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A 74 year old man presented to the Old Age Psychiatry Service with cognitive deficits while being treated for recurrent depressive episodes and essential tremor with Venlafaxine, Lithium, and Primidone. Neuropsychological testing revealed a medio-temporal pattern of deficits with pronounced impairment of episodic memory, particularly delayed recall. Likewise, cognitive flexibility, semantic fluency, and attention were impaired. Positron emission tomography (PET) with fluorodeoxyglucose was performed and revealed a pattern of glucose utilization deficit resembling AD. On cessation of treatment with Lithium and Primidone, cognitive performance improved, particularly episodic memory performance and cognitive flexibility. Likewise, glucose metabolism normalized. Despite normalization of both, clinical symptoms and glucose utilization, the patient remained worried about possible underlying Alzheimer's disease pathology. To rule this out, an amyloid-PET was performed. No cortical amyloid was observed.
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Essential tremor is one of the most common movement disorders. Treatment primarily consists of pharmacological agents. While primidone and propranolol are well-established treatments in clinical practice, they may be ineffective in 25% to 55% of patients and can produce serious adverse events in a large percentage of them. For these reasons, it is worth evaluating the treatment alternatives for essential tremor. Some specialists have suggested that pregabalin could be a potentially useful agent, but there is uncertainty about its efficacy and safety.
The influence of risk factors predisposing to recurrences was assessed in 103 children with febrile convulsions who were given prophylactic treatment with phenobarbitone, primidone or sodium valproate at adequate doses and whose compliance with treatment was monitored. There was a greater risk of recurrence among girls. Increasing risk was observed with decreasing age at which children suffered the first febrile convulsion. Neither a family history of epilepsy, failure of previous treatment, history of perinatal incidents, focal or prolonged febrile convulsions, recognition of neurological disease nor the number of previous febrile convulsions led to any significantly greater risk in these children. There was an increased tendency for recurrence with increasing interval between the first febrile convulsion and the start of prophylactic treatment.
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The data demonstrate that the partial BZD receptor agonist ELB 138 exerts significant anticonvulsant efficacy without tolerance in a dog seizure model as well as in epileptic dogs with spontaneously recurrent seizures. These data thus substantiate that partial agonism at the BZD site of GABAA receptors offers advantages versus full agonism and constitutes a valuable approach for treatment of seizures.
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Patients with epilepsy have excess morbidity and mortality due to ischemic cardiovascular disease. Many of these patients have elevated concentrations of plasma total homocysteine (Hcy), which is an acknowledged risk factor for cardiovascular disease, venous thromboembolic disease, foetal malformations and dementia. Hyperhomocysteinemia may have negative effects through mechanisms involving oxidative damage. In the present study, we have investigated the aminothiol redox-status in patients on antiepileptic drugs. Thereafter, in a subset of patients with elevated total Hcy, we evaluated the effect of B-vitamin therapy.
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Tremor is a symptom of many disorders, including Parkinson's disease, essential tremor, orthostatic tremor, cerebellar disease, peripheral neuropathy and alcohol withdrawal. Tremors may be classified as postural, rest or action tremors. Symptomatic treatment is tailored to the tremor type. Combination therapy with carbidopa and levodopa remains the first-line approach for parkinsonian tremor. Essential tremor may be amenable to propranolol or primidone. Propranolol may be useful in treating alcohol withdrawal tremor, and isoniazid may control the cerebellar tremor associated with multiple sclerosis. Clonazepam may relieve orthostatic tremor. Other agents are also available for the treatment of tremor. When medical therapy fails to control the tremor, surgical options such as thalamotomy, pallidotomy and thalamic stimulation should be considered in severe cases. Thalamic stimulation, the most recent of these surgical approaches, offers the advantage over ablative procedures of alleviating tremor without the creation of a permanent lesion.
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Although animal models, such as electroshock seizures, pentylenetetrazol (PTZ)-induced seizures and the rotorod test, are widely employed in the search for and evaluation of new anticonvulsant drugs, the important role of diverse technical, biological and pharmacological factors in the interpretation of results obtained with these models is often not recognized. In order to delineate factors other than strain, sex, age, diet, climate, and circadian rhythms, which are generally known, a series of studies was undertaken. In the experiments described here, the influence of administration vehicles and drug formulations on bioavailability, potency and time course of anticonvulsant drugs was studied in mice. Two standard anticonvulsant drugs, primidone and carbamazepine, with poor aqueous solubility were used for these experiments, because water insolubility is a common problem in the laboratory evaluation of anticonvulsant agents. Since vehicles, especially organic solvents or detergents, may exert effects of their own, sensitive electroshock and PTZ seizure threshold tests were used for the assessment of vehicle-related actions. Of various aqueous or lipophilic vehicles tested, only glycofurol increased seizure thresholds, when concentrations exceeding 10% were administered. However, even at a concentration of 30%, the solubilizer did not exert measurable effects in the maximal electroshock seizure (MES) test in mice, but markedly potentiated the effect of primidone. In contrast, polyethylene glycol 400 (PEG 400) up to a concentration of 30% did not affect electrical or chemical seizure thresholds nor did it alter the pharmacological potency of primidone. When primidone or carbamazepine were administered as a suspension in a Tween/water vehicle, their anticonvulsant effects were considerably lower compared to injections of the same doses as a solution.(ABSTRACT TRUNCATED AT 250 WORDS)
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A rapid gas-liquid chromatographic method has been developed for the analysis of phenobarbitone, primidone and phenytoin in small (50 microliter) volumes of either blood plasma or serum. Neither solvent transfer nor evaporation are required in the extraction, which takes less than 3 min to complete, and a quantitative analysis may be performed, in duplicate, within 20 min. Sources of interference in the assay are minimal, and prior treatment of the column with gamma-glycidoxypropyltrimethoxysilane facilitates the measurement of as little as 10 ng of underivatized drug "on-column" using a flame-ionisation detector. The method has proved valuable when used for detection and measurement of these three compounds at concentrations of 2 mg/1 or greater.
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The interlaboratory variability in the assay of theophylline and various anticonvulsant drugs was evaluated in a 16-month prospective study by using two independent experimental approaches: (a) a conventional method based on the distribution of quality control (QC) lyophilized human sera spiked with the test drugs (phenytoin, phenobarbital, carbamazepine, valproic acid, primidone, theophylline); and (b) reanalysis by two to four reference laboratories of patients' samples randomly selected among those routinely assayed for phenytoin and theophylline by the 52 participating laboratories. For all tested drugs, precision as assessed by results on spiked QC samples was generally satisfactory, interlaboratory coefficients of variation (CV) being below 18.5% for all drugs tested except primidone (CV = 24.1%) at clinically relevant drug concentrations. For both phenytoin and theophylline, there was a good agreement between results obtained by individual reference laboratories (reference results) on routine samples. The correlation coefficients relating the original values to the means of the reference results were greater than 0.94. It is concluded that interlaboratory variability in the assay of the drugs included in this survey is relatively low not only when assessed by using conventional QC material, but also under strictly routine conditions.
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Levels of alpha 1-acid glycoprotein (alpha 1-AGP) were determined in 40 epileptic patients who had been also treated with carbamazepine (CBZ) and, in some patients, phenobarbital (PB) for at least 3 months. alpha 1-AGP levels were also determined in 28 controls. CBZ dit not alter blood levels of alpha 1-AGP while CBZ-PB decreased them. Such results are at variance with recent studies which suggested an increase of alpha 1-AGP in epileptic patients treated either with phenytoin or phenytoin + PB, or + CBZ, or + primidone.
Global water shortage is placing an unprecedented pressure on water supplies. Treated wastewater is a valuable water resource, but its reuse for agricultural irrigation faces a roadblock: the public concern over the potential accumulation of contaminants of emerging concern (CECs) into human diet. In the present study, we measured the levels of 19 commonly occurring pharmaceutical and personal care products (PPCPs) in 8 vegetables irrigated with treated wastewater under field conditions. Tertiary treated wastewater without or with a fortification of each PPCP at 250 ng/L, was used to irrigate crops until harvest. Plant samples at premature and mature stages were collected. Analysis of edible tissues showed a detection frequency of 64% and 91% in all vegetables from the treated wastewater and fortified water treatments, respectively. The edible samples from the two treatments contained the same PPCPs, including caffeine, meprobamate, primidone, DEET, carbamazepine, dilantin, naproxen, and triclosan. The total concentrations of PPCPs detected in edible tissues from the treated wastewater and fortified irrigation treatments were in the range of 0.01-3.87 and 0.15-7.3 ng/g (dry weight), respectively. Annual exposure of PPCPs from the consumption of mature vegetables irrigated with the fortified water was estimated to be only 3.69 μg per capita. Results from the present study showed that the accumulation of PPCPs in vegetables irrigated with treated wastewater was likely limited under field conditions.
Contraceptive management in women with epilepsy is critical owing to the potential maternal and fetal risks if contraception or seizure management fails. This article briefly describes the pharmacokinetic interactions between antiepileptic drugs (AEDs) and hormonal contraceptives and the rational strategies that may overcome these risks. Hormonal contraception, including the use of oral contraceptives (OCs), is widely used in many women with epilepsy - there is no strong evidence of seizures worsening with their use. AEDs are the mainstay for seizure control in women with epilepsy. However, there are many factors to consider in the choice of AED therapy and hormonal contraception, since some AEDs can reduce the efficacy of OCs owing to pharmacokinetic interactions. Estrogens and progestogens are metabolized by cytochrome P450 3A4. AEDs, such as phenytoin, phenobarbital, carbamazepine, felbamate, topiramate, oxcarbazepine and primidone, induce cytochrome P450 3A4, leading to enhanced metabolism of either or both the estrogenic and progestogenic component of OCs, thereby reducing their efficacy in preventing pregnancy. OCs can also decrease the concentrations of AEDs such as lamotrigine and, thereby, increase the risk of seizures. Increased awareness of AED interactions may help optimize seizure therapy in women with epilepsy.
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We measured the concentrations of phenobarbital, phenytoin, primidone, ethosuximide, antipyrine, and caffeine in paired samples of saliva and plasma by gas chromatograph-mass spectrometer-computer (GC/MS/COM) and enzyme immunoassay. Mixed saliva was collected for the antipyrine and caffeine studies, parotid saliva for the phenobarbital, primidone, ethosuximide and phenytoin studies. The saliva/plasma (S/P) ratios (by weight) obtained by GC/MS/COM were: phenobarbital, 0.31-0.37; phenytoin, 0.11; ethosuximide, 1.04; antipyrine, 0.83-0.95; caffeine, 0.55. The S/P ratio obtained by enzyme immunoassay were: phenobarbital, 0.32; phenytoin, 0.12; primidone, 0.85. The concentrations of phenytoin, primidone, ethosuximide and antipyrine in saliva correspond to the free fraction of the drug in plasma. When we analyzed samples containing phenobarbital or phenytoin (plasma or saliva) by both techniques, we found that the enzyme immunoassay values were generally higher than GC/MS/COM values, suggesting that the metabolites as well as the parent drug were measured in the immunoassay.
Postural tremor is the most common movement disorder in psychiatry, and often a difficult problem for clinicians. It can be classified as physiological, essential, drug-induced, and postural tremor in Parkinson's disease. Drugs used in psychiatry that can produce postural tremor, include lithium, valproic acid, lamotrigine, antidepressants, and neuroleptics. Clinical characteristics of postural tremor induced by each of these drugs are described. Pharmacological strategies for therapy in disabling drug-induced tremor include beta-blockers, primidone, gabapentin, topiramate, and benzodiazepines; their utility, doses and side-effects are also discussed.
Phenobarbital and primidone frequently have adverse effects on mental functions. Therefore, an attempt was made to taper barbiturates in 85 patients out of a resident population with epilepsy and intellectual disability who were selected according to clinical criteria. The objectives were to reduce the use of barbiturates, to improve the patients' cognitive and psychological state, and to reduce polypharmacy while avoiding seizure exacerbation. Four months after complete withdrawal changes in seizure frequency were assessed as well as changes in cognitive abilities, psychological state and behaviour (using the clinical global impression scale). In 13 patients the tapering failed due to complications (seizure increase in 11 patients). In 72 patients the barbiturate was completely withdrawn (mean duration of tapering: 393 days). Cognitive improvement was achieved in 17 patients (23.6%), 5 patients (6.9%) deteriorated. Seizure frequency remained unchanged in 33 patients (45.8%), in another 15 patients (20.8%) the seizure frequency decreased. Reduction in polypharmacy was obtained in 61 patients (84.7%). In an overall judgement (clinical global impression scale) of cognitive abilities AND seizure control, 25 patients (34.7%) were improved. 31 patients (43.1%) remained unchanged while 12 patients deteriorated (4 patients: impossible to judge). For statistical analysis three outcome groups were defined: the improved group (N=25), the unchanged group (N=31), and the deteriorated/failed group (N=25) consisting of the 12 deteriorated patients plus the 13 patients in whom tapering failed. Stepwise logistic regression revealed a history of an attempt to withdraw phenobarbital/primidone (p=0.017; OR 3.8), age (p=0.012) and seizure frequency (marginally significant: p=0.097) as outcome predictors. Older age was associated with better outcome. A high seizure frequency before tapering was related to good outcome, while seizure freedom and a history of failed withdrawal were associated with deterioration/failure. Outcome did not depend on duration of barbiturate therapy, dosage or serum concentration, co-medication, reduction rate, degree of intellectual disability, or epilepsy syndrome. In summary, the number of barbiturate medications has been considerably reduced, but the principal aim of the project, to relieve patients from assumed barbiturate side effects, has been achieved only in one out of four patients.
Essential tremor is a common neurologic problem seen widely at all levels of patient care. It should be differentiated from secondary causes of tremor and Parkinson disease. It can be managed with commonly used drugs. However, severe, resistant, or atypical cases should be referred to a specialist for evaluation and the possible use of botulinum toxin or deep brain stimulation.
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With the aid of our own method of gas chromatography we determined serum concentrations of anticonvulsants in a large number of children who were being treated with diphenylhydantoin, primidone and phenobarbitone. The drugs were being prescribed either as monotherapy, or in combination with each other, or with other substances which have anticonvulsive activity. Regression lines showed good correlations between the quantity of drugs administered (total daily dose) and serum concentrations. The regression lines for diphenylhydantoin and primidone, however, showed no differences, irrespective of whether they were being given alone or in combination. In view of the frequency of symptoms of intoxication and of non-responders, we established a therapeutic range for diphenylhydantoin and primidone (diphenylhydantoin: 5--16 mcg/ml; primidone: 4--14 mcg/ml). The required serum concentrations could be obtained by giving 8--12 mg/kg of diphenylhydantoin, and 15-22 mg/kg of primidone. In spite of the satisfactory correlation between total daily dose and serum concentrations, however, many patients showed departures from this normal behaviour, especially where combination treatments were being conducted. This demonstrates the necessity for routine controls of serum levels.
Primidone represents a possible adjuvant therapy in theophylline-resistant apnea of prematurity. Caution is advised, because of primidone's complex pharmacologic characteristics, until there are further controlled prospective studies.
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Seventy-four patients received single drug treatment with carbamazepine (CBZ), phenytoin (PHT), and either phenobarbital (PB) or primidone (PRM). Medical intractability was established if seizure control was not obtained despite maximum tolerable doses of the drug. In all, 120 single drug treatments were administered with the drugs that has not been administered at maximal doses in monotherapy before the study.
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Our study showed that primidone is tolerable in MS patients and effectively reduces severe cerebellar tremor in such patients.
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The aim of the present study was to evaluate the risk of intrauterine growth delay in the offspring of epileptic mothers and to quantify the risks of intrauterine exposure to antiepileptic drugs (AEDs). Data concerning 870 newborns, prospectively collected in Canada, Japan and Italy, using the same study design, were pooled and analyzed. The overall proportion of newborns whose body weight (7.8%) or head circumference (11.1%) at birth were below the 10th percentile was not increased. However, logistic regression analysis showed that the risk of small head circumference was significantly higher in Italian than in Japanese (RR 4.2; 95% CI: 2.2-8.0) or Canadian children (RR 2.6; 95% CI: 1.1-6.5), and in children exposed to polytherapy (RR 2.7; 95% CI: 1.2-6.3), phenobarbital (PB) (RR 3.6; 95% CI: 1.4-9.4) and primidone (PRM) (RR 4.5; 95% CI: 1.5-13.8). Country was also the only factor affecting low body weight, with Italian children having a higher risk than Japanese (RR 5.2; 95% CI: 2.6-10.4) or Canadian (RR 8.8; 95% CI: 2.0-38.1) children. Due to the small categories, the influence of AED doses and plasma concentrations was studied for each individual AED, without adjustment for the other potential confounding factors. A clear dose-dependent effect was found for PB and PRM in terms of both small head circumference and low body weight, and a concentration-dependent effect for PB in terms of small head circumferences. The size of the difference between the Italian and the other two populations, which is only partially explained by differences in therapeutic regimens, suggests that genetic, environmental and ethnic factors also need to be taken into account when considering possible explanations.
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Multiple pharmacologic treatments have been studied, but propranolol and primidone have proven to be the most effective medications. It is unlikely that a patient will respond miraculously to another medication if his or her response to propranolol and primidone is minimal. Some subsets of essential tremor, however, such as the kinetic predominant type, may respond better to other medications. Mildly affected patients may not need treatment at all, and the potential benefits must always be weighed against the possible side effects. The main benefit of botulinum toxin injection is for head tremor, whereas its efficacy in hand tremor is variable. If a patient does not respond to adequate doses of propranolol or primidone, deep brain stimulation should be considered because it carries the lowest risk of the available surgical procedures; usually, it should be given preference over thalamotomy. It is important for the physician to realize the multitude of symptomatic treatments available. Beyond the conventional and often effective oral medications, use of newer treatments such as botulinum toxin, thalamotomy, and deep brain stimulation can often reduce tremor and lead to a greater quality of life for patients with ET.
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In the treatment of epilepsy often several substances with anticonvulsive effect are combined. Possible drug interactions in these cases can change the desired effect of treatment. Simultaneous administration of clonazepam or dipropylacetate (the latter in a short term combination) with diphenylhydantoin can cause a significant increase of diphenylhydantoin serum concentrations and intoxications. The combination of carbamazepin with diphenylhydantoin can cause a decrease of diphenylhydantoin serum concentrations. The simultaneous administration of diphenylhydantoin and phenobarbital can produce a significant increase of phenobarbital levels in the statistical average and in the case of a combination of primidon and diphenylhydantoin an intoxication by the primidon metabolite phenobarbital. These possible interactions which are not obvious at the beginning of therapy are supplemented by other factors as intercurrent diseases or erratic drug intake. With routine measurements of serum concentrations of anticonvulsive drugs some of these interfering factors can be eliminated by realizing them in time. Treatment becomes more effective and side effects are reduced. The development of a new check list for the treatment of epileptic patients should also improve the control and give better informations about the course of the disease.
A simple, sensitive and precise gas-chromatographic method for simultaneous extraction, derivatization and determination of methsuximide, ethosuximide, diphenylhydantoin, carbamazepine, phenobarbital and primidone in the presence of other drugs has been described. The method is especially useful for drug monitoring in patients on multiple anticonvulsant therapy while also on combination therapy with psychotropic drugs. It overcomes the analytical interferences between mephenytoin and phenobarbital; methsuximide and primidone; kemadrin and primidone; cholesterol and primidone; prolixin, haldol and other drugs; encountered in other methods using underivatized, trimethylsilylated or methylated drugs. As little as 0.5 microgram/ml of a drug can be determined and if needed the method can be scaled down to 0.3 ml plasma. The method yielded recoveries of 97-103% with standard deviations of 0.7-1.8. For a constant check of the precision, an internal quality control using daily analysis of a sample from a frozen plasma pool supplemented with known concentrations of the anticonvulsants was used. The method is suitable for use in routine clinical laboratory.
The long-term efficacy of primidone (375-750 mg/day) in essential tremor was evaluated prospectively in 11 patients who had shown a favorable response to 4-week treatment with the drug under placebo-controlled conditions. On accelerometric evaluation, the magnitude of tremor after 3, 6, and 12 months on primidone was still significantly reduced compared with the initial placebo period. After discontinuation of primidone, tremor amplitude reverted to the placebo levels. Some loss of efficacy during long-term administration, however, was suggested by the results of self-assessment, physician's assessment, and performance tests. Three patients discontinued prematurely the drug because the sedative effects outweighed the potential therapeutic benefit. Side effects (especially drowsiness and sedation) were common at 4 weeks and 3 months but tended to subside thereafter. It is concluded that primidone retains at least part of its tremorolytic effect for up to 1 year, although the overall clinical benefit is limited in most patients.
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In the present study we investigated the effect of antiepileptic drugs on high potassium (50 mM) stimulated somatostatin release in rat cortical slices in a superfusion system. The somatostatin-like immunoreactivity (SLI) in superfusate was determined by radioimmunoassay. The antiepileptic drugs studied, vigabatrin, valproate, carbamazepine, phenobarbital, primidone, clonazepam and phenytoin were tested at a concentration range of 1-1000 microM). Of the drugs used vigabatrin had the most significant inhibitory effect on SLI release (IC50 = 240 microM). Vigabatrin also caused a concomitant, dose-dependent increase in superfusate gamma-amino butyric acid (GABA) level. A 30% decrease in the release of SLI followed incubation with valproate and carbamazepine, but only at high drug concentrations (1000 microM). Phenobarbital, primidone, clonazepam and phenytoin did not affect SLI release. Addition of GABA to superfusate caused a dose-dependent decrease in the amount of SLI release (IC50 = 56 microM). In conclusion, at low concentrations the antiepileptic drugs had only minor effects on SLI release. At higher concentrations, however, vigabatrin and valproate decreased the release of SLI, which may relate to their ability to elevate tissue levels of GABA.
An 18 year old girl is reported, who ingested 15 g of primidone (Liskantin), 330 mg/kg, to commit suicide. Continuous monitoring of the serum levels of primidone, PEMA, and phenobarbital revealed increased elimination of primidone by forced diuresis (6000 ml/24 hours). It is concluded that forced diuresis inhibits the otherwise mandatory increase in primidone metabolites, PEMA and phenobarbital. It is suggested that even after improvement of the clinical symptoms forced diuresis should be continued for at least 48 hours. In epileptic patients the reinstitution of primidone therapy should be considered only on the third day after accidental ingestion, if the clinical symptoms have improved, and if there is no possibility of immediate determination of primidone serum levels.
Three men and two women, aged 20-50 years who had ULD confirmed by molecular biology, followed in two epilepsy centers, received add-on LTG at 50-300 mg/d. All of them had valproate. The other drugs used in cotherapy were high-dose piracetam, benzodiazepines phenobarbital, topiramate, and primidone. The assessment of LTG was based on detailed interview and clinical examination. Aggravation was diagnosed when myoclonic jerks (MJ) increased without irregular intake of medication, inappropriate lifestyle, encephalopathic or metabolic complications, or overdosage.