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Brain Slice Model of Epilepsy: Neuronal Networks and Actions of Antiepileptic Drugs
Published in Carl L. Faingold, Gerhard H. Fromm, Drugs for Control of Epilepsy:, 2019
Suzanne Clark, Wilkie A. Wilson
Ashton et al.83 evaluated the rank order of potency of several anticonvulsants in low calcium ACSF. EGSs were suppressed by the following: (the drugs are listed in order of potency; parentheses enclose IC50 for a decrease in frequency or amplitude, in μM): phenytoin (1.0, 0.82) > carbamazepine (5.0, 5.0) > midazolam (12.0, 8.3) > pentobarbital (31.0, 31.0) > chlordiazepoxide (32.0, 32.0) > flurazepam (76.0, 76.0) > phenobarbital (83.0, >100). The following drugs were ineffective at the highest concentrations employed (100 μM): 2-APH, ethosuximide, and valproate. As discussed previously, the authors got a different rank order of potency for 0-magnesium-elicited EB activity. This is not entirely unexpected since (1) the two models evoke epileptiform activity by different mechanisms and (2) EBs and EGSs have displayed different pharmacologic profiles in other models. Accordingly, in designing experiments to screen new drugs, it may be advantageous to employ a combination of several models to assure the detection of drugs acting through different mechanisms. Such an approach was taken by Alzheimer and ten Bruggencate.132 They evaluated BRL 34915 (Chromakalim), a new “potassium channel opener”, on the following models: 0-magnesium, low calcium, and high potassium. BRL 34915 dampened triggered activity in low calcium ACSF, it decreased the frequency (but not duration) of EGSs in the 0-magnesium model, and it decreased the frequency of EB activity evoked in high potassium.
The Cardiovascular System
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Calvert Louden, David Brott, Chidozie J. Amuzie, Bindu Bennet, Ronnie Chamanza
In models of drug-induced vascular injury, plasma vWF was evaluated to assess its utility as a potential marker of vascular injury in the rat and dog (Brott et al. 2005a; Newsholme et al. 2000). Minor increases in plasma vWF were observed following administration of a potassium channel opener (Brott et al. 2005a) and fenoldopam (Newsholme et al. 2000). This observation, in conjunction with other reports, raises the possibility that the transient, 2–6 hour increase in circulating plasma vWF, could be an indicator of endothelial cell activation/perturbation prior to morphologic evidence of vascular damage (Brott et al. 2005a; Newsholme et al. 2000), because levels returned to baseline prior to vascular injury being confirmed histologically (Brott et al. 2005b). Additional studies in the dog indicated that minimal lesions induced by a potassium channel opener did not result in increased vWF levels (Katein et al. 2008); thus, vWF does not seem to be a suitable marker for use in toxicology studies to monitor progressive vascular damage. It has been suggested that analyzing the vWF:vWFpp ratio in humans, dogs, and baboons allows discrimination between chronic and acute phases of endothelial cell perturbation, activation, and injury (Brott et al. 2005b; Louden et al. 2006; van Mourik et al. 1999).
Parasympathomimetic Amines
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
The second mechanism for the direct negative chronotropy and atrial inotropy by muscarinic agonists is through inhibition of Ca2+ influx via L-type Ca2+ channels. This is usually believed to occur only where Ca2+ influx is elevated, for example, by catecholamines. However, there is evidence that Ach can also reduce basal activity. The intracellular second messenger of this action has not been identified, but an elevation of the levels of cGMP has been proposed. This may activate phosphodiesterase which then reduces cAMP levels. Interference with elevated cAMP levels certainly appears to be the main mechanism for the indirect action of muscarinic receptor stimulation in all areas of the heart. Raised rate and force of contraction by β-adrenoceptor stimulation is effectively reduced by Ach. It is only cAMP-dependent positive inotropes that are inhibited by Ach, indicating the involvement of cAMP. The increase in force of ventricular contraction by the Ca2+ channel opener, BayK 8644, is not affected by muscarinic agonists (Urquhart & Broadley 1992). Although the increased force of cardiac contraction by forskolin (a direct activator of adenylyl cyclase) and phosphodiesterase inhibitors are inhibited by Ach, they are not always associated with changes in cAMP levels (Buckley & Caulfield 1992).
Genome-edited zebrafish model of ABCC8 loss-of-function disease
Published in Islets, 2022
Jennifer M. Ikle, Robert C. Tryon, Soma S. Singareddy, Nathaniel W. York, Maria S. Remedi, Colin G. Nichols
We crossed SUR1 mutant fish to ins:GFP expressing fish to assess morphology and insulin gene promoter activity. GFP fluorescence was used to identify β-cells in isolated islets via confocal microscopy. There was no obvious deficit of β-cell density or GFP density in SUR1 mutants compared to WT (not shown). Inside-out patch clamp recordings from β-cells isolated from primary islets of SUR1 homozygous mutant and wild-type fish, both containing ins:GFP transgene, were also identified by the presence of green fluorescence. Excised inside-out patch-clamp experiments (Figure 2a,b) confirmed the effective knockout, with complete absence of KATP channels in SUR1 homozygous mutant β-cells. These recordings additionally confirmed no responsivity to the channel opener diazoxide, consistent with a severe loss of function.
Epilepsy: expert opinion on emerging drugs in phase 2/3 clinical trials
Published in Expert Opinion on Emerging Drugs, 2022
Amanda W Pong, Jonathan Ross, Ivana Tyrlikova, Alexander J Giermek, Maya P Kohli, Yousef A Khan, Roger D Salgado, Pavel Klein
A randomized, double-blind, placebo controlled, parallel group, phase 2b clinical trial (NCT03796962) of adjunctive Xen 1101 (10 mg, 20 mg and 25 mg) for safety and efficacy in 285 adults with refractory focal epilepsy has been conducted [61]. The primary endpoint median seizure frequency reduction was 18.2% for placebo and 33.2%, 46.4%, and 52.8% for the 10, 20 and 25 mg/day doses, respectively. Secondary outcomes included responder rates of 14.9%, 28.3%, 43.1%, and 54.6% in the four dose groups. Common AEs were dizziness (24.6%), somnolence (15.6%), fatigue (10.9%) dysarthria (4.3%) and gait disturbance (9.0 %). The commonest AEs leading to discontinuation (4%) were dizziness (4.7%), balance disorder (1.9%), and gait disturbance (1.9%) [61]. The results suggest that this class of K-channel opener may have a robust effect on seizure control. There are plans to move forward with Phase 3.
The role of levosimendan in phosphine-induced cardiotoxicity: evaluation of electrocardiographic, echocardiographic, and biochemical parameters
Published in Toxicology Mechanisms and Methods, 2021
Maryam Armandeh, Behnaz Bameri, Maryam Baeeri, Hamed Haghi-Aminjan, Mahban Rahimifard, Shokoufeh Hassani, Mohammad Reza Hooshangi Shayesteh, Madiha Khalid, Mahedeh Samadi, Rohollah Hosseini, Majid Masoudi Fard, Mohammad Abdollahi
Levosimendan is a troponin C stabilizer enhancing cardiac contractility without any significant augmentation in the intracellular calcium concentration. It is also known as a KATP channel opener in mitochondria that can be involved in cardioprotection. According to some studies, levosimendan could prevent deterioration of some hemodynamic parameters, including reduction of HR, BP, and cardiac function in the different models of cardiotoxicity. The primary favorable effects of levosimendan might be due to its ability to exert an efficient inotropic effect, carried out through sensitization of contractile apparatus to calcium (Leppikangas et al. 2009; Kandemir et al. 2013). Despite other inotrope agents with an arrhythmogenic effect due to intracellular calcium overload (Scoote and Williams 2004), no considerable arrhythmogenic effect of levosimendan in experimental and clinical studies was seen (Du Toit et al. 1999; Lilleberg et al. 2004). According to a study done on the model of acute myocardial ischemia, levosimendan reduced infarct size by preserving local coronary blood flow to the ischemic myocardial zone and consequently reduced the incidence of arrhythmia (Papp et al. 2006).