“absence status” and “temporal lobe status.” Epilepsia 12:77-87, 1971 8. Henriksen GF: Status epilepticus partialis with fear as clinical expression. Epilepsia 14:39-46, 1973 9. Escueta AV, Boxley J , Stubbs N, e t al: Prolonged twilight state a n d automatisms: A case report. Neurology -. (Minneap) 241331-339, 1974 10. Markand ON. Wheeler GL. Pollack SL: Comulex uartial s t a t u s e p i l e p t i c u s (psychornotor s t a t u s ) . Neurology 28:189-196, 1978 11.Juul-Jensen P, Denny-Brown D: Epilepsia partialis continua. Arch Neurol 15:563-577, 1966 12. Thomas JE, Reagan T J , Klass DW: Epilepsia partialis continua. Arch Neurol 34:226-275, 1977 13. Klass DW: Electroencephalographic manifestations of complex partial seizures. In Penry J K , Daly D (Editors): Advances in Neurology. New York, Raven Press, 1975, vol 11, pp 113-140
.
.
14.Daly D: Ictal clinical manifestations of complex partial seizures. In Penry J K , Daly D (Editors): Advances in Neurology. New York, Raven Press, 1975, vol 11,pp 57-83 15. Schwartz M, Prior P, Scott D: The occurrence and evolution in the EEG of a lateralized periodic phenomenon. Brain 96:613-622, 1973 16. Gastaut H, Roger J, Lob H: Les etats de ma1 epileptiques. Paris, Masson, 1967 17. Goldensohn ES, Gold AP: Prolonged behavioral disturbances as ictal phenomena. Neurology (Minneap) 2:l-9, 1952 18. Roger J, Lob A, Tassinari CA: Status epilepticus. In Vinken PJ, Bruyn GW (Editors): Handbook of Clinical Neurology. Amsterdam, North-Holland Publishing Company, 1974, V O ~15, pp 145-188 19. Oller-Daurella L: Crises epileptiques psychiques de langue duree. Rev Neuropsychiatr Infant 18:547-557, 1970
Article abstract-Altered hepatic function tests occurred in four of 25 patients treated with valproic acid. An average dose reduction in three patients of 10 mg per kilogram per day resulted in reversion of serum glutamic oxaloacetic transaminase (SGOT)and serum glutamic pyruvic transaminase (SGPT) to normal. The drug was discontinued in one patient. Careful monitoring of hepatic function is required of patients being treated with valproic acid, but our experience suggests that dose reduction alone may be effective in preventing untoward hepatic side effects.
Effect of valproic acid on hepatic function I
NEUROLOGY 28: 961-964, September 1978
L.J. Willmore, M.D., B.J. Wilder, M.D., J. Bruni, M.D., and H.J. Villarreal, M.D. The medical management of patients with recurrent seizures requires chronic administration of anticonvulsant drugs. Abnormal laboratory data from such patients usually signal the development of secondary illness or side effects and require the discontinuation of the suspect drug. ’ Valproic acid,“>a drug recently approved for use in this country, is a branched-chain carboxylic acid that is particularly effective in the treatment of generalized nonconvulsive seizures. Although safe, Volzke and Doose” reported transient minor elevation of serum glutamic oxaloacetic transaminase (SGOT) in four of 64 patients having hepatic function tests while on valproate. Several fatalities have occurred in patients receiving valproic acid in combination with other anticonvulsant drugs.‘ We now report altered hepatic function tests in 4 of 25 patients treated with valproic acid. Methods. Approval was given by the Health Center Committee for the Protection of Human Subjects and the Research and Development Committee of the Veterans Administration Hospital, and informed consent was obtained from the patients. Twenty-five epileptic patients were treated. Patients ranged in age from 14 to 39 years (average 24 years) and included 14 men and 11 women.
After a 2-week placebo pre-entry period, valproic acid in 250 mg capsules was administered orally beginning a t 7.5 to 13.6 (average 11.2) mg per kilogram per day. Valproic acid dosage was increased each week to a maximum dose of 17.9 to 62.5 (average 42.7) mg per kilogram per day. Baseline and then weekly blood samples were obtained for measurement of SGOT, SGPT, alkaline phosphatase, total protein, calcium and phosphorus, uric acid, lactic dehydrogenase, glucose, blood urea nitrogen, creatinine, hemoglobin, hematocrit, platelet count and complete urinalysis. Patients were maintained on pre-entry anticonvulsants, including phenytoin, carbamazepine, clonazepam, primidone, phenobarbital, a n d ethosuximide. Daily dose was adjusted as necessary to maintain pre-study anticonvulsant blood levels. Commonly, d a i l y r e q u i r e m e n t s for phenobarbital were reduced after attaining therapeutic blood levels of valproic acid. The details of drug interaction and efficacy will be reported in greater detail elsewhere. C a s e 1. This 20-year-old man had absence seizures for 6 years. Numerous medications, including clonazepam, trimethadione, and ethosuximide, were ineffective in
September 1978 NEUROLOGY 28 961
Valproic acid and hepatic function
UlI
3000 -
175 -
2000-
150-
1000-
125-
0
6
4
6
10
12
14
16
100-
18
week
Figure I A . Dosc
of
75-
50-
valproic acid in rng per da,y,
controlling his seizures. He was started on valproic acid. Seizure control was achieved at 3500 mg per day or 50 mg per kilogram per day (figure 1A).Twelve weeks after beginning treatment, SGOT and SGPT increased to six times normal (figure 1B). Serum level of valproic acid was 103 pg per milliliter (figure 1C). Medication was reduced to 2000 mgi24 hours or 28.5 mgper kilogram per day. The serum hepatic enzymes returned to t h e normal range within 6 weeks. He remained free of symptoms during this time. C a s e 2. This 29-year-old woman had generalized convulsive and nonconvulsive seizures for 16 years. The EEG showed bursts of generalized 3-cycles-per-second spike-and-wave discharges, in runs of 2 to 5 seconds. Over several years, she was treate'd with all of the appropriate available anticonvulsant drugs. S h e continued to have 10 to 30 absence seizures each day and one grand ma1 seizure each month. Medication prior to the use of sodium valproate included phenytoin 6.5 mg per kilogram per day, ethosuximide 28 nig per kilogram per day, and phenobarbital 2.5 mg per kilogram per day, all resulting in serum levels within therapeutic range. Valproic acid dose was increased until complete seizure control was obtained by 8 weeks at a consumption of 40 mgper kilogram per day (figure2A),yielding a serum level of 63 pg per milliliter of valproic acid (figure 2C). By week 12, she complained of malaise a n d ankle edema. Laboratory data revealed elevation of SGOT and SGPT (figure 2B), prolonged prothrombin time, decreased serum albumin a n d normal alkaline phosphatase. Antinuclear antibody and hepatitis-associated antigen tests were negative. Valproic acid was discontinued. Her sense of well-being returned and t h e abnormal laboratory values reverted to normal within 4 weeks. Seizures returned within 7 days of discontinuing valproic acid a t a frequency similar to t h a t prior to treatment. C a s e 3. This 36-year-old woman experienced 20 to 40 simple absence seizures each day since age 8. Her seizures were partially controlled with ethosuximide. Marked mood changes and depression led to discontinuation of ethosuximide therapy. She was treated with valproic acid in gradually increasing doses, attaining complete seizure control a t 3000 mg per day, or 19 mg per kilogram per day. By 10 weeks of treatment, SGOT and SGPT increased to four times normal. Dosage was decreased to 2250 mg per day or 14 mg per kilogram per day. The isolated abnormal laboratory values reverted to the normal range within 2 weeks.
962 NEUROLOGY 28 September 1978
n
51
250
'
4
6
8
10
12
1's
is
is
week
Figure 1B. SGOT (dot) and SGPT (triangle) measured weekly during administration of valproic acid. I
25
I
4 O-'
6
8
10
12
14
16
18
week
Figure 1 C. S e r u m levels of valproic acid in ,ug per milliliter.
Case 4. This 15-year-oldboy had 25 to 50 simple absence seizures each day since age 8. Numerous medications, including paradione, ethosuximide, and clonazepam, were ineffective. Excellent seizure control was achieved with valproic acid at 3000 mg per day or 54 mg per kilogram per day. Eight weeks after beginning valproic acid, SGOT and SGPT increased. Valproic acid dose was reduced to 2250 mg per day, 41 mg per kilogram per day, with subsequent reversion of serum enzymes to normal within 2 weeks.
Discussion. Hepatic cytoplasmic and mitochondrialHtransaminases catalyze interconversion of amino acids and oxoacids by transfer of amino groups.!' For example, L-glutamic acid and pyruvic acid form a-ketoglutaric acid and L-alanine by the action of glutamic-pyruvic transaminase with the coenzyme pyridoxal-5-phosphate. Increased serum levels of these transaminases occur in response to tissue injury such as hepatocellular necrosis." Anticonvulsants, particularly phenytoin, are metabolized in the liver by parahydroxylation."' Liver injury with focal hepatitis and
150-
loo--
I
0-1
week
4
6
8
10
&
1'2 14
week
Figure 2A. Dose of valproic acid in mg per day. Figure 2C. Serum levels of valproic acid in pg per milliliter.
300 -
A
250200150 100 50 0
-1
4
6
8
10
12
14
16
week
Figure 2B. SGOT (dot) and SGPT (triangle) response during treatment, and after discontinuation of valproic acid.
prothrombin time, or alkaline phosphatase appear abnormal, the drug should be discontinued. Acknowledgments The authors wish to express appreciation to Barbara Barbour, Fred Bauman, a n d Lisa Benedict for their assistance i n this study. Valproic acid was supplied by Abbott Laboratories.
From the Neurology Service. Veterans Administration Hospital, and the Department ofNeurology. University of Florida College ofMedicine, Gainesville, Florida. Supported by the Medical Research Service ofthe Veterans Administration and t h e Epilepsy Research Foundation of Florida, Inc. Dr. Bruni is sponsored by the Ministry of Health, Ontario, Canada; Dr. Villarreal is sponsored by ANUIES, Mexico. and the Epilepsy Research Foundation of Florida, Inc. Accepted for publication May 17, 1978 Dr. Willmore's address is Neurology Service I 1'271, Veterans Administration Hospital, Gainesville, FL 32602.
eosinophilic response h a s been attributed to hypersensitivity reaction to phenytoin."-'" That portion of serum valproic acid not bound to plasma protein^'^,'^ is eliminated by flow-independent clearance related directly to the metabolic capacity of the liver."' In our study, hepatic function tests altered a t a dose of valproic acid from 19 to 50 (average 40.7) mg per kilogram per day. All patients had taken valproic acid for a t least 10 weeks. Reversion of altered serum enzymes to normal occurred after reduction of dose to a n average of 27.7 mg per kilogram per day. The drug was discontinued in one patient. None of our patients was exposed to a known case of hepatitis, and the prompt response of the abnormal laboratory data to dose reduction seems to corroborate the association of enzyme alteration with the use of valproic acid. We suggest that isolated altered hepatic function tests during valproate administration should be treated by total daily dose reduction of a t least 10 mg per kilogram per day. If systemic symptoms or other laboratory data, such as serum albumin,
References 1. Glaser GH: Diphenylhydantoin toxicity. In Woodbury DM, Penry, J K , Schmidt R P (Editors):Antiepileptic Drugs. New York, Raven Press, 1972, pp 219-226 2. Simon D, Penry J K : Sodium di-n-propylacetate (DPA) in t h e treatment of epilepsy. A review. Epilepsia 16549-573, 1975 3. Pinder RM, Brogden RN, Speight TM, et al: Sodium valproate: A review of i t s pharmacological properties and therapeutic efficacy in epilepsy. Drugs 13:81-123, 1977 4. Adams DJ, Luders H, Pippenger C: Sodium valproate in the treatment of intractable seizure disorders: A clinical and electroencephalographic study. Neurology 28: 152-157, 1978 5 . Mattson RH, Cramer J A , Williamson PD, et al: Valproic acid in epilepsy: Clinical and pharmacological effects. Ann Neurol 3:20-25, 1978 6 . Volzke E, Doose H: Dipropylacetate (Depakene, Ergenyl) in the treatment of epilepsy. Epilepsia 14:185-193, 1973 7. De Jong R Personal communication 8. Boyd JW: Glutamate-oxaloacetate transaminase isoenzymes in r a t serum. Clin Chim Acta 7:424-431, 1962 9. Demetriou JA, Drewers PA, Gin JB: Enzymes. I n H e n r y R J , Cannon DC, Winkelman J W (Editors):Clinical Chemistry.
September 1978 NEUROLOGY 28 963
Valproic acid and hepatic function Priniciples and Techniques. Hagerstown, Harper and Row, 1974. pp 815-1001 10. Woodbury DM, Swinyard EA: Diphenylhydantoin absorption, distribution and excretion. I n Woodbury DM, Penry J K , Schmidt R P (Editors):Antiepileptic Drugs. New York, Raven Press, 1972, pp 113-123 11. Mendelbaum H, Kane L J : Dilantin sodium poisoning: Report of a case with dermatitis exfoliativa, pyrexia a n d hepatic and splenic enlargement. Arch Neurol Psychiatry 45:769-771, 1941 12. Chaiken BH, Goldberg BI, Segal J P : Dilantin sensitivity: Report of case of hepatitis with jaundice, pyrexia and ex-
Comparative effectiveness of two extracerebral DOPA decarboxylase inhibitors in Parkinson disease
foliative dermatitis. N Engl J Med 242:897-898, 1950 13. Crawford S E , J o n e s CK: F a t a l liver necrosis a n d diphenylhydantoin sensitivity. Pediatrics 30:595-600, 1962 14. Klotz U, Antonin KH: Pharmacokinetics and bioavailability of sodium valproate. Clin Pharmacol Ther 21:736-743, 1977 15. Patsalos PN, Lascelles PT: Valproate may lower serum phenytoin. Lancet 1:50-51, 1977 16. Ferrandes 8 , Eymard P: Metabolism of valproate sodium in rabbit, r a t , dog and man. Epilepsia 18:169-182, 1977
Article abstract-In four patients with Parkinson disease, we compared carbidopa combined with levodopa (Sinemet@)and benserazide combined with levodopa (Madopar@).All of these patients had responded to treatment, first with levodopa and then with Sinemet; after 6 years two continued to show a good response, while two developed marked “on-off” phenomena. Clinically, Sinemet and Madopar were similar; however, DOPA levels were higher, but with a shorter half-life, on Madopar. The higher DOPA levels may have been offset by the shorter half-life, resulting in no clinical change. DOPA levels were lower and half-life was shorter in patients with on-off phenomena. These differences may be responsible in part for the on-off phenomena.
NEUROLOGY 28: 964-968, September 1978
Abraham Lieberman, M.D., Elihu Estey, M.D., Govindan Gopinathan, M.D., Takeo Ohashi, B.S., Andre Sauter, Ph.D., and Menek Goldstein, Ph.D.
Levodopa combined with a n extracerebral DOPA decarboxylase inhibitor is widely used to treat Parkinson disease.’-* Two extracerebral decarboxylase inhibitors a r e i n general usecarbidopa, combined with levodopa in a 1 : l O ratio (Sinemet@),a n d benserazide combined with levodopa in a 1:4 ratio (Madopar@). I n most patients, initial improvement on levodopa alone or in combination with a decarboxylase inhibitor is not sustained, and disability Table 1. Prior treatment in four patients
964 NEUROLOGY 28 September 1978
increases after 2 to 5 years. The increase is usually associated with “on-off” phenomena: marked diurnal oscillations characterized by the relatively rapid onset of a n inability to move (“off”) followed by a n equally rapid return of movement (“on”). Several types of on-off phenomena have been described, based on their manner of precipitation, relationship to the last dose of levodopa, and association with abnormal involuntary movements. The most common type of on-off phenomenon is
Effect of valproic acid on hepatic function L. J. Willmore, B. J. Wilder, J. Bruni, et al. Neurology 1978;28;961 DOI 10.1212/WNL.28.9.961 This information is current as of September 1, 1978 Updated Information & Services
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1978 by the American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
.
.
14.Daly D: Ictal clinical manifestations of complex partial seizures. In Penry J K , Daly D (Editors): Advances in Neurology. New York, Raven Press, 1975, vol 11,pp 57-83 15. Schwartz M, Prior P, Scott D: The occurrence and evolution in the EEG of a lateralized periodic phenomenon. Brain 96:613-622, 1973 16. Gastaut H, Roger J, Lob H: Les etats de ma1 epileptiques. Paris, Masson, 1967 17. Goldensohn ES, Gold AP: Prolonged behavioral disturbances as ictal phenomena. Neurology (Minneap) 2:l-9, 1952 18. Roger J, Lob A, Tassinari CA: Status epilepticus. In Vinken PJ, Bruyn GW (Editors): Handbook of Clinical Neurology. Amsterdam, North-Holland Publishing Company, 1974, V O ~15, pp 145-188 19. Oller-Daurella L: Crises epileptiques psychiques de langue duree. Rev Neuropsychiatr Infant 18:547-557, 1970
Article abstract-Altered hepatic function tests occurred in four of 25 patients treated with valproic acid. An average dose reduction in three patients of 10 mg per kilogram per day resulted in reversion of serum glutamic oxaloacetic transaminase (SGOT)and serum glutamic pyruvic transaminase (SGPT) to normal. The drug was discontinued in one patient. Careful monitoring of hepatic function is required of patients being treated with valproic acid, but our experience suggests that dose reduction alone may be effective in preventing untoward hepatic side effects.
Effect of valproic acid on hepatic function I
NEUROLOGY 28: 961-964, September 1978
L.J. Willmore, M.D., B.J. Wilder, M.D., J. Bruni, M.D., and H.J. Villarreal, M.D. The medical management of patients with recurrent seizures requires chronic administration of anticonvulsant drugs. Abnormal laboratory data from such patients usually signal the development of secondary illness or side effects and require the discontinuation of the suspect drug. ’ Valproic acid,“>a drug recently approved for use in this country, is a branched-chain carboxylic acid that is particularly effective in the treatment of generalized nonconvulsive seizures. Although safe, Volzke and Doose” reported transient minor elevation of serum glutamic oxaloacetic transaminase (SGOT) in four of 64 patients having hepatic function tests while on valproate. Several fatalities have occurred in patients receiving valproic acid in combination with other anticonvulsant drugs.‘ We now report altered hepatic function tests in 4 of 25 patients treated with valproic acid. Methods. Approval was given by the Health Center Committee for the Protection of Human Subjects and the Research and Development Committee of the Veterans Administration Hospital, and informed consent was obtained from the patients. Twenty-five epileptic patients were treated. Patients ranged in age from 14 to 39 years (average 24 years) and included 14 men and 11 women.
After a 2-week placebo pre-entry period, valproic acid in 250 mg capsules was administered orally beginning a t 7.5 to 13.6 (average 11.2) mg per kilogram per day. Valproic acid dosage was increased each week to a maximum dose of 17.9 to 62.5 (average 42.7) mg per kilogram per day. Baseline and then weekly blood samples were obtained for measurement of SGOT, SGPT, alkaline phosphatase, total protein, calcium and phosphorus, uric acid, lactic dehydrogenase, glucose, blood urea nitrogen, creatinine, hemoglobin, hematocrit, platelet count and complete urinalysis. Patients were maintained on pre-entry anticonvulsants, including phenytoin, carbamazepine, clonazepam, primidone, phenobarbital, a n d ethosuximide. Daily dose was adjusted as necessary to maintain pre-study anticonvulsant blood levels. Commonly, d a i l y r e q u i r e m e n t s for phenobarbital were reduced after attaining therapeutic blood levels of valproic acid. The details of drug interaction and efficacy will be reported in greater detail elsewhere. C a s e 1. This 20-year-old man had absence seizures for 6 years. Numerous medications, including clonazepam, trimethadione, and ethosuximide, were ineffective in
September 1978 NEUROLOGY 28 961
Valproic acid and hepatic function
UlI
3000 -
175 -
2000-
150-
1000-
125-
0
6
4
6
10
12
14
16
100-
18
week
Figure I A . Dosc
of
75-
50-
valproic acid in rng per da,y,
controlling his seizures. He was started on valproic acid. Seizure control was achieved at 3500 mg per day or 50 mg per kilogram per day (figure 1A).Twelve weeks after beginning treatment, SGOT and SGPT increased to six times normal (figure 1B). Serum level of valproic acid was 103 pg per milliliter (figure 1C). Medication was reduced to 2000 mgi24 hours or 28.5 mgper kilogram per day. The serum hepatic enzymes returned to t h e normal range within 6 weeks. He remained free of symptoms during this time. C a s e 2. This 29-year-old woman had generalized convulsive and nonconvulsive seizures for 16 years. The EEG showed bursts of generalized 3-cycles-per-second spike-and-wave discharges, in runs of 2 to 5 seconds. Over several years, she was treate'd with all of the appropriate available anticonvulsant drugs. S h e continued to have 10 to 30 absence seizures each day and one grand ma1 seizure each month. Medication prior to the use of sodium valproate included phenytoin 6.5 mg per kilogram per day, ethosuximide 28 nig per kilogram per day, and phenobarbital 2.5 mg per kilogram per day, all resulting in serum levels within therapeutic range. Valproic acid dose was increased until complete seizure control was obtained by 8 weeks at a consumption of 40 mgper kilogram per day (figure2A),yielding a serum level of 63 pg per milliliter of valproic acid (figure 2C). By week 12, she complained of malaise a n d ankle edema. Laboratory data revealed elevation of SGOT and SGPT (figure 2B), prolonged prothrombin time, decreased serum albumin a n d normal alkaline phosphatase. Antinuclear antibody and hepatitis-associated antigen tests were negative. Valproic acid was discontinued. Her sense of well-being returned and t h e abnormal laboratory values reverted to normal within 4 weeks. Seizures returned within 7 days of discontinuing valproic acid a t a frequency similar to t h a t prior to treatment. C a s e 3. This 36-year-old woman experienced 20 to 40 simple absence seizures each day since age 8. Her seizures were partially controlled with ethosuximide. Marked mood changes and depression led to discontinuation of ethosuximide therapy. She was treated with valproic acid in gradually increasing doses, attaining complete seizure control a t 3000 mg per day, or 19 mg per kilogram per day. By 10 weeks of treatment, SGOT and SGPT increased to four times normal. Dosage was decreased to 2250 mg per day or 14 mg per kilogram per day. The isolated abnormal laboratory values reverted to the normal range within 2 weeks.
962 NEUROLOGY 28 September 1978
n
51
250
'
4
6
8
10
12
1's
is
is
week
Figure 1B. SGOT (dot) and SGPT (triangle) measured weekly during administration of valproic acid. I
25
I
4 O-'
6
8
10
12
14
16
18
week
Figure 1 C. S e r u m levels of valproic acid in ,ug per milliliter.
Case 4. This 15-year-oldboy had 25 to 50 simple absence seizures each day since age 8. Numerous medications, including paradione, ethosuximide, and clonazepam, were ineffective. Excellent seizure control was achieved with valproic acid at 3000 mg per day or 54 mg per kilogram per day. Eight weeks after beginning valproic acid, SGOT and SGPT increased. Valproic acid dose was reduced to 2250 mg per day, 41 mg per kilogram per day, with subsequent reversion of serum enzymes to normal within 2 weeks.
Discussion. Hepatic cytoplasmic and mitochondrialHtransaminases catalyze interconversion of amino acids and oxoacids by transfer of amino groups.!' For example, L-glutamic acid and pyruvic acid form a-ketoglutaric acid and L-alanine by the action of glutamic-pyruvic transaminase with the coenzyme pyridoxal-5-phosphate. Increased serum levels of these transaminases occur in response to tissue injury such as hepatocellular necrosis." Anticonvulsants, particularly phenytoin, are metabolized in the liver by parahydroxylation."' Liver injury with focal hepatitis and
150-
loo--
I
0-1
week
4
6
8
10
&
1'2 14
week
Figure 2A. Dose of valproic acid in mg per day. Figure 2C. Serum levels of valproic acid in pg per milliliter.
300 -
A
250200150 100 50 0
-1
4
6
8
10
12
14
16
week
Figure 2B. SGOT (dot) and SGPT (triangle) response during treatment, and after discontinuation of valproic acid.
prothrombin time, or alkaline phosphatase appear abnormal, the drug should be discontinued. Acknowledgments The authors wish to express appreciation to Barbara Barbour, Fred Bauman, a n d Lisa Benedict for their assistance i n this study. Valproic acid was supplied by Abbott Laboratories.
From the Neurology Service. Veterans Administration Hospital, and the Department ofNeurology. University of Florida College ofMedicine, Gainesville, Florida. Supported by the Medical Research Service ofthe Veterans Administration and t h e Epilepsy Research Foundation of Florida, Inc. Dr. Bruni is sponsored by the Ministry of Health, Ontario, Canada; Dr. Villarreal is sponsored by ANUIES, Mexico. and the Epilepsy Research Foundation of Florida, Inc. Accepted for publication May 17, 1978 Dr. Willmore's address is Neurology Service I 1'271, Veterans Administration Hospital, Gainesville, FL 32602.
eosinophilic response h a s been attributed to hypersensitivity reaction to phenytoin."-'" That portion of serum valproic acid not bound to plasma protein^'^,'^ is eliminated by flow-independent clearance related directly to the metabolic capacity of the liver."' In our study, hepatic function tests altered a t a dose of valproic acid from 19 to 50 (average 40.7) mg per kilogram per day. All patients had taken valproic acid for a t least 10 weeks. Reversion of altered serum enzymes to normal occurred after reduction of dose to a n average of 27.7 mg per kilogram per day. The drug was discontinued in one patient. None of our patients was exposed to a known case of hepatitis, and the prompt response of the abnormal laboratory data to dose reduction seems to corroborate the association of enzyme alteration with the use of valproic acid. We suggest that isolated altered hepatic function tests during valproate administration should be treated by total daily dose reduction of a t least 10 mg per kilogram per day. If systemic symptoms or other laboratory data, such as serum albumin,
References 1. Glaser GH: Diphenylhydantoin toxicity. In Woodbury DM, Penry, J K , Schmidt R P (Editors):Antiepileptic Drugs. New York, Raven Press, 1972, pp 219-226 2. Simon D, Penry J K : Sodium di-n-propylacetate (DPA) in t h e treatment of epilepsy. A review. Epilepsia 16549-573, 1975 3. Pinder RM, Brogden RN, Speight TM, et al: Sodium valproate: A review of i t s pharmacological properties and therapeutic efficacy in epilepsy. Drugs 13:81-123, 1977 4. Adams DJ, Luders H, Pippenger C: Sodium valproate in the treatment of intractable seizure disorders: A clinical and electroencephalographic study. Neurology 28: 152-157, 1978 5 . Mattson RH, Cramer J A , Williamson PD, et al: Valproic acid in epilepsy: Clinical and pharmacological effects. Ann Neurol 3:20-25, 1978 6 . Volzke E, Doose H: Dipropylacetate (Depakene, Ergenyl) in the treatment of epilepsy. Epilepsia 14:185-193, 1973 7. De Jong R Personal communication 8. Boyd JW: Glutamate-oxaloacetate transaminase isoenzymes in r a t serum. Clin Chim Acta 7:424-431, 1962 9. Demetriou JA, Drewers PA, Gin JB: Enzymes. I n H e n r y R J , Cannon DC, Winkelman J W (Editors):Clinical Chemistry.
September 1978 NEUROLOGY 28 963
Valproic acid and hepatic function Priniciples and Techniques. Hagerstown, Harper and Row, 1974. pp 815-1001 10. Woodbury DM, Swinyard EA: Diphenylhydantoin absorption, distribution and excretion. I n Woodbury DM, Penry J K , Schmidt R P (Editors):Antiepileptic Drugs. New York, Raven Press, 1972, pp 113-123 11. Mendelbaum H, Kane L J : Dilantin sodium poisoning: Report of a case with dermatitis exfoliativa, pyrexia a n d hepatic and splenic enlargement. Arch Neurol Psychiatry 45:769-771, 1941 12. Chaiken BH, Goldberg BI, Segal J P : Dilantin sensitivity: Report of case of hepatitis with jaundice, pyrexia and ex-
Comparative effectiveness of two extracerebral DOPA decarboxylase inhibitors in Parkinson disease
foliative dermatitis. N Engl J Med 242:897-898, 1950 13. Crawford S E , J o n e s CK: F a t a l liver necrosis a n d diphenylhydantoin sensitivity. Pediatrics 30:595-600, 1962 14. Klotz U, Antonin KH: Pharmacokinetics and bioavailability of sodium valproate. Clin Pharmacol Ther 21:736-743, 1977 15. Patsalos PN, Lascelles PT: Valproate may lower serum phenytoin. Lancet 1:50-51, 1977 16. Ferrandes 8 , Eymard P: Metabolism of valproate sodium in rabbit, r a t , dog and man. Epilepsia 18:169-182, 1977
Article abstract-In four patients with Parkinson disease, we compared carbidopa combined with levodopa (Sinemet@)and benserazide combined with levodopa (Madopar@).All of these patients had responded to treatment, first with levodopa and then with Sinemet; after 6 years two continued to show a good response, while two developed marked “on-off” phenomena. Clinically, Sinemet and Madopar were similar; however, DOPA levels were higher, but with a shorter half-life, on Madopar. The higher DOPA levels may have been offset by the shorter half-life, resulting in no clinical change. DOPA levels were lower and half-life was shorter in patients with on-off phenomena. These differences may be responsible in part for the on-off phenomena.
NEUROLOGY 28: 964-968, September 1978
Abraham Lieberman, M.D., Elihu Estey, M.D., Govindan Gopinathan, M.D., Takeo Ohashi, B.S., Andre Sauter, Ph.D., and Menek Goldstein, Ph.D.
Levodopa combined with a n extracerebral DOPA decarboxylase inhibitor is widely used to treat Parkinson disease.’-* Two extracerebral decarboxylase inhibitors a r e i n general usecarbidopa, combined with levodopa in a 1 : l O ratio (Sinemet@),a n d benserazide combined with levodopa in a 1:4 ratio (Madopar@). I n most patients, initial improvement on levodopa alone or in combination with a decarboxylase inhibitor is not sustained, and disability Table 1. Prior treatment in four patients
964 NEUROLOGY 28 September 1978
increases after 2 to 5 years. The increase is usually associated with “on-off” phenomena: marked diurnal oscillations characterized by the relatively rapid onset of a n inability to move (“off”) followed by a n equally rapid return of movement (“on”). Several types of on-off phenomena have been described, based on their manner of precipitation, relationship to the last dose of levodopa, and association with abnormal involuntary movements. The most common type of on-off phenomenon is
Effect of valproic acid on hepatic function L. J. Willmore, B. J. Wilder, J. Bruni, et al. Neurology 1978;28;961 DOI 10.1212/WNL.28.9.961 This information is current as of September 1, 1978 Updated Information & Services
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1978 by the American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
