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Phenytoin
Published in Stanley R. Resor, Henn Kutt, The Medical Treatment of Epilepsy, 2020
Because PHT exerts effects on many different areas in the nervous system, it is most appropriate to speak of its mechanisms of action. One of the major actions of PHT is the blockage of posttetanic potentiation, which may underlie its ability to prevent the spread of seizure activity. Another effect involves the modification of ionic conductance of excitable membranes (4). In cultures of spinal cord and cortical neurones, concentrations of PHT equivalent to those effective clinically were shown to inhibit sustained repetitive firing. This effect appeared to arise from action at the sodium channel (5). Patch voltage clamp analysis has shown that PHT reduces sodium currents (6). Autoradiographic studies in rat brain have confirmed that the batrachotoxin-binding site, which interacts allosterically with PHT, is localized to the sodium channel (7). Recent work has demonstrated that carbamazepine and PHT have very similar actions in inhibiting sustained repetitive firing at the sodium channel (5). In addition, some of the other actions of PHT are to reduce calcium influx, act on the Na+, K+—ATPase system, and regulate cyclic nucleotides (8).
Chemophobia and the Boy Who Cried Wolf
Published in David Lightsey, The Myths about Nutrition Science, 2019
All synthetic chemicals used in the food production and distribution process go through a gauntlet of safety and efficacy studies, unlike the supplements most Americans ingest, which go through zero. Yet, most of these supplements contain synthetic chemical versions of the nutrient. Additionally, just because a chemical is considered “natural” certainly does not mean it is safe. According to James Kennedy, who obtained his master’s degree from University of Cambridge in Natural Sciences and is the author of The Naturalness Fallacy, nine out of the top ten most dangerous compounds on Earth are naturally occurring [my emphasis]. These are botulinum toxin (as illustrated previously), tetanospasmin, palytoxin, diphtheria toxin, ciguatoxin, batrachotoxin, ricin, saxitoxin, and tetrodotoxin.4
Overview of Actions of Antiepileptic Drugs on Repetitive Neuronal Firing
Published in Carl L. Faingold, Gerhard H. Fromm, Drugs for Control of Epilepsy:, 2019
Without anticonvulsants, spinal cord neurons fired a continuous train of action potentials in response to a depolarizing current pulse (Figure 3). In the presence of 1 to 2 μg/ml PT, sustained repetitive firing was markedly attenuated, with either slowing of the rate of firing or complete cessation after a few action potentials. CBZ had similar effects on sustained repetitive firing. With both drugs, the Vmax of the sodium-dependent upstroke diminished with successive action potentials, suggesting a use-dependent process. In higher concentrations, PT reduced the Vmax of single action potentials (Figure 4), but CBZ did not, implying that PT partially blocks resting channels, but that CBZ produces a strictly use-dependent block. With both drugs, hyperpolarization of the cell reduced their effects on sustained repetitive firing, implying a voltage-dependent process. These results—the use-, concentration-, and voltage-dependent blockades of sustained repetitive firing associated with slowing of the maximal rate of rise of the action potential—implied that the effects were due to a direct action on the voltage-sensitive sodium channel (Figure 6). This conclusion is supported by biochemical studies showing that CBZ and PT inhibit binding of batrachotoxin, which binds to voltage-sensitive sodium channels with high affinity,19-21 and by voltage clamp studies showing a direct effect on sodium currents in squid13 and neuroblastoma cells22 (Figure 5).
Insecticide potential of two saliva components of the predatory bug Podisus nigrispinus (Heteroptera: Pentatomidae) against Spodoptera frugiperda (Lepidoptera: Noctuidae) caterpillars
Published in Toxin Reviews, 2022
Juliana Mendonça Campos, Luis Carlos Martínez, Angelica Plata-Rueda, Wolfgang Weigand, José Cola Zanuncio, José Eduardo Serrão
Insecticidal action of the saliva from P. nigrispinus and its components 1,2,5-trithiepane and DMA against S. frugiperda caterpillars is effective causing mortality, histological and cytological changes, following cell death mainly in the midgut. The toxicity of these components is dose-dependent such as found against Anticarsia gemmatalis Hübner (Lepidoptera: Noctuidae) (Martínez et al. 2016). Insect non-proteinaceous components such as alkyldimethylpyrazines produced by Phyllium westwoodii Wood-Mason (Phasmatodea: Phylliidae) (Dossey et al. 2009), batrachotoxin alkaloids by Choresine pulchra (Pic) (Coleoptera: Melyridae) (Dumbacher et al. 2004), pyridine alkaloids by Stenus comma LeConte (Coleoptera: Staphylinidae) (Lusebrink et al. 2009), and pyrones by Lampyris noctiluca Linnaeus (Coleoptera: Lampyridae) (Tyler et al. 2008) have been found to be toxic and used against other insects. In this study, data show that the salivary extract from P. nigrispinus and its components 1,2,5-trithiepane and DMA are toxic against S. frugiperda in small amounts (28–89 nL insect−1), suggesting a potential use as insecticide.
Nature and applications of scorpion venom: an overview
Published in Toxin Reviews, 2020
Saadia Tobassum, Hafiz Muhammad Tahir, Muhammad Arshad, Muhammad Tariq Zahid, Shaukat Ali, Muhammad Mohsin Ahsan
Toxins interact with VGSCs in two ways. It either results in a blockage of pore when the neurotoxin physically obstructs the pore and inhibits the conductance of sodium ions, or in a modification of the gating, that altered the voltage-dependence and gating kinetics of the ion channels. Toxins that interact with the site 1 use first mechanism. For example, tetrodotoxin (TTX) and sexitoxin (STX) are pore blockers of site 1. Grayanotoxin and batrachotoxin are site 2 toxins which prevent inactivation and therefore, channel remain persistently active (Stevens et al. 2011). Scorpion α-toxins and sea anemone toxins bind to site 3 and inhibit the inactivation (Possani et al. 2000). Scorpion β-toxins and spider β-toxins are site 4 toxins which shift the activation toward hyperpolarized state (Shichor et al. 2002). Site 5 toxins like ciguatoxins and brevetoxins display a real effect upon binding with VGSC, for example, inhibition of activation and the hyperpolarizing shift of voltage-dependence activation. Finally, δ-conotoxins interact with site 6 and produce similar outcomes as the site 3 neurotoxins by inhibiting inactivation (Figure 3) (Stevens et al. 2011).
Quantitative structure–activity relationship models for compounds with anticonvulsant activity
Published in Expert Opinion on Drug Discovery, 2019
Carolina L. Bellera, Alan Talevi
A second CoMFA model was obtained by expanding the previously described hydantoin training set with local anesthetics and α-hydroxyphenylamides [67]. The new model described a binding site predominately hydrophobic in nature and was used to design and predict a series of nine novel sodium channel blockers that utilized overlapping structural features of phenytoin, hydroxy amides, and lidocaine. Eight of them were able to significantly displace [3H]-batrachotoxin-benzoate ester (its binding site overlaps with the binding sites of both phenytoin and local anesthetics) at 40 µM concentration. The most potent compound, 2-[4-(2-Diethylamino-acetylamino)-3,5-dimethylphenyl]-2-hydroxy-nonanoic acid amide, showed a predicted IC50 = 7 µM, actual IC50 = 6 µM. A similar approach was used to design active hybrids of the anesthetic propofol and hydroxyamide anticonvulsants [68]. More recently, a more comprehensive CoMFA model was obtained by starting from a more diverse 67-compound training set, including anesthetics, phenytoin, and mixed calcium and sodium channel blockers, among others [69]. The authors hypothesized that such expanded training sample would result in the design of more potent sodium channel blockers. According to them, the resulting model is richer in spatial information regarding steric and electrostatic factors for the binding of ligands to the sodium channel. The predictive ability of this new model was estimated on a test set of 20 compounds, after which it was used to design new potent blockers whose predicted IC50 values ranged from 251 to 1000 nM. The experimentally determined values were correctly predicted by the model in almost all cases; with only one exception, the predictions did not differ from the observed values by more than 2-fold. One of the compounds, N-(2-Phenylethyl)-3-phenylpropanamine, was at that time among the smallest known low nM blockers of the neuronal sodium channel.