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EEG recording from the subthalamic nucleus in patients with epilepsy
Published in Hans O Lüders, Deep Brain Stimulation and Epilepsy, 2020
Dudley S Dinner, Silvia Neme, Hans O Lüders
There is only limited evidence in the animal model that stimulation of the above structures could influence seizure threshold. However, there is extensive evidence in the animal model of epilepsy that the substantia nigra pars reticulata (SNr) is implicated in the control of seizures. Lesions of the substantia nigra (SN),18 and also pharmacologic manipulation of the SN by injection of muscimol, a GABA agonist or gamma-vinyl GABA, which is a GABA transaminase inhibitor results in the suppression of seizures.19 Bilateral activation of the GABAergic transmission in the SN suppresses seizures in various animal models of epilepsy, including maximal electroshock, systemic or intra-cerebrally applied convulsants (bicuculline and pilocarpine), kindling and genetic absence seizures.20 Low dose pentylenetetrazole-induced seizures are also reduced by activation of the nigral control of epilepsy (NCE) system.20–22 In addition to the various animal models of generalized epilepsy, models of focal epilepsy have also been reported to respond to the activation of the NCE system including focal epilepsy induced by penicillin,23,24 and cortical 3–aminopyridine.25
Medical Countermeasures for Intoxication by Botulinum Neurotoxin
Published in Brian J. Lukey, James A. Romano, Salem Harry, Chemical Warfare Agents, 2019
Michael Adler, Ajay K. Singh, Nizamettin Gul, Frank J. Lebeda
The inability of 3,4-DAP infusion to produce complete reversal of BoNT/A-mediated paralysis in the infusion studies may have resulted from the dose being too low. Higher doses could not be examined because the dose used was at the limit of aqueous solubility, indicating a need for a more potent K+ channel blocker. To achieve this aim, a series of aminopyridines, from both commercial and custom sources, were tested in the mouse phrenic nerve–hemidiaphragm assay by Adler and Borrell (unpublished observations). Table 14.1 shows a sample of the compounds tested and the percentage potentiation of twitch tension achieved. Test compounds were added at 100 µM after tensions were depressed to ~20% of control by exposure to 2 pM BoNT/A. Most compounds were weak or inactive in this assay, as exemplified by 6-aminopyridine-3-carboxylic acid. The remaining compounds, including those with single amine groups (2-aminopyridine [2-AP], 3-aminopyridine [3-AP], 4-aminopyridine [4-AP]) or two amine groups (2,3-diaminopyridine [2,3-DAP]), were all found to be less potent than 3,4-DAP. These results agree with those of Molgó et al. (1985) and indicate the difficulty of discovering aminopyridine analogs more potent than 3,4-DAP for blocking K+ channels at motor nerve terminals.
The skin’s endogenous antioxidant network
Published in Roger L. McMullen, Antioxidants and the Skin, 2018
Another important component of the endogenous antioxidant system is the Trx system.17 It consists of two protein structures, Trx and Trx reductase (TrxR), which work in concert, resulting in antioxidant activities as well as the influence of other cellular functions. TrxR is often likened to GPX, as it is also a thiol redox system, and belongs to a family of enzymes known as the pyridine nucleotide oxidoreductases. However, similar to NAD(P)H:quinone reductase (discussed in the preceding section), TrxR is an avoprotein that contains four subunits (ca. 55–65 kDa per monomer), in which each subunit contains an active site with the amino acid, selenocysteine, and FAD. Trx is a small one-subunit protein (ca. 12 kDa) found in most tissues of the body. Further, TrxR utilizes NADPH for reducing equivalents, in which an electron is transferred first to FAD then to the enzyme (TrxR). As indicated in the scheme provided in Figure 3.10a, this action results in the cleavage of a disulfide bond in TrxR. The enzyme then donates an electron to its substrate, Trx, resulting in the reformation of a disulfide bond in TrxR and the cleavage of a disulfide bond in Trx. The structure of the four subunit enzyme, TrxR, along with four Trx molecules, each interacting with a subunit, is shown in Figure 3.10b. In the figure, TrxR is shown in yellow and gold, while Trx is colored gray. Also shown is FAD (purple sticks) and NADP+ (black sticks). In fact, the analog 3-aminopyridine adenine dinucleotide phosphate (AADP+) is shown instead of NADP+; however, the principal is the same.
Characteristics of recent clinical investigations into systemic therapy against cervical cancer: systematic analysis of trial details from Clinicaltrials.gov
Published in Journal of Obstetrics and Gynaecology, 2022
Biniyam Girma, Eyasu Makonnen, Workineh Shibeshi
From a drug development perspective, chemotherapy-based interventional trials have little to offer. As far as the chemotherapeutic regimens were concerned, we observed that virtually all were among the widely studied, approved or clinically recommended systemic therapy for cervical cancer (Kitchener et al. 2010; Canadian Cancer Scociety 2018). One notable exception, however, was the ribonucleotide reductase (RNR) inhibitor triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone). Initial Phase I and single-arm Phase IIb studies have found the triapine-cisplatin-radiotherapy combination to produce high rates of clinical and metabolic responses while being safe (Kunos et al. 2010, 2013). More importantly, a recent small randomised phase II trial has reported a non-statistically significant 15% (77 to 92%) increment in the 3-year progression-free survival estimate and a 23% (69 to 92%) higher rate of metabolic complete response (Kunos et al. 2019). Given these findings, the ongoing phase III study of triapine in advanced stage cervical and vaginal cancer patients presents a promising possibility for the development of a new chemotherapeutic drug.
Design and synthesis of new indole drug candidates to treat Alzheimer’s disease and targeting neuro-inflammation using a multi-target-directed ligand (MTDL) strategy
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Phoebe F. Lamie, Maha M. Abdel-Fattah, John N. Philoppes
In Scheme 1, novel stilbene mimic derivatives 3a–c were synthesised through perkin reaction31 by condensation of 3-indole carboxaldehyde derivative 232 and commercially available phenylacetic acid, p-chlorophenyl acetic acid, or 3,4,5-trimethoxyphenyl acetic acid in acetic anhydride and potassium carbonate. The produced compounds 3a–c were subjected to a condensation reaction with different secondary aliphatic amines, such as piperidine, 1–(2-pyrimidinyl)piperazine, and 1-benzylpipridine, or with primary aromatic amine, 3-aminopyridine, using HBTU (reagent used specifically for amidic bond formation), and DMF as a solvent to obtain amidic derivatives 4a–d. The yields ranged from 73 to 79%.
Cannabis and Epilepsy
Published in Journal of Dual Diagnosis, 2020
In 2002, Wallace et al. showed that anticonvulsant effects of cannabinoids are mediated by the CB1 receptor (Wallace, Martin, & DeLorenzo, 2002). It was also described that the endocannabinoid AEA was a potent anticonvulsant using the maximal electroshock model and that when there was pretreatment with the CB1 antagonist SR141716A the anticonvulsant effect of AEA was abolished (Wallace et al., 2002, 2003). Later a pilocarpine-induced seizure rat model was used, in which THC was shown to have a 100% reduction in seizures, and the animal models were shown to have upregulation of CB1 production and increases in endocannabinoid synthesis, implying a role of cannabinoids in neuroprotection as well as plasticity (Wallace et al., 2003). In 2004, Lorenz et al. described case reports of eight children affected with various conditions including neurodegenerative diseases, mitochondriopathy, hypoxic encephalopathy, epilepsy, and traumatic brain injury, in which they were given the synthetic derivative of THC, dronabinol, at 0.04–0.12 mg/kg/d; a reduction in seizures, improved spasticity, and dystonia and increased were seen (Lorenz, 2004). Pelliccia et al. described in 2005 treating drug-resistant epilepsy in 18 children with low-dose CBD in corn oil suspension, noting improvements in seizure frequency and severity in most (Pelliccia, Grassi, Romano, & Crocchiolo, 2005). In 2010, Jones et al. described the use of CBD in treating seizures in vitro Mg(2+)-free and 3-aminopyridine models in hippocampal brain slices via multi-electrode array recordings and found in the Mg(2+)-free model that CBD decreased epileptiform local field potentials, decreased burst duration, and increased burst frequency. In the 4-AP model, CBD decreased local field potentials, burst amplitude, burst duration, and burst frequency. An in vivo pentlyenetetrazole model was also used, and CBD given at 100 mg/kg was shown to have significant decreases in seizures and mortality. In this study, CBD was shown to have low affinity to CB1 receptors, suggesting that CBD may act in a CB1-independent manner (Jones et al., 2010).