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Lacosamide, the new anticonvulsant, effectively reduces harmaline-induced tremors in rats.
Eur J Pharmacol. 2008 Jun 14;
Stöhr T, Lekieffre D, Freitag J
The present study aimed at evaluating the efficacy of lacosamide (0.3 to 30 mg/kg), a new anticonvulsant drug, in a model of essential tremor in comparison to the reference compounds propranolol and primidone. We observed a high tremorlytic effect of lacosamide reducing the intensity of tremors following harmaline administration in a dose-dependent manner. The higher dose also modified the latency and intensity of tremor at onset. The effect of lacosamide was equal or even superior to propranolol and primidone indicating that lacosamide may be a new antitremorgenic drug that merits further clinical investigation.
Essential tremor: symptoms and treatment.
Consult Pharm. 2008 May; 23(5): 364-70, 375-7
Wick JY, Zanni GR
Essential tremor (ET), traditionally considered benign, is a serious neurologic condition with life-altering repercussions. Its involuntary, rhythmic oscillations involve alternating, irregular, or simultaneous contractions of agonist and antagonist muscles. It is the most common of the 20 known tremor disorders and often confused with Parkinson's disease. Numerous drugs can aggravate ET, and alcohol consumption may alleviate it. Its etiology is unknown. Proven drug treatments are currently limited to propranolol and primidone. This article reviews ET with examples from history to demonstrate points.
Epilepsia. 2008 May 21;
Perucca E, Cloyd J, Critchley D, Fuseau E
Rufinamide is a new, orally active antiepileptic drug (AED), which has been found to be effective in the treatment of partial seizures and drop attacks associated with the Lennox-Gastaut syndrome. When taken with food, rufinamide is relatively well absorbed in the lower dose range, with approximately dose-proportional plasma concentrations up to 1,600 mg/day, but less than dose-proportional plasma concentrations at higher doses due to reduced oral bioavailability. Rufinamide is not extensively bound to plasma proteins. During repeated dosing, steady state is reached within 2 days, consistent with its elimination half-life of 6-10 h. The apparent volume of distribution (V(d)/F) and apparent oral clearance (CL/F) are related to body size, the best predictor being body surface area. Rufinamide is not a substrate of cytochrome P450 (CYP450) enzymes and is extensively metabolized via hydrolysis by carboxylesterases to a pharmacologically inactive carboxylic acid derivative, which is excreted in the urine. Rufinamide pharmacokinetics are not affected by impaired renal function. Potential differences in rufinamide pharmacokinetics between children and adults have not been investigated systematically in formal studies. Although population pharmacokinetic modeling suggests that in the absence of interacting comedication rufinamide CL/F may be higher in children than in adults, a meaningful comparison of data across age groups is complicated by age-related differences in doses and in proportion of patients receiving drugs known to increase or to decrease rufinamide CL/F. A study investigating the effect of rufinamide on the pharmacokinetics of the CYP3A4 substrate triazolam and an oral contraceptive interaction study showed that rufinamide has some enzyme-inducing potential in man. Findings from population pharmacokinetic modeling indicate that rufinamide does not modify the CL/F of topiramate or valproic acid, but may slightly increase the CL/F of carbamazepine and lamotrigine and slightly decrease the CL/F of phenobarbital and phenytoin (all predicted changes were
[Zonisamide in refractory essential tremor]
Rev Neurol. 2008 Feb 1-15; 46(3): 139-42
Bermejo PE, Ruiz-Huete C, Dorado R, Anciones B
INTRODUCTION: Essential tremor is one of the most frequent movement disorders. It is characterized by postural and action tremor that may affect different regions of the body. Among current treatments propranolol and primidone are included. However, these two drugs have demonstrated a limited efficacy and several adverse events. Additionally, they are contraindicated in patients with cardiac insufficiency and several respiratory diseases. New antiepileptic drugs are revealing as a possibility in the treatment of this disease. AIM. To evaluate efficacy and tolerability of zonisamide in the treatment of essential tremor. PATIENTS AND METHODS: We perform a retrospective study about 13 patients with essential tremor refractory to an average of 2.8 drugs. Age, sex, zonisamide dosage, adverse events, duration and response to the treatment before and after the treatment were collected and analysed. Average zonisamide dosage was 215 mg/day and average duration of the treatment was 121 days. RESULTS: Nine of 13 patients included in our study experienced a good response. A positive response was understood as a decrease on the limitation of daily activities and an improvement on neurological examination. Zonisamide was well tolerated and no patient abandoned the study for this reason. CONCLUSIONS: Our data suggest that zonisamide is effective and well tolerated in the treatment of essential tremor. Placebo-controlled and bigger studies are warranted to confirm these results.
Simultaneous determination of antiepileptic drugs and their two active metabolites by HPLC.
J Sep Sci. 2008 Jan; 31(1): 1-8
Budakova L, Brozmanova H, Grundmann M, Fischer J
An HPLC procedure for the determination of lamotrigine (LAM) simultaneously with other antiepileptic drugs, primidone (PD), phenobarbital (PB), phenytoin (DPH), carbamazepine (CMZ), and two active metabolites 2-phenyl-2-ethyl-malonamide (PEMA) and 10,11-dihydro-10,11-epoxycarbamazepine (EPO) was developed and validated. The method involves an ordinary RP system and a liquid-liquid extraction. The mobile phase consisting of water/ACN/methanol/triethylamine in the ratio 72:23:5:0.1 with pH 7.0 was selected as the best one after the assays testing both pH and triethylamine contents. UV detection was carried out at a wavelength of 220 nm and the whole analysis took 15 min. The method was linear in the range of 0.5-25 mg/L for PEMA and LAM; 1.25-25 mg/L for PD and CMZ; 0.625-12.5 mg/L for EPO; 1.5-60 mg/L for PB; and 1.25-50 mg/L for DPH, respectively. Within-day CV% and between-day CV% were within 10%. The developed HPLC method can be used for routine therapeutic drug monitoring both in children and adults.
Mitochondrial complex I encephalomyopathy and cerebral 5-methyltetrahydrofolate deficiency.
Neuropediatrics. 2007 Aug; 38(4): 184-7
Ramaekers VT, Weis J, Sequeira JM, Quadros EV, Blau N
Folate transport to the brain depends on ATP-driven folate receptor-mediated transport across choroid plexus epithelial cells. Failure of ATP production in Kearns-Sayre syndrome syndrome provides one explanation for the finding of low spinal fluid (CSF) 5-methyltetrahydrofolate (5MTHF) levels in this condition. Therefore, we suspect the presence of reduced folate transport across the blood-spinal fluid barrier in other mitochondrial encephalopathies. In the present patient with mitochondrial complex I encephalomyopathy a low 5-methyltetrahydrofolate level was found in the CSF. Serum folate receptor autoantibodies were negative and could not explain the low spinal fluid folate levels. The epileptic seizures did not respond to primidone monotherapy, but addition of ubiquinone-10 and radical scavengers reduced seizure frequency. Add-on treatment with folinic acid led to partial clinical improvement including full control of epilepsy, followed by marked recovery from demyelination of the brainstem, thalamus, basal ganglia and white matter. Cerebral folate deficiency is not only present in Kearns-Sayre syndrome but may also be secondary to the failure of mitochondrial ATP production in other mitochondrial encephalopathies. Treatment with folinic acid in addition to supplementation with radical scavengers and cofactors of deficient respiratory enzymes can result in partial clinical improvement and reversal of abnormal myelination patterns on neuro-imaging.
[Therapeutical strategies for essential tremor]
Med Clin (Barc). 2007 Nov 3; 129(16): 632-7
Gironell A
Essential tremor is the most common adult movement disorder. Traditionally considered as a benign disease, it can cause an important physical and psychosocial disability. Drug treatment remains poor and often unsatisfactory. Current therapeutical strategies are reviewed according to the level of discomfort caused by tremor: mild tremor, non-pharmacological strategies, alcohol, acute pharmacological therapy; moderate tremor, pharmacological therapies (propranolol, gabapentin, primidone, topiramate, alprazolam and other drugs), and severe tremor, the role of functional surgery is emphasized (thalamic deep brain stimulation, thalamotomy). It is also described the more specific treatment of head tremor with the use botulinum toxin. Finally, several points are exposed to guide the immediate research of this disease in near future.
BJOG. 2008 Jan; 115(1): 98-103
Kjaer D, Horvath-Puhó E, Christensen J, Vestergaard M, Czeizel AE, Sørensen HT, Olsen J
OBJECTIVE: To investigate whether folic acid supplementation in early pregnancy modifies the association between the prevalence of congenital abnormalities in the offspring and maternal use of carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and primidone (PRI). DESIGN: A population-based case-control study. SETTING: The Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA) (1980-1996) and its information on children from the Hungarian Congenital Abnormality Registry and the Hungarian National Birth Registry. POPULATION: Children with congenital abnormalities (cases; n= 20 792, of whom 148 had been exposed to antiepileptic drugs [AEDs]) and unaffected children (controls; n= 38 151, of whom 184 had been exposed to AEDs). METHODS: Information on drug exposure and background variables for the mothers were collected from antenatal logbooks, discharge summaries, and structured questionnaires completed by the mothers at the time of HCCSCA registration. MAIN OUTCOME MEASURES: Congenital abnormalities detected at termination of pregnancy, at birth or until 3 months of age according to CBZ, PB, PHT, or PRI exposure at 5-12 weeks from first day of the last menstrual period (LMP), stratified by folic acid supplementation. RESULTS: Compared with children unexposed to AEDs and folic acid, the odds ratio of congenital abnormalities was 1.47 (95% CI 1.13-1.90) in children exposed to AEDs without folic acid supplementation and 1.27 (95% CI 0.85-1.89) for children exposed to AEDs with folic acid supplementation. CONCLUSION: The results indicate that the risk of congenital abnormalities in children exposed in utero to CBZ, PB, PHT, and PRI is reduced but not eliminated by folic acid supplementation at 5-12 weeks from LMP. The statistical precision in our study is limited due to rarity of the exposures, and further studies are needed.
Inhibition of human aromatase complex (CYP19) by antiepileptic drugs.
Toxicol In Vitro. 2008 Feb; 22(1): 146-53
Jacobsen NW, Halling-Sørensen B, Birkved FK
Antiepileptic drugs and epilepsy are often associated with sexual disorder in women such as hyperandrogenism, menstrual disorders and ovarian cysts. In children, until puberty, a hormone imbalance may influence many aspects of development, e.g. growth and sexual maturation. The aromatase complex is the enzyme system that converts androgens to estrogens and consequently an inhibition may induce a hormone imbalance. Twelve antiepileptic drugs, used in mono or polytherapy for the treatment of children, were tested for their ability to inhibit aromatase (CYP19) with commercially available microsomes from transfected insect cells using dibenzylfluorescein as substrate. The drugs inhibiting CYP19 were: lamotrigine, oxcarbazepine, tiagabine, phenobarbital, phenytoin, ethosuximide, and valproate. The inhibitory effects (50% reduction in activity compared to enzymes without inhibitor present) were in the range of 1.4-49.7 mM. Carbamazepine, gabapentin, primidone, topiramate and vigabatrin showed no inhibition. Additionally, binary drug combinations were tested to investigate if combination therapy could potentiate the aromatase inhibition. Additive inhibition was seen in combination experiments with valproate and phenobarbital. When adding carbamazepine to a range of valproate concentrations no additional inhibition was seen. The data for some of the AEDs show that side effects on steroid synthesis in humans due to inhibition of aromatase should be considered.
Anal Bioanal Chem. 2007 Nov; 389(6): 2019-28
Gupta VK, Singh AK, Gupta B
Newly developed, simple, low-cost and sensitive ion-selective electrodes have been proposed for determination of some antiepileptic drugs such as lamotrigine, felbamate, and primidone in their pharmaceutical preparations as well as in biological fluids. The electrodes are based on poly(vinyl chloride) membranes doped with drug-tetraphenyl borate (TPB) or drug-phosphotungstic acid (PT) ion-pair complexes as molecular recognition materials. The novel electrodes displayed rapid Nernstian responses with detection limits of approximately 10(-7) M. Calibration graphs were linear over the ranges 5.2 x 10(-7)-1.0 x 10(-3), 1.5 x 10(-6)-1.0 x 10(-3), and 2.6 x 10(-7)-1.0 x 10(-3 )M for drug-TPB and 5.8 x 10(-7)-1.0 x 10(-3), 1.8 x 10(-7)-1.0 x 10(-3), and 6.6 x 10(-7)-1.0 x 10(-3) M for drug-PT electrodes, respectively, with slopes ranging from 52.3 to 62.3 mV/decade. The membranes developed have potential stability for up to 1 month and proved to be highly selective for the drugs investigated over other ions and excipients. The results show that the selectivity of the ion-selective electrodes is influenced significantly by the plasticizer. The proposed electrodes were successfully applied in the determination of these drugs in pharmaceutical preparations in four batches of different expiry dates. Statistical Student's t test and F test showed insignificant systematic error between the ion-selective electrode methods developed and a standard method. Comparison of the results obtained using the proposed electrodes with those found using a reference method showed that the ion-selective electrode technique is sensitive, reliable, and can be used with very good accuracy and high percentage recovery without pretreatment procedures of the samples to minimize interfering matrix effects.