed when lymphocytes were cultured in the presence of the different concentrations of the native drug. However, in the experiments with sera, there was a significant proliferative response to the serum collected after drug intake, compared with serum collected before drug ingestion (Figure I). In the healthy volunteer simultaneously studied, no proliferative responses were observed either in cultures with the parental drug or in cultures with sen! (Figure I).
Although there are cases of drug-induced liver injury with beta-blockers, its frequency is very low."" However, several cases of dilevalol-induced liver injury have been reported with a frequency well above that reported for other beta-blockers.':' In July 1990, Schering-Plough submitted a report to the Food and Drug Administration containing data on 15 patients with possible dilevalol-associated hepatotoxicity. The relationship between liver injury and dilevalol was classified as probable in 7 patients and possible in 4 by means of clinical criteria. Additional cases have been reported subsequently in Portugal and Japan, the two countries where dilevalol was marketed. The worldwide dilevalol hepatotoxicity incidence rate was calculated to be I in 1015 for cases with a period of exposure longer than three months and classified as probable or possible.' The diagnosis of drug-induced hepatitis usually is based on the temporal relationship between drug intake and the occurrence of the liver injury with exclusion of alternative causes for the hepatitis." These criteria were used for the diagnosis of the cases of dilevalol-associated hepatitis previously reported, but no studies of possible mechanisms were done. The lymphocyte transformation test has been used in cases in which an immunologic mechanism probably was involved, in an attempt to demonstrate lymphocyte sensitization to the suspected drug. However, negative
Z
z 2
o
~
::>
~
1
CJ)
0"'----........__ CONTROL
PATIENT
Figure I. Lymphocyte responses to serum with dilevalol antigens. 0 = cultures with serum collected before dilevalol intake; • = cultures with serum collected after dilevalol oral intake.
results have often been reported in cases with clinical evidence, suggesting a hypersensitivity drug reaction; thus, the test usually is considered to have a low sensitivity," We have previously analyzed the possibility of detecting lymphocyte reactivity not only to the native drug but also to serum collected from healthy volunteers after ingestion of the drug. We assumed that such serum could contain ex vivo drug antigens or drug metabolites and thus increase the sensitivity of the test,6,14 This methodology, although complex, may be helpful in cases in which confirmation of the clinical diagnosis appears to be important, particularly in cases in which several drugs may be involved. It is possible to speculate that the native drug or its metabolites present in the sera could act as haptens that, after binding to plasma proteins, would form stable compounds with antigenic properties and thus be capable of inducing lymphocyte responses in vitro. This methodology was applied in our patient and evidence for lymphocyte sensitization to sera containing ex vivo dilevalol antigens or metabolites was detected. These results suggest that dilevalol-induced hepatitis can occur by an immunologic mechanism and they represent further evidence in favor of the association of dilevalol with liver injury. ~ We are grateful to Professor Carneiro de Moura, director of the Department of Medicine 2, for the support given to our work and to Dr. Julio Veloso for referring the patient for immunologic studies.
References I, Chrisp P, Goa KL. Dilevalol: a review of its pharmacodynamic and pharrnacokinetic properties and therapeutic potential in hypertension, Drugs 1990;39:234-63.
2, Arvengt C. Labetalol hepatotoxicity (letter), Ann Intern Med 1991;114: 341.
3, Report on the analysis of cases of drug induced liver injury associated to dilevaloL Kenilworth. NJ: Schering-Plough, 1990. 4, Sherlock S. The spectrum of hepatotoxicitydue to drugs, Lancet 1986;2: 440-4,
5, Kaplowitz N, Aw TY, Simon FR, Stolz A. Drug-inducedhepatotoxicity, Ann Intern Med 1986;104:826-39,
The Annals ofPharmacotherapy
•
1992 July/August, Volume 26
•
925
6. Victorino RMM, Maria VA, Correia AP, de Moura Me. Floxacillininduced cholestatic hepatitis with evidence of lymphocyte sensitization.
Arch Intern Med 1987;147:987-9. 7. Victorino RMM, Hodgson HJR. Relationship between T cell subpopulations and the mitogen responsiveness and suppressor cell function of peripheral blood mononuclear cells in normal individuals. Clin Exp lm-
munoI1980;42:571-8. 8. Larrey D, Henrion J, Heller F, Babany G, Degott C, Pessayre D, et al. Metoprolol-induced hepatitis: rechallenge and drug oxidation phenotyping. Ann Intern Med 1988;108:67-8. 9. Tanner LA, Bosco LA, Zimmerman HJ. Hepatic toxicity after acebutolol therapy. Ann Intern Med 1989;111:533-4. 10. Schwartz MS, Frank MS, Yanoff A, Morecki R. Atenolol-associated cholestasis. Am J Gastroenterol 1989;84:1084-6.
II. Clark JA, Zimmerman HJ, Tanner LA. Labetalol hepatotoxicity. Ann
Intern Med 1990;113:210-3. 12. Shearman DJC, Finlayson NDe. Drugs, toxins and the liver. In: Diseases of the gastrointestinal tract and liver. London: Churchill Livingstone, 1982:527-54. 13. Rotmensch HH, Leiser A, Dan M, Klejman A, Livni E, I\lie B, et al. Evaluation of prajrnalium-induced cholestasis by immunological tests.
Arch Intern Med 1981;141:1797-801. 14. Victorino RMM, Maria V AJ. Modifications of the lymphocyte transformation test in a case of drug-induced cholestatic hepatitis. Diagn Immunol 1985;3:177-81.
PROPAFENONE-INDUCED LIVER INJURY Sarah A. Spinler, Cheryl A. Elder, and K. Elizabeth Kindwall
OBJECTIVE: DFSIGN:
To describe propafenone-induced liver injury.
Retrospective case report.
Referred care in a large tertiary care center. Laboratory tests were performed at the auxiliary site and the tertiary care center.
SETIlNG:
PATIENT: A 71-year-old woman with atrial fibrillation developed elevations of greater than two times the upper limit of normal in alkaline phosphatase (ALK), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyltransferase (GOT) after initiation ofpropafenone therapy.
INTERVENTIONS:
Studies included serial measurements of ALK, ALT,
AST, and GOT.
this case, the pattern demonstrated by elevations in liver enzymes may be classified as acute cholestatic liver injury. Because the reported incidence is 0.1-0.2 percent and there are no known fatalities secondary to propafenone liver injury, routine monitoring of liver function tests in all patients receiving propafenone cannot be recommended at this time. Baseline liver function tests prior to initiating propafenone therapy with follow-up laboratory studies one month later are recommended in patients with known liver dysfunction. If elevations are noted, a reduction in dose may result in lower liver enzyme concentrations, although discontinuation of therapy may be required in some cases.
Ann Pharmacother 1992;26:926-8.
The patient developed elevations of greater than two times the upper limit of normal in ALK, ALT, and AST, one month after initiating propafenone therapy. The propafenone dose was decreased from 900 to 675 mg/d and, ten days later, the ALK, AL T, and AST were decreased slightly, but still above the upper limit of normal. One month later, serum transaminases had returned to baseline, but propafenone therapy was discontinued because of recurrent atrial fibrillation, persistent elevation in ALK, and elevation in GOT. Two months after discontinuing propafenone, serum arninotransaminase and ALK concentrations had normalized and GOT had decreased and remained only slightly elevated. RFSULTS:
The occurrence of liver injury secondary to propafenone therapy is rare. Reported cases appear to be secondary to hepatocellular injury, cholestasis, or a combination of the two. In
CONCLUSIONS:
SARAH A. SPINLER, Pharm.D., is an Assistant Professor of Clinical Pharmacy, Philadelphia College of Pharmacy and Science, and an Adjunct Assistant Professor of Pharmacy in Medicine, University of Pennsylvania, Cardiovascular Section, Hospital of the University of Pennsylvania: CHERYL A. ELDER, B.S.Pharm.• is a Pharm.D. Student, Philadelphia College of Pharmacy and Science; and K. ELIZA· BETH KINDW ALL, M.D.. is an Assistant Professor of Medicine, University of Pennsylvania, Cardiovascular Section. Hospital of the University of Pennsylvania. Reprints: Sarah A. Spinier, Pharm.D .• Philadelphia College of Pharmacy and Science, 600 S. 43rd St., Philadelphia. PA 19104.
926
•
The Annals ofPharmacotherapy
•
PROPAFENONE HYDROCHLORIDE is a class IC antiarrhythmic agent indicated for the treatment of life-threatening ventricular arrhythmias. t Although not labeled for use in the treatment of supraventricular arrhythmias, propafenone has also been found to be effective in atrial flutter, atrial fibrillation, and re-entrant arrhythmias associated with the WolffParkinson-White syndrome.' By blocking the fast inward sodium channel, propafenone causes a reduction in upstroke velocity of phase 0 of the action potential (Vrnax ) and decreases conduction velocity in the atria, ventricles, and Purkinje fibers. Propafenone lengthens AH and HV conduction time and thereby prolongs the PR interval and QRS duration on the electrocardiogram. The drug reduces spontaneous automaticity and prolongs the Vma. duration and effective refractory period. In addition, propafenone has weak beta-adrenergic blocking (only 1/40 of the activity of propranolol) and some calcium-antagonist activity,' Propafenone is generally well tolerated but may cause both cardiovascular and noncardiovascular adverse effects. Cardiovascular adverse effects include proarrhytlunia, wors-
1992 July/August, Volume 26
