1353
Dental
Infrared spectra of gallstone of
case
1
(a)
and of pure
dipyridamole (b). - =calcium palmitate and bilirubinate.
Case 2 (female aged 83, history of myocardial infarction, admitted for investigation of recurrent cholangitis over the past
year). Laboratory investigations revealed leucocytosis (white cells ll’3xl0"/l)) cholestasis (bilirubin 51-7 pmol/1, alkaline phosphatase 255 IU/1 [normal < 110]), yGT 417 IU/1), and evidence of cytolysis (aspartate aminotransferase 120 IU/1, alanine aminotransferase 209 IU/1). The patient had taken three tablets per day of dipyridamole 75 mg for the past 10 years. Other medication included trinitrite, bepridil, and aspirin. Ultrasonography showed dilation of the main bile duct. An orange-brown stone (8 mm diameter) was extracted endoscopically. It was friable with bright yellow concentric layers. Analysis of the two stones by Fourier transform infrared spectrometry (Bruker IFS 48 spectrometer, KBr disc) demonstrated unusual bands at 1535,1470,1360,1217,1080,1053,
1016, and 760 per cm (±22 per cm). They were identified in our library of reference spectra5 as dipyridamole (figure). Thin-layer chromatography (silica gel 60 F254 plates eluted with n-butanol/ methylethylketone/ammonium hydroxide, 80/16/4) confirmed the presence of unconjugated dipyridamole (RfO’92) in both gallstones. The
stones
contained
dipyridamole/calcium-acid-bilirubinate/
calcium-palmitate 70/15/15 (case 1) and 15/80/5 (case 2). No cases of iatrogenic gallstones induced by dipyridamole have been reported the French Pharmacovigilance Service or to the manufacturer (Boehringer-lngelheim). Dipyridamole is mainly excreted in the bile as a monoglucuronide conjugate (about 90% of bile metabolites6). The development of these stones may stem from length of treatment with the drug, deficiency in hepatic glucuronide conjugation in patients treated with many drugs, or bacterial deconjugation. Some bacteria, especially enterobacteria, have 0-glucuronidase activity, which may be responsible for cleavage of the dipyridamole glucuronide and precipitation of the practically insoluble drug. Iatrogenic gallstones have been attributed to drugs that change bile composition to a lithogenic medium (eg, oral contraceptives, dofibrate).7 Drug-induced gallstones may also contain insoluble drugs or drug derivatives (eg, dipyridamole, glaphenine, to
ceftriaxone). Department of Organic Chemistry, Faculty of Pharmacy, 87025 Limoges, France, and Department of Gastroenterology, Chru Dupuytren, Limoges
CHRISTIAN MOESCH DENIS SAUTEREAU ALAIN GAINANT BERNARD PILLEGAND
prophylaxis for endocarditis
SIR,-Earlier this year the Endocarditis Working Party of the British Society for Antimicrobial Chemotherapy gave its initial brief response! to the paper by Dr van der Meer and colleagues2 who attempted to assess the value of antibiotic prophylaxis for dental patients with a nationwide case control study in the Netherlands. We said at the time that we firmly believed that our recommendations for prophylaxis should stand-ie, that prophylactic antibiotics should be given to patients known to be at risk of endocarditis before dental extractions, scaling, or surgery involving the gingival tissues. Since May, 1992, we have had the opportunity to discuss the Dutch paper both inside and outside the working party and to assess general reactions to it in the UK. We are concerned that some doctors seem to believe that van der Meer et al showed that it is not worth giving prophylactic antibiotics to patients at risk before dental procedures. This is not so. They concluded that prophylactic antibiotics had a protective efficacy of 49% and went on to state that, although this may be worthwhile for the individual patient, the effect was negligible in the whole population. This is hardly surprising. Only 5-10% of cases of endocarditis arise after dental procedures, and in 40% of them the patient has no pre-existing heart condition justifying antibiotic prophylaxis.3 Thus, even if prophylaxis were 100% effective, it would only reduce the number of cases by between 3% and 6%. If we assume that the total number of cases of bacterial endocarditis in the UK per year is 1500, a reduction of this size would be almost impossible to detect-but that does not mean that prophylactic antibiotics are not worth giving. If, as van der Meer et al suggest, antibiotics halve the risk of this serious disabling illness for the susceptible patient, prophylaxis is certainly worthwhile. Some other aspects of the paper have also caused us concern. For example, although 559 patients suspected of having endocarditis were initially considered for entry into the trial, only 48 eventually formed the case group and only 8 of these received adequate prophylaxis. Furthermore, the data for the control group was collected only late in the study and was derived from the medical records of patients at only a few hospitals. Finally, having taken advice from statisticians and epidemiologists, we have examined the feasibility of conducting a prospective controlled trial of the efficacy of prophylaxis in European Community countries, as suggested in your editorial." We have concluded that even with our wide international contacts it would be a Herculean task involving enormous expense that would, at best, only refine van der Meer’s figure rather than alter the policy for prophylaxis. N. A. Department of Clinical Bacteriology, Guy’s Hospital, London SE1 9RT, UK
Cameron
Hospital, Fife
Guy’s Hospital, London St Thomas’ London London
Hospital, London
SIMMONS,
Chairman, Working Party of the British Society for Antimicrobial
Chemotherapy
A. P. BALL R. A. CAWSON
S. J. EYKYN
Hospital Medical College,
R. FELDMAN
University of Birmingham
W. A. LITTLER
Unversity of Glasgow
D. A. MCGOWAN
Royal Postgraduate Medical School, 1. Schaad UB, Wedgwood-Krucko J, Tschaeppeler H. Reversible ceftriaxoneassociated biliary pseudolithiasis in children. Lancet 1988; ii: 1411-13. 2. Pigrau C, Pahissa A, Gropper S, Sureda D, Martinez-Vasquez JM. Ceftriaxoneassociated biliary pseudolithiasis in adults. Lancet 1989; i: 165. 3. Moesch C, Gainant A, Sautereau D. Lithiase biliaire de glafenine. Identification par spectrophotométrie infrarouge. Gastroenterol Clin Biol 1988; 12: 387-89. 4. Moesch C, Daudon M, Leymarie J, Raby C. Glaphenine-induced gallstones Eur J Clin Chem Clin Biochem (in press). 5. Moesch C, Sautereau D, Berry P, et al. Library of reference infrared spectra for the analysis of gallstones. Gastroenterology 1991; 100 (5 part 2): A776. 6.Beisenhertz G, Koss F, Klatt L, Binder B. The absorption and excretion of 2,6-bis (diethanolamino-4, 8 dipiperidino)-pyrimido-(5,4-d) pyrimidine after oral administration. Arch Int Pharmacodyn 1965; 158: 380-88. 7. Drugs and gallstones. Lancet 1977; ii: 177.
London Cross and Westminster Medical School, London
C. M. OAKLEY
Charing
D. C. SHANSON
1. Simmons NA, Ball AP, Cawson RA, et al Antibiotic prophylaxis and infective endocarditis. Lancet 1992; 339: 1292-93. 2. van der Meer, JTM, van Wijk W, Thompson J, Vandenbroucke JP, Valkenburg HA, Michel MF. Efficacy of antibiotic prophylaxis for prevention of native-valve endocarditis. Lancet 1992; 339: 135-39. 3. Bayliss R, Clarke C, Oakley C, et al. The teeth and infective endocarditis. Br Heart J 1983; 50: 506-12. 4. Editorial. Chemoprophylaxis for infective endocarditis: faith, hope, and chanty challenged. Lancet 1992; 339: 525-26.
Dental
Infrared spectra of gallstone of
case
1
(a)
and of pure
dipyridamole (b). - =calcium palmitate and bilirubinate.
Case 2 (female aged 83, history of myocardial infarction, admitted for investigation of recurrent cholangitis over the past
year). Laboratory investigations revealed leucocytosis (white cells ll’3xl0"/l)) cholestasis (bilirubin 51-7 pmol/1, alkaline phosphatase 255 IU/1 [normal < 110]), yGT 417 IU/1), and evidence of cytolysis (aspartate aminotransferase 120 IU/1, alanine aminotransferase 209 IU/1). The patient had taken three tablets per day of dipyridamole 75 mg for the past 10 years. Other medication included trinitrite, bepridil, and aspirin. Ultrasonography showed dilation of the main bile duct. An orange-brown stone (8 mm diameter) was extracted endoscopically. It was friable with bright yellow concentric layers. Analysis of the two stones by Fourier transform infrared spectrometry (Bruker IFS 48 spectrometer, KBr disc) demonstrated unusual bands at 1535,1470,1360,1217,1080,1053,
1016, and 760 per cm (±22 per cm). They were identified in our library of reference spectra5 as dipyridamole (figure). Thin-layer chromatography (silica gel 60 F254 plates eluted with n-butanol/ methylethylketone/ammonium hydroxide, 80/16/4) confirmed the presence of unconjugated dipyridamole (RfO’92) in both gallstones. The
stones
contained
dipyridamole/calcium-acid-bilirubinate/
calcium-palmitate 70/15/15 (case 1) and 15/80/5 (case 2). No cases of iatrogenic gallstones induced by dipyridamole have been reported the French Pharmacovigilance Service or to the manufacturer (Boehringer-lngelheim). Dipyridamole is mainly excreted in the bile as a monoglucuronide conjugate (about 90% of bile metabolites6). The development of these stones may stem from length of treatment with the drug, deficiency in hepatic glucuronide conjugation in patients treated with many drugs, or bacterial deconjugation. Some bacteria, especially enterobacteria, have 0-glucuronidase activity, which may be responsible for cleavage of the dipyridamole glucuronide and precipitation of the practically insoluble drug. Iatrogenic gallstones have been attributed to drugs that change bile composition to a lithogenic medium (eg, oral contraceptives, dofibrate).7 Drug-induced gallstones may also contain insoluble drugs or drug derivatives (eg, dipyridamole, glaphenine, to
ceftriaxone). Department of Organic Chemistry, Faculty of Pharmacy, 87025 Limoges, France, and Department of Gastroenterology, Chru Dupuytren, Limoges
CHRISTIAN MOESCH DENIS SAUTEREAU ALAIN GAINANT BERNARD PILLEGAND
prophylaxis for endocarditis
SIR,-Earlier this year the Endocarditis Working Party of the British Society for Antimicrobial Chemotherapy gave its initial brief response! to the paper by Dr van der Meer and colleagues2 who attempted to assess the value of antibiotic prophylaxis for dental patients with a nationwide case control study in the Netherlands. We said at the time that we firmly believed that our recommendations for prophylaxis should stand-ie, that prophylactic antibiotics should be given to patients known to be at risk of endocarditis before dental extractions, scaling, or surgery involving the gingival tissues. Since May, 1992, we have had the opportunity to discuss the Dutch paper both inside and outside the working party and to assess general reactions to it in the UK. We are concerned that some doctors seem to believe that van der Meer et al showed that it is not worth giving prophylactic antibiotics to patients at risk before dental procedures. This is not so. They concluded that prophylactic antibiotics had a protective efficacy of 49% and went on to state that, although this may be worthwhile for the individual patient, the effect was negligible in the whole population. This is hardly surprising. Only 5-10% of cases of endocarditis arise after dental procedures, and in 40% of them the patient has no pre-existing heart condition justifying antibiotic prophylaxis.3 Thus, even if prophylaxis were 100% effective, it would only reduce the number of cases by between 3% and 6%. If we assume that the total number of cases of bacterial endocarditis in the UK per year is 1500, a reduction of this size would be almost impossible to detect-but that does not mean that prophylactic antibiotics are not worth giving. If, as van der Meer et al suggest, antibiotics halve the risk of this serious disabling illness for the susceptible patient, prophylaxis is certainly worthwhile. Some other aspects of the paper have also caused us concern. For example, although 559 patients suspected of having endocarditis were initially considered for entry into the trial, only 48 eventually formed the case group and only 8 of these received adequate prophylaxis. Furthermore, the data for the control group was collected only late in the study and was derived from the medical records of patients at only a few hospitals. Finally, having taken advice from statisticians and epidemiologists, we have examined the feasibility of conducting a prospective controlled trial of the efficacy of prophylaxis in European Community countries, as suggested in your editorial." We have concluded that even with our wide international contacts it would be a Herculean task involving enormous expense that would, at best, only refine van der Meer’s figure rather than alter the policy for prophylaxis. N. A. Department of Clinical Bacteriology, Guy’s Hospital, London SE1 9RT, UK
Cameron
Hospital, Fife
Guy’s Hospital, London St Thomas’ London London
Hospital, London
SIMMONS,
Chairman, Working Party of the British Society for Antimicrobial
Chemotherapy
A. P. BALL R. A. CAWSON
S. J. EYKYN
Hospital Medical College,
R. FELDMAN
University of Birmingham
W. A. LITTLER
Unversity of Glasgow
D. A. MCGOWAN
Royal Postgraduate Medical School, 1. Schaad UB, Wedgwood-Krucko J, Tschaeppeler H. Reversible ceftriaxoneassociated biliary pseudolithiasis in children. Lancet 1988; ii: 1411-13. 2. Pigrau C, Pahissa A, Gropper S, Sureda D, Martinez-Vasquez JM. Ceftriaxoneassociated biliary pseudolithiasis in adults. Lancet 1989; i: 165. 3. Moesch C, Gainant A, Sautereau D. Lithiase biliaire de glafenine. Identification par spectrophotométrie infrarouge. Gastroenterol Clin Biol 1988; 12: 387-89. 4. Moesch C, Daudon M, Leymarie J, Raby C. Glaphenine-induced gallstones Eur J Clin Chem Clin Biochem (in press). 5. Moesch C, Sautereau D, Berry P, et al. Library of reference infrared spectra for the analysis of gallstones. Gastroenterology 1991; 100 (5 part 2): A776. 6.Beisenhertz G, Koss F, Klatt L, Binder B. The absorption and excretion of 2,6-bis (diethanolamino-4, 8 dipiperidino)-pyrimido-(5,4-d) pyrimidine after oral administration. Arch Int Pharmacodyn 1965; 158: 380-88. 7. Drugs and gallstones. Lancet 1977; ii: 177.
London Cross and Westminster Medical School, London
C. M. OAKLEY
Charing
D. C. SHANSON
1. Simmons NA, Ball AP, Cawson RA, et al Antibiotic prophylaxis and infective endocarditis. Lancet 1992; 339: 1292-93. 2. van der Meer, JTM, van Wijk W, Thompson J, Vandenbroucke JP, Valkenburg HA, Michel MF. Efficacy of antibiotic prophylaxis for prevention of native-valve endocarditis. Lancet 1992; 339: 135-39. 3. Bayliss R, Clarke C, Oakley C, et al. The teeth and infective endocarditis. Br Heart J 1983; 50: 506-12. 4. Editorial. Chemoprophylaxis for infective endocarditis: faith, hope, and chanty challenged. Lancet 1992; 339: 525-26.
