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PubMed2005

[Hyperhomocysteinemia and treatment with antiepileptic drugs. Effects of different doses of folic acid].

BACKGROUND AND OBJECTIVE: An increase homocysteine values, which is an independent risk factor for atherotrombotic disease, can be produced with antiepileptic treatment. The aims of this study were: 1) to assess the frequency and determinant factors of hyperhomocysteinemia in adult patients receiving antiepileptic drugs, and 2) to know the effect of different doses of folic acid. PATIENTS AND METHOD: Ninety eight patients and 100 healthy controls similar in age and gender were studied. Eighty six patients were treated with hepatic enzyme inductors (diphenylhydantoine and/or phenobarbital and/or primidone and/or carbamazepine), 5 received non inductors (valproate) and 7 were treated with both in combination. Thirty eight patients were randomized to receive in an open and concurrent way folic acid, 0.2 mg (n = 18) or 5.2 mg (n = 20) daily for 3 months. RESULTS: Homocysteine values were increased in patients in relation with controls (mean [SD]12.2 [6.7] 95% confidence interval [CI],10.0-13.5 vs 8.8[2.2] 95% CI, 8.3-9.2 micromol/l; p < 0.001). Hyperhomocysteinemia was found in 28 patients and 4 controls (28.6% vs 4.0%; p < 0.001). In a multivariate analysis hyperhomocysteinemia was positively associated with treatment with antiepileptic inductors and negatively with folate values and female gender. Homocysteine values decreased after treatment with folic acid at high and low doses (p < 0.001 for both groups), and the values observed in the latter group were similar to those in healthy controls. CONCLUSIONS: Hyperhomocysteinemia is frequent in patients treated with antiepileptic drugs. Treatment with hepatic enzyme inductors and low folate values are predictors of hyperhomocysteinemia. Administration of folic acid, even at very low doses, produces a significant decrease of homocysteinemia in these patients.

Adult↗
PubMed1992

Salivary excretion of drugs in children: theoretical and practical issues in therapeutic drug monitoring.

Studies suggest that saliva could be used instead of blood in the therapeutic monitoring of many drugs. This has distinct advantages in pediatrics and neonatology as saliva sampling is painless and spares blood. Stimulation of saliva secretion with a chemical stimulus (i.e. citric acid applied over the tongue) facilitates the study of younger patients. Secretory and reabsorptive processes which take place in the ductal system of the salivary glands, and the rate of flow of the secretion play major roles in the determination of the concentration of solutes in saliva. Drug passage into saliva follows the general principles of movement of drugs across biologic membranes. Only the unbound fraction of the drug in plasma is available for diffusion into saliva and a relationship exists between saliva pH and the saliva/plasma concentration ratio of many polar drugs (tolbutamide, propranolol, procainamide, etc.). However, deviations from the pH theory exist and the inter -and intra-individual variations in saliva/plasma concentration ratios of salicylate and procainamide cannot be explained solely on the basis of fluctuations of salivary pH; on the other hand, a useful relationship exists between plasma and saliva phenobarbital concentrations with no need to correct for saliva pH. The use of stimulated saliva has several advantages over resting saliva: a larger volume of the sample is obtained, the pH gradient between plasma and saliva is smaller, the variability in saliva/plasma concentration ratios of some drugs is narrowed, and less specimens are too viscous or discolored to allow drug analysis. Thorough rinsing of the mouth is required prior to saliva sampling as remnants of orally administered medicines may contaminate saliva specimens and give spuriously high values. Deviation from a simple but strict methodology accounts for some of the discrepancies found in the literature. Studies in children uniformly recommend saliva for therapeutic monitoring of phenytoin, carbamazepine and phenobarbital. Saliva sampling for therapeutic monitoring of ethosuximide, primidone and digoxin in infants and children, and of theophylline and caffeine in the neonate is promising, but little pediatric experience is available as yet. The value of saliva in therapeutic monitoring of theophylline in children is still controversial. Little of highly polar compounds such as aminoglycosides, and of polar highly protein bound drugs such as valproic acid is present in saliva. More data are still needed on the excretion of drugs in saliva in infants and in acutely ill children, and few data exist in the premature and full-term neonate.

Child↗
PubMed1988

Subtle and underrecognized side effects of neuroleptic treatment in children with Tourette's disorder.

A variety of side effects developed in children treated with neuroleptics for Tourette's disorder. Of 208 children, 34 manifested dose-related symptoms of dysphoria, nine experienced a worsening of symptoms of Tourette's disorder that was attributed to akathisia, five became hostile and aggressive, three developed "fog states" that disappeared with discontinuation of neuroleptics or treatment with primidone, and three experienced symptoms of tardive dyskinesia that resolved with time. This data base of neuroleptic-treated children with Tourette's disorder demonstrates a variety of subtle and underrecognized side effects that may not be as readily discernible in children receiving neuroleptics for a primary psychiatric disorder.

Acute Disease↗
PubMed1992

Intracranial meningioma with pulmonary metastasis in three dogs.

Extracranial metastasis of primary central nervous system neoplasms is uncommon and has not been described in the dog. We report the clincopathologic features of intracranial meningioma with pulmonary metastasis in three dogs (case No. 1: 13-year-old castrated male Boxer dog; case No. 2: 14-year-old spayed female Dachshund; case No. 3: 6-year-old spayed female German Shepherd Dog). Case No. 1 presented with ataxia, lethargy, vomiting, and leaning and falling to the right, and had a transient remission following radiation and corticosteroid therapy; case No. 2 had a history of seizures that were unresponsive to primidone, left-sided postural reaction deficits, ataxia, and circling to the right; case No. 3 had only intermittent episodes of vomiting Computed tomography of case Nos. 1 and 2 revealed peripherally located homogeneous contrast-enhancing intracranial masses. Postmortem examination revealed intracranial masses with single or multiple pulmonary nodules in all three cases. Histologically, the intracranial and pulmonary masses were meningotheliomatous meningiomas with atypical features including brain infiltration, necrosis, nuclear atypia, prominent nucleoli, and moderate cell density. All of the primary meningiomas had low mitotic rates. The current interest in early diagnosis and aggressive clinical/surgical management of canine patients with meningioma and other primary central nervous system neoplasms will likely result in an increased detection of extracranial metastases.

Animals↗
PubMed1997

Interactions of clobazam with conventional antiepileptics in children.

Clobazam is a 1,5-benzodiazepine effective in antiepileptic therapy of children and adults. Presently it is mainly used as adjuvant therapy for intractable seizures. Our objective was to evaluate the effect of clobazam on the apparent clearance of other antiepileptic drugs at steady state, and to determine the factors that determine the plasma levels of clobazam and its active metabolite N-desmethylclobazam. Patients were 74 children with intractable seizures who received treatment with clobazam at our institution as part of the Canadian Cooperative Clobazam Study Group during the years 1987 to 1991. Serum concentrations of clobazam, N-desmethylclobazam, and of concomitant antiepileptic drugs were monitored and prospectively collected. The effect of clobazam treatment on the apparent clearance steady state of the other antiepileptic drugs was determined by statistical comparison of the clearances of each drug before and after initiation of clobazam treatment using Wilcoxon's signed rank test. The effects of dosage, age, and concomitant antiepileptic therapy on the levels of clobazam and N-desmethylclobazam was assessed by multivariate analysis. Response to treatment and incidence of adverse effects were evaluated for each conventional antiepileptic drug to possibly identify favorable or unfavorable combinations with clobazam. Whereas the clearances of most conventional antiepileptics are not affected by cotherapy with clobazam, the apparent clearances of valproic acid and primidone are significantly reduced in the presence of clobazam. Serum concentrations of clobazam increased with dosage and age, and decreased with phenobarbital cotherapy. Serum concentrations of N-desmethylclobazam significantly correlated with clobazam serum levels, age, or clobazam dosage and were significantly increased by cotherapy with phenytoin or carbamazepine. None of the concomitantly used drugs were associated with increased or decreased rate of seizure control. Twelve patients experienced mild adverse drug effects that were not associated with particular cotherapy, clobazam dose, or plasma concentrations. When clobazam is added to a therapy regimen that includes valproic acid, the patient should be closely followed for possible adverse drug reactions caused by elevated valproic acid serum concentrations, and monitoring of valproate serum levels should be considered. When clobazam doses are gradually increased to achieve an optimal clinical effect, the interactions with phenobarbital, carbamazepine, and phenytoin do not necessitate therapeutic drug monitoring of clobazam or N-desmethylclobazam, because there is a large therapeutic window and a poor correlation between plasma concentrations and therapeutic efficacy.

Adolescent↗
PubMed1986

Drug interactions with oral contraceptives.

In the very rare cases where a pregnancy occurs during oral contraceptive use, the blame is usually laid against the patient for having forgotten to take the pill. Evidence has started to accumulate to suggest that neither the patient nor the pill is at fault in some contraceptive failures. It may be because the patient is taking other medicines and these may be preventing the pill from suppressing ovulation. Most drug interactions reducing or negating contraceptive activity are due to concomitant use of drugs having microsomal enzyme-inducing activity (e.g., some antibiotics, especially rifampicin, and anticonvulsants, including phenobarbital, phenytoin, and primidone. Other antibiotics (e.g., tetracycline) may also interact by interruption of the enterohepatic circulation of contraceptive steroids. Less well appreciated, oral contraceptive steroids may themselves modify the metabolism and pharmacological activity of various other drugs (e.g., anticoagulants, benzodiazepines, beta-blockers, caffeine, corticosteroids, and tricyclic antidepressants); in this respect the oral contraceptives are acting as enzyme inhibitors. Contraceptive steroids may also interact with drugs that cause enzyme inhibition and this delays the metabolism of the hormonal agents. Interactions of this type would be expected to potentiate the action of the contraceptive steroids. It is suggested that the effects of such interaction might be presented in terms of increased incidence of side effects, including water retention, diabetogenic effects, hypertension, and an increased risk of thromboembolic disorders. The spectrum of interactions with oral contraceptives is presented in three tables.

Binding, Competitive↗
PubMed1978

Carbamazepine as a substitute treatment of single and compound seizures.

Carbamazepine is a suitable substitute for phenobarbital, primidone, and phenytoin, alone or in combination, when used in the treatment of generalized tonic-clonic or partial epilepsy. Seventy-five percent of 19 patients successfully transferred to carbamazepine and clinically their seizures were at least as well controlled during 18 months of observation. Carbamazepine, alone, is not a satisfactory substitute for drug combinations used in the treatment of compound epilepsy. Fifty percent of 18 patients were successfully transferred to carbamazepine but few of them were significantly improved during the 24 month follow-up. The gradual replacement of standard anticonvulsants with carbamazepine can be accomplished without seizure exacerbation, often with improved control and patient satisfaction. Unfavorable reactions usually are brief, provided serum levels are established between 5 and 12 micrograms/ml.

Adolescent↗
PubMed1982

Brainstem auditory evoked potential recording in patients with epilepsy.

The brain stem auditory evoked potential (BSAEP) was recorded in 32 normal control subjects and 81 epileptic patients. Statistically significant differences in regard to sex and laterality of ear stimulated were found to exist in both groups. The epileptic patients also had significantly longer latencies for all wave components and interwaves I-III as well as I-IV than the normal controls. There were no differences in regard to interwave latency III-V. Clinically significant latency prolongations (more than three standard deviations from the norm) were encountered especially in regard to waves I and III. Correlations of wave and interwave latencies with a large variety of clinical variables showed that statistically significant relationships existed mainly in regard to presence or absence of brain damage and the severity of the seizure disorder, as expressed by the number of different seizure types to which a given patient was subject. Waves II and III showed the most consistent latency prolongations for these variables. Anticonvulsant medication levels did affect wave latencies, but apart from Primidone, it involved waves IV through VII rather than II and III. Carbamazepine levels were related to prolongation of I-III interwave latency. It is concluded that severely brain-damaged epileptic patients have demonstrable brain stem dysfunction affecting mainly the medullo-pontine rather than midbrain or thalamic structures.

Adult↗
PubMed1995

The effect of age and liver disease on the pharmacokinetics of the calcium antagonist, nisoldipine.

Two studies were performed-one in elderly, hypertensive patients and one in patients with chronic liver disease-to investigate the effect of age and liver disease upon the pharmacokinetics of nisoldipine, a dihydropyridine-type calcium antagonist. The effect of acute and chronic administration of nisoldipine (once and twice daily) was investigated in 17 elderly hypertensive patients. Compared with previously published data from young healthy volunteers, the values for Cmax and AUC appear to be higher in elderly hypertensive patients while Tmax and half-life were unchanged. Nisoldipine significantly reduced both systolic and diastolic blood pressure when given acutely to elderly hypertensive patients. Major alterations in the pharmacokinetics of nisoldipine were found in 7 patients with chronic liver disease when compared with the elderly hypertensives and healthy volunteers. The values for AUC, Cmax, half-life and volume of distribution were all higher than expected from the volunteer data while clearance was lower. One patient receiving primidone had very low nisoldipine levels, suggesting that the concomitant administration of agents that may induce the metabolism of nisoldipine should be discouraged. Nevertheless, comparisons of nisoldipine plasma levels after acute and chronic administration showed no evidence of any accumulation in either patient population in the doses used. The drug was generally well tolerated although 1 patient with chronic liver disease was withdrawn due to fluid retention.

Administration, Oral↗
PubMed2003

Comparison of human exposures to selected chemicals with thresholds from NTP carcinogenicity studies in rodents.

The National Toxicology Program (NTP) Technical Reports online database was reviewed to find chemicals that were reported to show clear evidence of carcinogenicity in the NTP rodent studies and for which data on human exposure could be found. Six representative compounds were selected. Three volatile compounds: ethyl benzene, perchloroethylene, and methylene chloride; two drugs in current use: phenytoin and primidone; and one naturally occurring, widely used, flavor: allyl isothiocyanate, were selected. The carcinogenicity data from each of the NTP Technical Reports were plotted using the Rozman scale to determine the threshold for carcinogenicity from the rodent studies. The human exposures for each chemical were calculated and compared with that threshold. The thresholds for carcinogenicity of the three volatile compounds were several orders of magnitude above the levels present in ambient air in the USA. The Threshold Limit Value (TLV) of the American Conference of Governmental Industrial Hygienists (ACGIH) for these three compounds varied between several orders of magnitude below the carcinogenicity threshold to being at the threshold. The maximum recommended doses of both drugs were at the carcinogenicity threshold. The estimated mean daily human consumption of the natural flavor was less than 100 x below the carcinogenicity threshold. This method of comparison between human exposure and animal carcinogenicity studies is more objective and informative than those in current use.

Adenoma↗
PubMed2005

Practice parameter: therapies for essential tremor [RETIRED]: report of the Quality Standards Subcommittee of the American Academy of Neurology.

BACKGROUND: Essential tremor (ET) is one of the most common tremor disorders in adults and is characterized by kinetic and postural tremor. To develop this practice parameter, the authors reviewed available evidence regarding initiation of pharmacologic and surgical therapies, duration of their effect, their relative benefits and risks, and the strength of evidence supporting their use. METHODS: A literature review using MEDLINE, EMBASE, Science Citation Index, and CINAHL was performed to identify clinical trials in patients with ET published between 1966 and August 2004. Articles were classified according to a four-tiered level of evidence scheme and recommendations were based on the level of evidence. RESULTS AND CONCLUSIONS: Propranolol and primidone reduce limb tremor (Level A). Alprazolam, atenolol, gabapentin (monotherapy), sotalol, and topiramate are probably effective in reducing limb tremor (Level B). Limited studies suggest that propranolol reduces head tremor (Level B). Clonazepam, clozapine, nadolol, and nimodipine possibly reduce limb tremor (Level C). Botulinum toxin A may reduce hand tremor but is associated with dose-dependent hand weakness (Level C). Botulinum toxin A may reduce head tremor (Level C) and voice tremor (Level C), but breathiness, hoarseness, and swallowing difficulties may occur in the treatment of voice tremor. Chronic deep brain stimulation (DBS) (Level C) and thalamotomy (Level C) are highly efficacious in reducing tremor. Each procedure carries a small risk of major complications. Some adverse events from DBS may resolve with time or with adjustment of stimulator settings. There is insufficient evidence regarding the surgical treatment of head and voice tremor and the use of gamma knife thalamotomy (Level U). Additional prospective, double-blind, placebo-controlled trials are needed to better determine the efficacy and side effects of pharmacologic and surgical treatments of ET.

Adrenergic beta-Antagonists↗
PubMed1977

Carbamazepine as an anticonvulsant in children.

Forty-five children with major motor or psychomotor seizure disorders were treated with carbamazepine in place of sedative anticonvulsants (phenobarbital, primidone) because of chronic behavioral difficulties. A batter of measures believed to reflect attentional and perceptual abilities was administered initially and repeated 4 to 6 months later following the drug crossover. At the conclusion of the study, 37 of the 45 children were judged to be drug "successes"; that is, general alertness and attentiveness were improved, while seizures were adequately controlled. This study indicates that therapeutic regimens of carbamazepine are less likely to interfere with mental functions in children than are equivalent doses of sedative anticonvulsants.

Adolescent↗
PubMed1979

Low cerebrospinal fluid gamma-aminobutyric acid content in seizure patients.

Gamma-Aminobutyric acid (GABA) has been implicated in the neurochemistry of epilepsy. Lumbar cerebrospinal fluid (CSF) GABA concentrations determined using an ion-exchange fluorometric assay reflect brain GABA content. The mean lumbar CSF GABA concentration among 21 medicated patients with intractable seizures was significantly lower (p less than 0.001) than that of 20 unmedicated normal volunteers. Patients with generalized tonic-clonic (grand mal) and complex partial (psychomotor) seizures had significantly lower (p less than 0.05) CSF GABA concentrations than those with simple partial (focal sensory/motor) seizures. Although lumbar CSF GABA levels in our seizure patients did not significantly correlate with serum concentrations of phenytoin, phenobarbital, or primidone, additional study of medication-free epileptic patients may be required to evaluate the possibility of anticonvulsant-drug-induced CSF GABA alterations.

Adult↗
PubMed1980

Carbamazepine-induced orofacial dyskinesia.

Extrapyramidal syndromes have been described after administration of phenytoin and primidone. Although asterixis, dystonia, and tremor have been described with carbamazepine (Tegretol), there is no report of orofacial dyskinesia. We report a case in which a dose-related lingual-facial-buccal extrapyramidal reaction occurred in association with carbamazepine intoxication.

Aged↗
PubMed1981

Safety of anticonvulsants in hepatic porphyrias.

Because acute attacks of porphyria may be precipitated by anticonvulsants, a therapeutic dilemma arises when seizures complicate hepatic porphyria. The list of unsafe agents includes barbiturates, primidone, phenytoin, mephenytoin, ethotoin, ethosuximide, methsuximide, phensuximide, and trimethadione. Agents are considered unsafe if they induce experimental porphyria in animals, and short trials in patients are unreliable for screening. Using drug incubation in chick-embryo hepatocyte culture, we found that porphyrin was increased by carbamazepine, clonazepam, and valproate. These agents should probably be avoided or used with caution in porphyric patients. Alternative approaches to acute porphyric attacks with seizures are discussed.

Animals↗
PubMed1987

Causes of treatment failure with antiepileptic drugs vary over time.

The V.A. Epilepsy Cooperative Study Group evaluated monotherapy with carbamazepine, phenobarbital, phenytoin, and primidone in a total of 622 patients with previously untreated partial seizures. In the 24 months following onset of treatment, 223 patients failed treatment. Analysis of these failures reveals that the majority occurred during the first 6 months with equal contributions to failure from systemic toxicity, neurotoxicity, and seizures. The contribution of systemic toxicity to failure was significantly less in the next 18 months. An increase in the contribution of seizures to failure was seen in this latter period.

Adolescent↗
PubMed1988

Focal task-specific tremor and dystonia: categorization of occupational movement disorders.

We studied 28 patients with focal task-specific disorders. Three groups were identified, according to the occurrence of focal tremor alone (group I, n = 10), dystonia alone (group II, n = 8), and tremor-dystonia combination (group III, n = 10). Four of six patients in groups I and III showed improvement with beta blocking agents alone, and another patient improved with primidone and metoprolol. Four of seven patients in groups II and III improved at least moderately with only anticholinergic medication. The coexistence of focal tremor and focal dystonia in the same limb in 10 patients (group III) suggests a link between these focal disorders. We conclude that focal tremor and focal dystonia are related to generalized essential tremor and generalized dystonia. A scheme which conceptualizes these interrelationships is proposed.

Adolescent↗
PubMed1990

Cortical tremor: a variant of cortical reflex myoclonus.

Two patients with action tremor that was thought to originate in the cerebral cortex showed fine shivering-like finger twitching provoked mainly by action and posture. Surface EMG showed relatively rhythmic discharge at a rate of about 9 Hz, which resembled essential tremor. However, electrophysiologic studies revealed giant somatosensory evoked potentials (SEPs) with enhanced long-loop reflex and premovement cortical spike by the jerk-locked averaging method. Treatment with beta-blocker showed no effect, but anticonvulsants such as clonazepam, valproate, and primidone were effective to suppress the tremor and the amplitude of SEPs. We call this involuntary movement "cortical tremor," which is in fact a variant of cortical reflex myoclonus.

Aged↗