Noach et al. (1958) reported that diphenyl-hydantoin in the saliva of cats was in the unbound for... more Noach et al. (1958) reported that diphenyl-hydantoin in the saliva of cats was in the unbound form. Svensmark et al. (1960), Bab-cock and Nelson (1964), and Conard et al. (1973) extended the observations to humans receiving diphenylhydantoin. Bochner et al. (1974) found that ...
Little is known about the influence of phenytoin and ethosuximide on primidone. Therefore we stud... more Little is known about the influence of phenytoin and ethosuximide on primidone. Therefore we studied three groups of patients: 28 receiving primidone alone, 16 on comedication of primidone with phenytoin and 9 on primidone plus ethosuximide. Antiepileptic drug determinations were done with Kupferberg's gas chromatographic method. The results show that the addition of phenytoin--but not ethosuximide--does increase the plasma concentration of phenobarbital derived from primidone but not of primidone itself. The phenobarbital/primidone plasma concentration ratio is with 4.2 +/- 0.7 (+/- S.E.) significantly (P less than 0.001) higher in patients receiving primidone and phenytoin as compared to those on primidone alone (1.6 +/- 0.2) or together with ethosuximide (1.4 +/- 0.7). The effect of phenytoin occurs and persists for several days after the steady state plasma concentration of phenytoin has been reached. This effect is probably not due to induction of enzymes hydroxylating primidone but rather to inhibition of the metabolism and/or excretion of phenobarbital. A case of phenobarbital intoxication due to addition of phenytoin to primidone medication is described in detail.
Criteria that were developed for monitoring free (unbound) rather than total (free plus bound) co... more Criteria that were developed for monitoring free (unbound) rather than total (free plus bound) concentrations of antiepileptic drugs include extensive and variable binding to plasma proteins. Phenytoin and valproic acid belong to this category. It is shown that free drug concentration is independent of total drug concentration, whereas total drug concentration depends on free concentration and free fraction. Because antiepileptic drugs are predominantly bound to albumin, free fraction will increase in the presence of hypoalbuminemia (hepatic and renal disease, burns, and pregnancy). Free fraction also increases because of saturable binding (valproic acid) and competitive binding (valproic acid displacing phenytoin). There is suggestive evidence that side effects may be more closely related to the free, rather than to the total, plasma concentration of phenytoin. The clinical evidence that side effects or therapeutic effects are better correlated to the free, rather than the total, concentration of valproic acid or carbamazepine is not yet convincing. Knowledge of the free concentration improves our understanding of therapeutic and toxic effects of low total plasma concentrations. Further clinical trials are necessary for definitive assessment of the clinical relevance for free drug monitoring of valproic acid, carbamazepine, and phenytoin in the management of epileptic patients.
Clinical course and long-term seizure prognosis were studied in 155 patients with complex-partial... more Clinical course and long-term seizure prognosis were studied in 155 patients with complex-partial seizures during a follow-up of 10.1 +/- 1 (SD) years. In 79% of the patients generalized tonic-clonic seizures were recorded, mostly within the first 3 years of epilepsy but occurring as late as 20 years after the onset of epilepsy. Seizure control was defined as complete absence of all seizures, including auras, for a minimum of 2 years. Seizure control occurred in 20 of 32 patients (63%) with complex-partial seizures only and in 76 of 123 patients (62%) with complex-partial seizures and generalized tonic-clonic seizures. The onset of the epilepsy with generalized tonic-clonic seizures or complex-partial seizures did not influence the therapeutic outcome despite differences in their natural history. A family history of epilepsy and other generalized seizures (e.g., absence) were more frequent in patients with generalized tonic-clonic seizures at the onset of epilepsy. Seizure control was significantly lower (44%) in patients with a history of a maximum frequency of one or more generalized tonic-clonic seizures per month when compared to patients (79%) with a total of less than six generalized tonic-clonic seizures (p less than 0.05). The frequency of generalized tonic-clonic seizures is of predictive value for the seizure prognosis of patients with complex-partial seizures.
Fourteen epileptic women treated with primidone, either alone or in combination with other antiep... more Fourteen epileptic women treated with primidone, either alone or in combination with other antiepileptic drugs, were studied prospectively during their pregnancy. Plasma levels of primidone and its metabolites were monitored and correlated to findings in the offspring. Maternal serum concentrations of primidone and metabolites were generally low during pregnancy. The levels of its main metabolites--phenobarbital and PEMA--were found to drop within the first month of pregnancy in two cases. The plasma concentrations remained low until birth and rose sharply thereafter. The phenobarbital/primidone ratio (mean 0.84) and PEMA/primidone ratio (mean 0.56) in pregnant patients were found to be lower than in non-pregnant patients, except when primidone was given in combination with phenytoin in which case the expected phenobarbital/primidone (mean 2.5) and PEMA/primidone (mean 1.5) ratios were found. A ventricular septal defect was found in one of the offspring of the fourteen mothers and five children had microcephaly. There was a high incidence of poor somatic development with dystrophy (n=3) and short stature (n=2). Head circumferences (n=8), lengths (n=4) and/or weights (n=8) were below the 10th percentile in a number of children. Four children showed marked facial dysmorphy. Our preliminary data suggest that primidone intake during pregnancy may be important in the pathogenesis of minor anomalies and in the induction of poor somatic development.
Advanced psychophysical tests, performed in 42 patients who have seizures, showed that the widely... more Advanced psychophysical tests, performed in 42 patients who have seizures, showed that the widely used antiepileptic drugs, diphenylhydantoin and carbamazepine, can specifically affect retinal function, while valproic acid and the epileptic seizures do not. The Farnsworth-Munsell 100-Hue and Panel D-15 désaturé tests revealed an accumulation of errors along the tritan/tetartan axis and a high total error score. As shown by measurement of the so-called transient tritanopia and by determination of the spectral sensitivity, this blue vision defect is not only due to loss of postreceptoral interaction between long- and short-wavelength-sensitive cones, but is also based on a disturbance in the receptor mechanism itself. The dark adaptation curve was not affected. As determined by cone flicker thresholds during dark adaptation, the inhibitory action of rods on cones is reduced. The results obtained for mesopic vision and especially glare sensitivity measured by nyktometry were markedly affected in these patients compared to the normal population. The psychophysical methods provide a very sensitive test for early detection of drug-induced retinal dysfunction and allow clear differentiation between the loss of a receptor mechanism and a defect in the neuronal interaction between photoreceptors in the human visual system induced by antiepileptics.
Advanced psychophysical tests, performed in 42 epileptic patients, show that the antiepileptic dr... more Advanced psychophysical tests, performed in 42 epileptic patients, show that the antiepileptic drugs phenytoin and carbamazepine can specifically affect the retinal function, while Valproic Acid and the epileptic seizures do not. The Farnsworth-Munsell 100-Hue and Panel D-15 désaturé tests revealed an accumulation of errors along the tritan/tetartan axis (blue colour vision deficiencies) and a high total error score. The same defect was shown by measurement of the spectral sensitivity functions. The results obtained for mesopic vision and especially glare sensitivity measured by nyktometry were markedly affected in these patients compared to a normal population. The enhanced sensitivity to glare is mainly the only one symptom complained by the patient. We propose a screening method for early detection of phenytoin- and carbamazepine-induced neurotoxicity. The literature of ocular side effects of anticonvulsant drugs is carefully reviewed.
19 pooled plasma specimens were sent as unknowns to 13 participating research laboratories. The i... more 19 pooled plasma specimens were sent as unknowns to 13 participating research laboratories. The interlaboratory variability between the results was very high. Only 4 out of 13 laboratories had 6--12% of their results within the 95% confidence limit for each sample. The precision of repeated determinations was fairly good. 6 out of 10 participating laboratories had a coefficient of variation of less then 5%. The reproducibility and the agreement between the different procedures for quantitative analysis of dipropylacetate is similar to that reported for other major antiepileptic drugs.
7 Zusammenfassung Lacosa-mid (LCM, R-2-Acetamido-N-ben-zyl-3-methoxypropionamid) ge-hört zu der G... more 7 Zusammenfassung Lacosa-mid (LCM, R-2-Acetamido-N-ben-zyl-3-methoxypropionamid) ge-hört zu der Gruppe der funktionali-sierten Aminosäuren. In tierexperi-mentellen Studien erwies sich LCM als ein wirksames Medikament ge-gen fokale Anfälle und beeinflusst ...
7 Zusammenfassung Lacosa-mid (LCM, R-2-Acetamido-N-ben-zyl-3-methoxypropionamid) ge-hört zu der G... more 7 Zusammenfassung Lacosa-mid (LCM, R-2-Acetamido-N-ben-zyl-3-methoxypropionamid) ge-hört zu der Gruppe der funktionali-sierten Aminosäuren. In tierexperi-mentellen Studien erwies sich LCM als ein wirksames Medikament ge-gen fokale Anfälle und beeinflusst ...
Noach et al. (1958) reported that diphenyl-hydantoin in the saliva of cats was in the unbound for... more Noach et al. (1958) reported that diphenyl-hydantoin in the saliva of cats was in the unbound form. Svensmark et al. (1960), Bab-cock and Nelson (1964), and Conard et al. (1973) extended the observations to humans receiving diphenylhydantoin. Bochner et al. (1974) found that ...
Little is known about the influence of phenytoin and ethosuximide on primidone. Therefore we stud... more Little is known about the influence of phenytoin and ethosuximide on primidone. Therefore we studied three groups of patients: 28 receiving primidone alone, 16 on comedication of primidone with phenytoin and 9 on primidone plus ethosuximide. Antiepileptic drug determinations were done with Kupferberg's gas chromatographic method. The results show that the addition of phenytoin--but not ethosuximide--does increase the plasma concentration of phenobarbital derived from primidone but not of primidone itself. The phenobarbital/primidone plasma concentration ratio is with 4.2 +/- 0.7 (+/- S.E.) significantly (P less than 0.001) higher in patients receiving primidone and phenytoin as compared to those on primidone alone (1.6 +/- 0.2) or together with ethosuximide (1.4 +/- 0.7). The effect of phenytoin occurs and persists for several days after the steady state plasma concentration of phenytoin has been reached. This effect is probably not due to induction of enzymes hydroxylating primidone but rather to inhibition of the metabolism and/or excretion of phenobarbital. A case of phenobarbital intoxication due to addition of phenytoin to primidone medication is described in detail.
Criteria that were developed for monitoring free (unbound) rather than total (free plus bound) co... more Criteria that were developed for monitoring free (unbound) rather than total (free plus bound) concentrations of antiepileptic drugs include extensive and variable binding to plasma proteins. Phenytoin and valproic acid belong to this category. It is shown that free drug concentration is independent of total drug concentration, whereas total drug concentration depends on free concentration and free fraction. Because antiepileptic drugs are predominantly bound to albumin, free fraction will increase in the presence of hypoalbuminemia (hepatic and renal disease, burns, and pregnancy). Free fraction also increases because of saturable binding (valproic acid) and competitive binding (valproic acid displacing phenytoin). There is suggestive evidence that side effects may be more closely related to the free, rather than to the total, plasma concentration of phenytoin. The clinical evidence that side effects or therapeutic effects are better correlated to the free, rather than the total, concentration of valproic acid or carbamazepine is not yet convincing. Knowledge of the free concentration improves our understanding of therapeutic and toxic effects of low total plasma concentrations. Further clinical trials are necessary for definitive assessment of the clinical relevance for free drug monitoring of valproic acid, carbamazepine, and phenytoin in the management of epileptic patients.
Clinical course and long-term seizure prognosis were studied in 155 patients with complex-partial... more Clinical course and long-term seizure prognosis were studied in 155 patients with complex-partial seizures during a follow-up of 10.1 +/- 1 (SD) years. In 79% of the patients generalized tonic-clonic seizures were recorded, mostly within the first 3 years of epilepsy but occurring as late as 20 years after the onset of epilepsy. Seizure control was defined as complete absence of all seizures, including auras, for a minimum of 2 years. Seizure control occurred in 20 of 32 patients (63%) with complex-partial seizures only and in 76 of 123 patients (62%) with complex-partial seizures and generalized tonic-clonic seizures. The onset of the epilepsy with generalized tonic-clonic seizures or complex-partial seizures did not influence the therapeutic outcome despite differences in their natural history. A family history of epilepsy and other generalized seizures (e.g., absence) were more frequent in patients with generalized tonic-clonic seizures at the onset of epilepsy. Seizure control was significantly lower (44%) in patients with a history of a maximum frequency of one or more generalized tonic-clonic seizures per month when compared to patients (79%) with a total of less than six generalized tonic-clonic seizures (p less than 0.05). The frequency of generalized tonic-clonic seizures is of predictive value for the seizure prognosis of patients with complex-partial seizures.
Fourteen epileptic women treated with primidone, either alone or in combination with other antiep... more Fourteen epileptic women treated with primidone, either alone or in combination with other antiepileptic drugs, were studied prospectively during their pregnancy. Plasma levels of primidone and its metabolites were monitored and correlated to findings in the offspring. Maternal serum concentrations of primidone and metabolites were generally low during pregnancy. The levels of its main metabolites--phenobarbital and PEMA--were found to drop within the first month of pregnancy in two cases. The plasma concentrations remained low until birth and rose sharply thereafter. The phenobarbital/primidone ratio (mean 0.84) and PEMA/primidone ratio (mean 0.56) in pregnant patients were found to be lower than in non-pregnant patients, except when primidone was given in combination with phenytoin in which case the expected phenobarbital/primidone (mean 2.5) and PEMA/primidone (mean 1.5) ratios were found. A ventricular septal defect was found in one of the offspring of the fourteen mothers and five children had microcephaly. There was a high incidence of poor somatic development with dystrophy (n=3) and short stature (n=2). Head circumferences (n=8), lengths (n=4) and/or weights (n=8) were below the 10th percentile in a number of children. Four children showed marked facial dysmorphy. Our preliminary data suggest that primidone intake during pregnancy may be important in the pathogenesis of minor anomalies and in the induction of poor somatic development.
Advanced psychophysical tests, performed in 42 patients who have seizures, showed that the widely... more Advanced psychophysical tests, performed in 42 patients who have seizures, showed that the widely used antiepileptic drugs, diphenylhydantoin and carbamazepine, can specifically affect retinal function, while valproic acid and the epileptic seizures do not. The Farnsworth-Munsell 100-Hue and Panel D-15 désaturé tests revealed an accumulation of errors along the tritan/tetartan axis and a high total error score. As shown by measurement of the so-called transient tritanopia and by determination of the spectral sensitivity, this blue vision defect is not only due to loss of postreceptoral interaction between long- and short-wavelength-sensitive cones, but is also based on a disturbance in the receptor mechanism itself. The dark adaptation curve was not affected. As determined by cone flicker thresholds during dark adaptation, the inhibitory action of rods on cones is reduced. The results obtained for mesopic vision and especially glare sensitivity measured by nyktometry were markedly affected in these patients compared to the normal population. The psychophysical methods provide a very sensitive test for early detection of drug-induced retinal dysfunction and allow clear differentiation between the loss of a receptor mechanism and a defect in the neuronal interaction between photoreceptors in the human visual system induced by antiepileptics.
Advanced psychophysical tests, performed in 42 epileptic patients, show that the antiepileptic dr... more Advanced psychophysical tests, performed in 42 epileptic patients, show that the antiepileptic drugs phenytoin and carbamazepine can specifically affect the retinal function, while Valproic Acid and the epileptic seizures do not. The Farnsworth-Munsell 100-Hue and Panel D-15 désaturé tests revealed an accumulation of errors along the tritan/tetartan axis (blue colour vision deficiencies) and a high total error score. The same defect was shown by measurement of the spectral sensitivity functions. The results obtained for mesopic vision and especially glare sensitivity measured by nyktometry were markedly affected in these patients compared to a normal population. The enhanced sensitivity to glare is mainly the only one symptom complained by the patient. We propose a screening method for early detection of phenytoin- and carbamazepine-induced neurotoxicity. The literature of ocular side effects of anticonvulsant drugs is carefully reviewed.
19 pooled plasma specimens were sent as unknowns to 13 participating research laboratories. The i... more 19 pooled plasma specimens were sent as unknowns to 13 participating research laboratories. The interlaboratory variability between the results was very high. Only 4 out of 13 laboratories had 6--12% of their results within the 95% confidence limit for each sample. The precision of repeated determinations was fairly good. 6 out of 10 participating laboratories had a coefficient of variation of less then 5%. The reproducibility and the agreement between the different procedures for quantitative analysis of dipropylacetate is similar to that reported for other major antiepileptic drugs.
7 Zusammenfassung Lacosa-mid (LCM, R-2-Acetamido-N-ben-zyl-3-methoxypropionamid) ge-hört zu der G... more 7 Zusammenfassung Lacosa-mid (LCM, R-2-Acetamido-N-ben-zyl-3-methoxypropionamid) ge-hört zu der Gruppe der funktionali-sierten Aminosäuren. In tierexperi-mentellen Studien erwies sich LCM als ein wirksames Medikament ge-gen fokale Anfälle und beeinflusst ...
7 Zusammenfassung Lacosa-mid (LCM, R-2-Acetamido-N-ben-zyl-3-methoxypropionamid) ge-hört zu der G... more 7 Zusammenfassung Lacosa-mid (LCM, R-2-Acetamido-N-ben-zyl-3-methoxypropionamid) ge-hört zu der Gruppe der funktionali-sierten Aminosäuren. In tierexperi-mentellen Studien erwies sich LCM als ein wirksames Medikament ge-gen fokale Anfälle und beeinflusst ...
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