Third-Generation Antiseizure Medications for Adjunctive Treatment of Focal-Onset Seizures in Adults: A Systematic Review and Network Meta-analysis.

BACKGROUND: Brivaracetam (BRV), cenobamate (CNB), eslicarbazepine acetate (ESL), lacosamide (LCM) and perampanel (PER) are antiseizure medications (ASMs) approved for adjunctive treatment of focal-onset seizures. So far, no randomised controlled trial directly compared the efficacy and safety of these drugs. OBJECTIVE: We estimated the comparative efficacy and safety of these ASMs for the treatment of focal-onset seizures in adults with epilepsy using a network meta-analysis (NMA). METHODS: We systematically searched (June week 4, 2021) MEDLINE (accessed by PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and the US National Institutes of Health Clinical Trials Registry ( http://www.clinicaltrials.gov ). There were no date limitations or language restrictions. Randomised, double-blinded, controlled, parallel-group, add-on studies that compared oral BRV, CNB, ESL, LCM, and PER versus any comparator over maintenance periods of at least 12 weeks and included adult patients with focal seizures uncontrolled by concomitant ASMs were identified. The efficacy outcomes were the proportions of patients with ≥ 50% and 100% reduction in baseline seizure frequency during the maintenance period. The tolerability outcomes were the proportions of participants who experienced at least one treatment-emergent adverse event (TEAE) and experienced at least one TEAE leading to discontinuation. Effect sizes were estimated by network meta-analyses within a frequentist framework. The hierarchy of competing interventions was established using the surface under the cumulative ranking curve (SUCRA). RESULTS: Sixteen trials (BRV: n = 3, CNB: n = 1, ESL: n = 4, LCM: n = 4, PER: n = 4) were included, overall enrolling 4507 patients randomised to add-on active treatments (BRV = 803, CNB = 221, ESL =9 90, LCM = 1104, and PER = 1389) and 2246 to add-on placebo. Cenobamate was associated with a higher rate of ≥ 50% seizure frequency reduction than BRV [odds ratio (OR) 2.02, 95% confidence interval (CI) 1.11-3.66], ESL (OR 1.93, 95% CI 1.07-3.48), LCM (OR 1.86, 95% CI 1.04-3.32), and PER (OR 2.07, 95% CI 1.16-3.70). There was a not statistically significant trend favouring CNB over ESL, LCM and PER for the seizure freedom outcome. Brivaracetam (OR 0.61, 95% CI 0.44-0.86) and LCM (OR 0.60, 95% CI 0.40-0.88) were associated with a lower proportion of participants experiencing TEAEs compared to ESL, and patients treated with PER were associated with a higher risk to experience at least one TEAE (OR 1.42, 95% CI 1.02-1.96) than BRV. According to SUCRA, CNB had the greatest likelihood of being the best option for the ≥ 50% and 100% seizure frequency reduction, and BRV and LCM had the highest probabilities of being the best-tolerated treatments. CONCLUSIONS: Cenobamate ranked best for efficacy, and BRV and LCM were best tolerated over the other comparators. Although NMAs cannot replace direct comparisons, they may support physicians in clinical decision making.

New Drugs 2021, Part 2.

ABSTRACT: The second of a two-part series, this article describes eight recently approved drugs, including the first drug approved for the treatment of SARS-CoV-2, a first-in-class HIV attachment inhibitor, and a new intravenous injection indicated for the treatment of acute pain in adults for whom other treatments are ineffective.

Is Cenobamate the Breakthrough We Have Been Wishing for?

Close to one-third of patients with epilepsies are refractory to current anti-seizure medications; however, trials with cenobamate suggest effectiveness in such patients with focal onset seizures. We searched for data published or otherwise reported on cenobamate and outlined these here. Despite being marketed in the USA, few studies are yet published in full, and trials are ongoing. Nevertheless, cenobamate showed potential for a high degree of efficacy in reducing seizures with an unprecedented seizure-free rate of up to 28%. Rare cases of hypersensitivity reactions seen in early trials seem to be avoided by the current recommended titration schedule. Other adverse events were rated mild-to-moderate and most commonly included dizziness, drowsiness, and headache. If data are confirmed in further published trials, cenobamate will be a welcome new treatment and further analyses may identify those that will benefit the most.

Efecto del 4-Clorofenol sobre el músculo liso vascular de aorta abdominal de ratas Wistar / Effect of 4-Chlorophenol on the vascular smooth muscle of the abdominal aorta of Wistar rats

Introducción: Uno de los derivados de los clorofenoles más utilizado en Estomatología, lo constituye el p-clorofenol (4-clorofenol), empleado como agente antibacteriano en la desinfección del conducto radicular durante el tratamiento pulporradicular. Son escasos los reportes científicos sobre sus efectos en la musculatura lisa vascular arterial y la regulación del flujo sanguíneo local. Objetivo: Determinar el efecto del 4-clorofenol sobre el músculo liso vascular de aorta abdominal de ratas Wistar. Material y Métodos: Se realizó una investigación experimental preclínica, utilizando 30 anillos de aorta abdominal (porción superior) obtenidos de ratas Wistar adultas. Las preparaciones de unos 5 mm se colocaron en baño de órganos, registrándose la tensión desarrollada por el músculo liso vascular tras la adición de 4-clorofenol en diferentes concentraciones y durante diferentes intervalos de tiempo. Resultados: El 4-clorofenol, tras la preactivación del musculo liso vascular de anillos de aorta abdominal, indujo relajación del vaso, la que se incrementó durante todo el tiempo de estudio y al aumento de la concentración del medicamento. Existieron diferencias significativas entre los valores de tensión promedios registrados en los diferentes intervalos de tiempo con los de la tensión base inicial. Conclusiones: El p-clorofenol indujo in vitro, relajación del músculo liso vascular de aorta abdominal de ratas Wistar(AU)

Introduction: In Dentistry, p-chlorophenol (4-chlorophenol) is one of the most widely used derivatives of chlorophenols. It is used as an antibacterial agent in root canal disinfection during pulp-radicular treatment. There are few scientific reports on its effects on vascular smooth musculature and the regulation of local blood flow. Objective: To determine the effect of 4-chlorophenol on vascular smooth muscle of abdominal aorta from Wistar rats. Material and Methods: A preclinical experimental research was carried out using 30 abdominal aortic rings (upper portion) obtained from adult Wistar rats. The preparations of about 5 mm were placed in an organ bath, recording the tension developed by the vascular smooth muscle after the addition of 4-chlorophenol at different concentrations and during different time intervals. Results: The results demonstrate that 4-Chlorophenol induced vasorelaxation after the preactivation of the vascular smooth muscle of the abdominal aortic rings, which increased during the entire study time and with increased drug concentration. There were significant differences among average tension values registered at different intervals of time in relation to the initial base tension. Conclusions: It is concluded that in vitro, p-chlorophenol induced relaxation of abdominal aorta vascular smooth muscle in Wistar rats(AU)

Anti-seizure medications and efficacy against focal to bilateral tonic-clonic seizures: A systematic review with relevance for SUDEP prevention.

We conducted a systematic review of anti-seizure medications (ASMs) and their efficacy for the control of focal to bilateral tonic-clonic seizures (FBTCS). FBTCS, especially when nocturnal, are recognized as one of the major risk factors for Sudden Unexpected Death in Epilepsy (SUDEP). We searched different online databases for all the randomized, double-blinded, and placebo-controlled clinical trials of ASMs that were FDA-approved after 1990 and that reported specifically on the reduction in FBTCS; when possible, this was compared to reduction in focal impaired awareness (FIA) seizures. The ASMs that yielded the most data (3 or more studies) were topiramate (TPM), followed by tiagabine (TGB), brivaracetam (BRV), and lamotrigine (LTG). TPM trials showed a reduction in FBTCS of 44.8% to 100% (4.5-99% over placebo); TGB 21.8% to 46.7% (21.8-61% over placebo); BRV 33.9% to 82.1% (11.6-57.4% over placebo); and LTG 55.2% (20.3-52% over placebo). Promising results, but with data from only one or two studies, were seen with cenobamate (18-59% efficacy above placebo), lacosamide (45.1-78.7%), levetiracetam (40.1-60.3%), oxcarbazepine (58.5-81.5%), and gabapentin (50-53.8%). Higher responses were often seen at higher doses, including at doses above those currently approved by the FDA. Results specific to nocturnal FBTCS were never reported for any ASM. Moreover, complete freedom from FBTCS specifically was very rarely reported, despite its relevance for SUDEP prevention. In conclusion, there are few data specifically comparing the efficacy of ASMs for prevention of FBTCS despite the known strong association of BTCS with SUDEP. This review was our attempt at filling a gap in the literature and calling for universal reporting of data specific to BTC seizure reduction in all future studies, preferably including specific reporting on nocturnal BTCS. This will help enable rational ASM selection to minimize BTC seizures and thereby decrease the risk of SUDEP.

The ups and downs of alkyl-carbamates in epilepsy therapy: How does cenobamate differ?

Since 1955, several alkyl-carbamates have been developed for the treatment of anxiety and epilepsy, including meprobamate, flupirtine, felbamate, retigabine, carisbamate, and cenobamate. They have each enjoyed varying levels of success as antiseizure drugs; however, they have all been plagued by the emergence of serious and sometimes life-threatening adverse events. In this review, we compare and contrast their predominant molecular mechanisms of action, their antiseizure profile, and where possible, their clinical efficacy. The preclinical, clinical, and mechanistic profile of the prototypical γ-aminobutyric acidergic (GABAergic) modulator phenobarbital is included for comparison. Like phenobarbital, all of the clinically approved alkyl-carbamates share an ability to enhance inhibitory neurotransmission through modulation of the GABAA receptor, although the specific mechanism of interaction differs among the different drugs discussed. In addition, several alkyl-carbamates have been shown to interact with voltage-gated ion channels. Flupirtine and retigabine share an ability to activate K+ currents mediated by KCNQ (Kv7) K+ channels, and felbamate, carisbamate, and cenobamate have been shown to block Na+ channels. In contrast to other alkyl-carbamates, cenobamate seems to be unique in its ability to preferentially attenuate the persistent rather than transient Na+ current. Results from recent randomized controlled clinical trials with cenobamate suggest that this newest antiseizure alkyl-carbamate possesses a degree of efficacy not witnessed since felbamate was approved in 1993. Given that ceno-bamate's mechanistic profile is unique among the alkyl-carbamates, it is not clear whether this impressive efficacy reflects an as yet undescribed mechanism of action or whether it possesses a unique synergy between its actions at the GABAA receptor and on persistent Na+ currents. The high efficacy of cenobamate is, however, tempered by the risk of serious rash and low tolerability at higher doses, meaning that further safety studies and clinical experience are needed to determine the true clinical value of cenobamate.

Cenobamate: A New Adjunctive Agent for Drug-Resistant Focal Onset Epilepsy.

OBJECTIVE: To review the pharmacology, efficacy, and safety of oral cenobamate in the treatment of uncontrolled focal epilepsy. DATA SOURCES: The PubMed database and ClinicalTrials.gov were searched using the following terms: cenobamate, Xcopri, and YKP3089. STUDY SELECTION AND DATA EXTRACTION: Articles published in English between January 2000 and April 2020 related to pharmacology, safety, and clinical trials were assessed. DATA SYNTHESIS: In a phase 2 trial, cenobamate reduced the median percentage change in seizure frequency from baseline by 56% compared with 22% for placebo (P < 0.0001). In another phase 2 trial of multiple cenobamate doses, cenobamate reduced seizure frequency by 36% (P = 0.0071) in the 100-mg group and 55% (P < 0.0001) in both the 200- and 400-mg groups, compared to 24% with placebo. Adverse effects of cenobamate appear to be similar to those of other antiseizure medications and primarily affect the neurological system. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: In patients taking antiseizure medications who continue to have focal seizures, cenobamate has efficacy at multiple doses and is generally well tolerated. Cenobamate may be distinguished from other antiseizure medications by high rates of seizure freedom not seen in previous placebo-controlled trials, which has the potential to significantly improve quality of life. However, despite this efficacy, Drug Reaction with Eosinophilia and Systemic Symptoms may remain a significant concern with cenobamate. CONCLUSION: As seen in clinical trials, cenobamate as an adjunctive, once-daily treatment represents an efficacious and generally well-tolerated therapy for patients with drug-resistant focal epilepsy.

Pharmacological treatment of focal epilepsy in adults: an evidence based approach.

INTRODUCTION: Focal seizures represent the most common seizure type and focal epilepsies the most common epilepsy type. Anti-seizure medications (ASMs) still represent the main form of treatment for epilepsy. AREAS COVERED: The aim of this review article is to provide an overview of available evidence about current and upcoming pharmacological options and strategies for adults with focal epilepsy focusing on the last 5 years. EXPERT OPINION: Seventeen drugs are currently approved for the treatment of focal seizures including cenobamate as the very latest option. Ten of these drugs are also licensed for monotherapy. Level A evidence for initial monotherapy is available for seven drugs with no robust data supporting that one drug is superior to the other. Safety, tolerability as well as pharmacoeconomic reasons would then drive treatment decisions. Data on adjunctive treatment are available for 13 ASMs showing again no obvious difference in terms of efficacy. Evidence on specific drug combinations is almost non-existent and the final decision of combining specific drugs is based on the experience of the individual clinician rather than on robust evidence. Current outcome measures do not consider number of previously failed drugs and the observation period is often too short.

Cenobamate: Neuroprotective Potential of a New Antiepileptic Drug.

Central nervous system (CNS) injuries annually afflict approximately 2.7 million people in United States only, inflicting costs of nearly 100 billion US dollars. The gravity of this problem is a consequence of severe and prolonged disability of patients due to a scarce regeneration of CNS, along with the lack of efficient neuroprotective and neuroregenrative therapies. Therefore, the first and most important task in managing the CNS injury is reduction of the damaged area, and apoptosis of neurons occurs not only during the trauma, but in great extent within the following minutes and hours. This process, called secondary injury phase, is a result of trauma-induced metabolic changes in nervous tissue and neuron apoptosis. Cenobamate is a new antiepileptic drug approved by FDA on November 21, 2019. Regardless of its primary purpose, cenobamate, as a blocker of voltage-gated sodium channels and positive modulator of GABAa receptors, it appears to be a promising neuroprotective agent. Moreover, through activation of PI3K/Akt-CREB-BDNF pathway, it leads to the increase of anti-apoptotic factor levels and the decrease of pro-apoptotic factor levels, which induce inhibition of apoptosis and increase neuron survival. Similarly to riluzole, cenobamate could be an important part of a perioperative procedure in neurosurgery, decreasing the occurrence of neurological deficits. Provided that cenobamate will be effective in aforementioned conditions, it could improve treatment outcomes of millions of patients every year, thereby an extensive investigation of its efficacy as a neuroprotective treatment after central nervous system trauma should follow.

Cenobamate (XCOPRI): Can preclinical and clinical evidence provide insight into its mechanism of action?

Approximately one-third of people living with epilepsy are unable to obtain seizure control with the currently marketed antiseizure medications (ASMs), creating a need for novel therapeutics with new mechanisms of action. Cenobamate (CBM) is a tetrazole alkyl carbamate derivative that received US Food and Drug Administration approval in 2019 for the treatment of adult partial onset (focal) seizures. Although CBM displayed impressive seizure reduction in clinical trials across all seizure types, including focal aware motor, focal impaired awareness, and focal to bilateral tonic-clonic seizures, the precise mechanism(s) through which CBM exerts its broad-spectrum antiseizure effects is not known. Experimental evidence suggests that CBM differentiates itself from other ASMs in that it appears to possess dual modes of action (MOAs); that is, it predominately blocks persistent sodium currents and increases both phasic and tonic γ-aminobutyric acid (GABA) inhibition. In this review, we analyze the preclinical efficacy of CBM alongside ASMs with similar MOAs to better understand the mechanism(s) through which CBM achieves such broad-spectrum seizure protection. CBM's preclinical performance in tests, including the mouse 6-Hz model of treatment-resistant seizures, the chemoconvulsant seizure models of generalized epilepsy, and the rat hippocampal kindling model of focal epilepsy, was distinct from other voltage-gated sodium channel blockers and GABAA modulators. This distinction, in light of its proposed mechanism(s) of action, provides insight into the impressive clinical efficacy of CBM in the adult patient with focal onset epilepsy. The results of this comparative reverse translational analysis suggest that CBM is a mechanistically distinct ASM that offers an important advancement in drug development for treatment of therapy-resistant epilepsy.

Cenobamate for the treatment of focal epilepsies.

INTRODUCTION: Antiseizure drugs (ASDs) play a central and crucial role in the treatment of epilepsy patients because the majority require anticonvulsant treatment for an extended period of time. Due to the fact that 30% of patients are refractory to medical treatment, new therapeutic options are necessary. Cenobamate is the latest approved antiepileptic drug in focal epilepsy, and its mode of action is thought to be mediated by blocking voltage-gated sodium channels and interaction with the GABAergic system. AREAS COVERED: This article reviews animal studies, pharmacokinetics, pharmacodynamics, and the phase 1 to 3 trials and open-label extension data on cenobamate. EXPERT OPINION: Cenobamate has the potential to perform as an important ASD because trial data are indicative of remarkable responder and seizure freedom rates so far not seen with other ASDs. Cenobamate demonstrated significant efficacy at a dosage between 100 and 400 mg per day. The side-effect profile of this drug is comparable to other ASDs and is mainly CNS related; in particular, somnolence, dizziness, headache, diplopia, and nystagmus. However, slow titration is mandatory to decrease the risk of drug rash with eosinophilia and systemic symptoms (DRESS) that was observed in several patients with fast uptitration schemes.

Cenobamate for the treatment of focal epilepsy.

Focal-onset or partial seizures are localized to a specific brain area or areas of the cerebral hemisphere. Cenobamate (CNB, Xcopri, YKP-3089; SK Life Science) is a recent U.S. Food and Drug Administration (FDA)-approved drug for the treatment of focal-onset seizures in the adult population. CNB has demonstrated broad-spectrum efficacy in alternative preclinical models of epilepsy. The molecule exerts an antiseizure effect due to its dual mechanism of action: besides inhibiting the voltage-gated persistent component of the sodium currents, CNB is additionally an allosteric GABA(A) channel modulator in a non-benzodiazepine fashion. The superior clinical effect of this molecule over placebo in reducing seizure frequency may be observed after 2 weeks following a starting oral dose of 50 mg/day. The drug can be titrated up to a maximum daily maintenance dose of 400 mg/day. CNB has mild to moderate side effects. During initial development, a critical drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome was noticed in 3 patients. However, the DRESS effect was not observed in the large C021 safety study involving 1,347 patients, suggesting a maximum potential risk of no more than 0.3%. The present monograph describes the background, preclinical and clinical pharmacology, indication and safety of CNB for the treatment of partial/focal seizures.

An Ex Vivo Evaluation of Cenobamate Administered via Enteral Tubes.

BACKGROUND: Cenobamate is a new, Food and Drug Administration (FDA)-approved oral antiepileptic drug for treatment of focal seizures in adults. This study examined recovery of cenobamate from suspensions administered through ex vivo enteral feeding tubes. METHODS: Suspensions containing 100 and 200 mg of cenobamate were prepared (five duplicates for each dose), passed through five vertically standing tubes, and collected into flasks. The flasks containing the suspensions were rinsed with deionized water, and this content was also injected into the tubes and collected in the flasks. Acetonitrile, isopropyl alcohol, and trifluoroacetic acid were added to the flasks, followed by deionized water to a concentration of 500 (100-mg cenobamate) and 400 (200-mg cenobamate) µg/mL. A 3-mL aliquot from each suspension was placed into a 10-mL flask, diluted to volume, and mixed, resulting in final concentrations of 150 and 120 µg/mL, respectively. All suspensions were analyzed by high-performance liquid chromatography (LC). The % LC recovery of cenobamate was calculated for each suspension, and mean % LC for duplicates. RESULTS: The % LC recovery of cenobamate from the 100-mg suspensions ranged from 96.2 to 99.1%, with mean % LC recovery between 96.3 and 98.3%. The % LC recovery of cenobamate from the 200-mg suspensions ranged from 97.1 to 102.6%, with mean % LC recovery between 98.5 and 101.7%. CONCLUSION: The mean % LC recovery of cenobamate was within the predetermined acceptable range of 90.0-110.0%, suggesting no adhesion or adsorption of cenobamate to enteral feeding tubes. Delivery of cenobamate suspension via enteral feeding tubes may be a viable route of administration for patients who cannot swallow tablets.

Cenobamate: First Approval.

Cenobamate (XCOPRI®) is an oral, small molecule neurotherapeutic azole compound that is being developed by SK Life Science Inc. and Arvelle Therapeutics for the treatment of epilepsy. Based on results of two pivotal phase 2 trials, cenobamate was recently approved in the USA for use in the treatment of partial-onset seizures in adult patients. This article summarizes the milestones in the development of cenobamate leading to this first approval.

[Clinical observation on the inflammatory indexes in septic gastrointestinal dysfunction treated with acupuncture at Jiaji (EX-B 2)].

OBJECTIVE: To evaluate the effect on the inflammatory indexes of septic gastrointestinal dysfunction treated with acupuncture at Jiaji (EX-B 2). METHODS: A total of 118 patients of septic gastrointestinal dysfunction were randomized into an observation group and a control group, 59 cases in each one. In the control group, mosapride citrate was prescribed for oral administration, 5 mg each time, 3 times a day, bifidobacterium triple viable capsules, 420 mg each time, twice a day, intravenous drip with omeprazole, 40 mg, twice a day. Additionally, the antibiotics and the symptomatic treatment were selected rationally for maintaining the functions of the important organs, e.g. heart, lung, brain and kidney, and water-electrolyte balance. In the observation group, on the routine management as the control group, acupuncture at Jiaji (EX-B 2, T6-T12) was added, the needles were retained for 30 min in each treatment, once a day, 10 days as one course and 1 course was required. Separately, on the 1st, 3rd, 6th and 10th days of treatment, the white blood cell (WBC) count, the levels of hypersensitive C-reactive protein (hs-CRP) and procalcitonin (PCT) were observed, the enteral nutrition feeding dose and gastrointestinal dysfunction score before and after treatment as well as the clinical effect were assessed in the two groups. RESULTS: The differences were not significant in the indexes mentioned above on 1st and 3rd days of treatment between the two groups (P>0.05). On the 6th and 10th days of treatment, regarding the gastrointestinal dysfunction score and inflammatory indexes count, the results in the observation group were lower than the control group (all P<0.05), and feeding dose in the observation group was higher than the control group (P<0.05). After treatment, the gastrointestinal dysfunction scores and inflammatory indexes count were all reduced and feeding dose was increased as compared with those before treatment in the patients of the two groups (all P<0.05). After treatment, the total effective rate was 91.5% (54/59) in the observation group, higher than 76.3% (45/59) in the control group (P<0.05). CONCLUSION: Acupuncture at Jiaji (EX-B 2) points achieves the satisfactory effect on septic gastrointestinal dysfunction and reduces the inflammatory indexes count.

Suppression of the photoparoxysmal response in photosensitive epilepsy with cenobamate (YKP3089).

OBJECTIVE: To evaluate the effect of cenobamate in patients with photoparoxysmal-EEG response (PPR) to intermittent photic stimulation (IPS) as proof of principle of efficacy in patients with epilepsy. METHODS: In this multicenter, single-blind study, adults with photosensitive epilepsy, with/without concomitant antiepileptic drug therapy, underwent IPS under 3 eye conditions after a single dose of placebo (day -1, day 2) or cenobamate (day 1; 100, 250, or 400 mg). Complete suppression was a standardized photosensitivity range reduction to 0 over ≥1 time points for all eye conditions. Partial suppression was a ≥3-point reduction over ≥3 testing times vs the same time points on day -1 in ≥1 eye condition. Pharmacokinetics and safety were assessed. RESULTS: Of 6 evaluable patients, 5 reentered to receive higher doses. Cenobamate 100 mg produced partial suppression in 1 of 3 patients; 250 mg produced complete suppression in 1 of 4 and partial suppression in 4 of 4 patients; and 400 mg produced complete suppression in 1 of 4 and partial suppression in 2 of 4 patients. PPR was consistently reduced on days 1 and 2 (>24 hours after cenobamate) vs day -1 (placebo) with the 250- and 400-mg doses. Area under the plasma concentration-time curve (before dose to last measurable concentration) values between 201 and 400 µg/h/mL resulted in partial suppression in 4 of 6 (66%) patients. Most common adverse events were dizziness and somnolence. CONCLUSIONS: This proof-of-principle study demonstrated that cenobamate is a potentially effective product for epilepsy. CLINICALTRIALSGOV IDENTIFIER: NCT00616148. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that, for patients with photosensitive epilepsy, cenobamate suppresses IPS-induced PPR.

Complestatin exerts antibacterial activity by the inhibition of fatty acid synthesis.

Bacterial enoyl-acyl carrier protein (ACP) reductase has been confirmed as a novel target for antibacterial drug development. In the screening of inhibitors of Staphylococcus aureus enoyl-ACP reductase (FabI), complestatin was isolated as a potent inhibitor of S. aureus FabI together with neuroprotectin A and chloropeptin I from Streptomyces chartreusis AN1542. Complestatin and related compounds inhibited S. aureus FabI with IC50 of 0.3-0.6 µM. They also prevented the growth of S. aureus as well as methicillin-resistance S. aureus (MRSA) and quinolone-resistant S. aureus (QRSA), with minimum inhibitory concentrations (MICs) of 2-4 µg/mL. Consistent with its FabI-inhibition, complestatin selectively inhibited the intracellular fatty acid synthesis in S. aureus, whereas it did not affect the macromolecular biosynthesis of other cellular components, such as DNA, RNA, proteins, and the cell wall. Additionally, supplementation with exogenous fatty acids reversed the antibacterial effect of complestatin, demonstrating that it targets fatty acid synthesis. In this study, we reported that complestatin and related compounds showed potent antibacterial activity via inhibiting fatty acid synthesis.

Small-molecule inhibitors at the PSD-95/nNOS interface attenuate MPP+-induced neuronal injury through Sirt3 mediated inhibition of mitochondrial dysfunction.

Post-synaptic density protein 95 (PSD-95) links neuronal nitric oxide synthase (nNOS) with the N-methyl-D-aspartic acid (NMDA) receptor in the central nervous system, and this molecular complex has been implicated in regulating neuronal excitability in several neurological disorders. Here, small-molecule inhibitors of the PSD-95/nNOS interaction, IC87201 and ZL006 were tested for neuroprotective effects in an in vitro Parkinson's disease (PD) model. We now report that IC87201 and ZL006 reduced MPP(+)-induced neuronal injury and apoptotic cell death in a dose-dependent manner in cultured cortical neurons. These protective effects were associated with suppressed mitochondrial dysfunction, as evidenced by decreased reactive oxygen species (ROS) generation, cytochrome c release, mitochondrial membrane potential (MMP) collapse, and the preserved mitochondrial complex I activity and ATP synthesis. IC87201 and ZL006 also preserved intracellular homeostasis through mitigating mitochondrial Ca(2+) uptake and promoting mitochondrial Ca(2+) buffering capacity. Moreover, treatment with IC87201 and ZL006 significantly increased the expression of Sirt3 after MPP(+) exposure, and knockdown of Sirt3 using specific targeted small interfere RNA (siRNA) partially nullified the protective effects induced by these two inhibitors. These data strongly support the hypothesis that targeting the PSD-95/nNOS interaction produces neuroprotective effects and may represent a novel class of therapeutics for PD as well as other neurological diseases where detrimental NMDA receptor signaling plays a major role.

Small-molecule inhibitors at the PSD-95/nNOS interface have antidepressant-like properties in mice.

Previous studies have demonstrated that nitric oxide (NO) synthase inhibitors are as efficacious as tricyclic antidepressants in preclinical antidepressant screening procedures and in attenuating behavioural deficits associated with animal models of depression. The N-methyl-D-aspartate receptor (NMDA-R) complex gates Ca(2+), which interacts with calmodulin to subsequently activate NO synthase. We hypothesised that uncoupling neuronal nitric oxide synthase (nNOS) from the NMDA-R through the scaffolding protein postsynaptic density protein 95 (PSD-95) would produce behavioural antidepressant effects similar to NO synthase inhibitors. Small-molecule inhibitors of the PSD-95/nNOS interaction, IC87201 (0.01-2 mg/kg) and ZL006 (10 mg/kg) were tested for antidepressant properties in tests of antidepressant activity namely the tail suspension and forced swim tests in mice. We now report that IC87201 and ZL006 produce antidepressant-like responses in the forced swimming test (FST) and tail suspension test (TST) following a single administration in mice. By contrast to the tricyclic antidepressant imipramine (25 mg/kg), the effects are not observed 1 h following drug administration but are apparent 24 and 72 h later. Furthermore prior exposure to the TST or FST is required in order to observe the antidepressant-related activity. Similar delayed and sustained antidepressant-like effects were observed following TRIM (50 mg/kg) and ketamine (30 mg/kg) in the TST. The antidepressant-like effects of ZL006 also generalise to IC87201 in the TST. IC87201 was devoid of effects on locomotor activity and step-through latency in the passive avoidance cognition test. These data support the hypothesis that targeting the PSD-95/nNOS interaction downstream of NMDA-R produces antidepressant effects and may represent a novel class of therapeutics for major depressive disorders.