Acta Neurol. Scandinav. 56, 563-571, 1977
Departments of Neurology and Biochemistry, St. Finbarr's Hospital, Cork and the Mathematical Analysis Section, Ciba Geigy, Manchester.
T H E EFFECTS OF TOXIC AND NON-TOXIC SERUM PHENYTOIN LEVELS O N CARBOHYDRATE TOLERANCE AND INSULIN LEVELS N. CALLAGHAN, M. FEELY, M. ~'CALLAGHAN, B. DUGGAN,J. MCGARRY, B. CRAMER,J. WHEELAN and J. SELDRUP ABSTRACT The cffrct of toxic and non-toxic phenytoin levels o n carbohydrate tolerance and insulin levels was studied in 18 patients with epilepsy and 17 control subjects. Toxic levels were defined as a serum level greater t h a n 2 0 ~ g h n l .Toxic levels occurred i n 11 patients and nontoxic levels i n seven patients. Blood glucose and insulin levels were measured a t 30-min intervals f o r a period of 3 h following the ingestion of 50 g glucose. Blood glucose levels were measured by the ferricyanide method, and serum insulin levels by immunoassay of insulin with insulin antibody precipitate. Serum phenytoin levels were measured by gas liquid chromatography. The insulin profiles were the same f o r all three groups, b u t there was a significant delay in reaching peak glucose concentrations in patients with toxic levels of phenytoin. It was therefore confirmed that non-toxic levels of phenytoin do not affect carbohydrate tolerance or insulin levels when phenytoin is used i n the routine treatment of epilepsy, and i t has also been shown t h a t toxic levels of phenytoin do not affect carbohydrate tolerance when the high levels are detected a t a n early stage.
Large doses of phenytoin have been shown to cause hyperglycaemia (Belton et al. 1966, Peters & Samman 1969) when infused at high concentrations in an isolated rat pancreas. It has been found to inhibit the early peak and late rise of insulin secretion (Leuin et al. 1970). An inhibition of insulin release from the pancreas has also been documented when phenytoin was given to patients with insulinoma (Pelkonen & Taskinen 1973, Cohen et al. 1973). Phenytoin is an effective anticonvulsant drug which is frequently used in the treatment of epilepsy. Two previous studies have examined Carbohydrate tolerance in epileptic patients with non-toxic levels of 37.
564 phenytoin (Cunzinys et al. 1972, Madsen et al. 1974). Due to the saturahle nature of the metabolism of this drug, a slight increase in dosage may result in a disproportionate increase in serum levels (Richens 1976). In the absence of facilities for the measurement of serum Blevels, the increase may not become obvious until the patient develops the clinical complications of phenytoin intoxication. Therefore, the effect of toxic levels on carbohydrate tolerance in patients on routine treatment for epilepsy needs to be clarified. This paper reports the results of a study which investigated carbohydrate tolerance and insulin levels in patients with toxic and non-toxic phcnytoin levels.
METHODS
The patients were selected from subjects who were attending a seizure clinic where blood levels of anticonvulsant drugs were monitored a t frequent intervals. The patients with epilepsy were divided into two groups. Group 1 included patients with serum phenytoin levels which were less than 20 pg/ml, as documented, and Group 2. patients with serum levels greater than 20 &g/ml. Sulthiame was used i n combination with phenytoin in three patients i n Group 2, and phenytoin was used as a single drug i n t h e other four patients. I.evels greater than 20 pg/ml were regarded as within the toxic range. Group 3 includes healthy subjects. Details of patients with epilepsy and the control subjects are documented i n Table 1.
Table I . Niimber o f patients and control subjects together with details o f age, sex and weight.
Mean wgt.
Number
Mean
Age range
Sex
Group 1
11
31.1
14-71
5 males 6 females
66.6
Group 2
I
19.9
12-36
4 males 3 females
45.1
Group 3 (controls)
17
27.9
15.71
8 males 9 females
61.1
kg
Subjects were not included i n the study i f they were known to be diabetic, or if there was a family history of diabetes. They were also excluded if they were found to 50 per cent greater than their ideal body weight. Patients and control subjects were allowed a n unrestricted diet and physical activity for a t least 3 days before the GTT was done. This was carried out on t h e morning following a 12-h fast. A total of 50 g of glucose i n 500 cc water was taken orally. Fasting 30, 60, 120, 150, 180 min venous blood samples were taken f o r the
565 estimation of glucose levels. Samples were taken over a n extended period of 3 h i n order to detect a possible effect o n the late rise i n insulin secretion. Blood glucose was measured by the ferricyanide method (Hoffmann 1937), and serum insulin levels by t h e immunoassay of insulin with insulin antibody precipitate (Hales & Randle 1963). The GI’T was carried out as soon a s possible after a toxic level of phenytoin was detected in Group 2. The dosage of phenytoin was not adjusted i n the intervening period. Patients with non-toxic levels were randomly selected. Further specimens of serum for phenytoin estimation were taken a t the same time as the glucose tolerance test in both groups. Serum phenytoin levels were measured by gas liquid chromatography according to the method described by Roger et al. (1973). Statistical methods For the purpose of studying insulin and sugar profiles three parameters were used a s follows. The maximum concentration (CMAX), Time to maximum concentration (TMAX), and the area under the curves (AUC) when glucose and insulin levels were plotted at intervals of 30 min. Due t o the abnormality of the data, the non-parametric Knskal-Wallis technique was applied. Student’s t-test was used to compare significance of phenytoin dosage. The mean dnration of treatment with the dose of phenytoin which resulted i n a toxic level was 13 weeks with a range of 6-30 weeks, and .the mean duration of treatment with t h e dose range associated with non-toxic levels was 18 months with a range which varied between 6-26 months.
RESULTS
The mean and median levels for CMAX, TMAX and AUC for insulin and glucose levels, together with statistical comparisons are documented in Tables 2 and 3. On the basis of these tests, the insulin Table 2. Mean and median levels for C M A X , T M A X and AUC for insulin profiles, together w i t h statistical comparison of results.
Insulin CMAX (pg/ml)
Mean Median
Group 1
Group 2
Group 3
32.2 30
25.6 19
31.4 27
Test TMAX ( m i n )
Mean Median
H p 54.5 30
90.0 60
Mean Median Test
43.1 30
H = 4.417 p = .246
Test AUC
= 3.794 = .285
223..2 169.5
182.7 169.5
174.5 121.5
H
=
p
=
3.494 .322
Table 3. Mean and median levels f o r C M A X , TMAX and AUC for sugar profiles together with statistical comparison of results. ~
Group 1
Sugar
CMAX (mg %)
Mean Median
131.4 125.0
Group 2
Group 3
140.8 140.0
134.1 130.0
H = 2.000
Test
p
TMAX (min)
Mean Median
38.2 30
102.9 90
37.5 30
H = 13.547
Test
p AUC
Mean Median
= .572
1085.7 1053.8
1204.2 1283.8
=
.0036
1002.6 926.3
H = 5.353
'rest
p
= .148
profiles are the same for all three groups, but there was a significant delay in reaching peak glucose concentrations in group 2 with toxic levels of phenytoin. The insulin and glucose levels, plotted at 30 min intervals, are documented in Figures 1 and 2. Figure 2 demonstrates the delay in reaching peak glucose concentrations. The mean phenytoin dosage and plasma levels are shown in Table 4. There was a significant difference between phenytoin dosage expressed in mg per kg between groups 1 and 2 ( T = 2.148. P = 0.047).
DISCUSSION
In this study, we were unable to demonstrate an increase in blood glucose levels or alterations in insulin profiles in patients with toxic and non-toxic levels of phenytoin. Our findings in Group 1 are similar to those of Cumings et al. (1972), and of Madsen et al. (1973). CadZeden & Richens (1973) who carried out GTT tests on patients who were taking phenytoin in a therapeutic dose were unable to establish carbohydrate intolerance or a depression of insulin secretion. Cudworth & Cunningham ( 1974) demonstrated ,impaired insulin release in 14 healthy volunteer subjects who were taking 300 mg of phenytoin daily for a period of 14 days. High.phenytoin levels (23 pg/ml) were
567
150
100
50
I
I
1
2
I
x-x
Control
Q-A
Phenytoin (toxic l e v e l s ) Phenytoin ( t h e r a p e u t i c levels)
Q-o
hours
3
Figure 1. Mean insulin levels at half hourly intervals.
found in one patient only. Therefore, impaired insulin release may occur in some patients with non-toxic phenytoin levels, suggesting individual variations to the response of insulin release from non-toxic phenytoin levels.
568
30
20
10
I
I
1
I
2
3
x--x
A-A 0-0
hours
Control Phenytoin ( t o x i c l e v e l s ) Phenytoin ( t h e r a p e u t i c levels)
Figure 2. Mean sugar levels at half hourly intervals.
In previous studies, high phenytoin levels and hyperglycaemia with impaired insulin release have been reported following a sudden increase in serum phenytoin levels over a period of hours ( K l e i n 1966, Coldberg & Sanbar 1969) in an attempt to control seizures, or in healthy volun-
569 Table 4 . Mean phenutoin levels & S D together w i t h range of levels and dose in m g / k f o r groups 1 and 2. Group 1
Group 2
5.22
7.17
Plasma level (mg/ml)
8kSD4
46zk14
Plasma range (mg/ml)
2-1 5
29-70
Dose (mg/k)
teer subjects following a high dose of the drug (Malherbe et al. 1972). These findings would suggest an association between a sudden increase in serum phenyto'in levels and insulin release in some patients. Although, the findings in Group 2 have shown that a gradual increase in phenytoin levels when detected at an early stage does not interfere with insulin release or cause carbohydrate intolerance, previous studies have documented hyperglycaemia in two patients on routine treatment with phenytoin on doses which varied between 400 mg and 700 mg daily for periods from 3 months to 2 years (Peters & Samman 1968, Farris & Lufcher 1971). Early detection of high phenytoin levels may therefore protect some patients from this side effect. Hyperglycaemia has already been detected in a diabetic patient in association with high phenytoin levels (Goldberg & Sanbar 1969), and it has been shown that phenytoin can unmask the defects of insulin secretion in patients with glucose intolerance (Levin et al. 1973). As diabetics and potentials diabetic patients appear to be at greater risk, it is essential when phenytoin is used in the reatment of epilepsy in patients with diabetes o r with a family history of diabetes that blood levels should be monitored so that high levels are detected at an early stage. The exclusion of obese patients, o r patients with a family history of diabetes from our study possibly contributed to our findings. W e were unable to confirm the suggestion of Cummings et al. (1972) that the effect of phenytoin on carbohydrate metabolism is related to age as the ages of our patients varied between 12 and 71 years. The delay in reaching a peak concentration of glucose was probably due to a delay in the absorption of carbohydrate as anticonvulsant drugs interfere with the absorption of xylose (Matthews 1965, Reynolds et al. 1965). It is unlikely that delay in reaching a peak lcvel was related to a reduced output of glucose from the liver as it has been shown in dogs that phenytoin increases hepatic output (Sanbar et al. 1967).
570 ACKNOWLEDGEMENTS This work was financed by a grant from Ciba-Geigy & Bayer Laboratories. We wish to thank Drs. Alan Galbraith and Allen f o r their support. The gas chromatography is nodated by t h e Medical Research Council of Ireland.
REFERENCES Belton, N. R., J. E. Etheridge & J. G. Millichap (1965) : Effects of convulsions and anticonvulsants o n blood sugar in rabbits. Epilepsia 6, 243-249. Castleden, C. M. & A. Richens (1973) : Chronic phenytoin therapy and earbohydrate tolerance. Lancet ii, 966. Cohen, M. S., H. H. Bower, S. M. Fidler, R. T. Joansonbangh & Y. Sode (1973): Inhibition of insulin release by diphenylhydantoin and diazoxide i n a patient with benign insulinoma. Lancet i, 40. Cudworth, A. G. & J. L. Cunningham (1974): The effect of diphenylhydantoin o n insulin response. Clin. Sci. Mol. Med. 46, 131-136. Cumings, N. P., A. L. Rosenbloom, N. W. Kohlgr & B. Y. Wilder (1972) : The effect of long term diphenylhydantoin (DPH) therapy on glucose and insulin tolerance testing (OGTT) i n children. Diabetes 22, 355. Farris, B. L. & C. 0. Lutcher (1971) : Diphenylhydantoin-induced hyperglycaemia and impaired insulin release. Diabetes 1, 177-181.. Goldberg, E. M. & S. S. Sanbar (1969) : Hyperglycaemia non-ketretic coma following administration of dilantin (diphenylhydantoin). New Engl. J. Med. 281, 91-92. Hales, C. N. & P. J. Randle (1963) : Immunoassay of insulin with insulin antibody precipitate. Lancet i, 200. Hoffman, N. S. (1937): A rapid photosensitive method for t h e determination of glucose i n blood and urine. Lancet 122, 51-55. Klein, J. P. (1966) : Diphenylhydantoin intoxication associated with hyperglycaemia. J. Pediat. 69, 463-465. Levin, S. R., V. Booker, D. F. Smith & G. M. Grodsky (1970) : Inhibition of insulin secretion by diphenylhydantoin i n isolated perfused pancreas. J. Clin. Endocrin. Metabol. 30, 400-401. Levin, S. R., J. W. Reed, N. S. King, J. W. Davis, M. R. Blum & P. H. Forsham (1973) : Diphenylhydantoin, its use i n detecting early insulin secreting defects i n patients with mild glucose intolerance. Diabetes 3, 194-201. Madsen, S. N., Y. M. Hansen & V. Decker? (1974): Intravenous glucose intolerance during treatment with phenytoin. Acta neurol. scand. 50, 266-267. Malherbe, L., I. C. C. Burill, S. R. Levin, J. H. Karan & P. H. Forsham (1972): Effects of diphenylhydanto,in on insulin secretion i n man. New Engl. J. Med. 286, 339-342.
Matthews, D. M. (1965): Effects of phenylbarbitone and folic acid on D-xylose absorption. The Proceedings of t h e Physiological Society. 46-47. Pelkonen, R. & M. R. Taskinen (1973): Effects of diphenylhydantoin o n plasma insulin in insulinoma. Lancet i, 604. Peters, B. H. & N. A. Samaan (1969): Hyperglycaemia w i t h relative hypoinsulinaemia i n diphenylhydantoin toxicity. New Engl. J. Med. 281, 91-92. Reynolds, E. H., B. M. Hallpike, B. M. Philips & D. M. Matthews (1965): Reversible absorptive defects i n anticonvulsant megaloblastic anaemia. J. Clin. Path. 28, 593-598.
571 Richens, A. (1976) : Drug treatment i n epilepsy. Monographs of controlled medicine. Published by Henry Kimpton, London. Chapt. 1, Pp. 22. Roger, J. C., G. Rogers & A. So0 (1973) : Simultaneous determination of carbamazepine (tegretol) and other anticonvulsants i n plasma by gas liquid chromatography. Clin. Chem. 19, 590. Sanbar, S. S., F. J. Conway, A. J. Zweiffer & G. Smet (1967) : Diabetogenic effect of dilantin (diphenylhydantoin). Diabetes 26, 633. Received June 15, accepted August 29, 1977
N. Callaghan, M.D. St. Finbarr’s Hospital Cork, Ireland
Departments of Neurology and Biochemistry, St. Finbarr's Hospital, Cork and the Mathematical Analysis Section, Ciba Geigy, Manchester.
T H E EFFECTS OF TOXIC AND NON-TOXIC SERUM PHENYTOIN LEVELS O N CARBOHYDRATE TOLERANCE AND INSULIN LEVELS N. CALLAGHAN, M. FEELY, M. ~'CALLAGHAN, B. DUGGAN,J. MCGARRY, B. CRAMER,J. WHEELAN and J. SELDRUP ABSTRACT The cffrct of toxic and non-toxic phenytoin levels o n carbohydrate tolerance and insulin levels was studied in 18 patients with epilepsy and 17 control subjects. Toxic levels were defined as a serum level greater t h a n 2 0 ~ g h n l .Toxic levels occurred i n 11 patients and nontoxic levels i n seven patients. Blood glucose and insulin levels were measured a t 30-min intervals f o r a period of 3 h following the ingestion of 50 g glucose. Blood glucose levels were measured by the ferricyanide method, and serum insulin levels by immunoassay of insulin with insulin antibody precipitate. Serum phenytoin levels were measured by gas liquid chromatography. The insulin profiles were the same f o r all three groups, b u t there was a significant delay in reaching peak glucose concentrations in patients with toxic levels of phenytoin. It was therefore confirmed that non-toxic levels of phenytoin do not affect carbohydrate tolerance or insulin levels when phenytoin is used i n the routine treatment of epilepsy, and i t has also been shown t h a t toxic levels of phenytoin do not affect carbohydrate tolerance when the high levels are detected a t a n early stage.
Large doses of phenytoin have been shown to cause hyperglycaemia (Belton et al. 1966, Peters & Samman 1969) when infused at high concentrations in an isolated rat pancreas. It has been found to inhibit the early peak and late rise of insulin secretion (Leuin et al. 1970). An inhibition of insulin release from the pancreas has also been documented when phenytoin was given to patients with insulinoma (Pelkonen & Taskinen 1973, Cohen et al. 1973). Phenytoin is an effective anticonvulsant drug which is frequently used in the treatment of epilepsy. Two previous studies have examined Carbohydrate tolerance in epileptic patients with non-toxic levels of 37.
564 phenytoin (Cunzinys et al. 1972, Madsen et al. 1974). Due to the saturahle nature of the metabolism of this drug, a slight increase in dosage may result in a disproportionate increase in serum levels (Richens 1976). In the absence of facilities for the measurement of serum Blevels, the increase may not become obvious until the patient develops the clinical complications of phenytoin intoxication. Therefore, the effect of toxic levels on carbohydrate tolerance in patients on routine treatment for epilepsy needs to be clarified. This paper reports the results of a study which investigated carbohydrate tolerance and insulin levels in patients with toxic and non-toxic phcnytoin levels.
METHODS
The patients were selected from subjects who were attending a seizure clinic where blood levels of anticonvulsant drugs were monitored a t frequent intervals. The patients with epilepsy were divided into two groups. Group 1 included patients with serum phenytoin levels which were less than 20 pg/ml, as documented, and Group 2. patients with serum levels greater than 20 &g/ml. Sulthiame was used i n combination with phenytoin in three patients i n Group 2, and phenytoin was used as a single drug i n t h e other four patients. I.evels greater than 20 pg/ml were regarded as within the toxic range. Group 3 includes healthy subjects. Details of patients with epilepsy and the control subjects are documented i n Table 1.
Table I . Niimber o f patients and control subjects together with details o f age, sex and weight.
Mean wgt.
Number
Mean
Age range
Sex
Group 1
11
31.1
14-71
5 males 6 females
66.6
Group 2
I
19.9
12-36
4 males 3 females
45.1
Group 3 (controls)
17
27.9
15.71
8 males 9 females
61.1
kg
Subjects were not included i n the study i f they were known to be diabetic, or if there was a family history of diabetes. They were also excluded if they were found to 50 per cent greater than their ideal body weight. Patients and control subjects were allowed a n unrestricted diet and physical activity for a t least 3 days before the GTT was done. This was carried out on t h e morning following a 12-h fast. A total of 50 g of glucose i n 500 cc water was taken orally. Fasting 30, 60, 120, 150, 180 min venous blood samples were taken f o r the
565 estimation of glucose levels. Samples were taken over a n extended period of 3 h i n order to detect a possible effect o n the late rise i n insulin secretion. Blood glucose was measured by the ferricyanide method (Hoffmann 1937), and serum insulin levels by t h e immunoassay of insulin with insulin antibody precipitate (Hales & Randle 1963). The GI’T was carried out as soon a s possible after a toxic level of phenytoin was detected in Group 2. The dosage of phenytoin was not adjusted i n the intervening period. Patients with non-toxic levels were randomly selected. Further specimens of serum for phenytoin estimation were taken a t the same time as the glucose tolerance test in both groups. Serum phenytoin levels were measured by gas liquid chromatography according to the method described by Roger et al. (1973). Statistical methods For the purpose of studying insulin and sugar profiles three parameters were used a s follows. The maximum concentration (CMAX), Time to maximum concentration (TMAX), and the area under the curves (AUC) when glucose and insulin levels were plotted at intervals of 30 min. Due t o the abnormality of the data, the non-parametric Knskal-Wallis technique was applied. Student’s t-test was used to compare significance of phenytoin dosage. The mean dnration of treatment with the dose of phenytoin which resulted i n a toxic level was 13 weeks with a range of 6-30 weeks, and .the mean duration of treatment with t h e dose range associated with non-toxic levels was 18 months with a range which varied between 6-26 months.
RESULTS
The mean and median levels for CMAX, TMAX and AUC for insulin and glucose levels, together with statistical comparisons are documented in Tables 2 and 3. On the basis of these tests, the insulin Table 2. Mean and median levels for C M A X , T M A X and AUC for insulin profiles, together w i t h statistical comparison of results.
Insulin CMAX (pg/ml)
Mean Median
Group 1
Group 2
Group 3
32.2 30
25.6 19
31.4 27
Test TMAX ( m i n )
Mean Median
H p 54.5 30
90.0 60
Mean Median Test
43.1 30
H = 4.417 p = .246
Test AUC
= 3.794 = .285
223..2 169.5
182.7 169.5
174.5 121.5
H
=
p
=
3.494 .322
Table 3. Mean and median levels f o r C M A X , TMAX and AUC for sugar profiles together with statistical comparison of results. ~
Group 1
Sugar
CMAX (mg %)
Mean Median
131.4 125.0
Group 2
Group 3
140.8 140.0
134.1 130.0
H = 2.000
Test
p
TMAX (min)
Mean Median
38.2 30
102.9 90
37.5 30
H = 13.547
Test
p AUC
Mean Median
= .572
1085.7 1053.8
1204.2 1283.8
=
.0036
1002.6 926.3
H = 5.353
'rest
p
= .148
profiles are the same for all three groups, but there was a significant delay in reaching peak glucose concentrations in group 2 with toxic levels of phenytoin. The insulin and glucose levels, plotted at 30 min intervals, are documented in Figures 1 and 2. Figure 2 demonstrates the delay in reaching peak glucose concentrations. The mean phenytoin dosage and plasma levels are shown in Table 4. There was a significant difference between phenytoin dosage expressed in mg per kg between groups 1 and 2 ( T = 2.148. P = 0.047).
DISCUSSION
In this study, we were unable to demonstrate an increase in blood glucose levels or alterations in insulin profiles in patients with toxic and non-toxic levels of phenytoin. Our findings in Group 1 are similar to those of Cumings et al. (1972), and of Madsen et al. (1973). CadZeden & Richens (1973) who carried out GTT tests on patients who were taking phenytoin in a therapeutic dose were unable to establish carbohydrate intolerance or a depression of insulin secretion. Cudworth & Cunningham ( 1974) demonstrated ,impaired insulin release in 14 healthy volunteer subjects who were taking 300 mg of phenytoin daily for a period of 14 days. High.phenytoin levels (23 pg/ml) were
567
150
100
50
I
I
1
2
I
x-x
Control
Q-A
Phenytoin (toxic l e v e l s ) Phenytoin ( t h e r a p e u t i c levels)
Q-o
hours
3
Figure 1. Mean insulin levels at half hourly intervals.
found in one patient only. Therefore, impaired insulin release may occur in some patients with non-toxic phenytoin levels, suggesting individual variations to the response of insulin release from non-toxic phenytoin levels.
568
30
20
10
I
I
1
I
2
3
x--x
A-A 0-0
hours
Control Phenytoin ( t o x i c l e v e l s ) Phenytoin ( t h e r a p e u t i c levels)
Figure 2. Mean sugar levels at half hourly intervals.
In previous studies, high phenytoin levels and hyperglycaemia with impaired insulin release have been reported following a sudden increase in serum phenytoin levels over a period of hours ( K l e i n 1966, Coldberg & Sanbar 1969) in an attempt to control seizures, or in healthy volun-
569 Table 4 . Mean phenutoin levels & S D together w i t h range of levels and dose in m g / k f o r groups 1 and 2. Group 1
Group 2
5.22
7.17
Plasma level (mg/ml)
8kSD4
46zk14
Plasma range (mg/ml)
2-1 5
29-70
Dose (mg/k)
teer subjects following a high dose of the drug (Malherbe et al. 1972). These findings would suggest an association between a sudden increase in serum phenyto'in levels and insulin release in some patients. Although, the findings in Group 2 have shown that a gradual increase in phenytoin levels when detected at an early stage does not interfere with insulin release or cause carbohydrate intolerance, previous studies have documented hyperglycaemia in two patients on routine treatment with phenytoin on doses which varied between 400 mg and 700 mg daily for periods from 3 months to 2 years (Peters & Samman 1968, Farris & Lufcher 1971). Early detection of high phenytoin levels may therefore protect some patients from this side effect. Hyperglycaemia has already been detected in a diabetic patient in association with high phenytoin levels (Goldberg & Sanbar 1969), and it has been shown that phenytoin can unmask the defects of insulin secretion in patients with glucose intolerance (Levin et al. 1973). As diabetics and potentials diabetic patients appear to be at greater risk, it is essential when phenytoin is used in the reatment of epilepsy in patients with diabetes o r with a family history of diabetes that blood levels should be monitored so that high levels are detected at an early stage. The exclusion of obese patients, o r patients with a family history of diabetes from our study possibly contributed to our findings. W e were unable to confirm the suggestion of Cummings et al. (1972) that the effect of phenytoin on carbohydrate metabolism is related to age as the ages of our patients varied between 12 and 71 years. The delay in reaching a peak concentration of glucose was probably due to a delay in the absorption of carbohydrate as anticonvulsant drugs interfere with the absorption of xylose (Matthews 1965, Reynolds et al. 1965). It is unlikely that delay in reaching a peak lcvel was related to a reduced output of glucose from the liver as it has been shown in dogs that phenytoin increases hepatic output (Sanbar et al. 1967).
570 ACKNOWLEDGEMENTS This work was financed by a grant from Ciba-Geigy & Bayer Laboratories. We wish to thank Drs. Alan Galbraith and Allen f o r their support. The gas chromatography is nodated by t h e Medical Research Council of Ireland.
REFERENCES Belton, N. R., J. E. Etheridge & J. G. Millichap (1965) : Effects of convulsions and anticonvulsants o n blood sugar in rabbits. Epilepsia 6, 243-249. Castleden, C. M. & A. Richens (1973) : Chronic phenytoin therapy and earbohydrate tolerance. Lancet ii, 966. Cohen, M. S., H. H. Bower, S. M. Fidler, R. T. Joansonbangh & Y. Sode (1973): Inhibition of insulin release by diphenylhydantoin and diazoxide i n a patient with benign insulinoma. Lancet i, 40. Cudworth, A. G. & J. L. Cunningham (1974): The effect of diphenylhydantoin o n insulin response. Clin. Sci. Mol. Med. 46, 131-136. Cumings, N. P., A. L. Rosenbloom, N. W. Kohlgr & B. Y. Wilder (1972) : The effect of long term diphenylhydantoin (DPH) therapy on glucose and insulin tolerance testing (OGTT) i n children. Diabetes 22, 355. Farris, B. L. & C. 0. Lutcher (1971) : Diphenylhydantoin-induced hyperglycaemia and impaired insulin release. Diabetes 1, 177-181.. Goldberg, E. M. & S. S. Sanbar (1969) : Hyperglycaemia non-ketretic coma following administration of dilantin (diphenylhydantoin). New Engl. J. Med. 281, 91-92. Hales, C. N. & P. J. Randle (1963) : Immunoassay of insulin with insulin antibody precipitate. Lancet i, 200. Hoffman, N. S. (1937): A rapid photosensitive method for t h e determination of glucose i n blood and urine. Lancet 122, 51-55. Klein, J. P. (1966) : Diphenylhydantoin intoxication associated with hyperglycaemia. J. Pediat. 69, 463-465. Levin, S. R., V. Booker, D. F. Smith & G. M. Grodsky (1970) : Inhibition of insulin secretion by diphenylhydantoin i n isolated perfused pancreas. J. Clin. Endocrin. Metabol. 30, 400-401. Levin, S. R., J. W. Reed, N. S. King, J. W. Davis, M. R. Blum & P. H. Forsham (1973) : Diphenylhydantoin, its use i n detecting early insulin secreting defects i n patients with mild glucose intolerance. Diabetes 3, 194-201. Madsen, S. N., Y. M. Hansen & V. Decker? (1974): Intravenous glucose intolerance during treatment with phenytoin. Acta neurol. scand. 50, 266-267. Malherbe, L., I. C. C. Burill, S. R. Levin, J. H. Karan & P. H. Forsham (1972): Effects of diphenylhydanto,in on insulin secretion i n man. New Engl. J. Med. 286, 339-342.
Matthews, D. M. (1965): Effects of phenylbarbitone and folic acid on D-xylose absorption. The Proceedings of t h e Physiological Society. 46-47. Pelkonen, R. & M. R. Taskinen (1973): Effects of diphenylhydantoin o n plasma insulin in insulinoma. Lancet i, 604. Peters, B. H. & N. A. Samaan (1969): Hyperglycaemia w i t h relative hypoinsulinaemia i n diphenylhydantoin toxicity. New Engl. J. Med. 281, 91-92. Reynolds, E. H., B. M. Hallpike, B. M. Philips & D. M. Matthews (1965): Reversible absorptive defects i n anticonvulsant megaloblastic anaemia. J. Clin. Path. 28, 593-598.
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N. Callaghan, M.D. St. Finbarr’s Hospital Cork, Ireland
