Drug Sodium Valproate Research Articles

Physicochemical properties of an anticonvulsant drug sodium valproate in aqueous and in mixed aqueous solutions at different temperatures

The study of fundamental thermodynamic properties of aqueous solutions is very important to derive the information about (solute+solvent) and (solute+solute) interactions. Sodium valproate is a very important drug used for treatment of epilepsy, anorexia nervosa, panic attack, anxiety disorder etc. In this communication we report apparent molar volume of solute (Vϕ), limiting apparent molar volume of solute (Vϕ0), limiting apparent molar expansivity of solute (Eϕ0), thermal expansion coefficient (α∗), double derivative of limiting apparent molar volume (∂2Vϕ0/∂T2), Jones–Dole equation viscosity A, B and D coefficients, temperature derivative of B coefficient i.e., (dB/dT) and hydration number (nH) for aqueous solutions of sodium valproate and solutions of sodium valproate in aqueous solutions of sodium chloride and dextrose. The above parameters have been obtained from measured values of densities (ρ) and absolute viscosities (η) for aqueous binary mixtures of sodium valproate and for the ternary mixtures of sodium valproate in 0.06mol⋅kg−1 aqueous solutions of sodium chloride and in 0.06mol⋅kg−1 aqueous solutions of dextrose in the concentration range (0.01 to 0.1)mol⋅kg−1 as a function of temperature at T/K=(288.15, 298.15 and 308.15) and at atmospheric pressure. The values of limiting apparent molar volume of transfer (ΔtrVϕ0), and viscosity B-coefficient of transfer (ΔtrB) have also been calculated. The transition state theory was used to obtain the Gibbs free energy of activation of viscous flow per mole of solvent (Δμ10#) and per mole of solute (Δμ20#).. The related activation parameters like ΔS20# and ΔH20# have also been derived. Co-sphere overlap model has been used to understand the results in terms of molecular interactions (hydrophilic, hydrophobic and ionic interactions). The results have been interpreted in terms of complex drug – water – co-solute (NaCl and Dextrose) interactions.

Antiepileptic potential of Fumaria schleicheri and Ocimum basilicum dry extracts

The results of investigation of the antiepileptic activity of promising herbal anticonvulsants – Fumaria schleicheri (FSDE) and Ocimum basilicum (OBDE) dry extracts – are presented. The herbal remedies were administered intragastrically in the conditionally effective dose of 100 mg/kg in the therapeutic and preventive mode during 3 days with the last time of 30 minutes before the experiments. As refe­ rence drugs sodium valproate and carbamazepine were chosen. Under the conditions of maximal electroshock (MES) test the ability of the chosen dry extracts to prevent the development of primarily generalized convulsions was studied. For the in­depth study of antiepileptic properties of FSDE and OBDE the model of pentylenetetrazole (corasole)­induced kindling has been chosen. In general the researched dry extracts in the condition of the MES test have shown the anticonvulsant effect on the level of sodium valproate, but they were slightly inferior in efficacy compared with carbamazepine. On the model of pentylenetetrazole­induced kindling it has been shown that FSDE unlike OBDE and sodium valproate has the ability to prevent convulsions under the conditions of experimental chronic epileptogenesis. Thus, it has been found that OBDE is able to prevent the development of primary generalized seizures, while FSDE prevents acute paroxysms stimulated by electrical impulse and chronic epileptogenesis.

Henoch‐Schönlein Purpura in a child induced by Valproic Acid

Case report A 14-year-old male was admitted with a five months history of recurrent purpuric papules on his buttocks and lower limbs lasting up to four days with a burning sensation. The patient had a 10 year medical history of epileptic absences treated with valproic acid 300 mg daily before the initiation of purpura. Laboratory screening for cutaneous vasculitis was unremarkable including full blood count with differential, liver function tests, renal and coagulation profile. Results of testing for celiac and thyroid antibodies were negative . Immunological testing for antiDNA antibodies, IgG, IgA, IgE, IgM, plasma levels of C3 and C4 factors were also negative. Plasma levels of valproic acid were 27,2 μg/ ml (therapeutic serum concentrations range from 50 to 100μg/ml). A skin biopsy showed a massive inflammatory infiltrate in the dermis extravasation of neutrophils and erythrocytes and deposition of fibrin. Direct immunofluorescence demonstrated deposits of IgA in the vascular wall that confirmed the diagnosis of Henoch–Schonlein purpura. On discontinuation of valproate, the child was fully recovered from purpura seven days after the withdrawal of the drug. The child was challenged via hyperventilation for seizures with negative results. He was followed up for more than one year with no recurrence of the rash or epilepsy. Conclusion This is the first reported case of Henoch–Schonlein purpura induced by valproic acid. Physicians should be aware of the range of severity of Henoch–Schonlein purpura and discontinue the drug Sodium valproate should be added to the list of drugs that may cause Henoch–Schonlein purpura.

Combined Blockade of AMPA and NMDA Receptors Produces Maximal Suppression of the Development of Corasol Kindling in Rats

Chronic enteral administration of the standard antiepileptic drug sodium valproate at a dose of 200 mg/kg suppressed the development of generalized clonic-tonic corasol-kindled convulsions in 100% of rats but prevented kindled clonic convulsions in only 57%. This dose of sodium valproate decreased the mean severity of corasol-kindled convulsions by a factor of 1.7. Chronic enteral administration of IEM-2121, which induces combined blockade of AMPA and NMDA glutamate receptors, and IEM-1676, which blocks AMPA and NMDA receptors, as well as n-cholinoreceptors, given at doses of 10 and 20 mg/kg, respectively, had greater anticonvulsive activity than sodium valproate, as they decreased the mean severity of corasol-kindled convulsions by factors of 2.4–2.7 as compared with controls and prevented kindled clonic convulsions in 87% of rats. Combined blockade of AMPA and NMDA receptors and, possibly, n-cholinoreceptors, produced the greatest suppression of epileptogenesis in relation to both clonic and clonic-tonic corasol-kindled convulsions.

The Role of Antiepileptic Treatment in the Recurrence Rate of Seizures After First Attack: A Randomized Clinical Trial.

Epilepsy is a serious, potentially life-shortening brain disorder that occurs in patients of all ages and races. A total of 2-4% of people have experienced seizures at least once in their lifetime. Although treatment usually begins after a seizure, it is an important question whether the first cases of seizure do need to be treated by antiepileptic drugs. In this manner, we compare the recurrence rates of epilepsy in first seizure patients treated with sodium valproic acid as an antiepileptic drug versus a placebo. In a randomized clinical trial study, 101 first seizure patients were randomly divided into two groups: one group was treated with antiepileptic drugs (sodium valproate 200mg, three times a day) and the other group was given a placebo. The recurrence rate of seizures was evaluated and compared between the groups after 6 months of follow up. Eight recurrence cases were detected. All recurrence cases came from the placebo group, with four patients suffering an additional seizure after four months and between 4-6 month follow up. A comparison of recurrence rate detected a statistically significant difference between the drug group and placebo group. Our data shows that the recurrences occurred only in the placebo group with the difference between the recurrence rates in the placebo versus drug-treated was significant. Our results suggest that drug therapy for people after their first seizure attack might reduce the probability of seizure recurrence.

New mixed ligand palladium(II) complexes based on the antiepileptic drug sodium valproate and bioactive nitrogen-donor ligands: Synthesis, structural characterization, binding interactions with DNA and BSA, in vitro cytotoxicity studies and DFT calculations

The complexes [Pd(valp)2(imidazole)2] (1), [Pd(valp)2(pyrazine)2] (2) (valp is sodium valproate) have been synthesized and characterized using IR, 1H NMR, 13C{1H} NMR and UV–Vis spectrometry. The interaction of complexes with CT-DNA has been investigated using spectroscopic tools and viscosity measurement. In each case, the association constant (Kb) was deduced from the absorption spectral study and the number of binding sites (n) and the binding constant (K) were calculated from relevant fluorescence quenching data. As a result, a non-covalent interaction between the metal complex and DNA was suggested, which could be assigned to an intercalative binding. In addition, the interaction of 1 and 2 was ventured with bovine serum albumin (BSA) with the help of absorption and fluorescence spectroscopy measurements. Through these techniques, the apparent association constant (Kapp) and the binding constant (K) could be calculated for each complex. Evaluation of cytotoxic activity of the complexes against four different cancer cell lines proved that the complexes exhibited cytotoxic specificity and significant cancer cell inhibitory rate. Moreover, density functional theory (DFT) calculations were employed to provide more evidence about the observed data. The majority of trans isomers were supported not only by energies, but also by the similarity of its calculated IR frequencies, UV adsorptions and NMR chemical shifts to the experimental values.

Low dose zinc supplementation beneficially affects seizure development in experimental seizure models in rats.

The role of zinc in seizure models and with antiepileptic drugs sodium valproate (SV) and phenytoin (PHT) was studied using experimental models of seizures in rats. Male Wistar rats, 150-250g were administered zinc 2, 20, and 200mg/kg, orally for 14days. Sixty minutes after the last dose of zinc, rats were challenged with pentylenetetrazole (PTZ, 60mg/kg, ip) or maximal electroshock (MES, 70mA, 0.2s duration). In another group, SV (150/300mg/kg, ip) or PHT (40mg/kg, ip) was administered after 30min of zinc administration followed by seizure challenge. Zinc pretreatment at all doses had no effect on MES seizures. In PTZ seizures, with the lowest dose used, i.e., 2mg/kg, a protective effect was observed. Neither the protection offered by the 100% anticonvulsant dose of SV (300mg/kg) in PTZ seizures was affected by pre-treatment with zinc nor a combination of subanticonvulsant dose of SV (150mg/kg) and zinc offer any statistically significant advantage over either drug alone. The combination of phenytoin with zinc had no effect on any of the parameters tested. Apart from this, chronic zinc administration hampered development of chemically (PTZ)-kindled seizures in rats. Zinc supplementation is unlikely to have any undesirable effect when used in epileptics rather it may offer advantage in epileptic and seizure prone patients.

Valproate improves memory deficits in an Alzheimer's disease mouse model: investigation of possible mechanisms of action.

Alzheimer's disease (AD) is a very common progressive neurodegenerative disorder affecting the learning and memory abilities in the brain. Key findings from recent studies of epigenetic mechanisms of memory suggest chromatin remodeling disorders via histone hypoacetylation of the lysine residue contribute to the cognitive impairment in AD. Therefore, the deinhibition of histone acetylation induced by histone deacetylases (HDACs) inhibitors contributes to recovery of learning and memory. We show here that the antiepileptic drug sodium valproate (VPA) potently enhanced long-term recognition memory and spatial learning and memory in AD transgenic mice. Possible mechanisms showed VPA could significantly elevate histone acetylation through HDACs activity inhibition and increase plasticity-associated gene expression within the hippocampi of mice. Our study suggests that VPA, serving as a HDACs inhibitor, can be considered as a potential pharmaceutical agent for the improvement of cognitive function in AD.

New mixed ligand zinc(II) complexes based on the antiepileptic drug sodium valproate and bioactive nitrogen-donor ligands. Synthesis, structure and biological properties

Starting from the precursor [Zinc Valproate complex] (1), new mixed ligand zinc(II) complexes of valproic acid and nitrogen-based ligands, formulating as, [Zn(valp)22,9-dmphen] (2), [Zn2(valp)4(quin)2] (3), [Zn(valp)2(2-ampy)2] (4), and [Zn(valp)2(2-ampic)2] (5) (valp = valproate, 2,9-dmphen = 2,9-dimethyl-1,10-phenanthroline, quin = quinoline, 2-ampy = 2-aminopyridine, 2-ampic = 2-amino-6-picoline) were synthesized and characterized using IR, 1H NMR, 13C{1H} NMR and UV–Vis spectrometry. The crystal structures of complexes 2, 3 and 4 were determined using single-crystal X-ray diffraction. The complexes were also evaluated for their anti-bacterial activity using in-vitro agar diffusion method against three Gram-positive (Micrococcus luteus, Staphylococcus aureus, and Bacillus subtilis) and three Gram-negative (Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis) species. Complex 2 showed considerable activity against all tested microorganisms and the effect of complexation on the anti-bacterial activity of the parent ligand of 2 was also investigated. The anti-bacterial activity of 2,9-dmphen against Gram-negative bacteria was enhanced upon complexation with zinc valproate. On the other hand, complexes 1 and 3 showed weak inhibition activity against the tested species and complexes 4 and 5 didn’t show any activity at all. Two methods were used for testing the inhibition of ferriprotoporphyrinIX bio-mineralization: a semi-quantitative micro-assay and a previously self-developed quantitative in-vitro method. Both were used to study the efficiency of these complexes in inhibiting the formation of the Malaria pigment which considered being the target of many known anti-malarial drugs such as Chloroquine and Amodiaquine. Results showed that the efficiency of complex 2 in preventing the formation of β-Hematin was 80%. The efficiency of Amodiaquine as a standard drug was reported to give 91%.

Synthesis and anticonvulsant evaluation of some new 1,3,4,5-tetrahydro-6-alkoxy-2H-1-benzazepin-2-one derivatives

A series of new 1,3,4,5-tetrahydro-6-alkoxy-2H-1-benzazepin-2-one derivatives were synthesized and screened for their anticonvulsant activities by the maximal electroshock (MES) test, subcutaneous pentylenetetrazol (scPTZ) test, and their neurotoxicity was evaluated by the rotarod neurotoxicity test. The results of these tests showed that 1,3,4,5-tetrahydro-6-octyloxy-2H-1-benzazepin-2-one (4f) was the most promising compound, with median effective dose (ED50) of 20.4 mg/kg, and protective index (PI) value of 20.1 in the MES test, which is much higher than the PI value of the prototype antiepileptic drug carbamazepine (PI = 8.1), phenytoin (PI = 6.9), phenobarbital (PI = 3.2), and sodium valproate (PI = 1.6). The scPTZ test displayed that 1,3,4,5-tetrahydro-6-heptyloxy-2H-1-benzazepin-2-one (4e) was the most active compound (ED50 = 64.4, PI = 2.6). The possible structure–activity relationship was discussed.

Evaluation of neurotoxic and neuroprotective pathways affected by antiepileptic drugs in cultured hippocampal neurons

In this study we evaluated the neurotoxicity of eslicarbazepine acetate (ESL), and of its in vivo metabolites eslicarbazepine (S-Lic) and R-licarbazepine (R-Lic), as compared to the structurally-related compounds carbamazepine (CBZ) and oxcarbazepine (OXC), in an in vitro model of cultured rat hippocampal neurons. The non-related antiepileptic drugs (AEDs) lamotrigine (LTG) and sodium valproate (VPA) were also studied. We assessed whether AEDs modulate pro-survival/pro-apoptotic pathways, such as extracellular-regulated kinase (ERK1/2), Akt and stress activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK).We found that neither ESL nor its metabolites, CBZ or LTG, up to 0.3mM, for 24h of exposure, decreased cell viability. OXC was the most toxic drug decreasing cell viability in a concentration-dependent manner, leading to activation of caspase-3 and PARP cleavage. VPA caused the appearance of the apoptotic markers, but did not alter cell viability. ESL, S-Lic and OXC decreased the levels of phospho-ERK1/2 and of phospho-Akt, when compared to basal levels, whereas CBZ decreased phospho-SAPK/JNK and phospho-Akt levels. LTG and VPA increased the phosphorylation levels of SAPK/JNK.These results suggest that ESL and its main metabolite S-Lic, as well as CBZ, LTG and VPA, are less toxic to hippocampal neurons than OXC, which was the most toxic agent.

Effects of antiepileptic drugs on reproductive endocrine function, sexual function and sperm parameters in Chinese Han men with epilepsy

The effects of the antiepileptic drugs sodium valproate (VPA) and levetiracetam (LEV) on reproductive endocrine function, sexual function, and spermatozoa were explored, together with their possible etiological mechanisms, in Chinese Han men with epilepsy. Following VPA treatment (n=32), luteinizing hormone and follicle-stimulating hormone levels were significantly lower than in controls (n=30). The bioactive testosterone/luteinizing hormone ratio and the prolactin level were significantly elevated in the VPA treatment group. There were no significant differences in these hormones between the LEV treatment (n=20) and control groups. The rates of sperm morphologic abnormality (head, body, and tail) were significantly higher in the VPA treatment group than the control group but did not differ significantly between the LEV treatment and control groups. The sperm motility rate was significantly lower in the VPA treatment group (grade A sperm motility rate <25%, grade A+B sperm motility rate <50%) than in controls, as well as in the LEV treatment group (grade A sperm motility rate <25%). Patients in the VPA and LEV treatment groups had lower scores on questions 1, 2 and 3 of a simplified International Index of Erectile Function Scale than controls, but no significant difference on questions 4 or 5. The total International Index of Erectile Function Scale scores were significantly lower in the VPA and LEV treatment groups. We conclude that treatment with VPA adversely affects reproductive endocrine function, sperm parameters and sexual function to varying degrees in Chinese men with epilepsy.

Interactions between carvedilol and sodium valproate along with neurobehavioural co-morbidities in various epilepsy models

ObjectiveThis study evaluated the effect of carvedilol (CRV) commonly used antihypertensive drugs on the antiepileptic drug sodium valproate (SVP) along with neurobehavioural co-morbidities in various models of epilepsy. MethodsFor this purpose, we used the Increasing Current Electroshock Seizure (ICES) test and Pentylenetetrazole (PTZ) test in mice. Additionally, adverse effects of combined treatment with the drugs in the Spontaneous Alternation Behavior (SAB) and rotarod were assessed. The levels of TBARS and the Reduced Glutathione (GSH) were determined in brains of mice for investigation of the oxidative stress. All drugs were administered orally. ResultsSVP (50 & 100 mg/kg) and CRV (1.25, 2.5 & 5.0 mg/kg) alone as well as in combination significantly enhanced the seizure threshold in the ICES test and PTZ test. CRV significantly increase the percentage alternation scores as compared to control group whereas combination of SVP with CRV did not affect the percentage alternation scores. In the present study, CRV and SVP alone as well as in combinations had no significant effect on motor parameters, at any of the given doses. CRV and SVP alone as well as in combination shown to inhibit the lipid peroxidation and increase in the level of GSH in brain tissue in a dose dependent manner which showed that it reduces the oxidative stress. ConclusionThe current study suggests that CRV potentiate the anticonvulsant activity of VPA. Therefore, the observed interaction could be pharmacodynamics in nature.

Valproic Acid silencing ofascl1b/ascl1results in the failure of serotonergic differentiation in a zebrafish model of Fetal Valproate Syndrome

Fetal valproate syndrome (FVS) is caused by in utero exposure to the drug sodium valproate. Valproate is used worldwide for the treatment of epilepsy, as a mood stabiliser and for its pain-relieving properties. In addition to birth defects, FVS is associated with an increased risk of autism spectrum disorder (ASD), which is characterised by abnormal behaviours. Valproate perturbs multiple biochemical pathways and alters gene expression through its inhibition of histone deacetylases. Which, if any, of these mechanisms is relevant to the genesis of its behavioural side effects is unclear. Neuroanatomical changes associated with FVS have been reported and, among these, altered serotonergic neuronal differentiation is a consistent finding. Altered serotonin homeostasis is also associated with autism. Here we have used a chemical-genetics approach to investigate the underlying molecular defect in a zebrafish FVS model. Valproate causes the selective failure of zebrafish central serotonin expression. It does so by downregulating the proneural gene ascl1b, an ortholog of mammalian Ascl1, which is a known determinant of serotonergic identity in the mammalian brainstem. ascl1b is sufficient to rescue serotonin expression in valproate-treated embryos. Chemical and genetic blockade of the histone deacetylase Hdac1 downregulates ascl1b, consistent with the Hdac1-mediated silencing of ascl1b expression by valproate. Moreover, tonic Notch signalling is crucial for ascl1b repression by valproate. Concomitant blockade of Notch signalling restores ascl1b expression and serotonin expression in both valproate-exposed and hdac1 mutant embryos. Together, these data provide a molecular explanation for serotonergic defects in FVS and highlight an epigenetic mechanism for genome-environment interaction in disease.

Carbamazepine, but not valproate, displays pharmacoresistance in lamotrigine-resistant amygdala kindled rats

The voltage gated sodium channel (VGSC) blocker lamotrigine (LTG), when administered during kindling acquisition, leads to the development of resistance to LTG. The present study aimed to assess whether LTG-resistant amygdala-kindled rats display subsequent resistance to the VGSC blocker carbamazepine (CBZ) and the broad-spectrum antiepileptic drug (AED) sodium valproate (VPA). Two groups of male Sprague Dawley rats received either 0.5% methylcellulose (MC) or LTG (5mg/kg, i.p.) 1h before each amygdala kindling stimulation. Treatments were stopped once both the groups were fully kindled. Two days later, both groups were challenged with a higher dose of LTG (15mg/kg, i.p.) to verify LTG-resistance in the experimental group (i.e., LTG-pretreated rats). The efficacy of CBZ and VPA was then evaluated in both groups. A higher dose of LTG blocked fully kindled seizures in the vehicle-treated rats but not seizures in the LTG-treated group. The mean seizure score, of the control group (1.2±0.3) was significantly lower (P<.05) than that of the LTG-treated population (3.5±0.7; n=8). A lower percent of the population in the control group was observed to display a generalized stage 4-5 seizure compared to the experimental group (i.e., those that received LTG during kindling acquisition) (28.5% vs. 62%, respectively). Interestingly, CBZ (10, 20, and 40mg/kg) displayed a dose-dependent anticonvulsant effect in the vehicle-kindled group, but was less effective in LTG-treated animals. In contrast, VPA (300mg/kg) effectively blocked the behavioral seizure and decreased the afterdischarge duration (ADD) in both vehicle and LTG groups. These findings suggest that the LTG-resistant, amygdala-kindled rat may represent a novel model of pharmacoresistant epilepsy.

Novel 4(3H)-quinazolinone analogs: synthesis and anticonvulsant activity

A new series of quinazoline analogs was designed, synthesized, and evaluated for their anticonvulsant activity. Compounds 6, 12, 21, 36, 37, and 38 showed 70–100 % protection against PTZ-induced seizures acting as GABAA receptor agonists. Compound N-(3,4,5,6-tetrachloro-phthalimido)-2-[(3-phenyl-4-oxo-6-methyl-3H-quinazolin-2-yl)-thio]acetamide (12) representing the moderate active compounds and 2-[6-iodo-4-oxo-2-(thiophen-2-yl)-quinazolin-3(4H)-yl]-isoindoline-1,3-dione (38) representing the remarkably active compounds in this stud, showed ED50 values of 457 and 251 mg/kg; TD50 values of 562 and 447 mg/kg; PI values of 1.22 and 1.78, LD50 values of 1,288 and 1,380 mg/kg, and TI values of 2.82 and 5.50, respectively. Compound 38 proved to be almost twofold more active than the standard drug sodium valproate.

Pharmacological and Biochemical Analysis of Interactions between N‐Acetylcysteine and Some Antiepileptic Drugs on Experimental Seizures in Mice

In view of a putative role of oxidative stress in the pathophysiology of seizures, this study addressed the interactions between N-acetylcysteine (NAC), a potent antioxidant and two antiepileptic drugs sodium valproate (SVP) and phenytoin (PHT) on experimental seizures in mice. The interaction was studied at three fixed ratio combinations (i.e., 1:1, 1:3, and 3:1) in the mouse maximal electroshock (MES) test using isobolographic analysis. Markers of oxidative stress (reduced glutathione [GSH] and malondialdehyde [MDA]) were estimated in the cortex of mice pretreated with either of these drugs alone or their 3:1 ratio combinations at the experimentally determined ED(50) values (ED(50 exp) values). The grip strength and spontaneous alternation behavior (SAB) were also assessed. In addition, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and calcium levels were estimated. We found an anticonvulsant action of NAC in the MES test. Further, the ED(50 exp) values for the combinations of PHT and NAC did not differ from the theoretically calculated ED(50) values indicating additive effects. In case of SVP and NAC, however, the ED(50 exp) values were lower than the theoretically calculated ED(50) values. The interaction of SVP with NAC at the fixed ratios of 1:3 and 3:1 was found to be synergistic. No significant changes were observed in the grip strength, SAB, cortical GSH and MDA levels, serum AST, ALT, ALP, or calcium levels. Our results thus hold promise for the use of NAC as an adjunct to PHT and SVP therapy.

Combination of valproate and paroxetine in mice exposed to picrotoxin

The frequent coexistence of depression in epileptic patients raises the issue of simultaneous use of antidepressants along with antiepileptic drugs in the management of such cases. However, it is necessary to evaluate the safety of these antiepileptic/antidepressant drug combinations. The present study investigates the effect of the antidepressant paroxetine (a selective serotonin reuptake inhibitor) administered alone or in combination with the antiepileptic drug sodium valproate on chemoconvulsions induced by picrotoxin (PTX). Seizure score was recorded in vivo, and the levels of thiobarbituric acid-reactive substances and gamma aminobutyric acid (GABA) were measured in the nucleus accumbens of the tested groups of mice. The results show enhancement of seizure severity with significant reduction in GABA levels upon PTX treatment that were reversed by its combination with sodium valproate. On the other hand, paroxetine administered in combination with sodium valproate provided significant protection against PTX-induced convulsions as well as a significant increase in GABA levels in selected brain areas. These results favor their application in management of epilepsy-depression comorbidities.

Synthesis and anticonvulsant evaluation of some new 2,3,8-trisubstituted-4(3H)-quinazoline derivatives

A new series of 2,3,8-trisubstituted-4(3H)-quinazoline derivatives were synthesized, evaluated for their anticonvulsant activity against electrically (MES) and chemically (PTZ, picrotoxin and Strychnine) induced seizures and compared with the standard drugs methaqualone and sodium valproate. Compounds 3, 17 and 22 proved to be the most potent compounds of this series with relatively low neurotoxicity and low toxicity in the median lethal dose test as compared with the reference drugs. The obtained results showed that the most active compounds could be useful as a template for future design, modification and investigation to produce more active analogs.

Use of Botulinum Neurotoxin Injections to Treat Recurrent Shoulder Dislocations in a Patient with Severe Epilepsy

The treatment of a shoulder dislocation sustained during an epileptic seizure can be a challenge to the orthopaedic surgeon. Severe drug-resistant epilepsy with multiple seizures may cause repeated dislocations of the shoulder, resulting in damage to the joint capsule and the glenoid. Any attempt at reconstructive surgery of the shoulder requires complete control of the seizures and prevention of dislocations for at least three months following the surgical procedure. We report our experience with one patient who had recurrent dislocations of the right shoulder due to uncontrollable seizures; we treated this patient with botulinum neurotoxin type A to prevent the dislocations. The patient was informed that data concerning her case would be submitted for publication, and she provided consent. The case report was approved by our institutional review board. A twenty-three-year-old woman had been diagnosed with acute intermittent porphyria and severe epilepsy at the age of fourteen. She had had repeated tonic-clonic seizures, which were unresponsive to therapy with multiple drugs (sodium valproate, carbamazepine, vigabatrin, sulthiame, clonazepam, levetiracetam, and topiramate). She had undergone implantation of a vagus nerve stimulator, which did not control the seizures but did shorten the postictal period. At the age of sixteen, the patient had sustained anterior glenohumeral dislocations of both shoulders during a seizure. By the time she was referred to our care at the age of nineteen, she had a chronic dislocation of the left shoulder and recurrent dislocations of the right shoulder. A computerized tomography (CT) examination of the right shoulder …