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POSSIBLE HAZARD OF VALPROMIDE-CARBAMAZEPINE COMBINATION THERAPY IN EPILEPSY
802 POSSIBLE HAZARD OF VALPROMIDE-CARBAMAZEPINE COMBINATION THERAPY IN EPILEPSY
SIR,-The valuable antiepileptic drug sodium valproate often gives rise to complaints of gastric irritation, and enteric-coated forms of the salt or the acid have been marketed to overcome this drawback. A recent development has been the introduction of valpromide, the acid-amide of valproic acid, which is marketed in several European countries as ’Depamide’. In contrast with sodium valproate, valpromide is tasteless and not hygroscopic, and it is chemically neutral and does not seem to produce gastrointestinal irritation. It has been assumed that valpromide is merely a pro-drug for valproate to which it is rapidly converted. Only 1% of an oral dose of valpromide is found in the blood, and the serum valproate level is virtually identical to that obtained with a similar dose of sodium valproate.2In the rat conversion ofvalpromide to valproate takes place chiefly in the gut.3 CARBAMAZEPINE,
CARBAMAZEPINE-10,11-EPOXIDE LEVELS (µg/ml) IN
SEVEN PATIENTS WHEN VALPROMIDE WAS SUBSTITUTED FOR VALPROATE CO-MEDICATION
Results
as mean
(and range) of
at least two estimations per
patient
on
different
days.
The assumption that valpromide is merely a pro-drug is called in question by a potentially dangerous interaction which we now report between valpromide and carbamazepine. Valproate with carbamazepine is a useful combination, especially in patients with secondarily generalising partial seizures. In seven patients on this treatment valpromide was substituted for valproate in the hope of avoiding gastrointestinal side-effects. In all patients this change in therapy was followed by a marked increase in serum concentration of the carbamazepine metabolite carbamazepine-10,11-epoxide (see table). In one instance the expoxide level rose from 4,00 to 20 -99 g/ml. When sodium valproate or valproic acid was again substituted for valpromide the epoxide levels fell, but in every case they remained above the original values of some 2 pg/rril for several weeks. Valproate, in common with other antiepileptic drugs, itself produces a slight increase in epoxide levels when added to carbamazepine monotherapy.44 Levels of carbamazepine-10, 11-diol, the main metabolic product of the epoxide, were essentially unchanged. The significance of a high carbamazepine epoxide level is uncertain but it was striking that five of the seven patients exhibited symptoms typical of carbamazepine intoxication during the period of increased epoxide levels although carbamazepine concentrations Meijer JWA, Kalff
R. Less usual ways of administering antiepileptic drugs. In: Schneider H, et al, eds. Clinical pharmacology of anti-epileptic drugs. Berlin: Springer, 1975: 222-28. 2. Pisani F, Fazio A, Oteri G, Di Perri R. Dipropylacetic acid plasma levels: Diurnal fluctuations during chronic treatment with dipropylacetamide. Ther Drug Monitoring 1981; 3: 297-301. 3. Pisani F, Fazio A, Oteri G, Di Perri R. A study on the metabolism of dipropylacetamide to dipropylacetic acid in rats. J Pharm Pharmacol 1982; 34: 45-46. 4. Brodie MJ, Forrest G, Rapeport WG. Carbamazepine-10,11-epoxide concentrations in epileptics on carbamazepine alone and in combination with other anticonvulsants. Br J Clin Pharmacol 1983; 16: 747-50. 1.
,
did not increase and remained below 10 pg/ml. A more urgent cause for concern is the fact that carbamazepine epoxide may be teratogenic.5This suspicion is based on the finding of a very high incidence of malformations in offspring of mothers taking carbamazepine in multiple drug combinations, which give a moderate elevation of epoxide levels (typically to some 5 g/ml). The epoxide levels encountered on valpromide-carbamazepine combination therapy may be considerably higher and we suggest that in, view of the probable teratogenic and possible carcinogenic risk, valpromide-carbamazepine combination therapy should be avoided until the possible hazard has been further investigated.
J. W. A. MEIJER Instituut
C. D. BINNIE R. M. CHR. DEBETS J. A. P. VAN PARYS N. K. B. DE BEER-PAWLIKOWSKI
Eliepsiebestrijding, PO Box 21, Heemstede, Netherlands voor
2100 AA
CHEMOPROPHYLAXIS FOR ENDOCARDITIS
SIR,-Your editorial of March 17 (p 603) prompts me to summarise the results of t4e questionnaire I sent to 1700 medical and dental practitioners in London in October, 1982. The full results are to be published.’ The questionnaire concerned current practice in the use of antibiotics to prevent endocarditis. The groups surveyed included general practitioners, general surgeons, general physicians, anaesthetists, and dentists. The overall response rate was 48%. 95% of responders use prophylaxis and most believe it of proven benefit. In general, predisposing cardiac abnormalities are well recognised as are the various diagnostic and therapeutic procedures likely to induce bacteraemia. The area of greatest disquiet is over the regimens used. Generally prophylaxis is started too soon, continued for too long, and consists of inadequate doses of often inappropriate antibiotics when judged against current recommendations.2-6 70% of general practitioners and 40% of dentists still prescribe prophylaxis more than 12 h before a procedure and 90% of general practitioners and 66% of dentists continue prophylaxis for 2 or more days. This is rather long in view of the duration of bacteraemia (15-30 min)5 that might be induced by any procedure performed by them. This practice is potentially dangerous in encouraging organisms to develop that are resistant to the prophylactic antibiotic and is a waste of antibiotics. Practitioners were asked for details of regimens used for various procedures-dental, genitourinary (GU), and upper and lower gastrointestinal (GI), with and without penicillin allergy. The table shows details of regimens used for dental and GU procedures. In only 2 areas do over 40% of any specialty use a recommended regimen-46% of dentists and 49% of physicians for dental procedures with no penicillin allergy and 53% of physicians for upper and lower GI procedures with no allergy (not included in table). For dental procedures the recommended antibiotics are used 5. Lmdhout
D, Hoppener RJEA. Memardi H. Teratogenicity of antepileptic drug
combinations with
special emphasis on epoxidation (of carbamazepine). Epilepsia
1984; 25: 77-83. 1. Gould IM. Chemoprophylaxis for bacterial endocarditis-A survey of current practice in London. J Antimicrob Chemother (in press). 2. Report ofa working party of the British Society for Antimicrobial Chemotherapy. The antibiotic prophylaxis of infective endocarditis Lancet 1982; ii: 1323-26. 3. American Heart Association Committee Report. Prevention of bacterial endocarditis.
Circulation 1977; 56: 139A-143A. Somerville W. Prevention of infective endocarditis. Br Heart J 1981; 45: 233-35. 5. Petersdorf RG. Antimicrobial prophylaxis of bacterial endocarditis. Am J Med 1978; 65: 220-23. 6. Recommendations on prophylaxis for bacterial endocarditis. British National Formulary 1982; no 3: 160-61. 4.
Oakley C,
PROPORTION OF PRACTITIONERS WHO USED A RECOMMENDED REGIMEN, WITH DETAILS OF THE MOST POPULAR REGIMENS
Pen = pencillin; Amox=amoxycillin; Ery = erythromycin; Co-trim = co-trimoxazole; Genta=gentamicin, Ceph=cephalosporin.
Doses
in
mg.
SIR,-The valuable antiepileptic drug sodium valproate often gives rise to complaints of gastric irritation, and enteric-coated forms of the salt or the acid have been marketed to overcome this drawback. A recent development has been the introduction of valpromide, the acid-amide of valproic acid, which is marketed in several European countries as ’Depamide’. In contrast with sodium valproate, valpromide is tasteless and not hygroscopic, and it is chemically neutral and does not seem to produce gastrointestinal irritation. It has been assumed that valpromide is merely a pro-drug for valproate to which it is rapidly converted. Only 1% of an oral dose of valpromide is found in the blood, and the serum valproate level is virtually identical to that obtained with a similar dose of sodium valproate.2In the rat conversion ofvalpromide to valproate takes place chiefly in the gut.3 CARBAMAZEPINE,
CARBAMAZEPINE-10,11-EPOXIDE LEVELS (µg/ml) IN
SEVEN PATIENTS WHEN VALPROMIDE WAS SUBSTITUTED FOR VALPROATE CO-MEDICATION
Results
as mean
(and range) of
at least two estimations per
patient
on
different
days.
The assumption that valpromide is merely a pro-drug is called in question by a potentially dangerous interaction which we now report between valpromide and carbamazepine. Valproate with carbamazepine is a useful combination, especially in patients with secondarily generalising partial seizures. In seven patients on this treatment valpromide was substituted for valproate in the hope of avoiding gastrointestinal side-effects. In all patients this change in therapy was followed by a marked increase in serum concentration of the carbamazepine metabolite carbamazepine-10,11-epoxide (see table). In one instance the expoxide level rose from 4,00 to 20 -99 g/ml. When sodium valproate or valproic acid was again substituted for valpromide the epoxide levels fell, but in every case they remained above the original values of some 2 pg/rril for several weeks. Valproate, in common with other antiepileptic drugs, itself produces a slight increase in epoxide levels when added to carbamazepine monotherapy.44 Levels of carbamazepine-10, 11-diol, the main metabolic product of the epoxide, were essentially unchanged. The significance of a high carbamazepine epoxide level is uncertain but it was striking that five of the seven patients exhibited symptoms typical of carbamazepine intoxication during the period of increased epoxide levels although carbamazepine concentrations Meijer JWA, Kalff
R. Less usual ways of administering antiepileptic drugs. In: Schneider H, et al, eds. Clinical pharmacology of anti-epileptic drugs. Berlin: Springer, 1975: 222-28. 2. Pisani F, Fazio A, Oteri G, Di Perri R. Dipropylacetic acid plasma levels: Diurnal fluctuations during chronic treatment with dipropylacetamide. Ther Drug Monitoring 1981; 3: 297-301. 3. Pisani F, Fazio A, Oteri G, Di Perri R. A study on the metabolism of dipropylacetamide to dipropylacetic acid in rats. J Pharm Pharmacol 1982; 34: 45-46. 4. Brodie MJ, Forrest G, Rapeport WG. Carbamazepine-10,11-epoxide concentrations in epileptics on carbamazepine alone and in combination with other anticonvulsants. Br J Clin Pharmacol 1983; 16: 747-50. 1.
,
did not increase and remained below 10 pg/ml. A more urgent cause for concern is the fact that carbamazepine epoxide may be teratogenic.5This suspicion is based on the finding of a very high incidence of malformations in offspring of mothers taking carbamazepine in multiple drug combinations, which give a moderate elevation of epoxide levels (typically to some 5 g/ml). The epoxide levels encountered on valpromide-carbamazepine combination therapy may be considerably higher and we suggest that in, view of the probable teratogenic and possible carcinogenic risk, valpromide-carbamazepine combination therapy should be avoided until the possible hazard has been further investigated.
J. W. A. MEIJER Instituut
C. D. BINNIE R. M. CHR. DEBETS J. A. P. VAN PARYS N. K. B. DE BEER-PAWLIKOWSKI
Eliepsiebestrijding, PO Box 21, Heemstede, Netherlands voor
2100 AA
CHEMOPROPHYLAXIS FOR ENDOCARDITIS
SIR,-Your editorial of March 17 (p 603) prompts me to summarise the results of t4e questionnaire I sent to 1700 medical and dental practitioners in London in October, 1982. The full results are to be published.’ The questionnaire concerned current practice in the use of antibiotics to prevent endocarditis. The groups surveyed included general practitioners, general surgeons, general physicians, anaesthetists, and dentists. The overall response rate was 48%. 95% of responders use prophylaxis and most believe it of proven benefit. In general, predisposing cardiac abnormalities are well recognised as are the various diagnostic and therapeutic procedures likely to induce bacteraemia. The area of greatest disquiet is over the regimens used. Generally prophylaxis is started too soon, continued for too long, and consists of inadequate doses of often inappropriate antibiotics when judged against current recommendations.2-6 70% of general practitioners and 40% of dentists still prescribe prophylaxis more than 12 h before a procedure and 90% of general practitioners and 66% of dentists continue prophylaxis for 2 or more days. This is rather long in view of the duration of bacteraemia (15-30 min)5 that might be induced by any procedure performed by them. This practice is potentially dangerous in encouraging organisms to develop that are resistant to the prophylactic antibiotic and is a waste of antibiotics. Practitioners were asked for details of regimens used for various procedures-dental, genitourinary (GU), and upper and lower gastrointestinal (GI), with and without penicillin allergy. The table shows details of regimens used for dental and GU procedures. In only 2 areas do over 40% of any specialty use a recommended regimen-46% of dentists and 49% of physicians for dental procedures with no penicillin allergy and 53% of physicians for upper and lower GI procedures with no allergy (not included in table). For dental procedures the recommended antibiotics are used 5. Lmdhout
D, Hoppener RJEA. Memardi H. Teratogenicity of antepileptic drug
combinations with
special emphasis on epoxidation (of carbamazepine). Epilepsia
1984; 25: 77-83. 1. Gould IM. Chemoprophylaxis for bacterial endocarditis-A survey of current practice in London. J Antimicrob Chemother (in press). 2. Report ofa working party of the British Society for Antimicrobial Chemotherapy. The antibiotic prophylaxis of infective endocarditis Lancet 1982; ii: 1323-26. 3. American Heart Association Committee Report. Prevention of bacterial endocarditis.
Circulation 1977; 56: 139A-143A. Somerville W. Prevention of infective endocarditis. Br Heart J 1981; 45: 233-35. 5. Petersdorf RG. Antimicrobial prophylaxis of bacterial endocarditis. Am J Med 1978; 65: 220-23. 6. Recommendations on prophylaxis for bacterial endocarditis. British National Formulary 1982; no 3: 160-61. 4.
Oakley C,
PROPORTION OF PRACTITIONERS WHO USED A RECOMMENDED REGIMEN, WITH DETAILS OF THE MOST POPULAR REGIMENS
Pen = pencillin; Amox=amoxycillin; Ery = erythromycin; Co-trim = co-trimoxazole; Genta=gentamicin, Ceph=cephalosporin.
Doses
in
mg.