Progress report on new antiepileptic drugs: a summary of the fourth Eilat conference (EILAT IV)

Bialer, Meir; Johannessen, Svein I.; Kupferberg, Harvey J.; Levy, René H.; Loiseau, P; Perucca, Emilio

doi:10.1016/s0920-1211(98)00108-9

Cited by 171 publications

(137 citation statements)

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“…did not cause any exencephaly, VGD might be a nonteratogenic VPA analogue (14). The major metabolite of VGD in humans is VGA, an inactive acid that accounts for 50-60% of the VGD dose or clearance in humans (15).…”

Section: Discussionmentioning

confidence: 99%

Anticonvulsant Profile of Valrocemide (TV1901): A New Antiepileptic Drug

et al. 2001

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Summary:Purpose: We sought to investigate the anticonvulsant activity of the new antiepileptic drug (AED), valrocemide or TV1901 (VGD) in various animal (rodent) models of human epilepsy to determine its anticonvulsant profile and safety margin.Methods: VGD was administered intraperitoneally to CF no. 1 mice and orally or intraperitoneally to Sprague-Dawley rats. The anticonvulsant activity of VGD was examined in nine different animal models of epilepsy for its ability to block electrically, chemically, or sensorily induced seizures.Results: In mice VGD afforded complete protection against maximal electroshock (MES)-, pentylenetetrazole-, picrotoxin-, and bicuculline-induced seizures and 6-Hz "psychomotor" seizures with median effective dose (ED 50 ) values of 151, 132, 275, 248, and 237 mg/kg, respectively. VGD was also effective in preventing sound-induced seizures in Frings audiogenic-seizure susceptible mice (ED 50 , 52 mg/kg). The median neurotoxic dose in mice was 332 mg/kg. After oral administration to rats, VGD was active in the MES test, with an ED 50 of 73 mg/kg, and the median neurotoxic dose was 1,000 mg/kg. Intraperitoneal administration of 300 mg/kg of VGD to hippocampal kindled Sprague-Dawley rats blocked generalized seizures and shortened the afterdischarge duration significantly. VGD also provided complete protection from focal seizures in the corneally kindled rats (ED 50 ,161 mg/kg).Conclusions: The results obtained in this study suggest that VGD has a broad spectrum of anticonvulsant activity and promising potential as a new AED.

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Section: Discussionmentioning

confidence: 99%

Anticonvulsant Profile of Valrocemide (TV1901): A New Antiepileptic Drug

et al. 2001

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“…Moreover, the use of these drugs is often precluded by the occurrence of unpleasant side-effects such as ataxia, diplopia, mental dulling, rash, blood dyscrasias, and hepatotoxicity. [1] Since the discovery of the anticonvulsant ability of valproic acid (Vpa) many similar compounds have been studied to find new structures that are more powerful and less neurotoxic. [2] Recently, the synthesis and biological evaluation in mice of novel antiepileptic ligand derivatives of valpromide (Vpd), such as N-ethylvalpromide (Etvpd), dimethylvalpromide (Dmvpd), Nisopropylvalpromide (Ipvpd), have been reported.…”

Section: Introductionmentioning

confidence: 99%

Spectroscopy properties of the amide group in valpromide and some derivatives with antiepileptic activity

Massa

Castro

Jubert

2009

J Raman Spectroscopy

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Infrared spectra at 300 and 77 K and Raman spectra at 300 K of the valpromide (Vpd), N-substituted derivatives, Nethylvalpromide (Etvpd), N-isopropylvalpromide (Ipvpd) and the N,N-disubstituted derivative, N,N-dimethylvalpromide (Dmvpd) with antiepileptic activity, have been measured and analyzed with results derived from computational chemistry calculation. In agreement with theoretical predictions, experimental data indicate that while in Etvpd, Dmvpd and Ipvpd there are four different conformational co-existing components (Etvpd: TTCG + , TCCG − , TTTC, G + G + C G + ; Dmvpd: TTCC, G − TTA + , G + A − TC, G + A − C A + ; Ipvpd: TTCT, TCCT, TCCC, G − TTT) in the Vpd there are only three distinct stable conformations of C 1 symmetry group: TTC, TCT, G + G + T. Based on the accuracy of the B3LYP calculation, with the 6-31+G * * basis set estimated by comparison between the predicted values of the vibrational modes and the available experimental data, we performed a structural and vibrational study of the amide group in the Vpd and their derivatives. We found that small nonplanarity deviations of C( O)N backbone induce significant changes on the structural and spectroscopic properties. These are not compatible with the decreasing of the resonance effect as it is produced when the twisting around the C( O)-N increases.From the Natural Bond Orbital (NBO) analysis the existence of stabilizing electrostatic interactions of type C-H· · ·O/N and C-H· · ·H-N/C, which induce significant structural changes and a complex electronic redistribution of charge on the π -system in those structures becomes evident. We view this as a consequence of the filled electron density change Lewis-type NBOs type lp O1,2 , lp N1 , σ (C -H)N -acyl and empty non-Lewis NBOs type σ * (C -H)N -acyl , σ * N -H .

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“…[1,2]. It possesses a broad spectrum of anticonvulsant activity, mainly through the following mechanisms: attenuation of voltage-gated Na + currents [3]; negative modulatory effects on AMPA/KA subtype of glutamate receptors [4,5]; inhibition of glutamate and aspartate release from the nerve terminal [6]; inhibition of carbonic anhydrase (CA) isozymes, particularly, CA II and CA IV [7]; enhancement of γ -amino butyric acid A-mediated neurotransmission [8,9]; modulatory effects on K + channel currents [10] and inhibition of neuronal L-type high voltage-activated Ca 2+ channels [11]. Heat intolerance with hypohidrosis or anhidrosis has been recently reported in children undergoing epilepsy treatment with topiramate [12][13][14][15][16][17].…”

mentioning

confidence: 99%

Effects of Topiramate on Mouse Eccrine Sweat Gland Responsiveness to Heat Exposure

Jiyu¹,

Huang²,

Deng³

et al. 2007

Basic Clin Pharma Tox

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Young mice (2 weeks old) were given topiramate daily for 1 month, and sudomotor function was evaluated utilizing impression mould techniques to determine the number of sweat glands reactive to heat exposure and sweat output per gland on the plantar surface of mice hind-paws. Immunohistochemical quantitation of protein gene product 9.5, choline acetyltransferase and tyrosine hydroxylase in footpads was determined after topiramate treatment. While a 25% decrease in the number of secreting sweat glands and a 42% decline in sweat output per gland were observed following topiramate treatment, no significant differences were noted in sudomotor innervation, expressed as length of choline acetyltransferase, tyrosine hydroxylase and protein gene product 9.5 immunoreactive nerve profiles in single secretory coils or in sweat gland sizes within the secretory coil area. Long-term topiramate stimulation resulted in a reduction in the number of reactive sweat glands, without changes in sweat gland innervation, suggesting that the diminished responsiveness of the glands to heat exposure induced by topiramate might have resulted from a decrease in the intrinsic regulatory activity of sweat glands, as opposed to the loss of periglandular neurotransmitters or the impairment of the structure of the glands. [12][13][14][15][16][17]. While the effect was reversible, and disappeared with the cessation of the treatment, the mechanism underlying this effect on sweating has not been fully elucidated. The ability of human beings to dissipate heat during exercise and in hot environments depends mainly on the evaporation of sweat secreted by eccrine sweat glands. Consequently, sweat production is essential for heat tolerance, preventing hyperthermia, and influences performance during physical activity [18]. Sweat glands are innervated by sympathetic postganglionic axons, which, in contrast to the ordinary sympathetic innervation, use acetylcholine as the principal neurotransmitter [19][20][21].In the current study, we investigated the effects of topiramate on the responsiveness of mouse eccrine sweat glands to heat exposure and evaluated sudomotor function utilizing silicone imprints, a method that allows accurate quantitation of sweat gland secretion repeatedly over time, and following different types of nerve lesions or treatments [22][23][24][25][26][27]. Additionally, immunolabelling was used to examine the effects of topiramate on choline acetyltransferase (ChAT) in cholinergic sudomotor nerves, tyrosine hydroxylase (TH) in noradrenalinergic nerves, as well as total innervation of sweat glands (protein gene product 9.5, PGP9.5) and sweat gland acinar size. The aim of this study was to investigate whether topiramate reduced the responsiveness of the glands to heat exposure in mice, and whether the effects on the eccrine sweat glands were related to changes in periglandular neurotransmitters and/or sweat gland structure. Materials and MethodsExperimental design. Animals were housed under standard conditions with water and foo...

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Progress report on new antiepileptic drugs: a summary of the fourth Eilat conference (EILAT IV)

Cited by 171 publications

References 50 publications

Anticonvulsant Profile of Valrocemide (TV1901): A New Antiepileptic Drug

Anticonvulsant Profile of Valrocemide (TV1901): A New Antiepileptic Drug

Spectroscopy properties of the amide group in valpromide and some derivatives with antiepileptic activity

Effects of Topiramate on Mouse Eccrine Sweat Gland Responsiveness to Heat Exposure

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