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PubMed1980

Integrated method for the gas chromatographic determination of antiepileptic drugs in human plasma.

The principles of three independent extraction methods were utilized to develop an integrated extraction scheme for use in routine therapeutic monitoring of seven antiepileptic agents. The final method, in which the three extraction methods were interfaced, permitted routine monitoring in a single 1 ml volume of human plasma of any one or combination of the following drugs: phenytoin (PHT), phenobarbital (PB), primidone (PD), 5-ethyl-5-phenylhydantoin (EPH), ethosuximide (ES), carbamazepine (CBZ), and valproic acid (VPA). An on-column methylation technique was used for simultaneous determination of PHT, PB, PD, EPH, and ES. CBZ and VPA were determined by independent methods as the underivatized compounds. Six appropriate internal standards were employed in the integrated method for quantitation of the drugs.

Anticonvulsants↗
PubMed1981

[Changes in serum levels of alkaline phosphatase, calcium, and inorganic phosphate following antiepileptic therapy (author's transl)].

Relationship of antiepileptics to serum alkaline phosphatase (ALP), serum calcium (Ca) and inorganic phosphate (P) were studied in 172 epileptic patients treated with antiepileptics for clarifying the related factors to produce osteomalacia following antiepileptics administration. Laboratory findings of ALP, Ca, and P were compared with normal value and determined as abnormal by exceeding the normal limit (mean +2SD (ALP), mean-2SD (Ca, P)). The following results were obtained: 1) In the 172 patients, 20 cases (11.6%) showed abnormal value of ALP, 12 cases (7.0%) of Ca and 41 cases (23.8%) of P (Single abnormal groups). On the other hand, 47 cases (27.3%) were found abnormal in two or three of ALP, Ca and P (Combined abnormal group). The rest 52 cases (30.2%) of the patients showed all normal value (Normal group). 2) Abnormal value of ALP and/or Ca were observed mostly before 20 years of age. The patients with abnormal P were more distributed in age than others. 3) The earlier and/or the longer administration of antiepileptics is prone to produce the more abnormal value. 4) Acetazolamide, metharbital, primidone, carbamazepine and mephobarbital were more used in combined group than in normal group, and polypharmaceutical use of these antiepileptics was supposed to be related to the abnormality of ALP, Ca and P. There was no different use of diphenyl-hydantoin and phenobarbital in frequency and amount between combined group and normal group. 5) Mental retardation and epileptic personality changes were observed more frequently in combined abnormal group than in normal group. 6) No significant relations were observed between clinical seizure types, seizure frequencies and abnormal laboratory findings.

Adolescent↗
PubMed1981

The teratogenicity of hydantoins and barbiturates in humans, with considerations on the etiology of malformations and cerebral disturbances in the children of epileptic parents.

A total of 194 children of epileptic mothers and 71 children of epileptic fathers were examined for mental retardation, neurologic disturbances, major malformations, and acrofacial dysmorphias typical for hydantoin-barbiturate embryopathy (HB-E). HB-E was observed in nearly 7% of the children of mothers on anticonvulsants during pregnancy. Barbiturates and/or primidone were observed to induce the same dysmorphic features as hydantoins. The teratogenic potential of hydantoins may be slightly increased in combination with barbiturates/primidone. Neither the 71 children of epileptic fathers nor the 46 children of epileptic mothers without anticonvulsants exhibited symptoms of HB-E. The frequency of major, unspecific malformations was increased in children of epileptic mothers as well as in children of epileptic fathers as compared with the general population. Cerebral disturbances without dysmorphias were increased in children of mothers with and without anticonvulsants, but this was rarely the case in children of epileptic fathers. Cerebral disturbances were observed more often in children of mothers with seizures during pregnancy than in children of mothers without seizures. Multifactorial genetic influences on major malformations and influences of maternal seizures on cerebral disturbances in the offspring are likely.

Abnormalities, Drug-Induced↗
PubMed1980

Pharmacokinetics of carbamazepine in the dog.

1. The pharmacokinetics of carbamazepine was studied in dogs after oral administration of two pharmaceutical preparations. Adsorption was rapid, however, the drug was much better absorbed from a liquid preparation than from tablets. Plasma concentrations declined with an elimination half-life of 1.5 hr. Carbamazepine-10,11-epoxide, which is equipotent with carbamazepine as an anticonvulsant, was rapidly formed and reached plasma concentrations higher than those of the mother compound. The concentrations of the epoxide remained high as long as plasma concentrations of carbamazepine were above 2--4 nmole/ml, then they fell with an average half-life of 2.2 hr. 2. During continued treatment with daily doses of 0.34--0.38 mmole/kg carbamazepine, plasma concentrations showed a pronounced and progressive decline from Day 2 which is considered as the result of induction of microsomal liver enzymes. 3. Carbamazepine and the epoxide pass into CSF at a rate comparable to that of phenobarbital or barbital and primidone, respectively. 4. Binding to serum proteins was about 70% for carbamazepine and 40% for the epoxide in dog serum; slightly higher values were found for human serum.

Animals↗
PubMed1980

Preliminary observations on the Quality Assurance Service Therapeutic Drug Monitoring Program.

In 1979, the College of American Pathologists introduced a Therapeutic Drug Monitoring Interregional Daily Quality Control Program. Each participant uses lyophilized, reconstituted control material at normal and elevated levels. Nine drugs are provided at each level. These include phenobarbital, primidone, carbamazepine, ethosuximide, phenytoin, theophylline, digoxin, quinidine, and gentamicin. These specimens are run daily in the individual participating laboratory as part of a routine quality control program. Results are submitted for data processing to the CAP Computer Center. This report presents preliminary data and observations from the Program.

Chemistry, Clinical↗
PubMed1995

Lithium tremor.

BACKGROUND: Tremor is a common problem for patients taking lithium, but little is known about its true prevalence, its effect on compliance, and effective treatments. METHOD: The data base of the Lithium Information Center in Madison, Wis., was searched for articles relating to lithium tremor. RESULTS: Studies show a wide range of incidence of lithium tremor--4% to 65%--due to differences in defining and reporting this side effect. While lithium tremor often decreases with time on lithium, other treatment options include changing the dose or preparation of lithium, decreasing or eliminating other drugs, and treating with beta-blocking drugs, primidone, fatty acids, or potassium. Severe tremor may be a sign of lithium toxicity. CONCLUSION: Patients should be evaluated for lithium tremor on a regular basis. Diagnostic criteria should be standardized by a double-blind, random assignment, multicenter study that could also investigate proposed treatments.

Adrenergic beta-Antagonists↗
PubMed1995

Tremor disorders. Diagnosis and management.

Tremor is commonly encountered in medical practice, but can be difficult to diagnose and manage. It is an involuntary rhythmic oscillation of a body part produced by reciprocally innervated antagonist muscles. Tremors vary in frequency and amplitude and are influenced by physiologic and psychological factors and drugs. Categorization is based on position, posture, and the movement necessary to elicit the tremor. A resting tremor occurs when the body part is in repose. A postural tremor occurs with maintained posture and kinetic tremor with movement. Various pathologic conditions are associated with tremors. Essential tremor, which is the most common, is postural and kinetic, with a frequency between 4 and 8 Hz, and involves mainly the upper extremities and head. Essential tremor responds to treatment with primidone, beta-blockers, and benzodiazepines. Parkinson's disease causes a 4- to 6-Hz resting tremor in the arms and legs that responds to the use of anticholinergics and a combination of carbidopa and levodopa. Tremor can also be a manifestation of Wilson's disease, lesions of the cerebellum and midbrain, peripheral neuropathy, trauma, alcohol, and conversion disorders. Treatment should be directed to the underlying condition. Stereotactic thalamotomy of thalamic stimulation is a last resort.

Humans↗
PubMed1994

Effects of MK-801 (dizocilpine) and ketamine on strychnine-induced convulsions in rats: comparison with benzodiazepines and standard anticonvulsants.

The effects of two non-competitive NMDA antagonists--MK-801 and ketamine--were studied in a model of generalized seizures elicited by s.c. injection of strychnine (2 or 3 mg/kg) in adult rats. The animals were observed in isolation for 30 min after strychnine administration. Pretreatment with MK-801 (0.5 or 2 mg/kg i.p.) suppressed the tonic, but not the clonic phase of generalized seizures following both doses of strychnine. A similar action of ketamine (20 or 40 mg/kg i.p.) was indicated but it did not attain statistical significance. Strychnine-induced lethality was not changed significantly. A comparison with antiepileptic drugs demonstrated that only phenobarbital (10-80 mg/kg i.p.) was clearly effective against strychnine-induced seizures; carbamazepine (25 or 50 mg/kg i.p.) and partly phenytoin (30 or 60 mg/kg i.p.) were able to suppress the incidence of the tonic phase. Primidone (40 or 80 mg/kg i.p.) as well as the benzodiazpines bretazenil (0.1 or 1 mg/kg i.p.) and midazolam (two lower doses of 0.5 and 1 mg/kg i.p.) were without significant effect. The 2 mg/kg dose of midazolam was partly effective. Only phenobarbital, carbamazepine and the highest dose of midazolam prevented strychnine-induced lethality.

Animals↗
PubMed1994

Pregnancy and movement disorders.

The concurrence of pregnancy and movement disorders is an uncommon event in a general neurologic practice. Even at specialized movement disorder referral centers, there is insufficient experience to adequately guide management of pregnancy, except perhaps in the case of WD. The questions posed most urgently by patients regard the safety of medication, an issue on which there is insufficient data, and their ability to care for a child for at least the next decade, an issue that differs by disease and social situation. The author's formulation of efficacy and toxicity suggests that certain medications commonly used in movement disorders should be discontinued before pregnancy, if possible. These medications include neuroleptics, amantadine, diazepam, primidone, selegiline, and reserpine. Pregnancy may unmask a pre-existing potential for chorea (i.e., chorea gravidarum) and frequently has a mild exacerbating effect on symptoms of PD; however, it has little effect on other movement disorders. Severe generalized dystonia would probably interfere with vaginal delivery, but the scant existing data suggest minimal effect of movement disorders on pregnancy, childbirth, and neonatal health.

Antiparkinson Agents↗
PubMed1993

Biopharmaceutical factors in seizure control and drug toxicity.

Problems related to bioequivalence and bioavailability for four antiepileptic drugs (AEDs) are reviewed. Bioequivalence and bioavailability of AEDs can be affected by many factors, including physicochemical characteristics of the agent, the dosage form, and physiological condition of the patient. In 1988, breakthrough seizures prompted an FDA investigation of one company's generic carbamazepine tablets. Results indicated that the manufacturer had changed its source of carbamazepine, which led to a wide range of dissolution characteristics for different lots of tablets. In two separate studies, clonazepam was shown to be more rapidly absorbed in patients with a normal gastric pH than in those with a higher-than-normal gastric pH. With phenytoin, which exhibits nonlinear pharmacokinetics, differences in the rate and extent of absorption can adversely affect the bioavailability of this agent. Finally, the bioequivalence of generic primidone was contested in an adolescent girl who appeared to experience more frequent seizures with a generic product than with a trade formulation. The effectiveness of a drug depends on complex interactions involving the drug, the drug product formulation, and the patient. Minimizing variability in the absorption process is particularly important with AEDs, because of their narrow therapeutic range.

Anticonvulsants↗
PubMed1993

Critical issues in the treatment of epilepsy.

Classification of seizure types and evaluation and treatment of seizure disorders are discussed. Once the diagnosis of a seizure is made, the seizure type must be identified; this will help in determining the treatment. In partial seizures, the electrical discharge occurs focally, while generalized seizures involve both cerebral hemispheres simultaneously. Magnetic resonance imaging is the preferred test in the evaluation of patients with seizures, although computed tomography and electroencephalography can also be helpful. Selection of an antiepileptic drug (AED) is based on efficacy, toxicity, and, to a lesser degree, cost. Adverse reactions occur in up to 50% of patients. First-line AEDs include carbamazepine, ethosuximide, phenobarbital, primidone, phenytoin, and valproic acid. Serum AED concentrations can be helpful in managing patients with epilepsy. The serum concentrations required to control seizures or resulting in toxicity may vary among patients. Most seizures are manageable with oral AEDs. Medications of choice in status epilepticus include diazepam, lorazepam, phenytoin, and phenobarbital. The key to treating epilepsy is correct diagnosis of the seizure type and, when possible, the type of epilepsy. Most patients with epilepsy respond to one of the first-line AEDs; second-line agents may be useful in patients who do not respond to one or a combination of the first-line agents.

Anticonvulsants↗
PubMed1993

[A 77-year-old woman with myoclonus and epilepsy].

We present a 77-year-old woman with myoclonus and epilepsy. She was well until 35 years of age, when she noted an onset of trembling of the legs upon standing. Her symptom slowly progressed, and she felt a difficulty in standing when she was 39-year-old. She had a major motor seizure without an apparent focal onset when she was 46-year-old. She also developed tremor in her hands, and she felt difficulty in holding a glass filled with water. She was admitted to our service for the first time in 1965 when she was 51-year-old. She showed wide-based ataxic gait with truncal titubation. In finger to nose test, myoclonic jerks were induced in the upper extremities. Otherwise neurological examination was unremarkable. She was treated with primidone and phenobarbital, and was discharged for out patient follow up. Her symptoms slowly progressed, and gait and station became more difficult. Mentally she was sound. Three months prior to the present admission, she developed more difficulty in gait, and decrease in food intake. On the 14th of September in 1991, she was seen by a local physician who found an abnormal shadow in her chest X-ray, and she was admitted to our service for further work-up on September 18, 1991. On admission, the patient was a chronically ill and emaciated woman. Her blood pressure was 140/84 mmHg, heart rate 115/minutes and regular, and the body temperature 36.9 degrees C. The palpebral conjunctivae were anemic. No cervical adenopathy was noted. The lung fields were clear, and no heart murmur was audible. The abdomen was soft, and no organomegaly was present. On neurologic examination, she looked somnolent with disorientation to time and place. Her memory was poor, and she could not do well serial 7s. The disc was flat and the ocular movements appeared intact. Other cranial nerves were also unremarkable. She showed diffuse muscle wasting. She was unable to stand or walk. Maintaining the sitting position was also difficult. She was able to raise her arms, but almost unable to move her lower extremities. The precise muscle testing was impossible. No abnormal involuntary movement was seen. Finger to nose test could not be performed.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗
PubMed1993

[Lennox syndrome associated with severe cerebellar dysfunction and peripheral neuropathy].

We reported a 33-year-old man with Lennox syndrome of 26 years' duration associated with unusual symptom complexes such as severe cerebellar ataxia and dysarthria, and peripheral neuropathy. His convulsive disorder was very intractable despite multiple anticonvulsants including phenytoin (PHT), phenobarbital (PB), primidone (PRM), valproate and so on. At the age of 25 he was no longer able to walk without help. PHT blood levels were kept almost within the therapeutic range, while PB blood levels tended to be greater than the therapeutic range. Needle EMG study revealed denervation pattern. Motor conduction velocity of the peroneal nerve was 25.2 m/s and sensory conduction velocity of the sural nerve could not be elicited. Brain CT and MRI showed the marked cerebellar atrophy predominant in the vermis. To our knowledge there were no previously reported cases of Lennox syndrome associated with such cerebellar dysfunctions and peripheral neuropathy. From the clinical course and laboratory findings, metabolic disorders and degenerative diseases were ruled out. We consider his cerebellar symptoms and peripheral neuropathy could be attributable to the long-term use of multiple anticonvulsants, i.e. PHT in combination with PB and PRM. These symptoms seem to be irreversible, because our patient's condition did not change after PHT and PB dose reduction, and discontinuation of PRM.

Adult↗
PubMed1995

Startle epilepsy presenting as drop attacks: a case report.

A case of startle epilepsy, induced by an unexpected touch on the left shoulder of a 3.5 year old boy, was investigated. The startle epilepsy manifested as an atonic drop attack. Neurological examination revealed a mild hemiparesis on the left side. Computed tomography (CT) scanning demonstrated an enhancement over the right parieto-frontal region, suggesting a hemangioma. Interictal electroencephalography (EEG) showed diffuse slowing and asymmetry of background activities with lower amplitude over the right centro-parieto-temporal region. The ictal EEG showed a paroxysmal bilaterally synchronized high amplitude single spike followed by a few slow waves lasting about one second over the bilateral centro-parieto-temporal regions. The seizure resisted anticonvulsant therapy and no significant responses were observed despite the use of combined therapy with valproic acid, phenytoin, primidone and clonazepam.

Child, Preschool↗
PubMed1996

[Theoretical and practical problems concerning therapeutic drug monitoring from the viewpoint of the pharmacologist].

Drug treatment is aimed at achieving a maximum therapeutic benefit while minimizing unwanted side-effects. The recognition that drug doses administered to patients were often inadequate or excessive has highlighted the importance of measuring serum levels of drugs - by the methods of Therapeutic Drug Monitoring, - for effective patient care. The clinical usefulness of TDM has been undoubtedly demonstrated for a number of drugs. During 1990-1995 four commonly used anticonvulsive drugs, - carbamazepine, phenytoin, primidone and valproic acid - were monitored by an Abbott TDx machine, and the usefulness of TDM was further strengthened. In spite of some difficulties the number of samples located in the therapeutic range gradually elevated, assuring a better individual therapy and cost-benefit ratio. During the last 18 months similar results were obtained with theophylline and digoxin as well.

Cost-Benefit Analysis↗
PubMedDate not supplied

Altered aromatic amine metabolism in epileptic patients treated with phenobarbital.

The fate of carcinogens differs among individuals who have different activities of drug-metabolizing enzymes that are important in activating and detoxifying carcinogens. A drug that profoundly alters the metabolism of the drugs and carcinogens is the anticonvulsive agent phenobarbital. To investigate why epileptic patients appear to have a low risk of cancer of the urinary bladder, and on the basis of the observation that levels of aromatic amine-hemoglobin adducts are strongly associated with various risk factors for cancer at that site, we determined aromatic amine-hemoglobin adducts in 62 epileptic patients as a surrogate measure of the reaction of carcinogenic metabolites with DNA in target tissue. Although adducts were detected in all subjects, the levels were proportional to daily tobacco consumption. When the subjects were stratified into groups smoking 20 g tobacco/day or more, smoking <20 g/day, and not smoking, an effect of medication was detected. Epileptic patients treated chronically with phenobarbital or primidone, which is effectively metabolized to phenobarbital, were found to have lower levels of 4-aminobiphenyl adducts than patients on the other treatment (P = 0.02; ANOVA). In nonsmokers, no effect of medication could be demonstrated above background variation; however, an increasing effect was seen with tobacco consumption with only one-half the increase in adducts per g of tobacco smoked as epileptic patients on other treatment. The difference in the increases (slopes of regression lines) was highly significant statistically. This reduction in the level of hemoglobin-aromatic amine adducts is probably due to induction of detoxification enzymes in the patients treated with phenobarbital.

Analysis of Variance↗
PubMed1977

Determination of plasma procainamide and N-acetylprocainamide concentration by high-pressure liquid chromatography.

We describe a routine method for determining concentrations of the antiarrhythmic drug procainamide and its active metabolite, N-acetylprocainamide, in plasma. A simple extraction of 1.0 ml of plasma is followed by separation and chromatographic analysis by use of a column containing microparticulate silica. p-nitro-N-(2-diethylaminoethyl)benzamide hydrochloride was synthesized and used as the internal standard. Total chromatographic time is only 7 min. The day-to-day CV during three months of daily use was less than 4% of the mean for each compound, and we saw no deterioration in column performance during this time. Phenobarbital, phenytoin, lidocaine, primidone, methsuximide, quinidine, and their metabolites do not interfere.

Anti-Arrhythmia Agents↗
PubMed1996

In vitro pharmacology of the novel phosphodiesterase type 4 inhibitor, CP-80633.

We present the in vitro pharmacology of a novel adenosine 3'-5' -cyclic monophosphate-specific phosphodiesterase (PDE) type 4 inhibitor, CP-80633 ((2'S)5-[3-(2' -exobicyclo[2.2.1]-heptyloxy)4-methoxyphenyl] tetrahydro-2(1H)-primidone), which has shown efficacy in phase II clinical trials for atopic dermatitis. CP-80633 inhibits PDE4 isozymes (human lung IC50 = 1.27 microM) in the absence of effects on PDE1, PDE2, PDE3 and PDE5 isozymes (IC50 > 100 microM). It exhibits no significant selectivity for any single cloned PDE4A, B, C or D isoform. CP-80633 inhibits adenosine 3'-5'-cyclic monophosphate hydrolysis in partially purified human peripheral blood monocyte cytosol (IC50 = 3.52 microM), eosinophil membrane (IC50 = 1.10 microM) and T cell membrane (IC50 = 2.28 microM) preparations. Inhibition of eosinophil PDE4 adenosine 3'-5'-cyclic mono-phosphate hydrolysis by CP-80,633 occurs in a noncompetitive manner. Unlike theophylline, CP-80,633 is inactive against ratrain adenosine (A1,A2) receptors. Consistent with its action as a PDE4 inhibitor in whole cells, CP-80633 potentiates PGE1 dependent increases in adenosine 3'-5'-cyclic monophosphate levels in human U937 cells, and in human eosinophils, monocytes and T cells (EC200 approximately 1.0 microM). Consequently, CP-80633 inhibits many inflammatory cell functions including 1) human eosinophil superoxide anion production (IC50 < 0.6 microM), 2 C5a-(IC50 = 0.40 microM) and LTB4-(IC50 = 0.20 microM) mediated guinea pig peritoneal eosinophil chemotaxis and 3) lipopolysac-charide-induced tumor necrosis factor-alpha release from human monocytes (IC50 = 0.219 microM). These data clearly demonstrate that CP-80633 is a selective inhibitor of PDE4 isozymes, and support its potential use as a therapeutic agent for a number of inflammatory and immune disorders.

3',5'-Cyclic-AMP Phosphodiesterases↗