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PubMedDate not supplied

Gamma-vinyl-GABA (vigabatrin) in the therapy of Lennox-Gastaut syndrome: an open study.

The antiepileptic effect of vigabatrin (gamma-vinyl GABA, VGB) in children has been demonstrated in controlled and open studies. According to the literature, results were good to excellent in partial seizures (with and without becoming secondarily generalized) and promising in infantile spasms (IS). In patients with myoclonic epilepsies of early childhood and especially those with Lennox-Gastaut syndrome (LGS), the effect of VGB has been investigated only to a limited extent and the pattern of response was variable. The present open, add-on, dose-ranging study was initiated to assess the long-term effect and safety of VGB in a cohort of 20 children with LGS who were not responding sufficiently to first-line drug monotherapy with valproate (VPA) instead of adding classical second-line antiepileptic drugs [AEDs: benzodiazepines (BZD), phenobarbital (PB), primidone (PRM)], which usually are associated with rapid diminution of their antiepileptic properties and a high frequency of side effects. Eighty-five percent of children experienced a 50-100% reduction in seizure frequency, even after dose reduction of VPA. No serious side effects occurred except in 1 patient who experienced dyskinesia. Mood changes, sedation, ataxia, and hypersalivation, well-known complications of other AEDs, were not observed.

Adolescent↗
PubMed1994

Standard approach to antiepileptic drug treatment in the United States.

Antiepileptic drugs (AEDs) are administered to patients for acute and long-term treatment of seizures. Most patients with acute convulsions receive intravenous (i.v.) benzodiazepine (BZD), frequently followed by i.v. loading with phenytoin (PHT), especially when seizures continue. For patients with absence status epilepticus, BZD is usually followed by ethosuximide (ESM) or valproate (VPA). The decision to continue AED therapy is based on the likelihood that seizures will continue or recur. Once epilepsy is diagnosed, long-term treatment with AEDs is recommended, beginning with monotherapy. Two studies sponsored by the U.S. Veterans Administration (VA), which compared the efficacy of carbamazepine (CBZ), PHT, phenobarbital (PB), primidone (PRM), and VPA, recommend that most adults with recurrent partial seizures receive either CBZ or PHT. The 1992 VA study suggests that VPA is equal to CBZ or PHT in efficacy when partial seizures become secondarily generalized. Primary generalized epilepsies are most frequently treated with VPA when combinations of generalized seizures exist. ESM is prescribed most often when typical childhood absence seizures exist alone. Although many authorities do not recommend long-term treatment of childhood febrile seizures, PB is administered by some when febrile seizures have complex symptomatology. In general, AED monotherapy is currently preferred, but those with more refractory epilepsy receive polytherapy. CBZ, PHT, PB, PRM, VPA, and ESM are the primary AEDs prescribed in the United States. PHT, followed by CBZ and VPA, is the most frequently prescribed AED as both new and total prescriptions. The introduction of felbamate, gabapentin,and lamotrigine may alter these patterns in the future.

Adult↗
PubMed1995

Efficacy and adverse effects of established and new antiepileptic drugs.

Antiepileptic drug (AED) selection is based primarily on efficacy for specific seizure types and epileptic syndromes. However, efficacy is often similar for the different AEDs, and other properties such as adverse effects, pharmacokinetic properties, and cost may also be of importance. For idiopathic generalized epilepsies with absence, tonic-clonic, and myoclonic seizures, the AED of choice is valproate (VPA). Secondarily generalized epilepsies with tonic, atonic, and other seizure types are difficult to treat with any single AED or combination of AEDs. The AEDs of choice for absence seizures are ethosuximide (ESM) and VPA. For control of primary generalized tonic-clonic seizures, any of the other major AEDs can be effective. If VPA cannot be prescribed, carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), or primidone (PRM) may be effective, but ESM or a benzodiazepine (BZD) must be added to control associated absence or myoclonic seizures. The AEDs of first choice for partial epilepsies with partial and secondarily generalized tonic-clonic seizures are CBZ and PHT. Increasing evidence suggests that VPA is a good alternative when CBZ and PHT fail. PB and PRM are second-choice selections because of adverse effects. A combination of two of the five standard AEDs may be necessary to treat intractable seizures, but no studies have been done to indicate an optimal combination. Other epilepsy syndromes such as neonatal and infantile epilepsies, febrile epilepsy, alcoholic epilepsy, and status epilepticus require specific AED treatment. Ultimately, AED selection must be individualized. No "drug of choice" can be named for all patients. The expected efficacy for the seizure type, the importance of the expected adverse effects, the pharmacokinetics, and the cost of the AEDs all must be weighed and discussed with the patient before a choice is made. A number of new AEDs with unique mechanisms of action, pharmacokinetic properties, and fewer adverse effects hold important promise of improved epilepsy treatment.

Adult↗
PubMed1996

Pharmacology of cortical epileptic afterdischarges in rats.

Afterdischarges (ADs) elicited by electrical stimulation of the sensorimotor cortical area are characterized by rhythmic spikes and spike-wave complexes in the EEG and by clonic face and forelimb seizures. We studied the sensitivity of such ADs to phenytoin (PHT), carbamazepine (CBZ), phenobarbital (PB), primidone (PRM), and valproate (VPA) in 78 adult male Wistar rats with implanted electrodes. Neither PHT (30 and 60 mg/kg intraperitoneally, i.p.) nor CBZ (25 and 50 mg/kg i.p.) suppressed cortical ADs. Indeed, ADs were prolonged by higher doses of both drugs. PRM had a similar effect: A dose of 40 mg/kg transiently shortened ADs, but a dose of 80 mg/kg prolonged ADs. PB (20 and 40 mg/kg) and VPA (200 and 400 mg/kg) were effective in suppressing ADs. Higher doses of VPA and PB reduced the intensity of motor phenomena related to the stimuli but had no effect on the motor correlates of ADs. These findings suggest that cortically induced ADs are not a good model of secondarily generalized seizures. The response to VPA and PB suggests that cortical ADs may represent a model of myoclonic seizures.

Animals↗
PubMed1999

Clinical experience with new antiepileptic drugs: antiepileptic drugs in Europe.

The use of antiepileptic drugs (AEDs), singly and in combination, has been marked by variation among European countries and by a slow progress toward a standard of care that is still far from uniform. Phenobarbital, phenytoin, trimethadione, and primidone, given in various combinations, were the predominant agents used in the first half of this century. Prescribing habits differed among the Latin countries, the United Kingdom, and Scandinavia, based on local trends, divergent teaching philosophies of medical schools, and the medical specialty of the prescribing physician. The advent of carbamazepine and valproate, in the early 1960s, changed European prescribing habits. Despite early fears regarding bone marrow toxicity, carbamazepine was found to be superior for treatment of complex partial seizures. Valproate, when the proper therapeutic dosage was belatedly realized, was seen as a superior treatment for generalized and partial epilepsies. Both agents are now considered first-line treatments for these seizure types. The role of the benzodiazepines as adjunctive anticonvulsant therapy remains controversial because of concerns about neurotoxicity and patient tolerance. The number of AEDs marketed in Europe has grown dramatically in the past decade, with agents such as felbamate, gabapentin, lamotrigine, and tiagabine having been approved as either adjunctive or sole therapy. However, not all new agents are available in each European country, and some variation in prescribing persists.

Anticonvulsants↗
PubMed2000

A multicenter randomized controlled trial on the clinical impact of therapeutic drug monitoring in patients with newly diagnosed epilepsy. The Italian TDM Study Group in Epilepsy.

PURPOSE: To assess the clinical impact of monitoring serum concentrations of antiepileptic drugs (AEDs) in patients with newly diagnosed epilepsy. METHODS: One-hundred eighty patients with partial or idiopathic generalized nonabsence epilepsy, aged 6 to 65 years, requiring initiation of treatment with carbamazepine (CBZ), valproate (VPA), phenytoin (PHT), phenobarbital (PB), or primidone (PRM) were randomly allocated to two groups according to an open, prospective parallel-group design. In one group, dosage was adjusted to achieve serum AED concentration within a target range (10-20 microg/ml for PHT, 15-40 microg/ml for PB, 4-11 microg/ml for CBZ, and 40-100 microg/ml for VPA), whereas in the other group, dosage was adjusted on clinical grounds. Patients were followed up for 24 months or until a change in therapeutic strategy was clinically indicated. RESULTS: Baseline characteristics did not differ between the two groups. Most patients with partial epilepsy were treated with CBZ, whereas generalized epilepsies were most commonly managed with PB or VPA. PHT was used only in a small minority of patients. A total of 116 patients completed 2-year follow-up, and there were no differences in exit rate from any cause between the monitored group and the control group. The proportion of assessable patients with mean serum drug levels outside the target range (mostly below range) during the first 6 months of the study was 8% in the monitored group compared with 25% in the control group (p < 0.01). There were no significant differences between the monitored group and the control group with respect to patients achieving 12-month remission (60% vs. 61%), patients remaining seizure free since initiation of treatment (38% vs. 41%), and time to first seizure or 12-month remission. Frequency of adverse effects was almost identical in the two groups. CONCLUSIONS: Only a small minority of patients were treated with PHT, the drug for which serum concentration measurements are most likely to be useful. With the AEDs most commonly used in this study, early implementation of serum AED level monitoring did not improve overall therapeutic outcome. and the majority of patients could be satisfactorily treated by adjusting dose on clinical grounds. Monitoring the serum levels of these drugs in selected patients and in special situations is likely to be more rewarding than routine measurements in a large clinic population.

Adolescent↗
PubMed2006

Lack of interactions between breast cancer resistance protein (bcrp/abcg2) and selected antiepileptic agents.

PURPOSE: Recent studies have indicated constitutive expression of efflux transporter, breast cancer resistance protein (BCRP, ABCG2), in endothelial cells of the blood-brain barrier (BBB). In epileptogenic brain tumors such as ganglioma, astrocytoma, anaplastic astrocytomas, or glioma multiforme, strong expression of BCRP in the microvasculature of the BBB was observed. Therefore it was hypothesized that this phenomenon could critically influence the bioavailability of drugs in these tumors and potentially contribute to the failure of antiepileptic treatment. The aim of this study was to test whether some commonly used antiepileptic drugs (AEDs) are substrates transported by human BCRP. In particular, we focused on phenobarbital, phenytoin, ethosuximide, primidone, valproate, carbamazepine, clonazepam, and lamotrigine. Furthermore, the inhibitory potency of these AEDs to BCRP was examined. METHODS: To study substrate affinity of tested AEDs to BCRP, transport experiments were performed in epithelial BCRP-expressing MDCKII-BCRP and MDCKII-parent cell lines cultured on microporous membrane. For detection of inhibitory potency of AEDs to BCRP, accumulation assays were carried out in MEF3.8-BCRP cells with known BCRP substrates, BODIPY FL prazosin and mitoxantrone. RESULTS: No obvious interactions of tested AEDs with BCRP transporter were observed. Therefore these drugs in relevant therapeutic concentrations are neither substrates nor inhibitors of BCRP. CONCLUSIONS: Based on our in vitro data we can conclude that resistance to treatment with the tested AEDs probably is not caused by the overexpression of BCRP in the BBB of epileptogenic brain tumors.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2006

Lack of efficacy and potential aggravation of myoclonus with lamotrigine in Unverricht-Lundborg disease.

PURPOSE: Unverricht-Lundborg disease (ULD) is a progressive myoclonus epilepsy with tonic-clonic seizures, action myoclonus, mild ataxia, without dementia. Persistence of invalidating action myoclonus is a major problem. Drugs like phenytoin can aggravate ULD. In this study, we retrospectively analyzed the effect of add-on lamotrigine (LTG) in the five patients under our care who received LTG. METHOD: 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. RESULTS: In two patients, LTG exacerbated MJ in a dose-dependent manner. In one patient, a delayed, severe exacerbation of myoclonus occurred that only ceased after LTG withdrawal and introduction of levetiracetam. These three patients had minor forms of ULD. In two patients with moderate to severe forms of ULD, LTG had no effect. CONCLUSION: Although symptoms may fluctuate in ULD, it was possible to pinpoint lack of improvement (2/5), dose-related exacerbation of myoclonus (2/5), and putative late-onset aggravation (1/5) in five patients treated with adjunctive LTG. LTG does not appear to be a sensible treatment option in ULD.

Acute Disease↗
PubMed2006

Epilepsy and the impact of an epileptology clinic for patients with mental retardation and associated disabilities in an institutional setting.

PURPOSE: Epilepsy is a common problem in institutionalized patients with multiple handicaps. Limited data exist on the characteristics of epilepsy in this patient population and the impact of systematic evaluation by an epilepsy service. METHODS: We evaluated 138 patients with epilepsy, institutionalized at a facility that cares for 324 patients with multiple handicaps. Evaluation included EEG, MRI, and video-EEG monitoring. The medication regimen was changed according to seizure diagnosis and the status of seizure control. Follow-up was available for >or=6 months in 110 patients, 1 year for 89, and 1.5 years for 49 patients. We analyzed the seizure and epilepsy diagnosis in this population, as well as the seizure frequency after evaluation and treatment. RESULTS: The 76 male and 62 female patients' ages ranged from 14 to 73 years. Seventy-three patients had fewer than one seizure per month, whereas 29 patients had at least one seizure per month. Of 131 patients taking antiepileptic drugs (AEDs), 62 were receiving monotherapy, and 69 were receiving two or more AEDs. At the last follow-up, overall 55% of patients had reduced seizure frequency, including 23% who became seizure free. Two of 36 patients had spontaneous seizure recurrence after being seizure free with no AEDs for 4 months in one patient and 3 years for the other. Attempts were made to discontinue phenobarbital, primidone, and clonazepam in 21 patients. However, these were discontinued in only five patients. CONCLUSIONS: Epilepsy is heterogeneous in institutionalized patients with multiple handicaps. It is often responsive to medical therapy. Evaluation and treatment by epilepsy specialists had an overall favorable impact on seizure control.

Adolescent↗
PubMed2006

Pathophysiology and management of syncope in Kearns-Sayre syndrome.

A 20-year-old woman with known Kearns-Sayre syndrome was transferred to the emergency department due to syncopal episodes. The electrocardiogram on admission showed complete atrioventricular block. The diagnosis of mitochondrial encephalomyopathy was made when she was 14 years old. At the time of the initial diagnosis, she displayed a normal electrocardiogram pattern. At the age of 17, electrocardiogram recordings demonstrated right bundle branch block with left anterior fascicular block and a prolonged QTc interval of 485 milliseconds (Figure). She was taking coenzyme Q10, oral nicotinamide adenine dinucleotide (reduced), piribedil, amantadine, and primidone. Transthoracic echocardiography revealed normal wall motion of both ventricles and mitral valve prolapse without regurgitation. A permanent dual-chamber pacemaker was immediately implanted.

Adult↗
PubMed1975

Carbamazepine in difficult to control epileptic out-patients.

Twenty-three difficult to control patients with 1 or more seizures per week despite diphenylhydantoin (DPH), phenobarbital and/or primidone in near and toxic doses and blood levels were entered in the study. 3 had grand mal. 8 psychomotor seizures and 12 had both. During a 6 1/2 month study period the patient received active drug and placebo for 3 months each; randomized, double-blind. The dose was to be increased within 4 weeks up to 6 capsules per day equal to 1,200 mg of carbamazepine (C), while the doses or previously taken (basis) anticonvulsants were to remain unchanged. Hematopoetic system and heptic functions were monitored. Complete seizure control attributable to C was not achieved in any, but up to 50% improvement occurred in 12 patients. Questionable improvement was thought to take place in 3 patients, no change occurred in 7, and psychomotor seizures became more frequent in 1 patient. A clear-cut psychotropic effect was not observed. Adverse effects attributable to C were a decline of WBC below 4,000 with relative neutropenia in 3 patients followed by at return to the previous after discontinuation of C. Nystagmus and unsteadiness were seen in about half of the patients, and some headache and drowsiness occurred in one quarter. The highest C blood level was 11.8 mug/ml, the lowest 3.8 mug/ml (average 5.6 mug/ml) during 1,200 mg intake. It seemed, generally, that intoxication occurred with lower blood levels of carbamazepine in those patients whose basis anticonvulsant blood levels were highest.

Adolescent↗
PubMed1985

Epilepsy with impulsive petit mal (juvenile myoclonic epilepsy).

Juvenile myoclonic epilepsy (JME) is a special syndrome within the primary generalized epilepsies which is characterized clinically by irregular jerks of shoulders and arms (so-called impulsive petit mal) after awakening and electroencephalographically by bilateral-synchronous 4-6/s spike-wave complexes, often in the form of multispike-waves. The age of onset for this syndrome which occurs in 4-6% of all epilepsies is predominantly between 12 and 18 years. It mostly starts with isolated jerks which as a rule are soon followed by generalized tonic-clonic seizures (TCS). Jerks and TCS are provoked by sleep deprivation and predominantly occur after awakening (awakening epilepsy). Sleep deprivation and photostimulation are also very efficient in provoking specific EEG patterns. Exogenous factors have no etiological significance. Genetic studies suggest a polygenetic mode of inheritance and a lower threshold of manifestation in women. JME can be controlled very well by valproate and/or primidone. A complete cure, nevertheless, does not seem to be possible. Within the group of primary generalized epilepsies beginning in adolescence JME is closely related nosologically to the syndrome of juvenile absences and the syndrome of pure grand mal on awakening.

Adolescent↗
PubMed1987

Effect of anticonvulsant drugs on (35S)t-butylbicyclophosphorothionate binding in vitro and ex vivo.

Using several concentrations of eight anticonvulsant drugs in clinical use (carbamazepine, clonazepam, phenytoin, phenobarbital, ethosuximide, primidone, sodium valproate, and D,L-gamma-vinyl GABA), we studied their abilities in vitro to displace (35S)t-butylbicyclophosphorothionate (35S-TBPS) from its binding site in a homogenate of rat brain. Thereafter ethosuximide (150 mg/kg), phenobarbital (30 mg/kg), clonazepam (0.3 mg/kg), or phenytoin (100 mg/kg) was injected intraperitoneally into rats for 16-20 days; and the effect of drug administration on 35S-TBPS binding was studied in the cortex and hippocampus ex vivo. Phenobarbital (100 microM, P less than 0.001), ethosuximide (500 microM, P less than 0.001), and phenytoin (40 microM, P less than 0.001) decreased the specific 35S-TBPS binding in vitro by 10-16%. After drug administration of phenobarbital (concentration in plasma 168 microM), the number of binding sites decreased and the binding affinity (P less than 0.05) in the cortex increased. Other anticonvulsants did not modulate 35S-TBPS binding in vitro at the concentration analogous to therapeutic plasma levels or ex vivo at the dose used. These results suggest that the use of phenobarbital may modulate the TBPS binding site, but the role of the present findings in the anticonvulsant action of phenobarbital needs to be further studied.

Animals↗
PubMed1985

Biotin status of epileptics.

Microbiologically determined plasma biotin levels in 404 epileptics under long-term treatment with anticonvulsants were markedly lower than in 112 controls (p less than 0.0005). Patients with partial epilepsy had lower biotin levels and higher average daily intake of AC than those with generalized epilepsy. Epileptics treated with valproate sodium in monotherapy showed considerably higher biotin levels than epileptics with monotherapy of primidone (PRM), carbamazepine (CBZ), phenytoin (PHT) or phenobarbital (PB). The group of epileptics with high average daily dose of anticonvulsants had lower biotin levels than the group with low dose. In three patients with newly recognized epilepsy biotin levels were normal before starting anticonvulsant medication, increased during the first week and fell under the starting level in the following weeks. Four epileptics treated with PHT, PB, PRM or CBZ had an increased urinary excretion of organic acids, as found in patients with a deficiency of biotin-dependent carboxylases. In 37 epileptics undergoing long-term treatment plasma lactate concentrations were determined; they had a higher mean concentration than that found in controls. Our results suggest, that the lowering of biotin in epileptics is caused by intake of anticonvulsants and has a biochemical effect in these patients. It is discussed, whether this could be a factor in the mode of action of anticonvulsants.

Adult↗
PubMed2004

Key structural features of ligands for activation of human pregnane X receptor.

The ligand-binding domain of human pregnane X receptor (hPXR) is highly hydrophobic and flexible, allowing promiscuity in accepting structurally diverse ligands. However, little information is available regarding the critical substituents of compounds involved in the activation of hPXR. The aim of this study was to determine the structure-activity relationships for hPXR-mediated transactivation by barbiturates, hydantoins, and macrolide antibiotics. Most of the barbiturates studied (mephobarbital, pentobarbital, phenobarbital, etc.) activated hPXR. However, barbital, which has a low hydrophobic moiety at the 5-position, and primidone, which has no carbonyl moiety at the 2-position, did not activate hPXR. Therefore, a hydrophobic moiety at the 5-position and a hydrogen-bond acceptor being sufficiently separated from the phenyl-ring are responsible for activation of hPXR by barbiturates. In the case of hydantoins, only mephenytoin and ethotoin, which have an alkylchain at the R1-position, strongly activated hPXR at 300 microM. Phenytoin and 5-(4-methylphenyl)-5-phenylhydantoin, which contain a phenyl or methylphenyl group at both R2- and R3-positions, also activated hPXR, whereas 5-(4-hydroxyphenyl)-5-phenylhydantoin did not activate the receptor. These results suggest that the presence of an alkyl-chain at the R1-position and the presence of bulky and hydrophobic moieties at both R2- and R3-positions are important factors for activation of hPXR by hydantoins. In the case of macrolide antibiotics, troleandomycin, but not oleandomycin, showed significant activation of hPXR. Therefore, triacetate esterification of oleandomycin might increase the hydrophobicity and enhance the activation of hPXR. These findings suggest that hydrophobicity of the ligand and adequate distance between the hydrogen-bond acceptor and the hydrophobic group are important for hPXR activation.

Anti-Bacterial Agents↗
PubMed2001

Inhibition of cytochrome P450 (CYP450) isoforms by isoniazid: potent inhibition of CYP2C19 and CYP3A.

Isoniazid (INH) remains the most safe and cost-effective drug for the treatment and prophylaxis of tuberculosis. The use of INH has increased over the past years, largely as a result of the coepidemic of human immunodeficiency virus infection. It is frequently given chronically to critically ill patients who are coprescribed multiple medications. The ability of INH to elevate the concentrations in plasma and/or toxicity of coadministered drugs, including those of narrow therapeutic range (e.g., phenytoin), has been documented in humans, but the mechanisms involved are not well understood. Using human liver microsomes (HLMs), we tested the inhibitory effect of INH on the activity of common drug-metabolizing human cytochrome P450 (CYP450) isoforms using isoform-specific substrate probe reactions. Incubation experiments were performed at a single concentration of each substrate probe at its K(m) value with a range of INH concentrations. CYP2C19 and CYP3A were inhibited potently by INH in a concentration-dependent manner. At 50 microM INH (approximately 6.86 microg/ml), the activities of these isoforms decreased by approximately 40%. INH did not show significant inhibition (<10% at 50 microM) of other isoforms (CYP2C9, CYP1A2, and CYP2D6). To accurately estimate the inhibition constants (K(i) values) for each isoform, four concentrations of INH were incubated across a range of five concentrations of specific substrate probes. The mean K(i) values (+/- standard deviation) for the inhibition of CYP2C19 by INH in HLMs and recombinant human CYP2C19 were 25.4 +/- 6.2 and 13 +/- 2.4 microM, respectively. INH showed potent noncompetitive inhibition of CYP3A (K(i) = 51.8 +/- 2.5 to 75.9 +/- 7.8 microM, depending on the substrate used). INH was a weak noncompetitive inhibitor of CYP2E1 (K(i) = 110 +/- 33 microM) and a competitive inhibitor of CYP2D6 (K(i) = 126 +/- 23 microM), but the mean K(i) values for the inhibition of CYP2C9 and CYP1A2 were above 500 microM. Inhibition of one or both CYP2C19 and CYP3A isoforms is the likely mechanism by which INH slows the elimination of coadministered drugs, including phenytoin, carbamazepine, diazepam, triazolam, and primidone. Slow acetylators of INH may be at greater risk for adverse drug interactions, as the degree of inhibition was concentration dependent. These data provide a rational basis for understanding drug interaction with INH and predict that other drugs metabolized by these two enzymes may also interact.

Algorithms↗
PubMed1981

Phenylethylmalonamide in essential tremor. A double-blind controlled study.

A randomised double-blind placebo-controlled trial of phenylethylmalonamide, the major metabolite of primidone was performed in eight patients with essential tremor. Phenylethylmalonamide was given in a daily dose of 400 mg for one week and 800 mg for a second week. The compound had no statistically significant effect on the amplitude of tremor assessed by an accelerometric method, tests of performance, clinical evaluation and patient self assessment. No side effects occurred. Serum levels of phenylethylmalonamide on a daily dose of 400 mg were 11-27 micrograms/ml and on 800 mg daily were 16-48.5 micrograms/ml.

Adult↗
PubMed1978

Epileptiform seizures in domestic fowl. IX. Implications of the absence of anticonvulsant activity of ethosuximide in a pharmacological model of epilepsy.

Acute dose--response studies were conducted to determine if ethosuximide had anticonvulsant activity against seizures evoked by stroboscopic stimulation of epileptic fowl and to correlate the observed effects with the concentration of the drug in the plasma. Ethosuximide, in doses that produced mean plasma concentrations of 366 microgram/ml and signs of sedation, did not reduce seizure susceptibility. Twice daily administration of ethosuximide produced mean plasma concentrations of 430 microgram/ml after 36 h without affecting seizure susceptibility even in the presence of marked sedation. Previous studies have shown that epileptic fowl are sensitive to the anticonvulsant effects of phenobarbital, phenytoin, and primidone at plasma concentrations similar to those required in humans. Since ethosuximide has a high specificity against petit mal seizures in humans, the failure of ethosuximide to provide protection indicates that epileptic fowl represent a relatively specific pharmacological model for drugs effective against generalized tonic--clonic and focal cortical epilepsies in humans.

Animals↗