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SIDE-EFFECTS INDUCED BY CARBAMAZEPINE-10, 11-EPOXIDE
1432 SIDE-EFFECTS INDUCED BY
CARBAMAZEPINE-10, 11-EPOXIDE SIR,—We accept the comments of Dr Tomson and Dr Bertilsson
(Nov 2, p 1010) concerning the lack of precise information on a therapeutic range for carbamazepine (CBZ) or indeed other anticonvulsants, that is applicable to all patients, especially in the context of multiple drug therapy. Nevertheless some reference is necessary in practice and these ranges are a valuable guide if applied flexibly. Our letter (Aug 31, p 496) concerns a specific case in which measurement of serum anticonvulsant drug levels, including those of the primary metabolite of CBZ, carbamazepine-10, 11-epoxide (CBZ-E), show that the patient improved remarkably, coinciding with a reduction in CBZ-E serum levels. With the small decrease in phenytoin dose (350 to 325 mg/daily), which occurred at the same time as the reduction in the CBZ-E level, the serum phenytoin level rose from 72 to 80 µmol/1, and we think that the contribution of phenytoin, if any, to our patient’s side-effects was not less when CBZ-E levels were lower. Our patient was ill with focal neurological deficits, was in hospital, and had been on anticonvulsant treatment for some years. By contrast Tomson and Bertilsson’s subjects were healthy volunteers,patients with trigeminal neuralgia,2or epileptic patients who "led normal lives, were employed full time, were alert and highly cooperative and showed no neurological deficits on clinical examination".3 Further, the biochemical data on their patients given CBZ monotherapy for trigeminal neuralgia2or as adjunct therapy for epilepsy3were different in that, if one compares equivalent CBZ levels, our patient’s CBZ-E is very much higher.4 Our experience with possible side-effects of CBZ-E in children points to the fact that by no means all patients with CBZ-E levels greater than 9 µmol/1 are affected, which is why we emphasised the difficulty in establishing an upper limit. The object of our letter was to direct attention to the unreliability in practice of routine anticonvulsant drug monitoring in some patients. Additional monitoring of CBZ-E in difficult cases may be helpful. P. N. PATSALOS
T. J. STEPHENSON Departments of Chemical Pathology and Neurology, National Hospital for Nervous Diseases, London WC1N 3BG
S. KRISHNA A. A. ELYAS P. T. LASCELLES C. M. WILES
1 Tomson
T, Tybring G, Bertilsson L. Single dose kinetics and metabolism of carbamazepine-10, 11-epoxide. Clin Pharmacol Ther 1983; 33: 58-65. 2. Tomson T, Tybring G, Bertilsson L, Ekbom K, Rare A Carbamazepine therapy in trigeminal neuralgia. Clinical effects in relation to plasma concentration. Arch Neurol 1980, 37: 699-703. 3. Tomson T. Interdosage fluctuations in plasma carbamazepine concentration determine intermittent side effects. Acta Neurol 1984, 41: 830-34. 4. Shoeman JF, Elyas AA, Brett EM, Lascelles PT. Correlation between plasma carbamazepine-10, 11-epoxide concentration and drug side-effects in children with epilepsy. Dev Med Child Neurol 1984; 26: 756-64
SPIRONOLACTONE AND POTASSIUM CANRENOATE METABOLISM
SIR,-The case-report and related discussion from Dr Dupont (Sept 28, p 731) on spironolactone, potassium canrenoate, and endocrine side-effects is of interest but is not the complete picture. The statement that canrenone is the major active metabolite of spironolactone and potassium canrenoate is based on a fluorimetric assay of plasma canrenone levels.’ High performance liquid chromatography (HPLC) shows that "canrenone" measured by fluorimetry is a considerable overestimate of true levels.2 The renal antimineralocorticoid potency of potassium canrenoate is only onethird that of spironolactone, despite similar plasma "canrenone" levels by fluorimetry.3 7 &agr;-thiomethylspirolactone may be the major metabolite of spironolactone, after a single dose, and the parent compound itself may be responsible for some of the activity. Data on "endocrine" side-effects and relative anti-androgenic activity of spironolactone and potassium canrenoate are difficult to interpret. Case-reports of a better endocrine profile for canrenone (and, by implication, potassium canrenoate) compared with spironolactone5 have yet to be confirmed by controlled clinical
studies. Indeed, similar long-term effects on plasma luteinising hormone, follicle stimulating hormone, plasma oestradiol, and testosterone levels have been found when spironolactone and canrenone were compared, although gynaecomastia was seen in the spironolactone group (4/13) but not in the canrenone group (0/12).6 Although the relative contribution of the metabolites of spironolactone and potassium canrenoate to both renal antimineralocorticoid activity and to endocrine side-effects requires further evaluation, it is no longer appropriate to state that canrenone is the major active metabolite of both compounds. European Clinical
Research and Medical Affairs, GD Searle & Co Ltd High Wycombe, Bucks HP12 4HL
P. GARDINER
1. Sadee
W, Dagcioglu M, Schroder R Pharmacokinetics of spironolactone, canrenone and canrenoate-K in humans. J Pharmacol Exp Ther 1973, 185: 686-95 2. Abshagen U, Besenfelder E, Endele R, Koch K, Neubert B Kinetics of canrenone after single and multiple doses of Spironolactone. Eur J Clin Pharmacol 1979; 16: 255-62. 3. Ramsey LE, Shelton JR, Harrison IR, Tidd M, Asbury MJ Spironolactone and potassium canrenoate in normal man. Clin Pharmacol Ther 1976, 20: 167-77. 4. Overdiek HWPM, Hermens WAJJ, Merkus FWHM. New insights into the pharmacokinetics of spironolactone. Clin Pharmacol Ther 1985, 3: 469-74 5. Marco HJ, Constans R, Allibelli MI. Effects sexuels secondaires au traitement par la Spironolactone Revue Toulouse 1980; 16: 174-82. 6. Fromantin M Surveillance clinique et hormonale des traitements prolonges de l’hypertension arterielle par les anti aldosterones Mises Jour Cardiol 1980; 19: 95-98
NECROTISING FASCIITIS AFTER DIFLUNISAL FOR MINOR INJURY
SIR,—Attention has lately been drawn to severe necrotising fasciitis after minor trauma in previously healthy patients who had received non-steroidal anti-inflammatory drugs (NSAID).1 Observations that granulocyte-mediated function is impaired by these drugs is supported by diminished in-vitro bactericidal activity and reduced inactivation of Staphylococcus aureus and group B streptococcus by granulocytes incubated with phenylbutazone.2 We report life-threatening necrotising fasciitis and severe depression of lymphocyte function after treatment with an NSAID. A healthy 23-year-old man took six diflunisal tablets over 24 hours after a minor injury with a superficial graze of his right knee. Pain and swelling in the area progressed over the next 5 days. Suspected cellulitis did not respond to intravenous penicillin and erythromycin given for 4 days. Addition of clindamycin produced no improvement. Clinical deterioration with progression of local signs and septicaemia required surgical exploration with a fasciotorny extending from the calf to thigh; serous pus was drained and necrotic subcutaneous tissue and fascia were excised. The underlying muscle was viable and the wound was left open. Culture of the pus grew group B streptococcus. The wound was closed with a split skin graft 2 weeks later. The patient recovered completely. He had no history of systemic illness, liver or renal disease, or diabetes. On presentation his white cell count was 6400/µl (75% polymorphonuclear cells, 13% band forms, and absolute lymphopenia [12%]). Lymphocyte function was depressed, the response to phytohaemagglutinin (PHA) being 22-25% of normal. Helper T cells (OKT4) were 27% and suppressor cells (OKT8) 18 - 5% (ratio 1.45). Serum immunoglobulins (mg/dl) were slightly raised: IgA 351 (normal 72-312), IgG 1890 (normal 639-1349), and IgM 70 (normal 56-352). C3 and C4 complement levels were normal. He did not have antibodies to human T-lymphotropic virus. 3 weeks after the operation his lymphocyte count was normal (1630/µl). 6 weeks after presentation the patient had a white cell count of 4900/µl (55% polymorphonuclear neutrophils, 34% lymphocytes, 807o monocytes, 2% eosinophils, and 1% atypical lymphocytes). Lymphocyte transformation to PHA had returned to normal (104% in his own serum and 124% of normal in AB serum). To investigate the possibility that the patient’s lymphocytes may have been unusually sensitive to NSAIDs the ability of his lymphocytes to transform to 1-25 µg/ml PHA in the presence of near-therapeutic levels of acetylsalicylic acid (0-1mmol/1) and indomethacin (0-11 mmol/1) was investigated. While control lymphocytes showed no depression of lymphocyte transformation to PHA in the presence of acetylsalicylate the patient’s lymphocytes showed a 22% depression. However, in the presence of indomethacin, normal
CARBAMAZEPINE-10, 11-EPOXIDE SIR,—We accept the comments of Dr Tomson and Dr Bertilsson
(Nov 2, p 1010) concerning the lack of precise information on a therapeutic range for carbamazepine (CBZ) or indeed other anticonvulsants, that is applicable to all patients, especially in the context of multiple drug therapy. Nevertheless some reference is necessary in practice and these ranges are a valuable guide if applied flexibly. Our letter (Aug 31, p 496) concerns a specific case in which measurement of serum anticonvulsant drug levels, including those of the primary metabolite of CBZ, carbamazepine-10, 11-epoxide (CBZ-E), show that the patient improved remarkably, coinciding with a reduction in CBZ-E serum levels. With the small decrease in phenytoin dose (350 to 325 mg/daily), which occurred at the same time as the reduction in the CBZ-E level, the serum phenytoin level rose from 72 to 80 µmol/1, and we think that the contribution of phenytoin, if any, to our patient’s side-effects was not less when CBZ-E levels were lower. Our patient was ill with focal neurological deficits, was in hospital, and had been on anticonvulsant treatment for some years. By contrast Tomson and Bertilsson’s subjects were healthy volunteers,patients with trigeminal neuralgia,2or epileptic patients who "led normal lives, were employed full time, were alert and highly cooperative and showed no neurological deficits on clinical examination".3 Further, the biochemical data on their patients given CBZ monotherapy for trigeminal neuralgia2or as adjunct therapy for epilepsy3were different in that, if one compares equivalent CBZ levels, our patient’s CBZ-E is very much higher.4 Our experience with possible side-effects of CBZ-E in children points to the fact that by no means all patients with CBZ-E levels greater than 9 µmol/1 are affected, which is why we emphasised the difficulty in establishing an upper limit. The object of our letter was to direct attention to the unreliability in practice of routine anticonvulsant drug monitoring in some patients. Additional monitoring of CBZ-E in difficult cases may be helpful. P. N. PATSALOS
T. J. STEPHENSON Departments of Chemical Pathology and Neurology, National Hospital for Nervous Diseases, London WC1N 3BG
S. KRISHNA A. A. ELYAS P. T. LASCELLES C. M. WILES
1 Tomson
T, Tybring G, Bertilsson L. Single dose kinetics and metabolism of carbamazepine-10, 11-epoxide. Clin Pharmacol Ther 1983; 33: 58-65. 2. Tomson T, Tybring G, Bertilsson L, Ekbom K, Rare A Carbamazepine therapy in trigeminal neuralgia. Clinical effects in relation to plasma concentration. Arch Neurol 1980, 37: 699-703. 3. Tomson T. Interdosage fluctuations in plasma carbamazepine concentration determine intermittent side effects. Acta Neurol 1984, 41: 830-34. 4. Shoeman JF, Elyas AA, Brett EM, Lascelles PT. Correlation between plasma carbamazepine-10, 11-epoxide concentration and drug side-effects in children with epilepsy. Dev Med Child Neurol 1984; 26: 756-64
SPIRONOLACTONE AND POTASSIUM CANRENOATE METABOLISM
SIR,-The case-report and related discussion from Dr Dupont (Sept 28, p 731) on spironolactone, potassium canrenoate, and endocrine side-effects is of interest but is not the complete picture. The statement that canrenone is the major active metabolite of spironolactone and potassium canrenoate is based on a fluorimetric assay of plasma canrenone levels.’ High performance liquid chromatography (HPLC) shows that "canrenone" measured by fluorimetry is a considerable overestimate of true levels.2 The renal antimineralocorticoid potency of potassium canrenoate is only onethird that of spironolactone, despite similar plasma "canrenone" levels by fluorimetry.3 7 &agr;-thiomethylspirolactone may be the major metabolite of spironolactone, after a single dose, and the parent compound itself may be responsible for some of the activity. Data on "endocrine" side-effects and relative anti-androgenic activity of spironolactone and potassium canrenoate are difficult to interpret. Case-reports of a better endocrine profile for canrenone (and, by implication, potassium canrenoate) compared with spironolactone5 have yet to be confirmed by controlled clinical
studies. Indeed, similar long-term effects on plasma luteinising hormone, follicle stimulating hormone, plasma oestradiol, and testosterone levels have been found when spironolactone and canrenone were compared, although gynaecomastia was seen in the spironolactone group (4/13) but not in the canrenone group (0/12).6 Although the relative contribution of the metabolites of spironolactone and potassium canrenoate to both renal antimineralocorticoid activity and to endocrine side-effects requires further evaluation, it is no longer appropriate to state that canrenone is the major active metabolite of both compounds. European Clinical
Research and Medical Affairs, GD Searle & Co Ltd High Wycombe, Bucks HP12 4HL
P. GARDINER
1. Sadee
W, Dagcioglu M, Schroder R Pharmacokinetics of spironolactone, canrenone and canrenoate-K in humans. J Pharmacol Exp Ther 1973, 185: 686-95 2. Abshagen U, Besenfelder E, Endele R, Koch K, Neubert B Kinetics of canrenone after single and multiple doses of Spironolactone. Eur J Clin Pharmacol 1979; 16: 255-62. 3. Ramsey LE, Shelton JR, Harrison IR, Tidd M, Asbury MJ Spironolactone and potassium canrenoate in normal man. Clin Pharmacol Ther 1976, 20: 167-77. 4. Overdiek HWPM, Hermens WAJJ, Merkus FWHM. New insights into the pharmacokinetics of spironolactone. Clin Pharmacol Ther 1985, 3: 469-74 5. Marco HJ, Constans R, Allibelli MI. Effects sexuels secondaires au traitement par la Spironolactone Revue Toulouse 1980; 16: 174-82. 6. Fromantin M Surveillance clinique et hormonale des traitements prolonges de l’hypertension arterielle par les anti aldosterones Mises Jour Cardiol 1980; 19: 95-98
NECROTISING FASCIITIS AFTER DIFLUNISAL FOR MINOR INJURY
SIR,—Attention has lately been drawn to severe necrotising fasciitis after minor trauma in previously healthy patients who had received non-steroidal anti-inflammatory drugs (NSAID).1 Observations that granulocyte-mediated function is impaired by these drugs is supported by diminished in-vitro bactericidal activity and reduced inactivation of Staphylococcus aureus and group B streptococcus by granulocytes incubated with phenylbutazone.2 We report life-threatening necrotising fasciitis and severe depression of lymphocyte function after treatment with an NSAID. A healthy 23-year-old man took six diflunisal tablets over 24 hours after a minor injury with a superficial graze of his right knee. Pain and swelling in the area progressed over the next 5 days. Suspected cellulitis did not respond to intravenous penicillin and erythromycin given for 4 days. Addition of clindamycin produced no improvement. Clinical deterioration with progression of local signs and septicaemia required surgical exploration with a fasciotorny extending from the calf to thigh; serous pus was drained and necrotic subcutaneous tissue and fascia were excised. The underlying muscle was viable and the wound was left open. Culture of the pus grew group B streptococcus. The wound was closed with a split skin graft 2 weeks later. The patient recovered completely. He had no history of systemic illness, liver or renal disease, or diabetes. On presentation his white cell count was 6400/µl (75% polymorphonuclear cells, 13% band forms, and absolute lymphopenia [12%]). Lymphocyte function was depressed, the response to phytohaemagglutinin (PHA) being 22-25% of normal. Helper T cells (OKT4) were 27% and suppressor cells (OKT8) 18 - 5% (ratio 1.45). Serum immunoglobulins (mg/dl) were slightly raised: IgA 351 (normal 72-312), IgG 1890 (normal 639-1349), and IgM 70 (normal 56-352). C3 and C4 complement levels were normal. He did not have antibodies to human T-lymphotropic virus. 3 weeks after the operation his lymphocyte count was normal (1630/µl). 6 weeks after presentation the patient had a white cell count of 4900/µl (55% polymorphonuclear neutrophils, 34% lymphocytes, 807o monocytes, 2% eosinophils, and 1% atypical lymphocytes). Lymphocyte transformation to PHA had returned to normal (104% in his own serum and 124% of normal in AB serum). To investigate the possibility that the patient’s lymphocytes may have been unusually sensitive to NSAIDs the ability of his lymphocytes to transform to 1-25 µg/ml PHA in the presence of near-therapeutic levels of acetylsalicylic acid (0-1mmol/1) and indomethacin (0-11 mmol/1) was investigated. While control lymphocytes showed no depression of lymphocyte transformation to PHA in the presence of acetylsalicylate the patient’s lymphocytes showed a 22% depression. However, in the presence of indomethacin, normal