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EFFECTS OF PREGNANCY ON SEIZURE THRESHOLD AND THE DISPOSITION OF

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EFFECTS OF PREGNANCY ON SEIZURE THRESHOLD AND THE DISPOSITION OF Powered By Docstoc
					Definition of epilepsy
The term epilepsy comes from the Greek word for seizure and
therefore the drugs used to control epilepsy or seizure are called
antiepileptics or anticonvulsant drugs. Epilepsy is a chronic
medical condition produced by sudden changes in the electrical
function of the brain. All human activity is made possible by the
constant discharge of electrical energy between brain cells, but in
persons with epilepsy the discharge is sometimes too great and the
visible result is an epileptic seizure. Epilepsy is not a disease, it is a
symptom of a disorder of the brain, it can affect any one, at any age
at any time. Between seizures, most people with epilepsy are
perfectly normal and healthy.


Causes of epilepsy
The etiology of idiopathic epilepsy is not well known. It has no
single cause but can be caused by any number of conditions that
injure or affect the function of the brain such as:


   Genetic Predisposition. About 30% of epileptic patients have
    a history of seizures in first degree relatives. Usually the mode
    of inheritance is uncertain; low seizure threshold appears to run
    in some families. Generalized typical absence seizure (petit
    mal) is sometimes inherited as autosomal dominant trait with
    variable penetrance.

                                    1
   Developmental Anomalies.           Primary generalized epilepsies
    are due to developmental abnormalities of neuronal control. It
    is uncertain whether they are anatomical, because of abnormal
    synaptic connection or due to anomalies in neurotransmitter
    distribution, release and control. Ectopic dysfunctional areas of
    cerebral cortex and hypothalamus are other examples of
    abnormalities present at birth which can cause seizures at some
    time, even in adult life.
   Trauma and Surgery. Parental trauma (causing cerebral
    contusion and hemorrhage) and fetal anoxia are common
    causes of seizures in childhood. Damage by hypnotics to the
    hippocampi (mesial temporal sclerosis) is another cause. Brain
    injury must be sufficient to cause coma (almost always). The
    presence of early epilepsy, depressed skull fracture, penetrating
    brain   injury,   cerebral   contusion,   dural   or   intracranial
    haematoma increases the incidence of late post-traumatic
    epilepsy. Surgery is followed by seizures in about 10% of
    patients.
   Metabolic Abnormalities. Seizures may be seen when there is
    some metabolic abnormalities, such as hypercalcaemia,
    hypoglycaemia, hyponatraemia and other metabolic disorders.
    Some infants lack certain enzymes essential for digesting food.
    This results in a condition called phenylketonuria (PKU), and if



                                   2
    it is not treated early, they develop severe mental retardation
    and may have seizures.
   Hyperthermia in children.              Convulsions sometimes occur
    when children under five years of age have high fevers (febrile
    convulsins).    In the majority there is no tendency for the
    seizures to recur in adult life.
   Brain tumor. Seventy-five percent of patients will have
    epilepsy before the age of twenty.           Brain tumor, including
    tuberculoma should be suspected when any patient over the age
    of twenty develops seizure for the first time. This is the so
    called late onset epilepsy.
   Intracranial Mass Lesions.              Mass lesions affecting the
    cerebral cortex can cause epilepsy - either partial or secondary-
    generalized seizures. If the onset of seizures is in adult life, the
    chance of an unsuspected mass lesion such as a tumor being
    present is around 3%. Hydrocephlous, of any cause, lowers the
    threshold for seizures.
   Vascular. Seizures can occasionally follow cerebral infarction,
    especially in the elderly.
   Encephalitis and other Inflammatory conditions of the
    brain.    Seizures are frequently the presenting feature of
    encephalitis, chronic meningitis (e.g. tuberculosis), cerebral
    abscess, cortical venous thrombosis and neurosyphilis.



                                       3
   Degenerative brain disorders.          Seizures can occur in
    Alzheimer’s disease and in many rarer degenerative diseases.
    Epilepsy is three times more common in patients with multiple
    sclerosis than in the general population.
   Drugs, Alcohol and drug withdrawal.             Phenothazines,
    monoamine oxidase inhibitors (MOAIs), tricyclic anti-
    depresants, amphetamines and lignocaine can sometimes
    provoke fits either in overdose or in therapeutic doses in
    individuals with a low seizure threshold. Abrupt withdrawal of
    drugs that depress the central nervous system (CNS), such as
    alcohol, barbiturates and benzodiazepines may precipitate
    convulsive episodes, particularly if the drug has been used in
    high doses for a prolonged period.
   Photosensitivity and other types of reflex epilepsy. Seizures
    are occasionally precipitated by flashing lights or a flickering
    television screen. This photosensitivity can be seen on the
    occipital recording of the EEG. Very rarely other stimuli (e.g.
    music) provoke attacks.
Triggers
Fatigue, stress, poor nutrition, alcohol, lack of sleep may trigger
seizures.

Epileptic disorders can be considered either Primary or
Secondary.


                                  4
1. Primary epilepsy: When no specific anatomic cause for the
   seizure, such as trauma or neoplasm is evident, the syndrome is
   called idiopathic or primary epilepsy. These seizures may be
   produced by an inherited abnormality in the central nervous
   system (CNS).          Patients are treated chronically with
   antiepileptic drugs, often for life.
2. Secondary epilepsy: A number of reversible disturbances,
   such as tumors, head injury, hypoglycemia, meningeal
   infection, or rapid withdrawal of alcohol from an alcoholic, can
   precipitate seizures. Antiepileptic drugs are given until the
   primary cause of the seizures can be corrected.         Seizures
   secondary to stroke or trauma may cause irreversible CNS
   damage.



Classification of epileptic seizures

The classification of epilepsy is best achieved by:
i) The clinical events.
ii) The abnormal electrophysiology.
iii) The anatomical site of seizures genesis.
iv) The pathological cause of the problem.


The classification of epileptic disorders plays an essential role in
the diagnosis and management for four major reasons.

                                   5
1. The diagnosis of epilepsy is often difficult because of the
   similarity between certain epileptic attacks and intermittent
   symptoms of non-epileptic disorders.       The classification by
   specific symptoms is useful for this purpose.
2. Differentiation between partial and generalized seizures is of
   great clinical value.
3. The seizure type determines the choice of antiepileptic drugs.
4. A number of epileptic syndromes have been defined on the
   basis of seizure manifestations and other clinical features.
Seizures have been classified into two broad groups, partial (or
focal), and generalized.




                                 6
1.   Partial: Partial seizures
     are those in which the          EPILEPSY
     electrical discharges are
     limited to one part of
                                         PARTIAL
     the cortex and may                   (Focal)

     remain localized. Their
                                     Simple
     incidence      increases        Complex

     with age. This could be
     simple without loss of          GENERALIZED
     consciousness or com-
     plex (altered conscious-        Tonic-clonic (grand mal)
                                     Absence (petit mal)
     ness). Partial seizures
                                     Myoclonic
     may    progress,   beco-        Atonic
                                     Febrile seizures in children
     ming generalized tonic-
                                     Status epilepticus
     clonic seizures.




                                 7
1.1.   Simple partial (Jacksonian epilepsy): These
       seizures are caused by a group of hyperactive
       neurons exhibiting abnormal electrical activity and
       are confined to a single focus in the brain; the
       electrical disorder does not spread. A simple seizure
       generally starts in the toes of one foot or the fingers
       of one hand or in one corner of the mouth. Suddenly
       the affected part trembles violently or just feels
       numb.    The patient does not lose consciousness.
       These simple seizures either remain focal or they
       may spread and become secondary generalyzed with
       tonic-clonic activity and loss of consciousness.


1.2.   Complex partial (Psychomotor epilepsy): These
       seizures exhibit complex sensory hallucinations,
       mental distortion, and change in the level of
       consciousness. Motor dysfunction may involve
       chewing movement, diarrhea, and/or urination.
       Patients may have short period of amnesia, sudden
       anxiety and moments of incoherent speech or
       speech arrest. Several times a week they would feel
       sudden sharp pain in the stomach and after they
       wake up they remember nothing except the pain and
       the fear. Most (80%) of individuals with complex


                          8
            partial epilepsy experience their initial seizures
            before the age of 20. The seizure usually lasts for
            few minutes, after which the patient recovers with
            no recollection of the event.


2.   Generalized: generalized seizures involve the whole brain,
     producing abnormal electrical discharge throughout both
     hemispheres of the brain. Generalized seizures may be
     convulsive or nonconvulsive; the patient usually has an
     immediate loss of consciousness.


     2.1.   Tonic-clonic (grand mal): This is the most
            commonly encountered and the most dramatic form
            of epilepsy. A tonic-clonic seizure consists of an
            initial epileptic cry followed by strong contraction
            of the whole musculature, causing a rigid extensor
            spasm. Respiration stops and the patient may bite
            his tongue and may also lose control of his bladder
            or bowl function. The tonic phase lasts for about
            one minute and is followed by a series of violent,
            synchronous jerks which gradually dies out in 2-4
            minutes. The patient stays unconscious for a few
            more minutes and then gradually recovers, feeling
            ill and confused. The patient is in no serious danger


                              9
       unless he/she falls on his head on something hard.
       Such patients should be put on side position with
       the neck a little extended so as to secure the airways
       and breathing.


2.2.   Absence (petit mal): Absence seizures are much
       less dramatic but may occur more frequently (many
       seizures each day) than tonic-clonic seizures. It
       involves a brief, abrupt and self-limiting loss of
       consciousness which generally lasts no more than a
       few seconds. The patient abruptly stopps whatever
       he was doing, sometimes stopping speaking in mid-
       sentence, stares vacantly, neither speaking nor
       apparently hearing what is said. There is little or no
       motor disturbance and patients recover abruptly
       with no after-effects. This type of epilepsy is
       especially prevalent in childhood and occur at ages
       3 to 5 years and lasts until puberty.


2.3.   Myoclonic: These seizures involve sudden, brief
       shock-like contractions which may involve the
       entire body or be confined to the face, trunk or
       extremities. Myoclonic seizures are rare and occur
       at any age. A special type is the so called Juvenile


                         10
       Myoclonic Epilepsy, an inherited type of Epilepsy
       (autosomal-recessive) relatively common in Saudi
       Arabia and Middle East.


2.4.   Atonic seizures (astatic):       It involves sudden
       diminution of muscle tone, affecting some muscle
       groups, or loss of all muscle tone; patients may have
       a brief loss of consciousness. It starts between the
       ages 2-5 years. The patient’s legs simply give under
       him and he drops down.         It lasts for about 10
       seconds to 1 minute.


2.5.   Febrile seizures: Young children (6 months to 5
       years of age) frequently develop seizures with
       illness accompanied by high fever. The febrile
       seizures   consist     of   generalized   tonic-clonic
       convulsions of short duration. They are benign and
       do not cause death, neurological damage, injury, or
       learning disorders.
              Two to 4% of children experience a
       convulsion associated with a febrile illness.
       Approximately 25% to 33% of these children will
       have another febrile convulsion. Only 2% to 3%
       will develop epilepsy in later years. Several factors


                         11
are associated with an increased risk of developing
epilepsy. These include pre-existing neurological
disorder, a family history of epilepsy or a
complicated febrile seizure (i.e., the febrile seizure
lasted more than 15 minutes).
       Brief febrile convulsions need only simple
treatment such as tepid sponging or bathing, or
antipyretic medication, e.g. paracetamol. Prolonged
febrile convulsions (those lasting 15 minutes or
longer), recurrent convulsions, or those occurring in
a child at known risk must be treated more actively,
as there is the possibility of resulting brain damage.
Diazepam is the drug of choice given either by slow
intravenous    injection   in    a   dose      of    250
micrograms/kg or preferably rectally in solution in a
dose of 500 micrograms/kg (max. 10 mg), repeated
if necessary. The rectal solution is preferred as
satisfactory absorption is achieved within minutes
and administration is much easier. Suppositories are
not suitable because absorption is too slow.
       Intermittent prophylaxis (i.e. the anticonvul-
sant administered at the onset of fever) is possible in
only a small proportion of children.                Again



                  12
              diazepam is the treatment of choice, orally or
              rectally.
                       However, the exact role of continuous
              prophylaxis in children at risk from prolonged or
              complex febrile convulsions is controversial. Thus,
              long-term anticonvulsant prophylaxis is rarely
              indicated.


       2.6.   Status       epilepticus     (re-occurring     seizures):
              Characterized by continuous seizures (episodes of
              grand       mal)   without   regaining   the   level   of
              consciousness again. It is serious and may be fatal
              unless rapidly treated.


Unclassified - Lennox-Gastaut
Syndrome
Lennox-Gastaut Syndrome is a disorder of childhood characterized
by multiple seizure types, mental retardation and refractoriness to
antiepileptic drugs.      Common seizure types include a typical
absence and generalized tonic and atonic spells; the two latter
seizure types can produce injuries from fall. Other seizure types
include generalized tonic-clonic, partial and myoclonic seizures.
Diagnosis of the disorder is usually quite clear from the patient’s
history, physical examination and EEG.

                                   13
Treatment of the child with Lennox-Gastaut syndrome represents
one of the great challenges in epilepsy. Because of the mixture of
aetiologies, response to treatment can be variable. Valproic acid is
the most frequently used medication because it is active against
multiple seizure types. Treatment with benzodiazepines, including
clobazam, clonazepam, diazepam, clorazepate or nitrazepam, has -
been successful, although tolerance to treatment develops in many
cases.


A   ketogenic    diet   or   treatment      with   corticotrophin   and
glucocorticoids have also been used, as have phenytoin,
carbamazepine and barbiturates, although this latter group may
exacerbate certain seizure types including myoclonic, atonic and
atypical absence. In an add-on study, felbamate appeared to be
effective, especially with atonic spells.


Some of the newer drugs, including felbamate, lamotrigine and
vigabatrin, may have a role in the future management of Lennox-
Gastaut syndrome, although there have been reports of idiopathic,
potentially lethal, hepatic toxicity as well as aplastic anaemia
during felbamate therapy, and this drug is now only recommended
if the patient’s epilepsy is so severe that the risk of these adverse
effects is deemed acceptable.


                                  14
The diagnosis of epilepsy
The first step in the treatment of epilepsy must inevitably be a
proper    diagnosis.   Practically        the   diagnosis    demands   the
documentation of two or more seizures occurring over a period of
time in the absence of any metabolic disturbance or drug treatment
associated with seizures. For most patients the diagnosis is made
on the basis of an adequate description of symptoms both from the
patient    and    from     eye   witnesses.         In      some   patients
neurophysiological evidence from the EEG may provide valuable
confirmatory evidence for epilepsy. There seems little doubt that
the diagnosis is often made in error, frequently because too much
weight is attached to minor nonspecific abnormalities reported
from standard EEG recordings. Thus, it was found that 20% of
patients admitted to a psychiatric hospital with a diagnosis of
epilepsy did not have the disorder. A similar high proportion of
patients admitted to epileptic institutions are incorrectly diagnosed.
Where diagnostic difficulty persists, the best thing is to let time
clarify things. One thing that must be avoided is a “therapeutic
trial” of antiepileptic drugs.


Treatment of Epilepsy
Today epilepsy is treated with medications targeting for optimal
drug therapy. Epilepsy is completely controlled in about 75% of

                                     15
patients. However, approximately 10% continue to have seizures at
intervals of one month or less, which severely disrupts their life
and work. Hence, there is a need to improve the efficacy of
therapy. It is to be noted that none of the currently used drugs can
cure epilepsy, but they have become increasingly successful in
preventing seizures as long as they are regularly taken. The choice
of a drug depends upon the form of epilepsy and upon the response
of the individual. Epilepsy is a chronic long-term problem, and
even in patients whose seizures have been well controlled for two
or more years, the relapse rate on withdrawal of therapy has been
20 to 40%. Therefore, it is usually necessary to take medications
for many years, decades or even life long.


PHENYTOIN

Phenytoin (Epanutin) is the oldest nonsedative antiepileptic drug
which was introduced in 1938. It was known for decades as
diphenylhydantoin (DPH) and is still one of the most widely used
anticonvulsant drugs.


Mechanism of action
Phenytoin stabilizes neuronal membranes to depolarization by
reducing the influx of sodium ions (Na+) across the cell membrane
in the resting state or during depolarization. It also reduces the

                                 16
influx of calcium ions (Ca2+) during depolarization and suppresses
repetitive firing of neurons.


Pharmacokinetics
Following oral administration, the absorption of phenytoin is slow
and usually complete, and takes place primarily in the duodenum.
Concurrent administration with antacid significantly reduces the
absorption of phenytoin. The intravenous route is sometimes used
to terminate seizures in status epilepticus. Intramuscular injection
should be avoided since absorption is erratic and unpredictable and
muscle damage can occur. Phenytoin is highly bound (about 90%)
to plasma proteins, mainly plasma albumin. Since several other
drugs can also bind to the same protein, phenytoin can be displaced
by other drugs, such as salicylates, valproic acid and thyroxine.
This increases the free phenytoin concentration, but also increases
hepatic clearance of phenytoin, and thus enhances or reduces the
effect of phenytoin in a paradoxical manner. Phenytoin is
metabolized by the hepatic mixed function oxidase system and is
excreted mainly as glucuronide. The metabolites are clinically
inactive and are excreted in the urine. Less than 5% of a given dose
is excreted unchanged in the urine.


The metabolism of phenytoin shows the characteristics of
saturation (zero-order kinetics). At low blood levels the rate of

                                17
metabolism of phenytoin is proportional to the drug’s blood levels
(i.e., first-order kinetics). However, at the blood levels usually
required to control seizures, the maximum capacity of the drug-
metabolizing enzymes is often exceeded (i.e., the enzyme is
saturated), and further increases in the dose of phenytoin may lead
to a disproportionate increase in the drug’s blood concentration.
Since plasma levels continue to increase in such a situation, steady-
state levels are not attained and toxicity may occur.


The half-life of phenytoin varies from 12 to 36 hours, with an
average of 24 hours for most patients with therapeutic blood levels
of 10 to 20 g/ml. However, when the dosage increases, the
enzyme system becomes saturated resulting in a higher
concentrations and longer half-lives. At low blood levels, it takes
5-7 days to reach steady-state blood levels after every dosage
change; at higher levels it may be 4-6 weeks before blood levels
are stable.


Phenytoin induces liver microsomal enzymes, and thus accelerates
the rate of metabolism of other drugs (e.g. oral anticoagulants, oral
contraceptives).


Unwanted effects


                                 18
Side effects of phenytoin begin to appear at plasma concentrations
exceeding 100 µmol/L and may be severe above 150 µmol/L.
Chronic Gingival hyperplasia, or overgrowth of the gums, is the
most common side effect in children (20% of patients). This
condition may be minimized by good oral hygiene. This
hyperplasia slowly regresses after termination of drug therapy.
Coarsening of facial features occurs in children. Depression of the
CNS occurs particularly in the cerebellum and vestibular system,
causing nystagmus, ataxia, vertigo and diplopia. Gastrointestinal
problems (nausea, vomiting) are common. Hirsutism, which
probably results from increased androgen secretion, occurs to some
degree in most patients. For this reason it is usual to avoid
prescribing phenytoin to young women. Megaloblastic anemia,
associated with a disorder of folate metabolism, sometimes occurs,
and can be corrected by giving folic acid. Hypersensitivity
reactions, mainly skin rashes, are quite common. Behavioral
abnormalities, such as confusion, hallucinations, and drowsiness
may also occur. Inhibition of antidiuretic hormone release occurs
as well as hyperglycemia and glycosuria caused by inhibition of
insulin secretion. Chronic use may also result in abnormalities of
vitamin D metabolism leading to osteomalacia. Phenytoin has also
been implicated as a cause of the increased incidence of foetal
malformations in children born to mothers with epilepsy,
particularly the occurrence of cleft lip, cleft palate, congenital heart


                                  19
disease; this appears to be due to the formation of an epoxide
metabolite. Cardiovascular collapse and a systemic lupus pattern
are   the   most   serious   side        effect   following   intravenous
administration of phenytoin.     Lymphadenopathy, had also been
reported as well as the Hydantoin fetal syndrome in newborn of
women taking phenytoin.


Intravenous administration of phenytoin (i.e. for treatment of status
epilepticus) should be slow and preferably it should be given with
sodium chloride (Na Cl).


Giving Phenytoin with Dextran must be avoided because of
precipitation of the drugs after reacting with sugar and that leads to
plugging and damage to the veins.




                                    20
       Agent that stimulates
      metabolism of phenytoin
          Carbamazepine




 Phenytoin
                         Inactive metabolite
 Phenytoin




      Agents that inhibit
      metabolism of phenytoin
       Chloramphenicol
       Dicumarol
       Cimetidine
       Sulfonamides
       Isoniazid




Drugs affecting the metabolism
of phenytoin.




                       21
Drug Interactions
Drug interactions involving phenytoin are primarily related either
to protein binding or to metabolism. Since phenytoin is highly
bound, other highly bound drugs, such as phenylbutazone,
sulfonamides, benzodiazepines, or anticoagulants, can displace
phenytoin from its binding site, leading to an elevation in free drug
concentrations and hence intoxication. The protein binding of
phenytoin is decreased in the presence of renal disease. A binding
inhibitor, which is produced in the presence of uremia, may cause
this displacement of phenytoin.


Drugs that inhibit the hepatic microsomal enzymes, such as
cimetidine, chloramphenicol, sulfonamides, isoniazid, dicumarol
and valproate, lead to an increase in the concentration of phenytoin
in the plasma by preventing its metabolism and hence result in
phenytoin toxicity. Phenytoin has been shown to induce
microsomal enzymes responsible for the metabolism of other
drugs, such as oral       contraceptives, doxycycline, cyclosporine,
quinidine, levodopa and other antiepileptics resulting in a reduced
blood levels of these drugs. Autostimulation of its own
metabolism, however, appears to be insignificant. On the other
hand, agents that induce liver microsomal enzymes such as
carbamazepine and chronic alcohol administration, decrease
phenytoin blood levels.

                                  22
Clinical uses
Phenytoin is highly effective for the treatment of generalized tonic-
clonic seizures and for the treatment of partial seizures with
complex symptomatology. It is also used for the treatment of status
epilepticus caused by recurrent tonic-clonic seizures. Phenytoin is
not effective for absence seizures, which often may worsen if
such a patient is treated with this drug. Other uses of phenytoin
include, treatment of disturbed psychotic patients without epilepsy,
treatment of trigeminal neuralgia, and as an antiarrhythmic agent,
particularly in the treatment of digitalis-induced arryhtmias.


The therapeutic plasma level of phenytoin for most patients is
between 10 and 20 µg/ml. A loading dose can be given either
orally or intravenously; the latter is the method of choice for
convulsive status epilepticus. When oral therapy is started, it is
common to begin adults at a dosage of 300 mg/d regardless of
body weight. If seizures continue, higher doses are usually
necessary to achieve plasma levels in the upper therapeutic range.
The phenytoin dosage should be increased each time by only 25-30
mg in adults, and ample time should be allowed for the new steady
state to be achieved before further increasing the dose. A common
clinical error is to increase the dose directly from 300 mg/d to 400
mg/d; toxicity frequently occurs at variable times thereafter. In



                                 23
children, a dose of 5 mg/kg/d should be followed by readjustment
after steady-state plasma levels are obtained.


CARBAMAZEPINE
Carbamazepine (Tegretol) is closely related to imipramine and
other antidepresssants, it is a       tricyclic compound originally
developed for the treatment of bipolar depression. It was initially
marketed for the treatment of trigeminal neuralgia but has proved
useful for epilepsy as well, and is now one of the most widely used
antiepileptic drugs.


Mechanism of action
The mechanism of action of carbamazepine appears to be similar to
that of phenytoin. At therapeutic concentrations, carbamazepine
reduces the propagation of abnormal impulses in the brain by
blocking sodium channels, thereby reducing the generation of
repetitive action potentials in the epileptic focus. Although
trigeminal neuralgia is not obviously associated with epilepsy, this
condition probably involves similar neuronal mechanisms.


Pharmacokinetics
Carbamazepine is absorbed slowly following oral administration.
Peak levels are usually achieved 6-8 hours after administration. It


                                 24
enters the brain rapidly because of its high lipid solubility. The
drug is only 70% bound to plasma proteins, no displacement of
other   drugs   from    protein    binding   has   been    observed.
Carbamazepine is metabolized in the liver to Carbamazepine - 10,
11-epoxide which has been shown to have anticonvulsant activity
and 10, 11-dihydroxide which is subsequently conjugated and
execreted in the urine. Only 2% of carbamazepine is execreted
unchanged in the urine. The drug has a notable ability to induce
liver microsomal enzymes, and its own half-life therefore decreases
with chronic administration. Typically, the half-life of 36 hours
observed in subjects following an initial single dose decreases to
much less than 20 hours over the first 2-3 weeks of treatment due
to “autoinduction” of its own metabolizing enzymes in the liver.
Seizure control may then require       an increase in dose. During
chronic therapy the half-life is extremely variable among
individuals. Carbamazepine also alters the clearance of other drugs.
For example, carbamazepine has been shown to increase the
clearance and decrease the half-life and steady-state blood levels of
several other antiepileptic drugs such as phenytoin, primidone,
valproic acid or clonazepam.


Unwanted effects
   Nausea and vomiting, especially early in treatment.



                                  25
   CNS toxicity: diplopia, dizziness, drowsiness. Ataxia occurs at
    high doses.
   Leukopenia is common, especially early in treatment, but
    severe bone marrow depression is rare.
   Hyponatraemia, due to potentiation of the action of antidiuretic
    hormone which can lead to water intoxication.
   Skin rashes (including Stevens-Johnson syndrome).
   Risk of teratogenesis including neural tube defects if used
    during the first trimester of pregnancy.
   Neonatal bleeding (prophylactic Vitamin K for mother before
    delivery is advised).




                                  26
Carbamazepine              Metabolite




            Agents that inhibit
            metabolism of
            carbamazepine
               Cimetidine
               Diltiazem
               Erythromycin
               Isoniazid
               Propoxyphene




     Drugs affecting the metabolism of
     carbamazepine.




                   27
Drug interactions
Drug interactions involving carbamazepine are almost exclusively
related    to    its   effects    on   microsomal   drug    metabolism.
Carbamazepine can induce its own metabolism (autoinduction)
after prolonged use; its half-life, and serum steady-state
concentrations may all be decreased. Carbamazepine also can
induce the enzymes that metabolize other antiepileptic drugs
including phenytoin, primidone, phenobarbital, valproic acid,
clonazepam, and ethosuximide, as well as the metabolism of other
drugs such as oral contraceptives and warfarin. Other drugs such as
propoxyphene, cimetidine, isoniazid and the macrolide antibiotics
(erythromycin and troleandomycin) may inhibit carbamazepine
clearance and increase steady-state carbamazepine blood levels.
Other antiepileptics, for instance, phenytoin and phenobarbital,
may decrease steady-state concentrations of carbamazepine
through enzyme induction. No clinically significant protein-
binding interactions have been reported.


Clinical uses
Carbamazepine is considered the drug of choice for the treatment
of all partial seizures (simple and complex). In addition the drug
may       be    effective   for    generalized   tonic-clonic   seizures.
Carbamazepine is nonsedative in its usual therapeutic range. Both
carbamazepine and phenytoin are effective in relieving pain

                                       28
associated with trigeminal neuralgia, an exceedingly painful
condition believed to result from a paroxysmal discharge of
neurons associated with the trigeminal sensory pathway. Similar to
phenytoin, carbamazepine is not effective in absence seizures and
might even make these seizures worse. It has occasionally been
used in manic-depressive patients to ameliorate the symptoms. It
is used successfully in reducing pain in peripheral neuropathy.
Carbamazepine is available only in oral form. The drug is effective
in children, in whom a dose of 15-25 mg/kg is appropriate. In
adults, doses of 1 g or even 2 g are tolerated. Higher doses are
achieved by giving multiple doses daily. In patients receiving three
or four daily doses, in whom the blood is drawn just before the
morning dose (trough level), the therapeutic level is usually 4-8
ug/ml; although many patients complain of diplopia above 7 ug/ml.
When blood samples are drawn randomly, levels are frequently
above 8 ug/ml, but fluctuations related to absorption make long-
term   comparisons    difficult.   The plasma concentration of
carbamazepine correlates well with its clinical efficacy and
measurement can be useful in monitoring treatment. Salivary
concentrations are an alternative guide. Studies have shown that
Carbamazepine has the least teratogenic effects when used as
monotherapy in pregnant women.




                                   29
PHENOBARBITAL
Phenobarbital (Gardinal) is a long-acting barbiturate and one of the
first barbiturates to be developed. It is the oldest of the currently
available antiepileptic drugs and its anticonvulsant properties were
in fact recognized in 1912. Its action against experimentally-
induced convulsions and clinical forms of epilepsy closely
resembles phenytoin. Like phenytoin, it is ineffective in treating
absence seizures. Although it has long been considered one of the
safest of the antiepileptic drugs, the use of other medications with
lesser sedative effects has been urged.


Mechanism of action
Phenobarbital limits the spread of seizure discharges in the brain
by elevating the seizure threshold. Its mechanism of action in
alleviating seizures is poorly understood. Like phenytoin,
phenobarbital suppresses high frequency repetitive firing in
neurons in-vitro through its action on Na+ conductance, but only at
high concentrations. Also, at high concentrations, barbiturates
block some Ca2+ currents. There is also evidence that it may act
through potentiation of the inhibitory effects of -aminobutyric
acid (GABA)-mediated neurons. Phenobarbital also blocks
excitatory responses induced by glutamate. Both the enhancement
of GABA-mediated inhibition and the reduction of glutamate-


                                 30
mediated     excitation are seen with therapeutically relevant
concentrations of phenobarbital.


Pharmacokinetics
Phenobarbital is well absorbed orally. Approximately 50% of the
drug in the blood is bound to plasma albumin. The drug freely
penetrates the blood brain barrier. It is eliminated slowly from the
plasma (half-life is very long, ranging from 2 and 6 days). about
75% of the drug is metabolized, mainly by oxidation and
conjugation, by the hepatic microsomal enzymes, the remaining
drug is excreted unchanged by the kidney. Phenobarbital is a potent
inducer of the P-450 system, and when given chronically, it
enhances the metabolism of other drugs and lowers their plasma
concentrations (e.g. steroids, oral contraceptives, warfarin, tricyclic
antidepressants). Since phenobarbital is a weak acid, its ionisation
and hence renal elimination are increased if the urine is made
alkaline.
The plasma concentrations of phenobarbital are not closely related
to control of seizures. They are only useful as a guide to
compliance with treatment.


Unwanted effects
The major unwanted effect of phenobarbital is sedation, which
often occurs at plasma concentrations within the therapeutic range

                                   31
for seizure control. Some degree of tolerance develops to this
effect on continued administration, but objective tests of cognition
and motor performance show impairment even after long-term
treatment. Impaired school performance has been shown to result
from treatment of children with phenobarbital. Other unwanted
effects that may occur with clinical dosage include megaloblastic
anaemia (similar to that caused by phenytoin), ataxia, nystagmus,
vertigo, mild hypersensitivity reactions and osteomalacia, as well
as hemorrhage in babies born to mothers receiving phenobarbital.
Like other barbiturates, it must not be given to patients with
porphyria. In overdose, phenobarbital produces coma, respiratory
and circulatory failure, as all barbiturates do. Dependence with a
physical withdrawal reaction is seen after long-term treatment.
Rebound seizures can occur upon rapid discontinuation of
phenobarbital.


Drug interactions
Phenobarbital interacts with other central nervous system
depressant drugs, leading to additive effects. Following continuous
use of phenobarbital, it induces hepatic microsomal enzyme
system. For example, in human, phenobarbital has been shown to
increase the rate of metabolism of dicumarol, phenytoin, digitalis
compounds, and griseofulvin - effects that could lead to decreased
response to these agents.     Concentrations of phenobarbital in

                                32
plasma may be elevated by as much as 40% during concurrent
administration of valproic acid and other drugs that inhibit hepatic
microsomal enzymes.


Clinical uses
Phenobarbital is useful in the treatment of generalized tonic-clonic
seizures and simple partial seizures, but it is not very effective for
complex partial seizures. There is little evidence for its
effectiveness in generalized seizures such as absence, atonic
attacks, or infantile spasms. The drug has been regarded as the first
choice in treating recurrent seizures in children, including febrile
seizures.   However,     phenobarbital    can   depress    coginitive
performance in children when it is used for febrile seizures, and the
drug should be used cautiously in this condition. Phenobarbital is
also used to treat status epilepticus, especially in patients who do
not respond to diazepam together with phenytoin.
The therapeutic levels of phenobarbital in most patients range from
15 to 40 ug/ml.


PRIMIDONE
Primidone (mysoline) was marketed in the early 1950s. It is
structurally related to phenobarbital. In fact, much of primidone’s
efficacy comes from its metabolites Phenobarbital and phenylethyl
malonamide, which have longer half-lives than the parent drug.

                                 33
Mechanism of action
Although primidone is converted to phenobarbital, the mechanism
of action of primidone itself may be more like that of phenytoin.


Pharmacokinetics
Primidone is well absorbed       following oral administration and
exhibits poor protein binding. It is converted in the liver to two
active metabolites: Phenobarbital and phenylethylmalonamide
(PEMA). Optimal blood levels of phenobarbital derived from the
metabolism of primidone are similar to those found when
Phenobarbital itself is given. Concentrations of unchanged
primidone should be maintained below 10ug/ml to prevent overt
CNS depression. Primidone has a larger clearance than other
antiepileptic drugs (2L/kg/d), corresponding to a half-life of 6-8
hours. PEMA clearance is approximately half that of primidone,
but phenobarbital has a very low clearance.


Unwanted effects
Rashes, leukopenia, thrombocytopenia and systemic lupus
erythematosus have been reported. Some personality changes and
megaloblastic anaemia have also occured. As with phenobarbital,
the most common side effects associated with primidone therapy
are related to CNS depression.


                                 34
Drug interactions
Drug interactions described for phenobarbital can also occur
following primidone administration.


Clinical uses
Primidone is effective against partial seizures and appears to be
more effective than phenobarbital. This result is presumably due
to the activity of its metabolite, PEMA. Primidone is also effective
in generalized tonic-clonic seizures and focal epilepsy.       It is
frequently combined with phenytoin, but since it is, in part,
converted to phenobarbital, combination        with phenobarbital
makes little sense.


Primidone is most efficacious when plasma levels are in the range
of 8-12 ug/ml. Concomitant levels of its metabolite, phenobarbital,
at steady state will usually vary from 15-30 ug/ml. Doses of 10-20
mg/kg/d are necessary to obtain these levels. It is very important,
however, to start primidone at low doses and gradually increase
over days to a few weeks to avoid prominent sedation and
gastrointestinal complaints.




                                35
VALPROIC ACID
Valproic acid (Depakene), also available as the sodium salt,
sodium valproate, was found to have antiepileptic properties when
it was used as a solvent in the search for other drugs effective
against seizures. It was marketed in France in 1967 but was not
licensed in the USA until 1978. It inhibits most kinds of
experimentally induced convulsions, and is effective in many
clinical types of epilepsy.


Mechanism of action
It is probable that valproic acid works by more than one
mechanism, since it has a very broad spectrum of anticonvulsant
activity. Although the precise mode of action of valproate remains
uncertain, attention, however, has been paid to the effects of
valproic acid on the inhibitory amino acid, -aminobutyric acid
(GABA). Several studies have shown that valproate causes a
significant increase in the GABA content of the brain, and also
decreases the amount of the excitatory neurotransmitter aspartate.
It is a weak inhibitor of two enzyme system that inactivate GABA,
namely     GABA-transaminase          and   succinic   semialdehyde
dehydrogenase.
At high concentrations, valproic acid has been shown to increase
membrane       potassium      conductance.      Furthermore,   low
concentrations of valproic acid tend to hyperpolarize membrane
                                 36
potentials. These findings have led to speculation that valproic acid
may exert an action through a direct effect on the potassium
channels of the membrane.


Pharmacokinetics
Valproic acid is well absorbed from the gut, with bioavailability
greater than 80%. Peak blood levels are observed within 2 hours.
To reduce the risks of gastric upset, conventional tablets should be
taken with food or enteric coated tablets can be given. The drug is
about 90% bound to plasma proteins, but the proportion of free
(and   therefore   active)   drug        rises   with   increasing   blood
concentration. Drug concentration in plasma does not correlate
well with therapeutic effect and routine monitoring is only useful
to assess compliance or to avoid toxic concentrations. Valproic
acid is extensively metabolized in the liver by the P-450 system,
but it does not induce P-450 enzyme synthesis. The glucuronylated
metabolites are excreted in the urine.
Clearance of valproic acid is very slow, corresponding to the small
volume of distribution and accounting for a half-life of 9-18 hours.


Unwanted effects
The most common dose-related adverse effects of valproic acid are
nausea, vomiting, and other gastrointestinal complaints such as
abdominal pain and “heart burn”. The drug should be started

                                    37
gradually to avoid these symptoms. Potentially the most serious
side effect is hepatotoxicity. An increase in serum glutamic
oxaloacetic transaminase (SGOT), which signals liver damage of
some degree, commonly occurs, but proven cases of valproate-
induced hepatitis are rare. In some patients, a rash and hair loss
(alopecia) may occur, but this effect is reversible. Bleeding times
may increase because of both thrombocytopenia and an inhibition
of platelet aggregation. Valproic acid inhibits phenobarbital
metabolism, thereby increasing circulating levels of phenobarbital.
Metabolic effects, including hyperglycemia and hyperammonemia,
have been reported. An increase in body weight has been noted.
There is evidence that valproic acid may be teratogenic, with
increased incidence of spina bifida and neural tube defects in first
trimester. Neonatal bleeding and neonatal hepatotoxicity have also
reported. Therefore, is not recommended for use during pregnancy.


Drug interactions
The clearance of valproic acid is dose-dependent, caused by
changes in both the intrinsic clearance and protein binding.
Valproic acid inhibits its own metabolism at low doses, thus
decreasing intrinsic clearance. At higher doses, there is an
increased free fraction of valproic acid, resulting in lower total
drug levels than expected. It may be clinically useful, therefore, to
measure both total and free levels. Valproic acid also displaces

                                 38
phenytoin from plasma proteins leading to an increase in unbound
phenytoin and hence its toxicity. The dosage of phenytoin should
be adjusted as required. In addition, valproic acid inhibits the
metabolism of several drugs, including phenobarbital, phenytoin
and carbamazepine, leading to higher steady-state concentrations.
The inhibition of phenobarbital metabolism may cause levels of the
barbiturate to rise causing stupor or coma. The concomitant use of
valproic acid and clonazepam may produce absence status.


Clinical uses
Valproic acid has become a major antiepileptic drug against several
seizure types. It was originally approved for use in absence
seizures, particularly in myoclonic types that had been difficult to
treat with other drugs, and this is still its major indication when it
is used alone. In addition, valproic acid can be used either alone or
in combination with other drugs for the treatment of generalized
tonic-clonic epilepsy and for partial seizures with complex
symptomatology and in febrile convulsions.
Doses of 25-30 mg/kg/d may be adequate in some patients, but
others may require 60 mg/kg or even more. Therapeutic levels of
valproic acid range from 50-100 ug/ml.




                                 39
ETHOSUXIMIDE
Ethosuximide (zarontin) was introduced in 1960 and belongs to the
succinamide class. It was developed by modifying the barbituric
acid ring structure. It is used in cases of petit mal epilepsy.


Mechanism of action
The mechanism of action of ethosuximide may be due to
antagonist activity in cell membrane on T-type calcium channels. It
also inhibits Na+, K+ - ATPase, depresses the cerebral metabolic
rate and inhibits GABA transaminase.



Pharmacokinetics
Ethosuximide is well absorbed when given orally. Peak levels are
observed 3-7 hours after oral administration of the capsules.
Plasma steady-state levels are reached after about 9 days of single -
daily dosing. Ethosuximide is uniformly distributed throughout
perfused tissues and does not penetrate fat. It is not bound to
plasma proteins. About 25% of the drug is excreted unchanged in
the urine, and 75% is converted to inactive metabolites in the liver
by the microsomal P-450 enzyme system. Ethosuximide does not
induce P-450 enzyme synthesis. The plasma half-life of
ethosuximide is about 30-40 hours.



                                  40
Unwanted effects
The most common dose-related side effect of Ethosuximide is
gastric distress, including pain, nausea and vomiting. This can
often be avoided by starting therapy at a low dose, with gradual
increase in the therapeutic range. Other dose-related adverse effects
include transient lethargy or fatigue and, much less commonly,
headache, dizziness, hiccup and euphoria. A variety of blood
dyscrasias, including pancytopenia and aplastic anaemia, have
occurred. Eosinophilia develops in about 10% of patients. Systemic
lupus erythematosus and Stevens-Johnson syndrome also have
been reported. The drug may precipitate tonic-clonic seizures in
susceptible patients.


Drug interactions
Administration of ethosuximide with valproic acid results in a
decrease in ethosuximide clearance and higher steady-state
concentrations due to inhibition of metabolism.


Clinical uses
The only indication for ethosuximide is in the treatment of
uncomplicated absence epilepsy (first choice drug). However, it
can be combined safely with other anticonvulsants in patients with
absence as well as other types of epilepsy (multiple seizure types).


                                 41
The optimal plasma ethosuximide levels are between 40-100
ug/ml; these levels provide control in 80% of patients with absence
epilepsy. The starting dose for children up to 6 years of age is 250
mg/d, and this increased gradually to the usual dose of 20 mg/kg/d.
Adults and children over 6 years are started with 500 mg/d, and
increased by 250 mg at 4-7 days interval to the usual dose of 1-1.5
g/d.


BENZODIAZEPINES
Several benzodiazepines play prominent roles in the treatment of
epilepsy, but their roles cannot be classified under a single seizure
disorder. Although many benzodiazepines are quite similar
chemically, subtle structural alterations result in differences in
activity. With most benzodiazepines, the sedative effect is too
pronounced to be used as maintenance anticonvulsant therapy. Of
all the antiepileptics, the benzodiazepines are the safest and most
free from severe side effects.


Mechanism of action
Benzodiazepines through binding to GABA-associated receptors,
promote influx of chloride ions and neuronal hyperpolarization.




                                 42
Pharmacokinetics
Benzodiazepines are well absorbed, widely distributed, and
extensively metabolized, with many active metabolites. The rate of
distribution of benzodiazepines within the body is different from
that of other antiepileptic drugs. Diazepam and lorazepam in
particular are rapidly and extensively distributed to the tissues,
with volume of distribution between 1 and 3 L/kg. The onset of
action, therefore, is also very rapid. Total body clearance of parent
drug and metabolites, however, is very slow, corresponding to half-
lives of 40-50 hours.



Unwanted effects
Two prominent aspects of benzodiazepines limit their usefulness.
The first is their pronounced sedative effects, which is unfortunate
both in the treatment of status epilepticus and in chronic therapy.
The second problem is tolerance, in which seizures may initially
respond, but within a few months the initial improvement may
diminish.
Respiratory depression and cardiac depression may occur when
given intravenously in acute situations. In addition, children may
manifest a paradoxic hyperactivity, as with barbiturates.




                                 43
Drug interactions
Benzodiazepines have additive or synergistic effects with other
centrally acting drugs such as antihistamines, alcohol and
barbiturates. This may increase the impairment of motor or
intelectual function or worsen respiratory depression.


Clinical uses
Diazepam (valium), given intravenously is the drug of choice to
treat status epilepticus, a life-threatening condition in which
epileptic seizures occur almost without a break. Its advantage in
this situation is that it acts very rapidly compared with other
antiepileptic drugs.
In adults, the drug is administered by intravenous injection in a
dose of 10-20 mg at a rate of 0.5 ml (2.5 mg) per 30 seconds,
repeated if necessary after 30-60 minutes, and may be followed by
intravenous infusion to a maximum dose of 3 mg/kg over 24 hours.
The dose in children is 200-300 µg/kg or 1 mg per year of age,
given intravenously. Diazepam can also be administered by the
rectal route as rectal solution in a dose of 500 µg/kg for adults and
children over 10 kg and 250 µg/kg in the elderly.


Clonazepam (Rivotril) is claimed to be a relatively selective
anticonvulsant. It is effective in absence, myoclonic, atonic, and
akinetic seizures. It is generally less effective than valproate or

                                 44
ethosuximide in absence seizures. Sedation is prominent,
especially on initiation of therapy and starting doses should be
small. Maximally tolerated doses are usually in the range of 0.1-0.2
mg/kg. Therapeutic blood levels are usually less than 0.1 ug/ml and
are not routinely measured in most laboratories.
It is given by either intravenous injection (over 30 seconds) or by
intravenous infusion in a dose of 1 mg, repeated if necessary,
whereas, for children of all ages, the dose is 500 µg.


Chlorazepate dipotassium (Tranxene) is a benzodiazepine
approved in the U.S.A. as an adjunct to treatment of complex
partial seizures in adults. Drowsiness and lethargy are its common
adverse effects.


Nitrazepam (Mogadon) is not marketed in the U.S.A., but is used
in many other countries, especially for infantile spasms, myoclonic
seizures; and Lennox-Gastaut syndrome. It is less potent than
clonazepam, and whether it has any clinical advantages over
clonazepam remains unclear.
For adults, it is given in a dose of 5-10 mg at bed time; whereas in
elderly it is given in a dose of 2.5-5 mg. It is not recommended in
children.




                                 45
Clobazam is not available in the U.S.A. but is marketed in most
countries. It is a 1,5-benzodiazepine (unlike the marketed
compounds, all of which are 1,4-benzodiazepines) and reportedly
has less sedative potential than other benzodiazepines. Whether the
drug has significant clinical advantages over other benzodiazepines
is not clear.
It is given in a dose of 20-30 mg/d, with maximum daily dose of 60
mg. The dose for children over 3 years of age is not more than half
of the adult dose.




                                46
NEW ANTI-EPILEPTIC DRUGS
In the last few years a number of new anticonvulsants have been
introduced into clinical practice mainly as add-on therapy in
patients whose epilepsy is resistant to standard antiepileptic drugs.
However, the precise role of these new agents in the overall
management of epilepsy remains             to   be clearly defined.
Lamotrigine, vigabatrin, gabapentin, felbamate, tiagabine and
topiramate, are among the most promising antiepileptic drugs.


Lamotrigine
Lamotrigine (lamictal) is a promising new antiepileptic drug which
is structurally unrelated to the major antiepileptics in current use.


Mechanism of action
Although its precise mechanism of action is unknown, current
evidence suggests that lamotrigine exerts its antiepileptic effects by
blocking the voltage-dependent sodium channels, stabilizing
neuronal membranes and thus inhibiting the release of excitatory
neurotransmitters, predominantly glutamate.


Pharmacokinetics
Lamotrigine is rapidly and completely absorbed after oral
administration and has a volume of distribution in the range of

                                  47
1-1.4L/kg.   Protein binding is only about 55%. It undergoes
biotransformation in the liver primarily by hepatic glucuronidation
to the inactive 2N-glucuronide metabolite. Hence, any drug which
is able to induce or inhibit this glucuronidation reaction may
potentially interact with lamotrigine. Its elimination reveals linear
Kinetics with a mean half-life of approximately 25.5  10.2 hours
in healthy young adults.


Unwanted effects
The most common adverse effects of lamotrigine include rash,
somnolence, blurred vision, dizziness, headache, diplopia, ataxia,
nausea and vomiting. The rash occurs in about 10% of treated
patients, usually within 2-8 weeks of starting lamotrigine, however
isolated cases have been reported after prolonged use. Although
the majority recover on drug withdrawal, however, in rare cases
these reactions may be fatal.      Hence, all patients (adults and
children) who develop a rash should be evaluated and lamotrigine
should be withdrawn immediately unless the rash is clearly not
drug related. It is important to note that early manifestations of
hypersensitivity (e.g. fever, lymphadenopathy) may occur without
evidence of a rash. It is therefore, recommended that patients
should be instructed to report any signs of hypersensitivity to
his/her physician immediately. The drug’s safety in pregnancy is



                                 48
unknown, so it is better to avoid its prescription to pregnant
women.


Contraindications
Hepatic impairment.


Drug interactions
The concurrent administration of lamotrigine together with
phenytoin, carbamazepine, phenobarbital or primidone has been
shown to reduce the half-life of lamotrigine to approximately 15
hours. Lamotrigine has also been reported to reduce the plasma
concentrations of valproic acid by approximately 25% over a few
weeks. Drugs which are known to accelerate gastric emptying,
such as metoclopramide may increase the rate of oral absorption of
lamotrigine from the gastrointestinal tract; whereas, those which
are known to delay gastric emptying, for example, imipramine,
may decrease the absorption of orally administered lamotrigine
from the gastrointestinal tract.


Clinical uses
Lamotrigine is effective as an add-on therapy for partial and
secondary generalized tonic-clonic seizures with dosages typically
between 100 and 300 mg/d and with a therapeutic blood level near


                                   49
3 µg/ml. It may also be effective for other types of epilepsy, such
as absence, myoclonic, tonic and clonic seizures and those
associated with the Lennox-Gastaut syndrome. In addition, it is
also of experimental interest in the therapy of other neurological
disorders, such as Parkinson’s disease. Pharmacological studies
have indicated that the anticonvulsant profile of lamotrigine is
similar to that of phenytoin and carbamazepine and it is better
tolerated.


VIGABATRIN
Mechanism of action
Vigabatrin (Sabril) is a structural analogue of gamma-aminobutyric
acid (GABA). It is an irreversible inhibitor of GABA
aminotransferase, the enzyme responsible for the degradation of
GABA at synaptic sites, thus enhancing inhibitory effect of GABA
against the generation of epileptic discharges.


Pharmacokinetics
Vigabatrin is rapidly absorbed from the gut and peak plasma levels
are attained in 1-3 hours. The half-life of the drug is short (6-8
hours) but because of its irreversible binding to the enzyme it
results in a long duration of action which is not related to the
plasma drug concentration. Hence, monitoring of plasma


                                 50
concentration is not required.        Unlike most of the older
antiepileptics, vigabatrin binds minimally to plasma proteins and is
devoid of significant enzyme inducing or inhibiting properties. It
is not metabolised through the cytochrome P450 enzyme system
and is excreted mostly unchanged in the urine.


Unwanted effects
Sedation and fatigue.
Psychotic reactions, especially in patients with a history of
psychiatric disorder. Hence, preexisting mental illness is a relative
contraindication.
Weight gain.
Vigabatrin reduces plasma phenytoin concentrations by an
unknown mechanism.
Visual disturbances including visual field defect, photophobia and
retinal disorders have been reported. Hence, regular testing of
visual field is recommended and the patient should be advised to
report any visual changes.



Clinical uses
It is effective for use in chronic epilepsy not satisfactorily
controlled by other antiepileptics.      It is useful primarily as
adjunctive treatment for patients with partial seizures refractory to


                                 51
the conventional antiepileptic drugs. In adults, vigabatrin should
be started at a dosage of 500 mg twice daily; a total of 1.5 g (or
more) daily may be required to produce its full effect.


GABAPENTIN
Mechanism of action
Gabapentin (neurontin) is an amino acid, chemically related to
GABA. However, it does not mimic GABA in the brain. It does
not interact with the excitatory neurotransmitter receptor sites or
with voltage-dependent sodium channels, nor does it influence
benzodiazepine, catecholamine, acetylcholine or opioid receptors.
Gabapentin binds with high affinity to a specific site in the brain,
which appear to be the amino acid transporter system that is
present occurs in many neurons and other cells.


Pharmacokinetics
Gabapentin is incompletely absorbed from the intestine. Food has
no effect on the rate and extent of absorption. It is not appreciably
metabolized in humans nor does it interfere with the metabolism of
the commonly used antiepileptic drugs. The drug does not bind to
plasma proteins and is excreted unchanged by the kidneys,
minimizing the likelihood of drug interactions. Dosage adjustment
in patients with compromised renal function or undergoing


                                 52
hemodialysis is recommended. Gabapentin elimination half-life is
5-7 hours which might require thrice daily dosing, although there is
some evidence that twice daily dosing is sufficient.


Unwanted effects
CNS effects including somnolence, dizziness, ataxia, fatigue,
nausea and/or vomiting and nystagmus have been reported. The
absorption of Gabapentin from the intestine depends on the amino
acid carrier system, and shows the property of saturability, which
means that increasing the dose does not proportionately increase
the amount absorbed. This makes Gabapentin relatively safe and
free of side effects associated with overdosing. Up to date no
serious drug interactions were reported.               There are no
teratogenicity data in man when it was used during pregnancy.


Clinical uses
Gabapentin is indicated as adjunctive (add-on) therapy in patients
over 12 years of age with partial seizures with and without
secondary generalization in adults with epilepsy. It is given orally
with or without food. The effective dose is 900 - 1800 mg/day and
given in divided doses (three times a day) using 300 or 400 mg
capsules.   It is not necessary to monitor gabapentin plasma
concentrations to optimize gabapentin therapy. Further, because
there are no significant pharmacokinetic interactions between

                                 53
gabapentin and other commonly used antiepileptic drugs, its
concurrent use with other antiepileptics does not significantly alter
the plasma levels of the latter.


FELBAMATE
Felbamate (Felbatol) is structurally similar to meprobamate, an
obsolete anxiolytic drug.


Mechanism of action
Felbamate’s mechanism of action is unknown, but in neuronal
cultures it blocks sustained repetitive neuronal firing, possibly
through an effect on sodium channels. Experiments on animals
suggest that felbamate has a broad spectrum anticonvulsant activity
and causes less behavioral toxicity than carbamazepine, valproate
or phenytoin.


Pharmacokinetics
Felbamate is available for oral use only. More than 90% is
absorbed, even in the presence of food or antacids. Serum
concentrations reach a peak in 1 to 3 hours. It circulates primarily
as free drug; only 20% to 25% is bound to plasma proteins. It is
partly metabolized in the liver (metabolites are inactive) and




                                   54
excreted in the urine. The half-life of felbamate is about 20-23
hours.


Unwanted effects
Headache,   insomnia,    anorexia,   fatigue,   nausea,   vomiting,
dyspepsia, weight loss, constipation and diarrhea were the most
frequent adverse effects reported with felbamate. They occurred in
less than 10% of patients, and were mainly mild to moderate in
severity, and seldom required discontinuation of the drug. Rash
developed in about 3% of patients taking felbamate and sometimes
required withdrawal of the drug. Leukopenia, thrombocytopenia,
agranulocytosis, and Stevens-Johnson syndrome have occurred
rarely, but only when felbamate was taken with other drugs.
Felbamate safety in pregnancy is unknown, so it is advised not to
be used during pregnancy.


Drug interactions
The metabolism of felbamate is complex; it apparently induces and
inhibits hepatic cytochrome P450 enzymes, leading to clinically
important interactions with several other antiepileptic drugs.
Felbamate decreases plasma concentrations of carbamazepine by
about 30%, but increases concentrations of the pharmacologically
active metabolite of carbamazepine, carbamazepine-10,11-epoxide
by about 60%. Felbamate increases serum concentrations of

                               55
phenytoin and valproate. Both phenytoin and carbamazepine
increase clearance of felbamate, but not that of valproate,
according to felbamate’s manufacturer.


Clinical uses
Felbamate appears to be effective against both partial and
generalized seizures. However, its main use today is in the
treatment of intractable seizures in children, associated with mental
retardation (Lennox-Gastaut syndrome).
The recommended starting dose for an adult is 1200mg of
felbamate per day in three or four divided doses. The dosage can be
increased biweekly in 600mg increments to 2400mg / day, if
necessary. It can be increased to a maximum of 3600mg / day. In
children with the Lennox-gastaut syndrome, the initial dosage of
felbamate is 15mg / kg / day in three or four divided doses,
increased weekly in 15mg / kg / day increments to a target dosage
of 45mg / kg / day. In both children and adults, a 20% to 30%
reduction in the daily dosage of phenytoin, valproate, or
carbamazepine when given concurrently with felbamate is usually
necessary to minimize adverse effects related to drug interactions.


TIAGABINE
Tiagabine is a derivative of nipecotic acid and was rationally
designed as an inhibitor of GABA uptake.

                                 56
Mechanism of action
Tiagabine inhibits GABA uptake into glial cells and neurones.


Pharmacokinetics
Tiagabine is very well absorbed when given orally. Food decreases
the peak plasma concentration but not the area under the curve
(AUC). It is highly protein bound with half-life of 5-8 hours. It
does not induce or inhibit liver microsomal enzymes and hepatic
impairment slightly decreases its clearance.



Unwanted effects
Dizziness, asthenia, nervousness, tremor, depression and emotional
lability.


Clinical uses
It appears to be effective against both partial and generalized tonic-
clonic seizures. The adult dose is 16-48 mg/day. The drug is given
three or four times per day.


TOPIRAMATE
Topiramate is a substituted monosaccharide structurally different
from all other antiepileptic drugs.
                                  57
Mechanism of action
Topiramate is a weak carbonic anhydrase inhibitor it probably acts
by blockade of sodium channels or within the GABA system.


Pharmacokinetics
Topiramate is well absorbed (about 4 hours), with an oral
bioavailability of 80 percent. Food does not affect its absorption,
minimal (15%) plasma protein binding, only moderate (20-50%)
metabolism and the metabolites are inactive, the remainder is
excreted unchanged in the urine. The lack of extensive metabolism
reduces its interactions with other antiepileptics. The half-life of
topiramate is about 20 to 30 hours. This renders it suitable for
once daily dosing. Increased plasma levels are seen with renal
failure and hepatic impairment.


Unwanted effects
These are primarily related to central nervous system and
gastrointestinal disturbances. They include impaired concentration
and memory, confusion, emotional lability with mood disorders
and depression, impaired speech, dizziness, drowsiness, fatigue,
visual disturbances, diplopia, nystagmus, taste disorder, abdominal
pain, nausea, anorexia and weight loss.


                                  58
Drug interactions
Topiramate decreases ethinylestradiol concentrations of oral
contraceptive preparations, and higher estrogen doses may be
required.   Inducers of hepatic enzymes such as phenytoin and
carbamazepine decrease topiramate plasma concentrations by
approximately 50 percent.


Clinical uses
The drug is indicated as adjunctive treatment of partial seizures
with or without secondary generalization.       Experience is still
limited with this drug. It is given initially as a single dose of 50-
100mg per day for a week and then very slowly increased to 200mg
daily in two divided doses for a further week, further dose
increments of 200mg daily should be made at weekly intervals;
usual dose 200-400mg daily in two divided doses.




                                 59
                         TREATMENT OF EPILEPSY
                                                           Usual Daily Oral Dosage        Usual Therapeutic
Seizure Type                  Drugs                        Adults             Children   serum concentrations
Tonic-clonic
(grand mal)
      Drug of choice:         Phenytoin                    300-400 mg        4-8 mg/kg            10-20 g/ml
                         OR   Valproate                  1000-3000 mg      15-60 mg/kg          50-120 g/ml
                         OR   Phenobarbital                 90-150 mg        2-5 mg/kg            15-35 g/ml
         Alternatives:        Lamotrigine                  100-500 mg     Not approved         Not established
                              Primidone                   750-1250 mg      10-20 mg/kg             6-12 g/ml
                              Carbamazepine               800-1600 mg      10-30 mg/kg             6-12 g/ml
Partial (focal)
(simple or complex)
      Drug of choice:         Carbamazepine               800-1600 mg      10-30 mg/kg             6-12 g/ml
                         OR   Phenytoin                    300-400 mg        4-8 mg/kg            10-20 g/ml
                         OR   Valproate                  1000-3000 mg      15-60 mg/kg          50-120 g/ml
         Alternatives:        Primidone                   750-1250 mg      10-20 mg/kg             6-12 g/ml
                              Phenobarbital                 90-150 mg        2-5 mg/kg            15-35 g/ml
                              Lamotrigine (as adjunct)     100-500 mg     Not approved         Not established
                              Gabapentin (as adjunct)     900-2400 mg     Not approved         Not established
Absence (Petit mal)
      Drug of choice:         Valproate                  1000-3000 mg      15-60 mg/kg          50-120 g/ml
                         OR   Ethosuximide                750-1250 mg      20-40 mg/kg          40-100 g/ml
         Alternatives:        Clonazepam                    1.5-20 mg         0.05-0.2            20-80 ng/ml
                              Lamotrigine                  100-500 mg           mg/kg          Not established
                                                                          Not approved
Myoclonic, Atonic
      Drug of choice:         Valproate                  1000-3000 mg      15-60 mg/kg          50-120 g/ml
         Alternatives:        Clonazepam                    1.5-20 mg         0.05-0.2            20-80 ng/ml
                              Felbamate (as adjunct)     1200-3600 mg           mg/kg          Not established
                                                                           15-60 mg/kg
Status Epilepticus
      Drug of choice:         Diazepam, i.v.                 10-20 mg    200-300 g/kg
                         OR   Phenytoin, i.v.             10-15 mg/kg                             10-20 g/ml
          Alternative:        Phenobarbital, i.v.           50-200 mg                             15-35 g/ml
Febrile Seizures              Diazepam,rectal*solutio               -        500 g/kg
                              n                                     -        250 g/kg
                              Diazepam, i.v.             1000-3000 mg      15-60 mg/kg          50-120 g/ml
                              Valproate
* Preferred

                                                    60
Guidelines for Anticonvulsant Therapy
   The decision whether or not to initiate drug therapy after a
    single major seizure remains controversial.
   Therapy should start with a single well-tried and relatively
    nontoxic drug. The majority of patients can be controlled on
    one drug (monotherapy). In patients receiving, and complying
    with optimal doses of a single antiepileptic drug, the addition
    of further agents is likely to result in a significant (>75%)
    improvement in seizure control in only approximately 10% of
    patients. Such a policy, however, inevitably increases the risks
    of dose-related, idiosyncratic reactions and chronic drug
    toxicity. Therefore, even when it is anticipated that multiple
    drug therapy will be required, medication is initiated with a
    single drug with gradual increases in the dose (over 2 to 3
    months) until seizures are controlled.
   If a single drug fails to control seizures it should not be
    replaced by another drug unless obvious toxicity or monitoring
    of drug concentration in plasma indicate that the patient is
    actually taking the medication as prescribed.
   If seizures continue despite high optimum blood levels after a
    single drug, either a second drug is added with a similar
    increase of the dose or to rapidly achieve optimum blood levels
    of the second drug and then gradually (to minimize the risk of
    precipitation of status epilepticus) withdraw the first drug. If

                                 61
    seizures continue despite optimum use of the two drugs, it is
    advisable not to add further drugs, but to explore non-
    pharmacological measures. It should be expected that some
    patients will continue to have seizures despite an optimum
    level of one or two drugs.
   Because of the many physical changes that take place as the
    child grows, it is not unusual for a seizure-free child to start
    having seizures again. This does not mean that medication is
    not effective or that the condition is getting worse, usually a
    change in the dose will control the seizure episodes.
   Abrupt withdrawal. Effective therapy must never be stopped
    suddenly either by the doctor or by the patient, or status
    epilepticus may occur. But if sudden withdrawal is imposed by
    occurrence of toxicity, a substantial dose of another
    antiepileptic should be given at once.
   This trial of drug after drug should be continued until the
    epilepsy is controlled, or until there are no more drugs to try.
    Up to 3 months may be needed to try a drug thoroughly in an
    individual.
   In cases where fits are liable to occur at a particular time of
    day, dosage should be adjusted to achieve maximal drug effect
    at that time.
   The patient should keep a diary of seizures.



                                 62
Pharmacokinetic Principles
Dose planning for individual antiepileptic drugs depends on
pharmacokinetics factors that determine the amount of available
drug in the blood. The therapeutic range refers to the range of
steady state levels of each drug that by trial and error have been
most effective in controlling seizures with minimal or no side
effects. The proper dose schedule for a newly introduced drug
depends on balancing the need for rapid control of seizures against
the avoidance of side effects. It is more important that the patient
accept the drug of first choice.     Patient can be encouraged to
remain on medication by beginning a drug regimen slowly, taking
the medication with meals when nausea is anticipated, using higher
doses at bedtime when sedation is anticipated, and reducing doses
transiently when ultrasound side effects occur. A loading dose can
be given practically for some drugs (phenytoin and phenobarbital)
when the risk of repeated seizures requires therapeutic levels to be
achieved rapidly despite side effects. Maintenance of steady-state
level of a drug can be achieved with an interdose interval of
approximately one-half life. A dose schedule that requires a drug
to be taken too frequently may be inconvenient and reduces
compliance. An interdose interval of 0.5 half-lives, which amounts
to one to four times a day for the commonly used medication is
usually recommended. Therapeutic failure using, recommended
dose schedules most commonly reflects noncompliance by the

                                63
patient, but also may result from aberrant absorption and
metabolism. Dose schedules must then be determined individually
from measurement of serum drug levels.            The recommended
therapeutic range for a given drug is based on average measures.
Once an effective maintenance schedule has been achieved,
determination of serum drug level, always drawn at some time after
a given dose, provide a reliable long-term record in steady state
conditions. Such measurements are useful when recurrent seizures
or side effects result from a decrease or an increase in the dose of
the drug.
Routine drug concentration monitoring is particularly useful with
phenytoin (which shows saturation kietics). It is seldom really
useful with other drugs unless there is a specific problem to be
solved.     Unnecessary monitoring wastes expensive resources.
Monitoring is useful in the following circumstances:
   2-4 weeks after commencing therapy
   When fits occur with standard dosage: the patient may be
    noncompliant, or compliant and simply needs a higher dose of
    the drug
   When adverse effects occur
   When       sodium   valproate    is   added   to   another   drug
    (pharmacokinetic interaction)
   When another antiepileptic drug is withdrawn in the presence
    of sodium valproate

                                    64
   During pregnancy
   When there is hepatic or renal disease.
Note. Many patients are controlled at plasma concentrations below
the lower limit of the therapeutic range, and substantial diurnal
fluctuations may occur.


Starting therapy
Antiepileptic treatment has been previously advocated before
seizure occurance. Such a prophylactic measure has been
undertaken in patients with a high prospective risk of epilepsy after
head injury and craniotomy.
Today single seizures are not routinely treated. This practice is
based on information from hospital-based surveys that indicate a
20-30% risk of a second seizure within 1-2 years of a first
unprovoked seizure. However, data from less selected populations
suggests that up to 80% of patients with a single seizure experience
a recurrence. Where two or more unprovoked seizures have
occurred within a short interval, antiepileptic therapy is usually
indicated. Problems do, however, arise in defining a short interval.
Most physicians would include period of 6 months to 1 year within
the definition, but difficulties arise regarding whether seizures
which occur in widely separated periods of time demand therapy or
not. Even when seizures occur in a close temporal relationship, the
identification of specific precipitating factors may make it more

                                 65
important to counsel patients than to commence drug therapy. The
most common examples are febrile convulsions in children and
alcohol-withdrawal seizures in adults. Less frequently seizures may
be precipitated in photosensitive subjects by television and other
photic stimuli.


Withdrawal
Considering that approximately 70% of patients achieve long-term
remission there is remarkably little data on the success or failure
rates following stoppage of antiepileptic therapy. Overall,
approximately 20% of children and 40% of adults are likely to
relapse when anticonvulsants are withdrawn after a seizure-free
period of 2 years or more. Some factors seem likely to influence
outcome. These include the duration of epilepsy and frequency of
seizures prior to the onset of remission, and whether the epilepsy is
symptomatic of an underlying cerebral disorder. The influence of
different seizure types on outcome and the question whether the
EEG may be predictive of outcome remain controversial, at least in
the adult patients.
To date it is hardly possible to identify groups of patients who are
particularly at high or low risk for relapse after discontinuation of
therapy. There is no indication of whether there is an optimal
period for continuing therapy while patients are in remission before



                                 66
drugs are withdrawn. It is also hardly possible to define an optimal
rate at which anticonvulsants should be withdrawn.


Abrupt withdrawal of antiepileptic drugs should be avoided as this
can cause increased seizure frequency and severity. Barbiturates
and benzodiazepines are the most difficult to discontinue.
Reduction in dosage should be carried out over weeks and in the
case of barbiturates, the withdrawal process may take months. The
change over from one antiepileptic drug regimen to another should
be made cautiously, withdrawing the first drug only when the new
regimen has been largely established. In patients receiving several
antiepileptic drugs, only one drug should be withdrawn at a time.
The decision to withdraw all antiepileptics from a seizure-free
patients, and its timing, is often difficult and may depend on
individual patient factors. Even in patients who have been seizure-
free for several years, there is a significant risk of seizure
recurrence on drug withdrawal. However, if a patient is seizure-
free for 3 or 4 years, gradual discontinuance is usually warranted.


Overdose
Antiepileptic drugs are central nervous system depressants, but are
rarely lethal. Highly elevated plasma levels are usually necessary
before overdoses can be considered life-threatening. Respiratory
depression is the most serious side effect seen after large overdoses

                                 67
of antiepileptics.     Treatment of antiepileptic drug overdose is
supportive; stimulants should not be used.        In addition, urine
alkalinization is usually ineffective to hasten removal of
antiepileptic drugs.


Common causes of failure of
antiepileptics
   Improper diagnosis of the type of seizures.
   Incorrect choice of drug.
   Inadequate or excessive dosage.
   Poor compliance by the patients.


Pregnancy, hormonal contraception and
anticonvulsants
The overall risk of birth defects in mothers who take an
anticonvulsant is around 5%, higher than in the general population.
Counseling before conception is essential. Some women choose to
withdraw the anticonvulsants prior to becoming pregnant. If drugs
are continued, monotherapy with a first-line drug is advisable
together with folic acid (5 mg a day) as supplement. Vitamin K
(20 mg) orally should also be prescribed daily to the mother during
the week prior to delivery, to prevent neonatal haemorrhage,
caused by inhibition of vitamin K transplacental transport.


                                  68
Anticonvulsants which induce hepatic enzymes (carbamazepine,
phenytoin and phenobarbitone) reduce efficacy of the contraceptive
pills. A combined contraceptive pill containing at least 50 g of
oestrogen, or an IUCD or barrier methods of contraception, should
be used.


Treatment             with        antiepileptic             drugs
during pregnancy
The effects of pregnancy on the antiepileptic drug disposition were
studied in humans and animals, but the results reported showed
great variability. At constant drug dosage the serum level of most
antiepileptic drugs tends to decrease during pregnancy, but returns
to pre-pregnancy levels within the first month after delivery. It is a
common practice to increase dosage whenever the plasma levels of
antiepileptic drugs are low. However, a decrease in plasma levels
of antiepileptic drugs alone does not generally justify an increase in
dose. The overall clinical state should be assessed.


Recent studies suggest that total carbamazepine serum levels are
slightly lower during the third trimester as compared with baseline,
whereas the unbound, pharmacologically active concentration
remains essentially unchanged. In contrast, while total phenytoin
serum levels decrease steadily as pregnancy progresses, unbound
                                 69
levels decrease far less. Total valproate serum levels also decrease
as pregnancy proceeds, but the change in unbound concentrations
may be significant. Serum levels of ethosuximide usually remain
fairly constant during pregnancy.


Recent findings indicate that total serum levels may be misleading,
and that monitoring of unbound concentrations may be
advantageous during pregnancy. Thus, preferably both total and
unbound serum levels should be closely monitored (once a month
in patients with unstable seizure control and less frequently in well
controlled patients) to determine the lowest effective dose and to
avoid the harmful effects of seizures and drugs to the mother and
fetus.


The changes in the pharmacokinetics of antiepileptic drugs
occurring during pregnancy may be due to decreased absorption of
the drugs, changes in the volume of distribution, protein binding
and hepatic elimination capacities. The use of antiepiliptic drugs
must be continued throughout the entire gestational period. Hence,
changes in their pharmacokinetics during pregnancy may have
important consequences both on the mother and the fetus.


A pregnant woman with epilepsy should be treated, whenever
possible, with a single antiepileptic drug, with the lowest effective


                                 70
dosage that protects against tonic-clonic seizures.       All major
changes in medication, if possible, should be made prior to
pregnancy.


Treatment during pregnancy demands a balance between the
possible teratogenic effects of antiepileptic drugs and the hazards
of seizures to mother and the foetus.


In recent years there has been an increased concern about the
potential teratogenic effects of antiepileptic drugs. A number of
epidemiological surveys in various parts of the world have reported
an increase in the incidence of cleft palate/lip, skeletal anomalies,
congenital heart disease, central nervous system abnormalities,
mental retardation and genitourinary anomalies in offsprings born
to mothers with epilepsy who are receiving antiepileptic drugs
during pregnancy when compared to the normal population.


Neonates born to mothers with epilepsy who have been treated
with antiepileptic drugs are at an increased risk of haemorrhage.
Neonatal hemorrhage can be prevented by giving women vitamin
K during pregnancy.


Studies have shown that children born to mothers with epilepsy
who had been taking drugs had roughly twice as many


                                 71
malformations as children of mothers in the population as a whole.
Since about 3% of all newborn babies have a significant congenital
abnormality the chance of the child of a mother with epilepsy
having a significant abnormality are about 6%. It is probably more
encouraging to talk to the mother in terms of a 94% chance of
having a normal child.       It is difficult in such a situation to
determine whether the increased malformation rate is due to the
disease or to the drugs used in its treatment.


Apart from the possibility of a genetic association between
epilepsy and the risk of fetal abnormality, seizures could cause
fetal damage through hypoxia or associated trauma.


Fetal monitoring during a maternal tonic-clonic seizure lasting
three minutes showed that the onset of the seizure was immediately
followed by fetal bradycardia lasting about 15 minutes. Prolonged
maternal seizures, or status epilepticus, could therefore harm the
fetus.


However, the incidence of malformations is higher in epileptics
receiving drug treatment during the relevant pregnancy.          The
evidence certainly seems fairly strong that the antiepileptic drugs
are teratogenic and this is supported by studies had been carried out
on these drugs in animals.


                                  72
All established major antiepileptic drugs (phenobarbital, phenytoin,
carbamazepine, ethosuximide and valpoate) have a teratogenic
potential. However, the available clinical data on the use of the
new drugs in human pregnancy are very limited and mainly
confined to new drugs used in combination with established
antiepileptic drugs. The documentation is not sufficient to allow
definitive conclusions on the teratogenic potential and profile, and
on the pharmacokinetics of the new drugs during pregnancy to be
drawn.


The prevalence of malformations appears to increase with
increasing numbers of antiepileptic drugs used concomitantly.
Hence, it is advisable to simplify anticonvulsant regimens to avoid
adverse effects and possible interactions between drugs.


Breast-feeding and antiepileptic drugs


Phenytoin
The levels of phenytoin in breast milk are much lower than in the
mother’s plasma, and the serum levels in nursing infants are
generally below the therapeutic levels. The clearance of phenytoin
in newborn infants who have been exposed to the drug prenatally


                                73
has been shown to be comparable to that in adults. Excessive
accumulation of the drug in infants would therefore not be
expected. Hence, there appears to be no risk to nursing infants if
phenytoin is given to the mother as monotherapy in normal doses.


Phenobarbital and Primidone
Phenobarbital, given directly or formed from primidone is
transferred via breast milk and can accumulate in the nursing
infant’s plasma.
The elimination of phenobarbital and primidone in neonates varies
greatly. Enzymes induction may play an important role. Infants
who have been exposed to phenobarbital or other drugs that induce
liver microsomal enzymes prenatally had generally show much
shorter half-lives for phenobarbitone or primidone than in the
unexposed neonates.


Due to the slow elimination of phenobarbital, especially in the first
weeks of life, accumulation of the drug to relatively high levels in
the infant’s plasma is possible. Sedation of the nursing infants is
seen during maternal use of phenobarbital.         Therefore, close
monitoring of the infant by determining the serum levels of
phenobarbital is recommended.




                                 74
Carbamazepine
Serum levels of carbamazepine in nursing infants have been found
to be low in general. Hence, breast feeding is considered to be safe
when the mother is on carbamazepine monotherapy at normal
doses.


Ethosuximide
Ethosuximide levels in breast milk are similar to those in maternal
plasma.   It can be transferred via breast milk to the child in
relatively high concentrations, and plasma concentrations in
nursing infants can be close to the recommended therapeutic levels.
However, it is not clear if such high concentrations would be
associated with any risk to the nursing child. Close monitoring of
the child is recommended, and plasma concentration measurements
may be useful.


Valproic acid
Concentrations of valproic acid in breast milk are low, usually less
than 10% of the concentrations in maternal plasma. Serum levels
of valproate in the nursing infant are low and not likely to cause
any adverse effects.    However, the possibility of idiosyncratic
reactions, even to low doses should be observed.


                                75
Clonazepam
Levels of clonazepam in breast milk have been reported to be 1:3
or 0.37 of the maternal plasma levels. These ratios are slightly
higher than those reported for diazepam (0.10 - 0.20). Respiratory
depression was reported in some infants who had been exposed to
clonazepam during pregnancy.


Lamotrigine, vigabatrin, gabapentin and
felbamate.
Lamotrigine is to a large extent glucuronidated via the so-called
UDP - glucuronyl transferase. In the newborn, the capacity to
glucuronidate is not fully developed, but increases gradually during
the first months of life. Hence, it is likely that the infant’s ability
to eliminate lamotrigine will be affected.           Vigabatrin and
gabapentin are mainly excreted unchanged in the urine.            It is
unlikely that infants with fully developed renal function will
accumulate these drugs.      Felbamate should be avoided during
breast feeding, because of the risk of serious haematological
adverse effects to the infant, which are probably not directly related
to the drug concentrations in plasma.

Index
absence seizure (petit mal), 1
acetylcholine, 51
                                  76
alopecia, 37
Alzheimer’s disease, 3
-aminobutyric acid (GABA), 29, 49
anorexia, 54, 57
antacids, 16, 53
anticoagulants, 17, 21
antihistamines, 43
aplastic anaemia, 13, 40
arrythmias, 22
ataxia, 18, 24, 31, 47, 52
atonic seizures, 10

benzodiazepines, 4, 13, 21, 41-43, 45, 66
blood brain barrier, 30
blood dyscrasias, 40
brain tumor, 3
breast milk, 72-75
breast-feeding, 72, 74-75

carbamazepine, 13, 20-21, 23-24, 26-28, 38, 48-49, 53-55,
                                        58-59, 68, 72, 74
cardiac depression, 42
cardiovascular collapse, 18
catecholamine, 51
cerebral abscess, 3
chloramphenicol, 20, 21
chlorazepate dipotassium, 44
cimetidine, 20, 21, 26, 27
cimetidine, 21, 27



cleft lip, 18, 70
cleft palate, 18, 70
clobazam, 13, 45
clonazepam, 13, 24, 27, 38, 43-44, 59, 75
complex partial seizures, 7, 32, 44
                               77
constipation, 54

Developmental anomalies, 2
diarrhea, 7, 54
diazepam, 11, 13, 32, 42-43, 59, 75
dicumarol, 20, 21, 31
digitalis, 22, 31
Diltiazem, 26
diplopia, 18, 24, 28, 47, 57
dizziness, 24, 40, 52, 56, 57
drowsiness, 18, 24, 44, 5
dyspepsia, 54

electroencephalogram (EEG), 4, 12, 14, 65
encephalitis, 3
eosinophilia, 40
erythromycin, 26, 27
ethinylestradiol, 58
ethosuximide, 27, 39, 40-41, 44, 59, 59, 72, 74
euphoria, 40

febrile seizures, 10, 32, 59
felbamate, 13, 46, 53-55, 59, 75
fetal bradycardia, 71
first-order kinetics, 16

gabapentin, 46, 51-52, 59, 75
GABA-transaminase, 35, 39
generalized seizures, 3, 6, 8, 32, 55


generalized tonic-clonic seizures, 6, 10, 12, 22, 27, 32,
                                               34,38, 48, 56
Gingival hyperplasia, 17
glucuronide, 16, 47
glucuronyl transferase, 75
glutamate, 29, 46
                                 78
glutamic oxaloacetic transaminase (GSGOT),   37
griseofulvin, 31

heart burn, 36
hemorrhage, 2, 31, 70
hepatic impairment, 48, 56-57
hepatotoxicity, 37
hirsutism, 18
hydantoin fetal syndrome, 19
hyperammonemia, 37
hyperglycemia, 2, 18, 37
hypersensitivity reactions, 18, 31
hyperthermia, 3
hyponatraemia, 2, 25

imipramine, 23, 48
infantile spasm, 32, 44
insomnia, 54
isoniazid, 20, 21, 26, 27

Jacksonian epilepsy, 7
juvenile myoclonic, 9

Ketogenic diet, 13

lamotrigine, 13, 46-49, 59, 75
Lennox-Gastaut syndrome, 12-13, 44, 49, 55
lethargy, 40, 44


leukopenia, 25, 33, 54
lymphadenopathy, 18, 47

megaloblastic anemia, 18, 33
mental retardation, 2, 12, 55, 70
meprobamate, 53
metabolic abnormalities, 2
                                79
microsomal enzymes, 17, 21, 24, 30, 32, 56, 73
myoclonic, 9, 12-13, 38, 43-44, 49, 59

neonatal bleeding, 25, 37
neurosyphilis, 3
nitrazepam, 13, 44

opioid receptors, 51
oral anticoagulants, 17
oral contraceptives, 17, 27, 30
osteomalacia, 18, 31
overdose, 4, 31, 66-67

pancytopenia, 40
paradoxic hyperactivity, 42
Parkinson’s disease, 49
partial seizures, 6, 22, 27, 32, 34, 44, 38, 44, 50, 52, 58
peripheral neuropathy, 28
phenobarbital, 27, 29-34, 37-38, 48, 59, 62, 72, 73
phenylbutazone, 21
phenylethyl malonamide, 32, 33
phenylketonuria, 2
Phenytoin, 13, 15-20, 21-23, 27-29, 31-34, 37-38, 48-50,
                              53-55, 58-59, 62-63, 68, 72-73
photosensitivity, 4
pregnancy, 25, 37, 47, 52, 54, 64, 67-72, 75
primary epilepsy, 4, 5
primidone, 24, 27, 32-34, 48, 59, 73

propoxyphene, 26, 27
Psychomotor epilepsy, 7

rash, 33, 37, 47, 54
rebound seizures, 31
respiratory depression, 42-43, 66, 75

secondary epilepsy, 5
                                  80
simple partial seizures, 7, 32
skin rashes, 18, 25
somnolence, 47, 52
starting therapy, 40, 64
status epilepticus, 12, 16, 19, 22, 32, 42-43, 59-61, 71
steroids, 30
Stevens-Johnson syndrome, 25, 40, 54
succinic semialdehyde dehydrogenase, 35
sulfonamides, 20, 21
systemic lupus erythematosus, 33, 40

teratogenesis, 25
teratogenic effects, 28, 70
thrombocytopenia, 33, 37, 54
tiagabine, 46, 55-56
toleandomycin, 27
tolerance, 13, 31, 42
tonic-clonic seizures, 6, 9, 22, 27, 32, 34, 40, 48, 56, 70
topiramate, 46, 56, 57, 58
tricyclic antidepressants, 4, 23, 30
trigeminal neuralgia, 22-23, 27-28
tuberculosis, 3

valproic acid, 13, 16, 24, 27, 32, 35-38, 40, 48, 74
venous thrombosis, 3
vertigo, 18, 31


vigabatrin, 13, 46, 49-50, 75
visual disturbances, 50, 57
vitamin D, 18
vitamin K, 25, 67, 70

warfarin, 27, 30
weight gain, 50
weight loss, 54, 57
withdrawal, 4-5, 15, 31, 47, 54, 61, 65-66
                                 81
zero-order kinetics, 16


REFERENCES:

Al-Humayyd, M.S. Effect of metoclopramide on lamotrigine
      absorption in rabbits. Int. J. Pharm., 144; 171-175, 1996.

Al-Humayyd, M.S. Elevation of Carbamazepine Plasma Level by
      diltiazem in rabbits: A Potentially Important Drug
      Interactions. Biopharm. Drug Dispos., 11; 411-417, 1990.

Al-Humayyd, M.S. Ciprofloxacin decreases plasma phenytoin
      concentrations in the rat. Eur. J. Drug Metab., 22; 35-39,
      1997.

Al-Humayyd, M.S. Diltiazem and verapamil elevate plasma
      phenytoin concentration in the rat. Int. J. Pharmaceutics,
      131; 153-158, 1996.

Al-Humayyd, M.S. Pharmacokinetic interaction between
      erythromycin, clarithromycin, roxythromycin and phenytoin
      in rat. Chemotherapy, 43; 77-85, 1997.

Al-Humayyd, M.S., Effect of pregnancy on the pharmacokinetics
      of lamotrigine in rabbits. Saudi Pharma. J., 5; 90-95, 1997.

Altafullah I., Talwar D., Loewenson R., Olson K., Lockman L.A.
        Factors influencing serum levels of carbamazepine and
        carbamazepine-10,11-epoxide in children. Epilepsy Res., 4
        (1); 72-80, 1989.

Alvarez N, Besag F, Iivanainen M. Use of antiepileptic drugs in the
       treatment of epilepsy in people with intellectual disability.
       J. Intellect. Disabil. Res., 42 Suppl 1; 1-15, 1998.

                                82
Alvarez N., Besag F., Iivanainen M. Use of antiepileptic drugs in
       treatment of people with intellectual disability. J. Intellect.
       Disabil. Res., 42 Suppl. 1; 1-15, 1998.

Appleton RE. The new antiepileptic drugs. Arch. Dis. Child., 75
       (3); 256-262, 1996.

Armijo JA, Cuadrado A, Bravo J, Arteaga R. Vigabatrin serum
      concentration to dosage ratio; influence of age and
      associated antiepileptic drugs. Ther. Drug. Monit., 19 (5);
      491-498, 1997.

Armijo JA. Which drugs should be chosen for the different types of
      epilepsy? Rev. Neurol., 25 (139); 356-366, 1997.

Arzimanoglou AA, Dumas C, Ghirardi L. Multicentre clinical
      evaluation of vigabatrin (Sabril); in mild to moderate
      partial epilepsies, French Neurologists Sabril Study Group.
      Seizure, 6 (3); 225-231, 1997.

Azarbayjani F, Danielsson BR. Pharmacologically induced
      embryonic dysrhythmia and episodes of hypoxia followed
      by reoxygenation, a common teratogenic mechanism for
      antiepileptic drugs? Teratology, 5 (3); 117-126, 1998.

Barron TF, Hunt SL. A review of the newer antiepileptic drugs and
       the ketogenic diet. Clin. Pediatr., 36 (9); 513-521, 1997.

Battino D, Croci D, Granata T, Estienne M, Pisani F, Avanzini G.
       Lamotrigine plasma concentrations in children and adults,
       influence of age and associated therapy. Ther. Drug.
       Monit., 19 (6); 620-627, 1997.

Battino D, Estienne M, Avanzini G. Clinical pharmacokinetics of
       antiepileptic drugs in paediatric patients - Part II.
       Phenytoin, carbamazepine, sulthiame, lamotrigine,
       vigabatrin,   oxcarbazepine     and    felbamate.  Clin.
       Pharmacokinet., 29 (5); 341-369, 1995/
                                 83
Battino D., Croci D., Granata T., Estienne M., Pisani F., Avanzini
       G. Lamotrigine plasma concentrations in children and
       adults: Influence of age and associated therapy. Ther.
       Drug. Monit., 19 (6); 620-627, 1997.

Battino D., Estienne M., Avanzini G. Clinical pharmacokinetics of
       antiepileptic drugs in paediatric patients.       Part I:
       Phenobarbital, primidone, valproic acid, ethosuximide and
       mesuximide. Clin. Pharmacokinetic, 29 (4); 257-286,
       1995.

Bauer J. Anticonvulsant combination therapy: rational concepts
      versus real effectiveness. Fortschr. Neurol. Pyschiatr., 66
      (9); 414-426, 1998.

Bauer J. Seizure-inducing effects of antiepileptic drugs. a review.
       Acta. Neurol. Scand., 94 (6); 367-377, 1996.

Bauer J. Anticonvulsant combination therapy. rational concepts
      versus real effectiveness. Fortschr. Neurol. Psychiatr., 66
      (9); 414-426, 1998.

Baulac M, Arzimanoglou A, Semah F, Cavalcanti D. Therapeutic
       options provided by new antiepileptic drugs. Rev. Neurol.,
       155 (1); 21-33, 1997.

Bazil C.W., Pedley T.A. Advances in the medical treatment of
       epilepsy. Annu. Rev. Med., 49; 135-162, 1998.

Bazil CW, Pedley TA. Advances in the medical treatment of
      epilepsy. Annu. Rev. Med., 49, 135-162, 1998

Belanger S, Coulombe G, Carmant L. Role of vigabatrin and
      lamotrigine in treatment of childhood epileptic syndromes.
      Epilepsia, 39 (8); 878-883, 1998.

Ben-Menachem E. Vigabatrin. Epilepsia, 36 Suppl 2; S95-104,
     1998.
                                84
Ben-Menachem E. Expanding antiepileptic drug options, clinical
     efficacy of new therapeutic agents. Epilepsia, 37 Suppl 2;
     S4-S7, 1996.

Berkovic SF . Aggravation of generalized epilepsies. Epilepsia, 39
      Suppl 3; S11-14, 1998.

Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Loiseau P,
       Perucca E. Progress report on new antiepileptic drugs, a
       summary of the Third Eilat Conference. Epilepsy Res., 25
       (3); 299-319, 1996.

Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Loiseau P,
       Perucca E. Progress report on new antiepileptic drugs, a
       summary of the fourth Eilat conference (EILAT IV).
       Epilepsy Res., 34 (1); 1-41, 1999.

Bialer M. Comparative pharmacokinetics of the newer antiepileptic
       drugs. Clin. Pharmacokinet., 24 (6); 441-452, 1993.

Blennow G., Heijbel J., Sandstedt P., Tonnby B. Discontinuation
      of antiepileptic drugs in children who have outgrown
      epilepsy: effects on cognitive function. Epilepsia, 31
      Suppl. 4; 50-53, 1990.

Bourgeois BF.        Important pharmacokinetic properties       of
      antiepileptic drugs. Epilepsia, 36 Suppl; S1-7, 1995.

Bourgeois BF. New antiepileptic drugs. Arch. Neurol., 55 (9);
      1181-1183, 1998.

Bourgeois BF. New antiepileptic drugs. Curr. Opin. Pediatr., 8 (6);
      543-548, 1996.

Brodie M.J., Dichter M.A. Established antiepileptic drugs.
      Seizure, 6 (3); 159-174, 1997.



                                85
Brodie MJ. Monostars - an aid to choosing an antiepileptic drug as
       monotherapy. Epilepsia, 40 Suppl 6; S17-22, discussion
       S73-74, 1999.

Browne TR . Pharmacokinetics of antiepileptic drugs. Neurology,
      51 (5 Suppl 4); S2-7, 1998.

Buoni S., Grosso S., Fois A. Lamotrigine in typical absence
      epilepsy. Brain Dev., 21 (5); 303-306, 1999.

Carvill S, Clarke D, Cassidy G. The management of epilepsy in a
        hospital for people with a learning disability. Seizures, 8
        (3); 175-180, 1999.

Chadwick DW, Marson T, Kadir Z. Clinical administration of new
      antiepileptic drugs, an overview of safety and efficacy.
      Epilepsia, 37 Suppl 6; S17-22, 1996.

Chadwick DW. An overview of the efficacy and tolerability of new
      antiepileptic drugs. Epilepsia, 38 Suppl 1; S59-62, 1997.

Chapman D.P., Giles W.H. Pharmacologic and dietary therapies in
     epilepsy: conventional treatments and recent advances.
     South Med. J., 90 (5); 471-480, 1997.

Chapman DP, Giles WH. Pharmacologic and dietary therapies in
     epilepsy. conventional treatments and recent advances.
     South. Med. J., 90 (5); 471-480, 1997.

Chiron C, Dulac O, Gram L. Vigabatrin withdrawal randomized
       study in children. Epilepsy Res., 25 (3); 209-215, 1996.

Chiron C. Role of physiopathological hypotheses in therapeutic
      choice in epilepsy in children. Rev. Neurol., 153 Suppl 1;
      S34-38, 1997.




                                86
Cockerell OC, Moriarty J, Trimble M, Sander JW, Shorvon SD.
      Acute psychological disorders in patients with epilepsy, a
      nation-wide study. Epilepsy Res., 25 (2); 119-131, 1996.

Connelly JF. Vigabatrin. Ann. Pharmacother., 27 (2); 197-204,
      1993.



Copovilla G., Beccaria F., Veggiotti P., Rubboli G., Melettti S.,
      Tassinari C.A. Ethosyximide is effective in the treatment
      of epileptic negative myoclonus childhood partial epilepsy.
      J. Child Neurol., 14 (6); 395-400, 1999.

Coulter D.A. Antiepileptic drug cellular mechanisms of action:
       where does lamotrigine fill in? J. Child Neurol., 12 Suppl.
       1; 2-9, 1997.

Coulter DA. Antiepileptic drug cellular mechanisms of action,
       where does lamotrigine fit in? J. Child. Neurol., 12 Suppl
       1; S2-9, 1997.

Cramer JA, Fisher R, Ben-Menachem E, French J, Mattson RH.
      New antiepileptic drugs. comparison of key clinical trials.
      Epilepsia, 40 (5); 590-600, 1999.

Czuczwar S.J., Gasior M., Kozicka M., Pietrasiewicz T., Turski
      W.A., Kleinrok Z. Influence of a potential anti-asthmatic
      drug, CR 2039, upon the anticonvulsive activity of
      conventional antiepileptics against maximal electroshock-
      induced seizures in mice. J. Neural. Transm., 103 (12);
      1371-1379, 1996.

Davies J.A. Mechanisms of action of antiepileptic drugs. Seizure,
       4 (4); 267-271, 1995.

Davies JA. Mechanisms of action of antiepileptic drugs. Seizure, 4
       (4); 267-271, 1995.
                               87
De Toffol B., Hommet C., Corcia P., Autret A. Anticonvulsant
      can aggravate idiopathic generalized epilepsy.   Rev.
      Neurol., 154 (11); 753-756, 1998.

Declerck A.C., Wauquier A. Influence of antiepileptic drugs on
       sleep patterns. Epilepsy Res. Suppl., 2; 153-163, 1991.



Divanoglou D., Orologas A., Iliadis S., Nathanael V.,
      Constantinidis T.C. Pharmacokinetic behaviour of
      carbamazepine and its main metabolite-10, 11 epoxide of
      carbamazepine in monotherapy or in combination with
      other anti-epileptic drugs. Eur. J. Neurol., 5 (4); 397-400,
      1998.

Divanoglou D., Orologas A., Iliadis S., Nathanael V.,
      Constantinidis T.C., Milona I. Pharmacokinetic behaviour
      of carbamazepine and its main metabolite-10,11 epoxide of
      carbamazepine in monotherapy or in combination with
      other anti-epileptic drugs. Eur. J. Neurol., 5 (4); 397-400,
      1998.

Dulac O, Chiron C, Luna D, Cusmai R, Pajot N, Beaumont D,
      Mondragon S. Vigabatrin in childhood epilepsy. J. Child.
      Neurol., Suppl 2; S30-37, 1991.

Duncan J.S., Patsalos P.N., Shorvon S.D.             Effects of
      discontinuation of phenytoin, carbamazepine, and valproate
      on concomitant antiepileptic medication. Epilepsia, 32 (1);
      101-115, 1991.

Elger CE, Bauer J, Scherrmann J, Widman G. Aggravation of focal
       epileptic seizures by antiepileptic drugs. Epilepsia, 39
       Suppl 3; S15-18, 1998.

Elger CE, Bauer J. New antiepileptic drugs in epileptology.
      Neuropsychobiology, 38 (3); 145-148, 1998.
                               88
Elwes RD, Binnie CD. Clinical pharmacokinetics of newer
      antiepileptic drugs; lamotrigine, vigabatrin, gabapentin and
      oxcarbazepine. Clin. Pharmacokinet., 30 (6); 403-415,
      1996.

Emilien G, Maloteaux JM. Pharmacological management of
       epilepsy; Mechanism of action, pharmacokinetic drug
       interactions, and new drug discovery possibilities. Int. J.
       Clin. Pharmacol. Ther., 36 (4); 181-189, 1998.

Emilien G., Maloteaux J.M. Pharmacological management of
       epilepsy: Mechanism of action, pharmacokinetic drug
       interactions, and new drug discovery possibilities. Int. J.
       Clin. Pharmacol. Ther., 36 (4); 181-194, 1998.

Encinas M.P., Santos Buelga D., Alonso Gonzales A.C., Garcia
       Sanchez M.J., Domingu-Gil Hurle A. Influence of length
       of treatment on the interaction between phenobarbital and
       phenytoin. J. Clin. Pharm. Ther., 17 (1); 49-50, 1992.

Eriksson A.S., Hoppu K., Nergardh A., Boreus L.
       Pharmacokinetic interactions between lamotrigine and
       other antiepileptic drugs in children with intractable
       epilepsy. Epilepsia, 37 (8); 769-773, 1996.

Eriksson AS, O'Connor WT. Analysis of CSF amino acids in
       young patients with generalised refractory epilepsy during
       an add-on study with lamotrigine. Epilepsy Res., 34 (1);
       75-83, 1999.

Ferrie CD, Robinson RO, Panayiotopoulos CP. Psychotic and
       severe behavioural reactions with vigabatrin - a review
       [see comments]. Acta. Neurol. Scand., 93 (1); 1-8, 1996.

Fisher R, Kalviainen R, Tanganelli P, Regesta G. Newer
       antiepileptic drugs as monotherapy. data on vigabatrin.
       Neurology, 47 (1 Suppl 1); S2-5, 1996.

                               89
Fisher RS. Emerging antiepileptic drugs. Neurology, 43 (11 Suppl
       5); S12-20, 1993.

Fraser C.M., Sills G.J., Forrest G., Thompson G.G., Brodie M.J.
       Effects of anti-epileptic drugs on glutamine synthetase
       activity in mouse brain. Br. J. Pharmacol., 126 (7); 1634-
       1638, 1999.

Frazer C.M., Sills G.J., Forrest G., Thompson G.G., Brodie M.J.
       British J. Pharmacol., 136 (7); 1634-1638, 1999.

French JA. Vigabatrin. Epilepsia, 40 Suppl 5; S11-16, 1999.

Gaily E., Kantola-Sorsa E., Granstrom M.L. Specific cognitive
       dysfunction in children with epileptic mothers. Dev. Med.
       Child Neurol., 32 (5); 403-414, 1990.

Garaizar C, Perez-Garcia J, Gil-Anton J, Prats JM. Therapeutic
       failure, treatment and non-treatment of childhood epilepsy.
       Rev. Neurol., 27 (157); 467-472, 1998.

Garduno-Espinosa A., Gonzales-Astiazaran A., Calvo-Gonzales
      M.S., Valderrabano-Ojeda L., Maulen-Radovan I. Status
      epilepticus in children. Study of 70 cases. Bol. Med. Hosp.
      Infant Mex., 47 (8); 567-575, 1990.

Gigli G.L., Scalise A., Silvestri G., Diomedi M., Placidi F.,
      Pomponi M.G., Masala C. Clinical case report: multiple
      idiosyncratic adverse effects of antiepileptic drugs in
      trisomy 9p. Int. J. Neurosci., 87 (3-4); 181-189, 1996.

Gillham R., Baker G., Thompson P., Birbeck K., McGuire A.,
       Tomlinson L., Eckersle L., Silveira C., Brown S.
       Standardization of a self-report questionnaire for use in
       evaluating cognitive, affective and behavioral side-effects
       of anti-epileptic drug treatments. Epilepsy Res., 24 (1); 47-
       55, 1996.

                                90
Gomez Bellver M.J., Garcia Sanchez M.J., Alonso Gonzales A.C.,
     Santos Buelga D., Dominguez-Gil A. Plasma protein
     binding kinetics of valproic acid over a broad dosage range:
     therapeutic implications. J. Clin. Pharm. Ther., 18 (3);
     191-197, 1993.

Gram L. Pharmacokinetics of new antiepileptic drugs. Epilepsia,
      37 Suppl 6; S12-16, 1996.

Graves N.M., Kriel R.L. Rectal administration of antiepileptic
      drugs in children. Pediatr. Neurol., 3 (6); 321-326, 1997.

Graves NM, Leppik IE. Advances in pharmacotherapy. recent
      developments in the treatment of epilepsy. J. Clin. Pharm.
      Ther., 18 (4); 227-242, 1993.

Grippo J . Treatment of the epilepsy - new drugs. Rev Neurol., 24
       (135); 1435-40, 1996.

Guberman A. Monotherapy or polytherapy for epilepsy? Can. J.
      Neurol. Sci., 25 (4); pS3-8, 1998.

Guerrini R, Belmonte A, Genton P. Antiepileptic drug-induced
       worsening of seizures in children. Epilepsia, 39 Suppl 3;
       S2-10, 1998.

Haider A, Tuchek JM, Haider S. Seizure control. how to use the
       new antiepileptic drugs in older patients. Geriatrics, 51 (9);
       42-45, 1996.

Henskens Y.M., Strooker H., van den Keibus P.A., Veerman E.C.,
      Nieuw Amerongen A.V. Salivary protein composition in
      epileptic patients on different medications. J. Oral Pathol.
      Med., 25 (7); 360-366, 1996.

Henskens Y.M., Strooker H., van den Keijbus P.A., Veerman E.C.,
      Nieuw Amerongen A.V. Salivary protein composition in


                                 91
       epileptic patients on different medications. J. Oral Pathol.
       Med., 25 (7); 360-366, 1996.

Herranz JL . Advantages and disadvantages of new antiepileptic
       drugs. Rev. Neurol, 24 (135); 1426-1434, 1996.

Herranz JL, Arteaga R, Farr IN, Valdizan E, Beaumont D, Armijo
       JA. Dose-response study of vigabatrin in children with
       refractory epilepsy. J. Child Neurol, Suppl 2; S45-51;
       1996.




Hiraoka A., Arato T., Tominaga I. Reduction in blood free
       cartinine levels in association with changes in sodium
       valproate (VPA) disposition in epileptic patients treated
       with VPA and other anti-epileptic drugs. Biol. Pharm.
       Bull., 20 (1); 91-93, 1997.

Hiraoka A., Arato T., Tominaga I. Reduction in blood free
       carnitine levels in association with changes in sodium
       valproate (VPA) disposition in epileptic patients treated
       with VPA and other anti-epileptic drugs. Biol. Pharm.
       Bull., 20 (1); 91-93, 1997.

Hiraoka A., Miura I., Sato M., Tominaga I., Hattori M. Effects of
       anti-epileptic drugs on the L-tryptophan binding to human
       serum albumin. Chem. Pharm. Bull., 40 (6); 1629-1630,
       1992.

Hiraoka A., Miura I., Sato M., Tominaga I., Hattori M. Effects of
       anti-epileptic drugs on the L-tryptophan binding to human
       serum albumin. Chem. Pharm. Bull., 40 (6); 1629-1630,
       1992.



                                92
Hunter J.C., Gogas K.R., Hedley L.R., Jacobson L.O., Kassotakis
       L., Thompson J., Font D.J. The effect of novel anti-
       epileptic drugs in rat experimental models of acute and
       chronic pain. Eur. J. Pharmacol., 324 (2-3); 153-160, 1997.

Iaria P, Blacher J, Asplanato M, Edric K, Safar M, Girerd X. A
        new cause of resistant arterial hypertension, coprescription
        with anticonvulsant treatments. Arch. Mal. Coeur, Vaiss.,
        92 (8); 1005-1008, 1999.

Ichikou N., Ieiri I., Higuchi 1s., Hirata K., Yamada H., Aoyama T.
       Analysis of the factors influencing anti-epileptic drug
       concentrations - carazepine. J. Clin. Pharm. Ther., 15 (5);
       337-349, 1990.



Ichikou N., Ieiri I., Higuchi S., Hirata K., Yamada H., Aoyama T.
       Analysis of the factors influencing anti-epileptic drug
       concentrations – carbamazepine. J. Cllin. Pharm. Ther., 15
       (5); 337-349, 1990

Ieiri I., Higuchi S., Hirata K., Yamada H., Aoyama T. Analysis of
          the factors influencing anti-epileptic drug concentrations -
          valporic acid. J. Clin. Pharm. Ther., 15 (5); 351-363, 1990.

Ieiri I., Higuchi S., Hirata K., Yamada H., Aoyama T. Analysis of
          the factors influencing anti-epileptic drug concentrations –
          Valproic acid. J. Clin. Pharm. Ther., 15 (5); 351-363,
          1990.

Isojarvi J.I., Tokola R.A. Benzodiazepines in the treatment of
        epilepsy in people with intellectual disability.      J.
        Intellectual Disabil. Res., 42 Suppl. 1; 80-92, 1998.

Jallon P. Monotherapy and polytherapy use of anti-epileptic drugs.
        Development of views. Rev. Neurol., 153 Suppl. 1; 29-33,
        1997.
                                 93
Johannessen SI. Pharmacokinetics and interaction profile of
      topiramate. review and comparison with other newer
      antiepileptic drugs. Epilepsia, 38 Suppl 1; S18-23, 1997.

Kamali F., McLaughlin W.S., Ball D.E., Seymour R.A. The effect
      of multiple anticonvulsant therapy on the expression of
      phenytoin induced gingival overgrowth.         J. Clin.
      Periodontol., 26 (12); 802-805, 1999.

Karande S.C., Joshi M.V., Kshirsagar N.A., Shah P.U. An analysis
      of epileptic patients nonresponsive to drugs. J. Assoc.
      Physicians India, 40 (7); 445-447, 1992.




Kasteleijn-Nolst Trenite D.G., Marescaux C., Stodieck S.,
       Edelbroek P.M., Oosting J. Photosensitive epilepsy: a
       model to study the effects of antiepileptic drugs.
       Evaluation of the piracetam analogue, levetiracetem.
       Epilepsy Res., 25 (3) 225-230, 1996.

Kasteleijn-Nolstlt Trenite DG, Edelbroek PM. Antiepileptic drug
       treatment in the nineties in The Netherlands. Pharm. World
       Sci., 19 (2); 60-69, 1997.

Ketter TA, Post RM, Theodore WH. Positive and negative
       psychiatric effects of antiepileptic drugs in patients with
       seizure disorders. Neurology, 53 (5 Suppl 2; S53-67, 1997.

Kim SS, Chang KH, Kim ST, Suh DC, Cheon JE, Jeong SW, Han
      MH, Lee SK. Focal lesion in the splenium of the corpus
      callosum in epileptic patients. antiepileptic drug toxicity?
      AJNR Am. J. Neuroradiol., 20 (1); 125-129, 1999.




                               94
Knake S, Hamer HM, Schomburg U, Oertel WH, Rosenow F.
      Tiagabine-induced absence status in idiopathic generalized
      epilepsy. Seizure, 8 (5); 314-317, 1999.

Knudsen F.U. Intermittent diazepam prophylazis in febrile
      convulsions - pros and cons. Acta. Neurol. Scand. Suppl.,
      135; 1-24, 1991.

Kochen S. Costing of antiepileptic drugs [letter]. Lancet, 347
      (8996); 266, 1996.

Kohler M, Hoffmann GF. Value of the new anticonvulsants in
      pediatrics. Klin. Padiatr., 210 (1); 17-23, 1998.

Kuenzle C, Steinlin M, Wohlrab G, Boltshauser E, Schmitt B.
      Adverse effects of vigabatrin in Angelman syndrome.
      Epilepsia, 39 (11); 1213-1215, 1998.



Kulkarni C., David J., Joseph T. Influence of adenosine,
      dipyridamole, adenosine antagonists and antiepileptic drugs
      on EEG after discharge following cortical stimulation.
      Indian J. Exp. Biol., 35 (4); 342-347, 1997.

Kuzuya T., Hasegawa T., Shimizu K., Nabeshima T. Effect of
      anti-epileptic drugs on serum zinc and copper
      concentrations in epileptic patients. Int. J. Clin. Pharmacol.
      Ther. Toxicol., 31 (2); 61-65, 1993.

Le Guellec C, Gaudet ML, Breteau M. Improved selectivity for
      high-performance liquid chromatographic determination of
      clonazepam in plasma of epileptic patients. J. Chromatogr.
      B. Biomed. Sci. Appl., 719 (1-2); 227-233, 1998.

Lee BI. New antiepileptic drugs. II - clinical use. J. Korean. Med.
       Sci., 11 (4); 289-304, 1996.


                                95
Leppik IE. Role of new and established antiepileptic drugs.
      Epilepsia, 39 Suppl 5; 2-6, 1998.

Levy R.H. Cytochrome P450 isozymes and antiepileptic drugs
      interactions. Epilepsia, 36 Suppl. 5; 8-13, 1995.

Liu H., Forman L.J., Montoya J., Eggers C., Barham C., Delgado
       M. Determination of valproic acid by high-performance
       liquid chromatography with photodiode-array and
       flourescence detection. J. Chromatogr., 576 (1); 163-169,
       1992.

Lopez L., Thomson A., Rabinowicz A.L. Assessment of colour
      vision in epileptic patients exposed to single-drug therapy.
      Eur. Neurol., 41 (4); 201-205, 1999.

Lortie A, Chiron C, Mumford J, Dulac O. The potential for
       increasing seizure frequency, relapse, and appearance of
       new seizure types with vigabatrin. Neurology, 43 (11 Suppl
       5); S24-27, 1993.

Loscher W., Rundfeldt C. Kindling as a model of drug-resistant
      partial epilepsy: selection of phenytoin-resistant and non-
      resistant rants. J. Pharmacol. Exp. Ther., 258 (2); 483-489,
      1991.

Loscher W., Rundfeldt C. Kindling as a model of drug-resistant
      partial epilepsy: selection of phenytoin-resistant and
      nonresistant rats. J. Pharmacol. Exp. Ther., 258 (2); 483-
      489, 1991.

Macdonald R.L. Is there a mechanistic basis for rational
     polypharmacy? Epilepsy Res. Suppl., 11; 79-93, 1996.

Macdonald R.L., Kelly K.M. Antiepileptic drug mechanisms of
     action. Epilepsia, 36 Suppl 2; 2-12, 1995.



                               96
Macdonald R.L., Kelly K.M. Antiepileptic drug mechanisms of
     action. Epilepsia, 34 Suppl. 5; 1-8, 1993.

Macdonald RL, Kelly KM. Antiepileptic drug mechanisms of
     action. Epilepsia, 36 Suppl 2; S2-12, 1995.

Macdonald RL. Is there a mechanistic basis for rational
     polypharmacy? Epilepsy Res., Suppl 11; 79-93, 1996.

Mahmood I., Balian J.D. Interspecies scaling - predicting
     pharmacokinetic parameters of antiepileptic drugs in
     humans from animals with special emphasis on clearance.
     J. Pharm. Sci., 85 (4); 411-414, 1996.

Malmgren K, Hedstrom A, Granqvist R, Malmgren H, Ben-
     Menachem E. Cost analysis of epilepsy surgery and of
     vigabatrin treatment in patients with refractory partial
     epilepsy. Epilepsy Res., 25 (3); 199-207, 1996.

Marescaux C., Hirsch E., Finck S., Maquet P., Schlumberger E.,
      Sellal F., Metz M.N., Alembik Y., Salmon E., Franck G.
      Lutz Landau-Kleffner syndrome: a pharmacologic study of
      five cases. Epilepsia, 31 (6); 768-777, 1990.

Margarit M.V., Rodriguez I.C., Cerezo A. Rectal bioavailability of
      water-soluble drugs: sodium valproate. J. Pharm.
      Pharmacol., 43 (10); 721-725, 1991.

Marson AG, Kadir ZA, Chadwick DW. New antiepileptic drugs - a
      systematic review of their efficacy and tolerability [see
      comments]. BMJ, 313 (7066); 1169-1174, 1996.

Marson AG, Kadir ZA, Hutton JL, Chadwick DW. The new
      antiepileptic drugs - a systematic review of their efficacy
      and tolerability [see comments] Epilepsia, 38 (8); 859-880,
      1997.



                               97
Martinez de Munoz D., Arenas R., Chavez Gonzales O. Liquid
       chromatographic assay in plasma of one of the members of
       a new series of anticonvulsants: D,L-3-hydroxy-3-ethyl-3-
       phenylpropiona-mide. J. Chromatogr. B. Biommed. Appl.,
       678 (2); 377-383, 1996.

Matar K.M., Nicholls P.J., Teckle A., Bawazir S.A., Al-Hassan
      M.I. Liquid chromatographic determination of six
      antiepileptic drugs and two metabolites in microsamples of
      human plasma. Ther. Drug Monit., 21 (5); 559-566, 1999.

Mattson R.H. Efficacy and adverse effects of established and new
      antiepileptic drugs. Epilepsia, 36 Suppl. 2; 13-26, 1995.

Mattson R.H. Selection of drugs for the treatment of epilepsy.
      Semin. Neurol., 10 (4); 406-412, 1990.

Mattson RH. Antiepileptic drug monitoring,         a reappraisal.
      Epilepsia, 36 Suppl 5; S22-29, 1995.

Mattson RH. The role of the old and the new antiepileptic drugs in
      special populations - mental and multiple handicaps.
      Epilepsia, 37 Suppl 6; S45-53, 1995.

McDonnell GV, Morrow JI. An audit of the new antiepileptic
     drugs in clinical neurological practice. Seizure, 5 (2); 127-
     30, 1996.

McFadyen M.L., Miller R., Juta M., Hodgson V. The relevance of
     a First-World therapeutic drug monitoring service to the
     treatment of epilepsy in Third-World conditions. S. Afr.
     Med. J., 78 (10); 587-590, 1990.

McFadyen M.L., Miller R., Juta M., Hodgson V. The relevance of
     a First-World therapeutic drug monitoring service to the
     treatment of epilepsy in Third-World conditions. S. Afr.
     Med. J., 78 (10); 587-590, 1990.

                               98
McGuire AM, Duncan JS, Trimble MR. Effects of vigabatrin on
      cognitive function and mood when used as add-on therapy
      in patients with intractable epilepsy. Epilepsia, 33 (1); 128-
      134, 1992.

McKee PJ, Blacklaw J, Friel E, Thompson GG, Gillham RA,
     Brodie MJ. Adjuvant vigabatrin in refractory epilepsy, a
     ceiling to effective dosage in     individual patients?
     Epilepsia, 34 (5); 937-943, 1993.

Meldrum BS . Update on the mechanism of action of antiepileptic
      drugs. Epilepsia, 37 Suppl 6; S4-11, 1996.

Mercade Cerda JM. Antiepileptic drugs, mechanism of action.
      Neurologia, 11 Suppl 4; 93-99, 1996.

Mikkelsen M, Dam M. Medical treatment of epilepsy. Nord. Med.,
      104 (5); 135-136, & 160, 1989.

Morrell MJ. The new antiepileptic drugs and women. efficacy,
       reproductive health, pregnancy, and fetal outcome.
       Epilepsia, 37 Suppl 6; S34-44, 1996.



Morris R.G., Black A.B., Harris A.L., Batty A.B., Sallustio B.C.
       Lamotrigine and therapeutic drug monitoring: retrospective
       survey following the introduction of a routine service. Br.
       J. Clin. Pharmacol., 46 (6); 547-551, 1998.

Morton LD, Pellock JM. Diagnosis and treatment of epilepsy in
      children and adolescents. Drugs, 51 (3); 399-414, 1996.

Musolino R., Gallitto G., De Domenico P., Bonazinga M.M.,
      Sturniolo R., Labate C., Perri R. Synergistic anticonvulsant
      effect of valproic acid and ethosuximide on
      pentylenetetrazole-induced epileptic phenomena in rats. J.
      Int. Med. Res., 19 (1); 55-62, 1991.
                                99
Naganuma Y., Konishi T., Jongou K., Okada T., Tohyama J.,
      Uchiyama M. Event-related potentials (P300) and EEG
      activity in childhood partial epilepsy. Brian. Dev., 19 (2);
      117-121, 1997.

Neufeld MY, Korczyn AD. New drugs and vagal stimulation for
       treatment of epilepsy--the Israeli experience. Neurol.
       Neurochir. Pol., 30 Suppl 2; 113-220, 1996.

Nordmann JP, Baulac M, Van Egroo C. Concentric changes in the
     visual field associated with GABA-mimetic antiepileptic
     agents. J. Fr. Ophtalmol., 22 (4); 418-422, 1999.

O'Donohoe NV. Use of antiepileptic drugs in childhood epilepsy.
      Arch. Dis. Child., 66 (10); 1173-1175, 1991.

Omtzigt J.G., Los F.J., Hagenaars A.M., Stewart P.A., Sachs E.S.,
      Lindhout D. Prenatal diagnosis of spina bifida aperta after
      first-trimester valproate exposure. Prenat. Diagn., 12 (11);
      893-897, 1992.

Pace A, Bove L, Innocenti P, Pietrangeli A, Carapella CM, Oppido
      P, Raus L, Occhipinti E, Jandolo B. Epilepsy and gliomas -
      incidence and treatment in 119 patients. J. Exp. Clin.
      Cancer. Res., 17 (4); 479-482, 1998.

Padro L, Arbizu T, Rovira R. New antiepileptic drugs. Rev.
      Neurol., 25 (138); 291-294, 1997.

Pallini R., Palestini M., Lauretti L., Rossi G.F. Effect of
       magnesium on amygdala-kindled seizures in the rat:
       comparison with sodium valproate. Neurol. Res., 11 (1);
       17-23, 1989.

Panjwani U., Singh S.H., sel Varmurthy W., Gupta H.L.,
      Mukhopadhyay S., Thakkur L. Brainstem auditory evoked
      potentials in epileptics on different anti-epileptic drugs.
      Indian J. Physiol. Pharmacol., 40 (1); 29-34, 1996.
                               100
Patsalos PN. New antiepileptic drugs. Ann. Clin. Biochem., 36 (Pt
       1); 10-19, 1999.

Pelekanos J., Camfield P., Camfield C., Gordon K. Allergic rash
       due to antiepileptic drugs: clinical features and
       management. Epilepsia, 32 (4); 554-559, 1991.

Pellock JM . Managing pediatric epilepsy syndromes with new
       antiepileptic drugs. Pediatrics, 104 (5 Pt 1); 1106-
       1116, 1999.

Pellock JM, Appleton R. Use of new antiepileptic drugs in the
       treatment of childhood epilepsy. Epilepsia, 40 Suppl 6;
       S29-38, discussion S73-74, 1999.

Pellock JM. Overview of lamotrigine and the new antiepileptic
       drugs, the challenge. J. Child. Neurol., 12 Suppl 1; S48-52,
       1997.

Pellock JM. Utilization of new antiepileptic drugs in children.
       Epilepsia, 37 Suppl 1; S66-73, 1996.

Perucca E, Bialer MT. the clinical pharmacokinetics of the newer
       antiepileptic drugs. Focus on topiramate, zonisamide and
       tiagabine. Clin. Pharmacokinet., 31 (1); 29-46, 1996.

Perucca E, Gram L, Avanzini G, Dulac O. Antiepileptic drugs as a
       cause of worsening seizures. Epilepsia, 39 (1); 5-17, 1998.

Perucca E. Established antiepileptic drugs.       Baillieres Clin.
       Neurol., 5 (4); 693-722, 1996.

Perucca E. Pharmacokinetic profile of topiramate in comparison
       with other new antiepileptic drugs. Epilepsia, 37 Suppl 2;
       S8-S13, 1996.




                               101
Perucca E. The new generation of antiepileptic drugs - advantages
       and disadvantages. Br. J. Clin. Pharmacol., 42 (5); 531-543,
       1996.

Petroff OA, Behar KL, Mattson RH, Rothman DL. Human brain
        gamma-aminobutyric acid levels and seizure control
        following initiation of vigabatrin therapy. J. Neurochem.,
        67 (6); 2399-2404, 1996.

Petroff OA, Hyder F, Mattson RH, Rothman DL. Topiramate
       increases brain GABA, homocarnosine, and pyrrolidinone
       in patients with epilepsy [see comments]. Neurology, 52
       (3); 473-478, 1999.

Petroff OA, Rothman DL. Measuring human brain GABA in vivo,
        effects of GABA-transaminase inhibition with vigabatrin.
        Mol. Neurobiol., 16 (1); 97-121, 1996.

Pillay S., Maharaj B. The use of drug level measurements in adult
        patients receiving theophylline anti-epileptic drugs and
        amikacin. Cent. Afr. J. Med., 38 (8); 331-333, 1992.

Pimentel J. Therapeutic strategies in epilepsy. Acta. Med. Port.,
      10 (8-9); 573-579, 1997.

Pisani F., Perucca E., Di Perri R. Clinically relevant anti-epileptic
       drug interactions. J. Int. Med. Res., 18 (1); 1-15, 1990.

Pisani F., Perucca E., Di Perri R. Clinically relevant anti-epileptic
       drug interactions. J. Int. Med. Res., 18 (1); 1-15, 1990.

Pitkanen A. Treatment with antiepileptic drugs, possible
       neuroprotective effects. Neurology, 47 (1 Suppl 1); S12-
       16, 1996.

Porter RJ, Rogawski MA. New antiepileptic drugs, serendipity to
       rational discovery. Epilepsia, 33 Suppl 1; pS1-6, 1992.


                                102
Pospisil J., Perlik F. Binding parameters of phenytoin during
       monotherapy and polytherapy. Int. J. Clin. Pharmacol.
       Ther. Toxicol., 30 (1); 24-28, 1992.

Pospisil J., Perlik F. Binding Parameters of phenytoin during
       monotherapy and polytherapy. Int. J. Clin. Pharmacol.
       Ther. Toxicol., 30 (1); 24-28, 1992.

Pranzatelli MR, Nadi NS. Mechanism of action of antiepileptic and
       antimyoclonic drugs. Adv. Neurol., 67; 329-360, 1995.

Rambeck B, Specht U, Wolf P. Pharmacokinetic interactions of
     the new antiepileptic drugs. Clin. Pharmacokinet., 31 (4);
     309-324, 1996.

Ratnaraj N, Doheny HC, Patsalos PN. A micromethod for the
       determination of the new antiepileptic drug levetiracetam
       (ucb LO59) in serum or plasma by high performance liquid
       chromatography. Ther. Drug Monit., 18 (2); 154-157,
       1996.

Ratnaraj N, Patsalos PN.            A high-performance liquid
       chromatography micromethod for the simultaneous
       determination of vigabatrin and gabapentin in serum. Ther.
       Drug Monit., 20 (4); 430-434, 1998.




Ratnaraj N., Doheny H.C., Patsalos P.N. A micromethod for the
       determination of the new antiepileptic drug levetiracetam
       (ucb LO59) in serum or plasma by high performance liquid
       chromatography. Ther. Drug. Monit., 18 (2); 154-157,
       1996.

Ratnaraj N., Patsalos P.N.    A high-performance liquid
       chromatoraphy micromethod for the simultaneous
                               103
       determination of vigabatrin and gabapentin in serum. Ther.
       Drug. Monit., 20 (4); 430-434, 1998.

Reddy P.A., Hsiang B.C., Latifi T.N., Hill M.W., Woodward K.E.,
      Rothman S.M., Ferrendelli J.A., Covey D.F. 3,3-Dialkyl
      and 3-alkyl-3-benzyl-substituted 2-pyrrolidinones: a new
      class of anticonvulsant agents. J. Med. Chem., 39 (9);
      1898-1906, 1996.

Remy C, Beaumont D. Efficacy and safety of vigabatrin in the
     long-term treatment of refractory epilepsy. Br. J. Clin.
     Pharmacol., 27 Suppl 1; 125S-129S, 1998.

Repke J.T., Friedman S.A., Kaplan P.W. Prophylaxis of eclamptic
      sezures: current controversies. Clin. Obstet. Gynecol., 35
      (2); 365-374, 1992.

Rey E, Pons G, Olive G. Vigabatrin. Clinical pharmacokinetics.
      Clin. Pharmacokinet., 23 (4); 267-78, 1992.

Reynolds EH, Ring HA, Farr IN, Heller AJ, Elwes RD. Open,
      double-blind and long-term study of vigabatrin in chronic
      epilepsy. Epilepsia, 32 (4); 530-538, 1991.

Richens A. New antiepileptic drugs [editorial]. Br. J. Hosp. Med.,
      44 (4); 241, 1991.

Richens A.      Pharmacology and clinical pharmacology of
      vigabatrin. J. Child. Neurol., Suppl 2; S7-10, 1991.

Riva R, Albani F, Contin M, Baruzzi A. Pharmacokinetic
      interactions between antiepileptic drugs - clinical
      considerations. Clin. Pharmacokinet., 31 (6); 470-493,
      1996.

Riva R., Albani F., Contin M., Baruzzi A. Pharmacokinetic
      interactions between antiepileptic drugs.  Clinical


                               104
       considerations.   Clin. Pharmacokinet., 31 (6); 470-493,
       1996.

Rodger C., Pleuvrt B.J. Protective effect of flunarizine and
      nifedipine alone and in combination with anticonvulsant
      drugs    against   PTZ-induced seizures      in   mice.
      Neuropharmacology, 32 (3); 257-263, 1993.

Rodger C., Pleuvry B.J. Protective effect of flunarizine and
      nifedipine alone and in combination with anticonvulsant
      drugs    against   PTZ-induced seizures     in    mice.
      Neuropharmacology, 32 (3); 257-263, 1993.

Rodriguez Moreno E, Acilona V, Boza F, Ortega JE, Carballo M,
      Palomino A, Arenas C. Concurrence of short and long
      lasting episodes of nocturnal paroxysmal dystonia in an
      epileptic patient]. Neurologia, 12 (3); 136-139, 1997

Rogvi-Hansen B, Gram L. Adverse effects of established and new
      antiepileptic drugs, an attempted comparison. Pharmacol.
      Ther., 68 (3); 425-434, 1995.

Salas-Puig J, Mateos V, Amorin M, Calleja S. Rational choice of
       antiepileptic treatment. Neurologia, 14 Suppl 3; 25-31,
       1999.

Salke-Kellermann R.A., May T., Boenigk H.E. Influence of
       ethosuximide on valproic acid serum concentrations.
       Epilepsy Res., 26 (2); 345-349, 1997.



Samren E.B., van Duijn C.M., Koch S., Hiilesmaa V.K. Maternal
      use of antiepileptic drugs and the risk of major congenital
      malformations - a joint European prospective study of
      human teratogenesis associated with maternal epilepsy.
      Epilepsia, 38 (9); 981-990, 1997.

                               105
Sanchez-Alcaraz A, Quintana B, Rodriguez I, Lopez E. Plasma
      concentrations of vigabatrin in epileptic patients. J. Clin.
      Pharm. Ther.,     21 (6); 393-398, 1996.

Sanchez-Alcaraz A., Quintana B., Rodriguez I., Lopez E. Plasma
      concentrations of vigabatrin in epileptic patients. J. Clin.
      Pharm. Ther., 21 (6); 393-398, 1996.

Schapel G, Chadwick D. A survey comparing lamotrigine and
      vigabatrin in everyday clinical practice. Seizure, 5 (4);
      267-270, 1996.

Schapel GJ, Black AB, Lam EL, Robinson M, Dollman WB.
      Combination vigabatrin and lamotrigine therapy for
      intractable epilepsy. Seizure, 5 (1); 51-56, 1996.

Schmitz B. Psychiatric syndromes related to antiepileptic drugs.
      Epilepsia, 40 Suppl 10; S65-70, 1999.

Schmutz A., Thormann W. Determination of phenobarbital,
      ethosuximide, and primidone in human serum by micellar
      electrokinetic capillary chromatography with direct sample
      injection. Ther. Drug Monit., 15 (4); 310-316, 1993.

Scollo-Lavizzari G, Marugg A. Therapy of epilepsy, trends and
       effectiveness of new anticonvulsants. Schweiz. Arch.
       Neurol. Psychiatr., 146 (4); 168-173, 1995.

Selai CE, Trimble MR .Adjunctive therapy in epilepsy with new
       antiepileptic drugs, is it of any value? Seizure, 17 (5); 417-
       418, 1998.

Shakespeare A., Simeon G. Economic analysis of epilepsy
      treatment: a cost minimization analysis comparing
      carbamazepine and lamotrigine in the UK. Seiaure, 7 (2);
      119-125, 1998.



                                106
Shorvon S, Stefan H. Overview of the safety of newer antiepileptic
      drugs. Epilepsia, 38 Suppl 1; S45-51, 1997.

Siemes H, Brandl U, Spohr HL, Volger S, Weschke B. Long-term
      follow-up study of vigabatrin in pretreated children with
      West syndrome. Seizure,      7 (4); 293-297, 1998.

Siemes H., Brandl U., Spohr H.L., Volger S., Weschke B. Long-
      term follow-up study of vigabatrin in pretreated children
      with West syndrome. Seizure, 7 (4); 293-297, 1998.

Sobaniec W. Certain aspects of interaction between sodium
       valproate and other anticonvulsant drugs in the therapy of
       epilepsy in children. Master Med. Pol., 24 (2); 115-119,
       1992.

Spanaki MV, Siegel H, Kopylev L, Fazilat S, Dean A, Liow K,
      Ben-Menachem E, Gaillard WD, Theodore WH. The effect
      of vigabatrin (gamma-vinyl GABA); on cerebral blood flow
      and metabolism. Neurology, 53 (7); 1518-1522, 1999.

Spina E., Pisani F., Perucca E.           Clinically significant
      parmacokinetic drug interactions with carbamazepine - an
      update. Pharmacokinet., 31 (3); 198-214.

Stables JP, Bialer M, Johannessen SI, Kupferberg HJ, Levy RH,
       Loiseau P, Peruc. Progress report on new antiepileptic
       drugs. A summary of the Second Eilat Conference.
       Epilepsy Res., 22 (3); 235-426, 1995.

Stefan H, Bernatik J, Knorr J. Visual field defects due to
       antiepileptic drugs. Nervenarzt., 70 (6); 552-555, 1999.

Steidele S, Flugel D, Bauer J, Elger CE . Epilepsy in the very old.
        Fortschr. Neurol. Psychiatr., 65 (5); 237-342, 1997.

Steinhoff BJ, Freudenthaler N, Paulus W. The influence of
       established and new antiepileptic drugs on visual
                               107
       perception. A placebo-controlled, double-blind, single-
       dose study in healthy volunteers. Epilepsy Res., 29 (1);
       35-47, 1997.

Steinhoff BJ, Freudenthaler N, Paulus W. The influence of
       established and new antiepileptic drugs on visual
       perception. II - A controlled study in patients with epilepsy
       under long-term antiepileptic medication. Epilepsy Res., 29
       (1); 49-58, 1997.

Stolarek IH, Brodie AF, Brodie MJ. Management of seizures in the
       elderly, a survey of UK geriatricians. J. R. Soc. Med., 88
       (12); 686-689., 1995,

Storici P, Capitani G, De Biase D, Moser M, John RA, Jansonius
        JN, Schirmer T. Crystal structure of GABA-
        aminotransferase, a target for antiepileptic drug therapy.
        Biochemistry, 38 (27); 8628-8634, 1999.

Thomas RJ. Seizures and epilepsy in the elderly [see comments].
     Arch. Intern. Med., 157 (6); 605-617, 1997.

Thomson AH, Brodie MJ. Pharmacokinetic optimisation of
     anticonvulsant therapy. Clin. Pharmacokine., 23 (3); 216-
     230, 1992.

Tomson T. Drug analysis during epilepsy treatment is valuable.
     Lakartidningen, 94 (26-27); 2461-2464, 1997.

Towne A.R., De Lorenzo R.J. Use of intramuscular midazolam for
      status epilepticus. J. Emerg. Med., 17 (2); 323-328, 1999.

Treiman DM. gamma Vinyl GABA - current role in the
      management of drug-resistant epilepsy. Epilepsia, 30
      Suppl 3; S31-35, 1992.

Ubeda-Martin N., Alonso-Aperte E., Achon M., Varela-Moreiras
      G., Puerta J., Pere de Miguelsanz J. Morphological changes
                                108
       induced by valproate and its administration concomitant
       with folinic acid or S-adenosylmethionine in pregnant rats.
       Nutri. Hosp., 13 (1); 41-49, 1998.

Uldall P., Buchholt J.M. Clinical experiences with topiramate in
       children with intractable epilepsy. Dianalund Epilepsy
       Hospital, Denmark. Europ. J. Paediatr. Neurol., 3 (3); 105-
       111,1999.

Vajda FJ. New anticonvulsants. Curr. Opin. Neurol. Neurosurg., 5
       (4); 519-525, 1992.

Vermeij TA, Edelbroek PM. High-performance liquid
      chromatographic analysis of vigabatrin enantiomers in
      human serum by precolumn derivatization with o-
      phthaldialdehyde-N-acetyl-L-cysteine    &    fluorescence
      detection. J. Chromatogr. B. Biomed. Sci. Appl., 716 (1-2);
      233-238, 1998.

Voigt J.P., Morgenstern E. Comparative effects of carbamaze-
       pine, phenytoin, diazepam and clonazepam on inhibitory
       avoidance learning in mice. Psychopharmacology, 108 (1-
       2); 131-135, 1992.

Volmut J., Matisova E., Pham Thi Ha.              Simultaneous
      determination of six antiepileptic drugs by capillary gas
      chromatography. J. Chromatogr., 527 (2); 428-435, 1990.

Wada K, Kiryu K, Kawata Y, Chiba T, Mizuno K, Okada M,
     Tasaki H, Fukushima Y, Saito F, Kaneko S. Prognosis and
     clinical features of intractable epilepsy, a prospective study.
     Psychiatry Clin. Neurosci., 51 (4); 233-235, 1997.

Wakai S., Ito N., Sueoka H., Kawamoto Y., Hayasaka H.,
      Tsutsumi H., Chiba S. Complex partial status epilepticus
      in childhood. Pediatr. Neurol., 13 (2); 137-141, 1995.


                                109
Walker MC, Patsalos PN. Clinical pharmacokinetics of new
      antiepileptic drugs. Pharmacol. Ther., 67 (3); 351-384,
      1995.

Wallace S.J. Myoclonus and epilepsy in childhood: a review of
      treatment with valproate, ethosuximide, lamotrigine and
      zonisamide. Epilepsy Res., 29 (2); 147-154, 1998.

White HS. Comparative anticonvulsant and mechanistic profile of
      the established and newer antiepileptic drugs. Epilepsia, 40
      Suppl 5; S2-10, 1999.

Wild JM, Martinez C, Reinshagen G, Harding GF. Characteristics
      of a unique visual field defect attributed to vigabatrin.
      Epilepsia, 40 (12); 1784-1794, 1999.

Wilder BJ. Antiepileptic drugs--current use. Can. J. Neurol. Sci.,
       23 (4); S18-23, 1996.

Wilson EA, Brodie MJ. New antiepileptic drugs. Baillieres Clin.
      Neurol., 5 (4); 723-747, 1996.

Wong IC, Chadwick DW, Fenwick PB, Mawer GE, Sander JW.
     The long-term use of gabapentin, lamotrigine, and
     vigabatrin in patients with Chronic epilepsy. Epilepsia, 40
     (10); 1439-1445, 1999.

Wyler AR, Vossler DG . Recent advancements in epilepsy. Surg.
      Neurol., 48 (2); 106-109, 1997.

Yagi K., Watanabe M. Neurotoxicity of antiepileptic drugs. No
      To Shinkei, 44 (12); 1067-1075, 1992.



Yukawa E., Suzuki A., Higuchi S., Aoyama T. Influence of age
     and concurrent medication on steady-state valproic acid


                               110
       serum level-dose ratios in Japanese paediatric patients. J.
       Clin. Pharm. Ther., 16 (4); 291-297, 1991.

Zamponi N, Cardinali C. Open comparative long-term study of
     vigabatrin vs carbamazepine in newly diagnosed partial
     seizures in children. Arch. Neurol., 56 (5); 605-607, 1999.

Ziemann U, Lonnecker S, Steinhoff BJ, Paulus W. Effects of
      antiepileptic drugs on motor cortex excitability in humans,
      a transcranial magnetic stimulation study [see comments].
      Ann. Neurol., 40 (3); 367-378, 1996.




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