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173
LEVODOPA AND POSITIVE DIRECT ANTIGLOBULIN TESTS In view of the close pharmacological relationship between methyldopa and levodopa, patients receiving levodopa were screened for the occurrence of positive direct antiglobulin (DAG) tests. Eighty-five patients attending the neurological out-patient department in Aberdeen and seventeen neurological out-patients in Dundee were screened on at least one occasion with the co-operation of the clinical and laboratory staff and yielded five and one positive tests respectively. The antihuman globulin used in the former is prepared from goat serum and detects both complement and Ig G antibodies while a commercially available serum was used in the latter. Of the six patients who showed a deviation from the 'normal' DAG test, only one showed a positive result of the Ig G type associated with auto-immunization to methyldopa. On repeat examination this DAG was less strongly positive despite the dose of levodopa remaining unchanged and there was, at no time, any evidence of anaemia. The other variants were probably due to adsorption to the red cells in vitro of weak cold autoagglutinins and are of no
significance. Positive DAG tests in patients receiving levodopa have been documented in the American Journals by Treciokas, Ansel and Markham who reported four in one hundred patients in 1971 and Joseph found positive tests in thirty-two of three hundred and sixty-five patients screened in 1972. Henry, Goldberg, Sturgeon & Ansel (1971) reported five positive antiglobulin tests in eighty patients receiving levodopa. In three of these
Ig G was demonstrated on the red cells while complement only was detected in the remaining two. Weiner (1965) documented a series of twenty-one positive DAG tests in seemingly normal people and estimated that the likelihood of this occurrence was between 1 and 3/10,000 of the population. Our local figures are therefore similar to the American data and it is of interest to note that Ig G is only demonstrable in some of those with positive tests. D.C. MOIR, A.J.J. WOOD, J.F. DAVIDSON & S.C. GALLON Medicines Evaluation and Monitoring Group, Aberdeen Section (Pharmacy Department), Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB9 2ZB
(Received June 27, 1974) References HENRY, R.E., GOLDBERG, L.S., STURGEON, P. &
ANSEL, R.D. (1971). Serologic abnormalities associated with 1-dopa therapy. Vox Sang., 20, 306-316. JOSEPH, C. (1972). Occurrence of positive Coombs Test in patients treated with 1-dopa. New Engl. J. Med., 286, 1401-1402. TRECIOKAS, L.J., ANSEL, R.D. & MARKHAM, C.H.
(1971). One to two year treatment of Parkinson's disease with 1-dopa. California Med., 114, 7-14. WEINER, W. (1965). Coombs' positive 'normal' people. Proceedings of the 10th Congress International Society of Blood Transfusion, 35.
INTERACTION OF PHENYTOIN WITH CHLORPHENIRAMINE A 17 year old female patient, developed grand mal and psychomotor seizures in 1969. She was discharged from follow-up in October 1970 taking phenobarbitone (30 mg twice daily) and phenytoin (100 mg three times a day). The most recent seizure was a minor episode in July 1973 but she remained well and started work in the same year. For no apparent reason she stopped taking phenytoin in December 1973. Two weeks prior to admission the patient developed a rash on her face following the use of a new cosmetic. Chlorpheniramine (4 mg three times
a day) was prescribed and one week later she was alert and well apart from a few minor dizzy spells. The antihistamine was continued and phenytoin (100 mg three times a day) was recommenced, her practitioner having discovered the omission of the drug. Over the ensuing week she rapidly developed drowsiness, ataxia, diplopia, tinnitus, and episodes of occipital headaches associated with vomiting. On admission she was drowsy and unable to stand, with gross bilateral horizontal nystagmus and cerebellar ataxia. The fundi were normal and there were no lateralizing neurological signs.
174
Br. J. clin. Pharmac. ( 1975), 2
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4
i;
-
Snk1
28
35
42
4
I: Figure 1 Daily dose of chiorpheniramine (hatched) and phenytoin (stippled) and plasma levels of phenytoin (e) and phenobarbitone (U).
Reflexes were normal and equal and the plantar responses flexor. Routine investigations, including skull X-ray, revealed no abnormality. Chlorpheniramine was withdrawn and both anticonvulsants continued, the daily dose of phenytoin being varied as illustrated in Figure 1. Serial plasma anticonvulsant levels were determined by an isothermal g.l.c. method (Toseland, Grove & Berry, 1972) from blood samples taken 2 to 4.5 h following the morning dose of the two anti-epileptic drugs. Plasma levels of phenytoin were initially in the toxic range but subsequently fell to within accepted therapeutic levels, despite increasing the dose of phenytoin on two occasions to the pre-admission regime of 100 mg three times a day. The decrease in the plasma phenytoin level corresponded with spontaneous resolution of neurological signs and symptoms. Plasma phenobarbitone levels remained throughout within the lower therapeutic range. The patient was discharged home taking phenobarbitone (15 mg three times a day) together with phenytoin in a reduced dose of 50 mg three times a day and was symptom-free when reviewed 4 weeks later. Phenobarbitone, phenytoin and chlorpheniramine are all extensively used compounds. Many drugs, including the antihistamines, which
can cause CNS depression may have an increased depressant effect if taken together with phenobarbitone. Chlorpheniramine alone can cause drowsiness and dizziness; the latter was observed in the present patient prior to the administration of phenytoin and was presumably potentiated by phenobarbitone. Gross neurological symptoms, however, only developed after phenytoin administration, many of the features being typical of those seen in phenytoin toxicity. Phenytoin is normally hydroxylated in the liver and then excreted as a glucuronide. Several drugs, including chlordiazepoxide, diazepam, chlorpromazine, and the oestrogens, can interfere with phenytoin metabolism (Kutt & McDowell, 1968). Other inducers of phenytoin toxicity includes bishydroxycoumarin (Hansen, Kristensen, Skovsted & Christensen, 1966), sulthiame (Hansen, Kristensen & Skovsted, 1968; Olesen & Jensen, 1969; Houghton & Richens, 1974), isoniazid and PAS (Murray, 1962; Kutt, Winters & McDowell, 1966), chloramphenicol (Christensen & Skovsted, 1969), phenyramidol (Solomon and Schrogie, 1967), and digoxin (Viukari & Aho, 1970). The present report suggests that chlorpheniramine also interacts with phenytoin, thereby delaying the hepatic metabolism of the anticonvulsant and increasing the plasma phenytoin levels, thus precipitating the acute neurological syndrome described above. Consideration should be given to providing epileptic patients with a card listing the names of drugs which could interact adversely with their anti-convulsant therapy. R.N.H. PUGH & A.M. GEDDES Department of Cummunicable and Tropical Diseases, East Birmingham Hospital, Birmingham B9 SST
W.B. YEOMAN Regional Toxicology Laboratory, Dudley Road Hospital, Birmingham B18 7QH Received August 21, 1974
References L.K. & SKOVSTED, L. (1969). Inhibition of drug metabolism by chloramphenicol. Lancet, ii, 1397-1399. HANSEN, J.M., KRISTENSEN, M., SKOVSTED, L. & CHRISTENSEN, L.K. (1966). Dicoumarol-induced diphenylhydantoin intoxication. Lancet, ii, 265-266. HANSEN, J.M., KRISTENSEN, M. & SKOVSTED, L. (1968). Sulthiame (Ospolot) as inhlbitor of diphenylhydantoin metabolism. Epilepsia, 9, 17-22. HOUGHTON, G.W. & RICHENS, A. (1974). Inhibition of
CHRISTENSEN,
Br. J. clin. Pharmac. (1975), 2 phenytoin metabolism by sulthiame in epileptic patients. Br. J. cli. Pharmac., 1, 59-66. KUTT, H., WINTERS, W. & McDOWELL, F. (1966). Depression of parahydroxylation of diphenylhydantoin by antituberculous chemotherapy. Neurology, 16, 594-602. KUTT, H. & McDOWELL, F. (1968). Management of epilepsy with diphenyIhydantoin sodium. Dosage regulation for problem patients. J. Am. med Ass., 203, 969-972. MURRAY, F.J. (1962). Outbreak of unexplained reactions among epileptics taking isoniazid. Am. Rev. Resp, Dis., 86, 729-732.
LETTERS TO THE EDITORS
175
OLESEN, O.V. & JENSEN, O.N. (1969). Drug interaction between sulthiame (Ospolot (R)) and phenytoin in the treatment of epilepsy. Dan. med. Bull., 16, 154-158. SOLOMON, H.M. & SCHROGIE, J.J. (1967). The effect of phenyramidol on the metabolism of diphenylhydantoin. Clin. Pharmac. Ther., 8, 5 54-5 56. TOSELAND, P.A., GROVE, J. & BERRY, D.J. (1972). An isothermal G.L.C. determination of the plasma levels of carbamazepine, diphenylhydantoin, phenobarbitone, and primidone. Clin. Chim. Acta., 38, 312-328. VIUKARI, N.M.A. & AHO, K. (1970). Digoxin-phenytoin interaction. Br. med. J., 2, 51.
LETTERS TO THE EDITORS
173
LEVODOPA AND POSITIVE DIRECT ANTIGLOBULIN TESTS In view of the close pharmacological relationship between methyldopa and levodopa, patients receiving levodopa were screened for the occurrence of positive direct antiglobulin (DAG) tests. Eighty-five patients attending the neurological out-patient department in Aberdeen and seventeen neurological out-patients in Dundee were screened on at least one occasion with the co-operation of the clinical and laboratory staff and yielded five and one positive tests respectively. The antihuman globulin used in the former is prepared from goat serum and detects both complement and Ig G antibodies while a commercially available serum was used in the latter. Of the six patients who showed a deviation from the 'normal' DAG test, only one showed a positive result of the Ig G type associated with auto-immunization to methyldopa. On repeat examination this DAG was less strongly positive despite the dose of levodopa remaining unchanged and there was, at no time, any evidence of anaemia. The other variants were probably due to adsorption to the red cells in vitro of weak cold autoagglutinins and are of no
significance. Positive DAG tests in patients receiving levodopa have been documented in the American Journals by Treciokas, Ansel and Markham who reported four in one hundred patients in 1971 and Joseph found positive tests in thirty-two of three hundred and sixty-five patients screened in 1972. Henry, Goldberg, Sturgeon & Ansel (1971) reported five positive antiglobulin tests in eighty patients receiving levodopa. In three of these
Ig G was demonstrated on the red cells while complement only was detected in the remaining two. Weiner (1965) documented a series of twenty-one positive DAG tests in seemingly normal people and estimated that the likelihood of this occurrence was between 1 and 3/10,000 of the population. Our local figures are therefore similar to the American data and it is of interest to note that Ig G is only demonstrable in some of those with positive tests. D.C. MOIR, A.J.J. WOOD, J.F. DAVIDSON & S.C. GALLON Medicines Evaluation and Monitoring Group, Aberdeen Section (Pharmacy Department), Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB9 2ZB
(Received June 27, 1974) References HENRY, R.E., GOLDBERG, L.S., STURGEON, P. &
ANSEL, R.D. (1971). Serologic abnormalities associated with 1-dopa therapy. Vox Sang., 20, 306-316. JOSEPH, C. (1972). Occurrence of positive Coombs Test in patients treated with 1-dopa. New Engl. J. Med., 286, 1401-1402. TRECIOKAS, L.J., ANSEL, R.D. & MARKHAM, C.H.
(1971). One to two year treatment of Parkinson's disease with 1-dopa. California Med., 114, 7-14. WEINER, W. (1965). Coombs' positive 'normal' people. Proceedings of the 10th Congress International Society of Blood Transfusion, 35.
INTERACTION OF PHENYTOIN WITH CHLORPHENIRAMINE A 17 year old female patient, developed grand mal and psychomotor seizures in 1969. She was discharged from follow-up in October 1970 taking phenobarbitone (30 mg twice daily) and phenytoin (100 mg three times a day). The most recent seizure was a minor episode in July 1973 but she remained well and started work in the same year. For no apparent reason she stopped taking phenytoin in December 1973. Two weeks prior to admission the patient developed a rash on her face following the use of a new cosmetic. Chlorpheniramine (4 mg three times
a day) was prescribed and one week later she was alert and well apart from a few minor dizzy spells. The antihistamine was continued and phenytoin (100 mg three times a day) was recommenced, her practitioner having discovered the omission of the drug. Over the ensuing week she rapidly developed drowsiness, ataxia, diplopia, tinnitus, and episodes of occipital headaches associated with vomiting. On admission she was drowsy and unable to stand, with gross bilateral horizontal nystagmus and cerebellar ataxia. The fundi were normal and there were no lateralizing neurological signs.
174
Br. J. clin. Pharmac. ( 1975), 2
LETTERS TO THE EDITORS
4
i;
-
Snk1
28
35
42
4
I: Figure 1 Daily dose of chiorpheniramine (hatched) and phenytoin (stippled) and plasma levels of phenytoin (e) and phenobarbitone (U).
Reflexes were normal and equal and the plantar responses flexor. Routine investigations, including skull X-ray, revealed no abnormality. Chlorpheniramine was withdrawn and both anticonvulsants continued, the daily dose of phenytoin being varied as illustrated in Figure 1. Serial plasma anticonvulsant levels were determined by an isothermal g.l.c. method (Toseland, Grove & Berry, 1972) from blood samples taken 2 to 4.5 h following the morning dose of the two anti-epileptic drugs. Plasma levels of phenytoin were initially in the toxic range but subsequently fell to within accepted therapeutic levels, despite increasing the dose of phenytoin on two occasions to the pre-admission regime of 100 mg three times a day. The decrease in the plasma phenytoin level corresponded with spontaneous resolution of neurological signs and symptoms. Plasma phenobarbitone levels remained throughout within the lower therapeutic range. The patient was discharged home taking phenobarbitone (15 mg three times a day) together with phenytoin in a reduced dose of 50 mg three times a day and was symptom-free when reviewed 4 weeks later. Phenobarbitone, phenytoin and chlorpheniramine are all extensively used compounds. Many drugs, including the antihistamines, which
can cause CNS depression may have an increased depressant effect if taken together with phenobarbitone. Chlorpheniramine alone can cause drowsiness and dizziness; the latter was observed in the present patient prior to the administration of phenytoin and was presumably potentiated by phenobarbitone. Gross neurological symptoms, however, only developed after phenytoin administration, many of the features being typical of those seen in phenytoin toxicity. Phenytoin is normally hydroxylated in the liver and then excreted as a glucuronide. Several drugs, including chlordiazepoxide, diazepam, chlorpromazine, and the oestrogens, can interfere with phenytoin metabolism (Kutt & McDowell, 1968). Other inducers of phenytoin toxicity includes bishydroxycoumarin (Hansen, Kristensen, Skovsted & Christensen, 1966), sulthiame (Hansen, Kristensen & Skovsted, 1968; Olesen & Jensen, 1969; Houghton & Richens, 1974), isoniazid and PAS (Murray, 1962; Kutt, Winters & McDowell, 1966), chloramphenicol (Christensen & Skovsted, 1969), phenyramidol (Solomon and Schrogie, 1967), and digoxin (Viukari & Aho, 1970). The present report suggests that chlorpheniramine also interacts with phenytoin, thereby delaying the hepatic metabolism of the anticonvulsant and increasing the plasma phenytoin levels, thus precipitating the acute neurological syndrome described above. Consideration should be given to providing epileptic patients with a card listing the names of drugs which could interact adversely with their anti-convulsant therapy. R.N.H. PUGH & A.M. GEDDES Department of Cummunicable and Tropical Diseases, East Birmingham Hospital, Birmingham B9 SST
W.B. YEOMAN Regional Toxicology Laboratory, Dudley Road Hospital, Birmingham B18 7QH Received August 21, 1974
References L.K. & SKOVSTED, L. (1969). Inhibition of drug metabolism by chloramphenicol. Lancet, ii, 1397-1399. HANSEN, J.M., KRISTENSEN, M., SKOVSTED, L. & CHRISTENSEN, L.K. (1966). Dicoumarol-induced diphenylhydantoin intoxication. Lancet, ii, 265-266. HANSEN, J.M., KRISTENSEN, M. & SKOVSTED, L. (1968). Sulthiame (Ospolot) as inhlbitor of diphenylhydantoin metabolism. Epilepsia, 9, 17-22. HOUGHTON, G.W. & RICHENS, A. (1974). Inhibition of
CHRISTENSEN,
Br. J. clin. Pharmac. (1975), 2 phenytoin metabolism by sulthiame in epileptic patients. Br. J. cli. Pharmac., 1, 59-66. KUTT, H., WINTERS, W. & McDOWELL, F. (1966). Depression of parahydroxylation of diphenylhydantoin by antituberculous chemotherapy. Neurology, 16, 594-602. KUTT, H. & McDOWELL, F. (1968). Management of epilepsy with diphenyIhydantoin sodium. Dosage regulation for problem patients. J. Am. med Ass., 203, 969-972. MURRAY, F.J. (1962). Outbreak of unexplained reactions among epileptics taking isoniazid. Am. Rev. Resp, Dis., 86, 729-732.
LETTERS TO THE EDITORS
175
OLESEN, O.V. & JENSEN, O.N. (1969). Drug interaction between sulthiame (Ospolot (R)) and phenytoin in the treatment of epilepsy. Dan. med. Bull., 16, 154-158. SOLOMON, H.M. & SCHROGIE, J.J. (1967). The effect of phenyramidol on the metabolism of diphenylhydantoin. Clin. Pharmac. Ther., 8, 5 54-5 56. TOSELAND, P.A., GROVE, J. & BERRY, D.J. (1972). An isothermal G.L.C. determination of the plasma levels of carbamazepine, diphenylhydantoin, phenobarbitone, and primidone. Clin. Chim. Acta., 38, 312-328. VIUKARI, N.M.A. & AHO, K. (1970). Digoxin-phenytoin interaction. Br. med. J., 2, 51.
