Feasibility, safety, efficacy and potential scaling-up of sofosbuvir-based HCV treatment in Central and West Africa: (TAC ANRS 12311 trial).

Access to Hepatis C treatment in Sub-Saharan Africa is a clinical, public health and ethical concern. The multi-country open-label trial TAC ANRS 12311 allowed assessing the feasibility, safety, efficacy of a specific care model of HCV treatment and retreatment in patients with hepatitis C in Sub Saharan Africa. Between November 2015 and March 2017, with follow-up until mid 2019, treatment-naïve patients with HCV without decompensated cirrhosis or liver cancer were recruited to receive 12 week-treatment with either sofosbuvir + ribavirin (HCV genotype 2) or sofosbuvir + ledipasvir (genotype 1 or 4) and retreatment with sofosbuvir + velpatasvir + voxilaprevir in case of virological failure. The primary outcome was sustained virological response at 12 weeks after end of treatment (SVR12). Secondary outcomes included treatment adherence, safety and SVR12 in patients who were retreated due to non-response to first-line treatment. The model of care relied on both viral load assessment and educational sessions to increase patient awareness, adherence and health literacy. The study recruited 120 participants, 36 HIV-co-infected, and 14 cirrhotic. Only one patient discontinued treatment because of return to home country. Neither death nor severe adverse event occurred. SVR12 was reached in 107 patients (89%): (90%) in genotype 1 or 2, and 88% in GT-4. All retreated patients (n = 13) reached SVR12. HCV treatment is highly acceptable, safe and effective under this model of care. Implementation research is now needed to scale up point-of-care HCV testing and SVR assessment, along with community involvement in patient education, to achieve HCV elimination in Sub-Saharan Africa.

Treatment of patients with BRAFV600E-mutated metastatic colorectal cancer after progression to encorafenib and cetuximab: data from a real-world nationwide dataset.

BACKGROUND: Targeted therapy (TT) with encorafenib and cetuximab is the current standard for patients with BRAFV600E-mutated metastatic colorectal cancer (mCRC) who received one or more prior systemic treatments. However, the median progression-free survival (mPFS) is ∼4 months, and little is known about the possibility of administering subsequent therapies, their efficacy, and clinicopathological determinants of outcome. METHODS: A real-world dataset including patients with BRAFV600E-mutated mCRC treated with TT at 21 Italian centers was retrospectively interrogated. We assessed treatments after progression, attrition rates, and outcomes. RESULTS: Of the 179 patients included, 85 (47%), 32 (18%), and 7 (4%) received one, two, or three lines of treatment after TT, respectively. Those receiving TT in the second line were more likely to receive at least one subsequent therapy (53%), as compared with those treated with TT in the third line or beyond (30%; P < 0.0001), and achieved longer postprogression survival (PPS), also in a multivariate model (P = 0.0001). Among 62 patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) tumors receiving one or more lines of treatment after second-line TT, combinatory chemotherapy ± anti-vascular endothelial growth factor (anti-VEGF) was associated with longer PFS and PPS as compared with trifluridine-tipiracil or regorafenib (mPFS: 2.6 versus 2.0 months, P = 0.07; PPS: 6.5 versus 4.4 months, P = 0.04). CONCLUSIONS: Our real-world data suggest that TT should be initiated as soon as possible after the failure of first-line treatment in BRAFV600E-mutated mCRC. Among patients with pMMR/MSS tumors, combinatory chemotherapy ± anti-VEGF appears the preferred treatment choice after TT failure.

Retigabine and gabapentin restore channel function and neuronal firing in a cellular model of an epilepsy-associated dominant-negative KCNQ5 variant.

KCNQ5 encodes the voltage-gated potassium channel KV7.5, a member of the KV7 channel family, which conducts the M-current. This current is a potent regulator of neuronal excitability by regulating membrane potential in the subthreshold range of action potentials and mediating the medium and slow afterhyperpolarization. Recently, we have identified five loss-of-function variants in KCNQ5 in patients with genetic generalized epilepsy. Using the most severe dominant-negative variant (R359C), we set out to investigate pharmacological therapeutic intervention by KV7 channel openers on channel function and neuronal firing. Retigabine and gabapentin increased R359C-derived M-current amplitudes in HEK cells expressing homomeric or heteromeric mutant KV7.5 channels. Retigabine was most effective in restoring K+ currents. Ten µM retigabine was sufficient to reach the level of WT currents without retigabine, whereas 100 µM of gabapentin showed less than half of this effect and application of 50 µM ZnCl2 only significantly increased M-current amplitude in heteromeric channels. Overexpression of KV7.5-WT potently inhibited neuronal firing by increasing the M-current, whereas R359C overexpression had the opposite effect and additionally decreased the medium afterhyperpolarization current. Both aforementioned drugs and Zn2+ reversed the effect of R359C expression by reducing firing to nearly normal levels at high current injections. Our study shows that a dominant-negative variant with a complete loss-of-function in KV7.5 leads to largely increased neuronal firing which may explain a neuronal hyperexcitability in patients. KV7 channel openers, such as retigabine or gabapentin, could be treatment options for patients currently displaying pharmacoresistant epilepsy and carrying loss-of-function variants in KCNQ5.

A Comprehensive Review of Solriamfetol to Treat Excessive Daytime Sleepiness.

Purpose of Review: This is a comprehensive review of the literature regarding the use of Solriamfetol for excessive daytime sleepiness. It covers the background and current therapeutic approaches to treating excessive daytime sleepiness, the management of common comorbidities, and the existing evidence investigating the use of Solriamfetol for this purpose. Recent Findings: Excessive daytime sleepiness leads to worse quality of life, a medical sequela and significant economic cost. There are multiple phenotypes of excessive daytime sleepiness depending on the comorbidity making treatment challenging. Due to the complexity of etiology there is not a cure for this ailment. Solriamfetol is a norepinephrine/dopamine dual reuptake antagonist that can be used to manage daytime sleepiness. Solriamfetol was first approved by the FDA in 2018 for use in excessive daytime sleepiness associated with obstructive sleep apnea and narcolepsy. Ongoing literature has proved this drug to be a safe and effective alternative pharmacotherapy. Summary: Recent epidemiological data estimate up to one-third of the general adult population suffers from excessive daytime sleepiness. There is no cure to daytime somnolence and current pharmacotherapeutic regimens have worrisome side effect profiles. Solriamfetol is a new class of drug that offers a safe and effective alternative option for clinical providers treating excessive daytime sleepiness.

Comparative analysis of organophosphorus versus carbamate pesticide poisoning: a case study.

Organophosphorus poisoning is a critical condition that can cause central nervous system depression, respiratory failure, and death early on. As its clinical manifestations closely resemble those of carbamate pesticide poisoning, the aim of this case study is to present a case of misdiagnosis, initially identifying carbofuran poisoning as organophosphate in a patient suspect of a heatstroke. We also present a case of intentional self-poisoning with organophosphate dichlorvos to underline the likelihood of pesticide poisoning in patients exhibiting acute cholinergic symptoms when the ingested substance is not known. In such cases, empirical treatment with atropine and oxime can be started pending timely differential diagnosis to adjust treatment as necessary.

Reductions in concomitant antiseizure medication drug load during adjunctive cenobamate therapy: Post-hoc analysis of a subset of patients from a phase 3, multicenter, open-label study.

OBJECTIVE: Many patients with epilepsy require polytherapy, which increases their antiseizure medication (ASM) drug load, a measure that considers the doses of all ASMs a patient is taking. Changes in concomitant ASM drug load after adding cenobamate were evaluated post-hoc in a subset of the open-label, phase 3 study. METHODS: Patients 18-70 years old with uncontrolled focal seizures taking 1-3 ASMs were enrolled. Total concomitant ASM drug load (not including cenobamate) was calculated by dividing the patient's prescribed dose for each ASM by its defined daily dose, per the World Health Organization, then summing the ratios. Changes in concomitant ASM drug load were measured from baseline in 3-month intervals up to 24 months by both total and class-specific ASM drug load. Subgroups of interest included: older adults (65-70 years), prior epilepsy-related surgery vs none, and baseline seizure frequency < 3 vs ≥ 3 seizures/28 days. RESULTS: Data from 240 patients were available (mean age 41.8 years, mean baseline drug load 3.57). Following cenobamate initiation, the mean concomitant ASM drug load was reduced by 29.4 % at Month 12 % and 31.8 % at Month 24. Reductions occurred in all assessed ASM drug classes, with the largest reduction in benzodiazepines (55.2 % at Month 24). Each assessed subgroup exceeded a 30 % reduction in concomitant ASM drug load at Month 24. Over 24 months, maintenance of ≥ 50 % response occurred in 89.3 %, 86.4 %, and 90.6 % of patients with low (-0.25 to <0), moderate (-0.59 to -0.25), or high (-3.3 to -0.59) numerical reductions in concomitant ASM drug load from baseline, respectively, compared with 86.0 % in patients with no change in drug load; maintenance of 100 % response occurred in 80.7 %, 84.3 %, and 70.0 % of patients with low, moderate, or high numerical reductions in concomitant ASM drug load, compared with 82.0 % in patients with no change. CONCLUSIONS: Adding cenobamate led to reduced mean concomitant ASM drug loads during 1 and 2 years of treatment. Reductions occurred regardless of ASM drug class, patient age, or epilepsy disease characteristics and did not impact maintenance of response rates.

Cenobamate in refractory epilepsy: Overview of treatment options and practical considerations.

Management of drug resistant epilepsy (DRE) represents a challenge to the treating clinician. This manuscript addresses DRE and provides an overview of treatment options, medical, surgical, and dietary. It addresses treatment strategies in polytherapy, then focuses on the role cenobamate (CNB) may play in reducing the burden of DRE while providing practical advice for its introduction. CNB is a recently approved, third generation, anti-seizure medication (ASM), a tetrazole-derived carbamate, thought to have a dual mechanism of action, through its effect on sodium channels as well as on GABAA receptors at a non-benzodiazepine site. CNB, having a long half-life, is an effective add-on ASM in refractory focal epilepsy with a higher response rate and a higher seizure-freedom rate than is usually seen in regulatory clinical trials. Experience post-licensing, though still limited, supports the findings of clinical trials and is encouraging. Its spectrum of action in relation to generalized epilepsies and seizures remains to be established, and there are no data on its efficacy in monotherapy. At the time of writing, CNB has been prescribed for some 50 000 individuals with DRE and focal epilepsy. A larger number is needed to fully establish its safety profile. It should at all times be introduced slowly to minimize the risk of serious allergic drug reactions. It has clinically meaningful interactions which must be anticipated and managed to maximize tolerability and likelihood of successful treatment. Despite the above, it may well prove to be of major benefit in the treatment of many patients with drug resistant epilepsy.

Carbamate as a potential anti-Alzheimer's pharmacophore: A review.

Alzheimer's disease (AD) is a progressive age-related neurodegenerative brain disorder, which leads to loss of memory and other cognitive dysfunction. The underlying mechanisms of AD pathogenesis are very complex and still not fully explored. Cholinergic neuronal loss, accumulation of amyloid plaque, metal ions dyshomeostasis, tau hyperphosphorylation, oxidative stress, neuroinflammation, and mitochondrial dysfunction are major hallmarks of AD. The current treatment options for AD are acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and NMDA receptor antagonists (memantine). These FDA-approved drugs mainly provide symptomatic relief without addressing the pathological aspects of disease progression. So, there is an urgent need for novel drug development that not only addresses the basic mechanisms of the disease but also shows the neuroprotective property. Various research groups across the globe are working on the development of multifunctional agents for AD amelioration using different core scaffolds for their design, and carbamate is among them. Rivastigmine was the first carbamate drug investigated for AD management. The carbamate fragment, a core scaffold of rivastigmine, act as a potential inhibitor of acetylcholinesterase. In this review, we summarize the last 10 years of research conducted on the modification of carbamate with different substituents which primarily target ChE inhibition, reduce oxidative stress, and modulate Aß aggregation.

Real-world experience with cenobamate: A systematic review and meta-analysis.

PURPOSE: Despite many new ASM, the rate of patients with drug-resistant epilepsy (DRE) has not changed. Cenobamate (CNB) is a novel ASM for the treatment of focal-onset seizures in adults with high seizure freedom rates in randomized controlled trials (RCT). Although CNB appears to be effective, it is not commonly prescribed to patients with DRE, resulting in a lack of "real-world data". METHODS: To evaluate the real-world effect of CNB and to assess the generalizability of RCT data, a systematic review and meta-analysis was conducted. Pooled proportions were calculated using a random intercept logistic regression model. RESULTS: The analysis included seven studies with a total of 229 patients with DRE, 77.3 % of whom were adults and 91.5 % had focal-onset seizures. Seizure reduction >50 % was achieved in 68 % of patients [54.54; 79.07], with seizure freedom in 16.2 % [8.38; 28.97]. There was no difference between pediatric and adult patients. CNB was discontinued in 10 % [6.74; 14.6] of patients, mostly due to lack of efficacy (39 %) or adverse effects (AE, 43 %). AE, observed in 57.3 % [39.7; 73.2] of patients, included fatigue and vertigo. A comparison of the rates calculated in this meta-analysis to the active arm of equivalent RCTs revealed no significant difference. CONCLUSION: CNB achieves a good treatment response in patients with DRE in real-world settings, like the effect reported in RCTs. The high heterogeneity between studies calls for studies focusing on specific DRE subpopulations.

Cenobamate (YKP3089) and Drug-Resistant Epilepsy: A Review of the Literature.

Cenobamate (CNB), ([(R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl], is a novel tetrazole alkyl carbamate derivative. In November 2019, the Food and Drug Administration approved Xcopri®, marketed by SK Life Science Inc., (Paramus, NJ, USA) for adult focal seizures. The European Medicines Agency approved Ontozry® by Arvelle Therapeutics Netherlands B.V.(Amsterdam, The Neatherlands) in March 2021. Cenobamate is a medication that could potentially change the perspectives regarding the management and prognosis of refractory epilepsy. In this way, this study aims to review the literature on CNB's pharmacological properties, pharmacokinetics, efficacy, and safety. CNB is a highly effective drug in managing focal onset seizures, with more than twenty percent of individuals with drug-resistant epilepsy achieving seizure freedom. This finding is remarkable in the antiseizure medication literature. The mechanism of action of CNB is still poorly understood, but it is associated with transient and persistent sodium currents and GABAergic neurotransmission. In animal studies, CNB showed sustained efficacy and potency in the 6 Hz test regardless of the stimulus intensity. CNB was revealed to be the most cost-effective drug among different third-generation antiseizure medications. Also, CNB could have neuroprotective effects. However, there are still concerns regarding its potential for abuse and suicidality risk, which future studies should clearly assess, after which protocols should be changed. The major drawback of CNB therapy is the slow and complex titration and maintenance phases preventing the wide use of this new agent in clinical practice.

Carbamate JNK3 Inhibitors Show Promise as Effective Treatments for Alzheimer's Disease: In Vivo Studies on Mouse Models.

We have been developing new inhibitors for c-Jun N-terminal kinase 3 (JNK3) as a potential treatment for Alzheimer's disease (AD). We identified potential JNK3 inhibitors through pharmacodynamic optimization studies, including benzimidazole compounds 2 and 3, but their unreliable pharmacokinetic properties led us to develop carbamate inhibitors 2h and 3h. In vitro studies validated carbamate inhibitors 2h and 3h as potent and highly selective JNK3 inhibitors with favorable pharmacokinetic profiles. Oral administration of 2h and 3h to both APP/PS1 and 3xTg AD mouse models improved cognitive function, indicating their potential as effective treatments for Alzheimer's disease. Carbamate JNK3 inhibitor 3h, in particular, restored cognitive function to near-normal levels in the 3xTg mice model of AD and led to pTau reduction in the hippocampal tissues of 3xTg-AD mice during in vivo behavioral evaluations. We intend to further develop these carbamate JNK3 inhibitors in preclinical studies as a potential first-in-class treatment for AD.

Potent dual MAGL/FAAH inhibitor AKU-005 engages endocannabinoids to diminish meningeal nociception implicated in migraine pain.

BACKGROUND: Engaging the endocannabinoid system through inhibition of monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), degrading endocannabinoids (endoCBs) 2-arachidonoylglycerol (2-AG) and anandamide (AEA), was proposed as a promising approach to ameliorate migraine pain. However, the activity of MAGL and FAAH and action of endoCB on spiking activity of meningeal afferents, from which migraine pain originates, has not been explored thus far. Therefore, we here explored the analgesic effects of endoCB enhancement in rat and human meningeal tissues. METHODS: Both MAGL and FAAH activity and local 2-AG and AEA levels were measured by activity-based protein profiling (ABPP) and LC-MS/MS, respectively, in rat meninges obtained from hemiskulls of P38-P40 Wistar rats and human meninges from elderly patients undergoing non-migraine related neurosurgery. The action on endoCBs upon administration of novel dual MAGL/FAAH inhibitor AKU-005 on meningeal afferents excitability was tested by investigating paired KCl-induced spiking and validation with local (co-)application of either AEA or 2-AG. Finally, the specific TRPV1 agonist capsaicin and blocker capsazepine were tested. RESULTS: The basal level of 2-AG exceeded that of AEA in rat and human meninges. KCl-induced depolarization doubled the level of AEA. AKU-005 slightly increased spontaneous spiking activity whereas the dual MAGL/FAAH inhibitor significantly decreased excitation of nerve fibres induced by KCl. Similar inhibitory effects on meningeal afferents were observed with local applications of 2-AG or AEA. The action of AKU-005 was reversed by CB1 antagonist AM-251, implying CB1 receptor involvement in the anti-nociceptive effect. The inhibitory action of AEA was also reversed by AM-251, but not with the TRPV1 antagonist capsazepine. Data cluster analysis revealed that both AKU-005 and AEA largely increased long-term depression-like meningeal spiking activity upon paired KCl-induced spiking. CONCLUSIONS: In the meninges, high anti-nociceptive 2-AG levels can tonically counteract meningeal signalling, whereas AEA can be engaged on demand by local depolarization. AEA-mediated anti-nociceptive effects through CB1 receptors have therapeutic potential. Together with previously detected MAGL activity in trigeminal ganglia, dual MAGL/FAAH inhibitor AKU-005 appears promising as migraine treatment.

Acute Treatment with the M-Channel (Kv7, KCNQ) Opener Retigabine Reduces the Long-Term Effects of Repetitive Blast Traumatic Brain Injuries.

We investigated whether pharmacological increase of "M-type" (KCNQ, Kv7) K + channel currents by the M-channel opener, retigabine (RTG), acutely after repetitive traumatic brain injuries (rTBIs), prevents or reduces their long-term detrimental effects. rTBIs were studied using a blast shock air wave mouse model. Animals were monitored by video and electroencephalogram (EEG) records for nine months after the last injury to assess the occurrence of post-traumatic seizures (PTS), post-traumatic epilepsy (PTE), sleep-wake cycle architecture alterations, and the power of the EEG signals. We evaluated the development of long-term changes in the brain associated with various neurodegenerative diseases in mice by examining transactive response DNA-binding protein 43 (TDP-43) expression and nerve fiber damage ~ 2 years after the rTBIs. We observed acute RTG treatment to reduce the duration of PTS and impair the development of PTE. Acute RTG treatment also prevented post-injury hypersomnia, nerve fiber damage, and cortical TDP-43 accumulation and translocation from the nucleus to the cytoplasm. Mice that developed PTE displayed impaired rapid eye movement (REM) sleep, and there were significant correlations between seizure duration and time spent in the different stages of the sleep-wake cycle. We observed acute RTG treatment to impair injury-induced reduction of age-related increase in gamma frequency power of the EGG, which has been suggested to be necessary for a healthy aged brain. The data show that RTG, administered acutely post-TBI, is a promising, novel therapeutic option to blunt/prevent several long-term effects of rTBIs. Furthermore, our results show a direct relationship between sleep architecture and PTE.

Development of the "hidden" multi-target-directed ligands by AChE/BuChE for the treatment of Alzheimer's disease.

Accumulation of evidences suggested that excessive amounts of AChE and BuChE in the brain of AD patients at the different stage of AD, which could hydrolyze ACh and accelerated Aß aggregation. To develop new "hidden" multifunctional agents through AChE/BuChE would be a promising strategy to treat AD. To this end, firstly, a series of chalcone derivatives with chelating property was designed and synthesized. The in vitro results showed that compound 3f indicated significant selective MAO-B inhibitory activity (IC50 = 0.67 µM) and remarkable anti-inflammatory property. It also significantly inhibited self-induced Aß1-42 aggregation and showed remarkable neuroprotective effects on Aß25-35-induced PC12 cell injury. Furthermore, compound 3f was a selective metal chelator and could inhibit Cu2+-induced Aß1-42 aggregation. Based on this, the carbamate fragment was introduced to compound 3f to obtain carbamate derivatives. The biological activity results exhibited that compound 4b showed good BBB permeability, good AChE inhibitory potency (IC50 = 5.3 µM), moderate BuChE inhibitory potency (IC50 = 12.4 µM), significant MAO-B inhibitory potency, anti-inflammation potency on LPS-induced BV-2 cells and neuroprotective effects on Aß25-35-induced PC12 cell injury. Compared with 3f, compound 4b did not show obvious chelation property. Significantly, compound 4b could be activated by AChE/BuChE following inhibition of AChE/BuChE to liberate an active multifunctional chelator 3f, which was consistent with our original intention. More importantly, compounds 3f and 4b presented favorable ADME properties and good stability in artificial gastrointestinal fluid, blood plasma and rat liver microsomes. The in vivo results suggested that compound 4b (0.0195 µg/mL) could significantly improve dyskinesia and reaction capacity of the AlCl3-induced zebrafish AD model by increasing the level of ACh. Together our data suggest that compound 4b was a promising "hidden" multifunctional agent by AChE/BuChE, and this strategy deserved further development for the treatment of AD.

A retrospective non-interventional study evaluating the pharmacokinetic interactions between cenobamate and clobazam.

Cenobamate is an antiseizure medication (ASM) approved for the treatment of partial-onset seizures in adults. As both an inductor and an inhibitor of hepatic enzymes, cenobamate affects the metabolism of other ASMs, among which is clobazam. To our knowledge, the extent of interaction between cenobamate and clobazam and its clinical significance have not been studied yet. In this retrospective study we assessed serum concentrations of clobazam and N-desmethylclobazam (NCLB)in five patients before and after co-medication with cenobamate and calculated the percentage increase in concentration-to-dose ratio (CDR) of both. We were able to demonstrate that the addition of cenobamate resulted in an increase in serum concentration and consequently in CDR of NCLB in all patients. However this occurred in variable degrees: NCLB concentration showed an increase of 1208 µg/L (CDR145%) in one patient and between 1691 µ/L (CDR 819%) and 3995 µ/L (CDR 1852%) in the other four. This resulted in fatigue, which improved after dose reduction of CLB. Therefore, it is to be concluded that concomitant administration of cenobamate and clobazam can lead to a substantial increase in serum concentrations of NCLB. This can have a positive therapeutic effect on one hand; however, on the other hand, this can lead to unwanted fatigue.

Retigabine suppresses loss of force in mouse models of hypokalaemic periodic paralysis.

Recurrent episodes of weakness in periodic paralysis are caused by intermittent loss of muscle fibre excitability, as a consequence of sustained depolarization of the resting potential. Repolarization is favoured by increasing the fibre permeability to potassium. Based on this principle, we tested the efficacy of retigabine, a potassium channel opener, to suppress the loss of force induced by a low-K+ challenge in hypokalaemic periodic paralysis (HypoPP). Retigabine can prevent the episodic loss of force in HypoPP. Knock-in mutant mouse models of HypoPP (Cacna1s p.R528H and Scn4a p.R669H) were used to determine whether pre-treatment with retigabine prevented the loss of force, or post-treatment hastened recovery of force for a low-K+ challenge in an ex vivo contraction assay. Retigabine completely prevents the loss of force induced by a 2 mM K+ challenge (protection) in our mouse models of HypoPP, with 50% inhibitory concentrations of 0.8 ± 0.13 µM and 2.2 ± 0.42 µM for NaV1.4-R669H and CaV1.1-R528H, respectively. In comparison, the effective concentration for the KATP channel opener pinacidil was 10-fold higher. Application of retigabine also reversed the loss of force (rescue) for HypoPP muscle maintained in 2 mM K+. Our findings show that retigabine, a selective agonist of the KV7 family of potassium channels, is effective for the prevention of low-K+ induced attacks of weakness and to enhance recovery from an ongoing loss of force in mouse models of type 1 (Cacna1s) and type 2 (Scn4a) HypoPP. Substantial protection from the loss of force occurred in the low micromolar range, well within the therapeutic window for retigabine.

Prevalence of Hepatitis C Virus Infection and Efficacy of Sofosbuvir-Velpatasvir and Sofosbuvir-Daclatasvir Treatment Regimens in End-stage Renal Disease Patients on Maintenance Hemodialysis.

Patients with end-stage renal disease (ESRD) are at an increased risk of hepatitis C virus (HCV) infection. This study evaluated the prevalence of HCV infection in patients with ESRD on maintenance hemodialysis (MHD) and studied the effectiveness of sofosbuvir-velpatasvir and sofosbuvir-daclatasvir regimens in these patients. This study included patients with ESRD on MHD between January 2019 and December 2021 who were screened for HCV serology status. HCV-positive patients received sofosbuvir-velpatasvir or sofosbuvir-daclatasvir. Efficacy was assessed by the sustained virological response (SVR), and safety assessments included monitoring adverse events and laboratory parameters. Out of 1330 patients, 188 patients (14.1%) were positive for anti-HCV, with Genotype 1 being the most common genotype. Of these, 106 patients were included. The majority were males (61.3%), and the mean age was 48.4 years. Hypertension (45.3%) was the most common cause of renal failure, followed by diabetes (31.1%). Most patients (63.2%) were positive for HCV in the first 2 years of their dialysis treatment. Out of 106 patients, only 54 had received blood transfusions. Ninety-four (88.7%) patients received sofosbuvir-velpatasvir, whereas 12 (11.3%) received sofosbuvir-daclatasvir. SVR at 12 and 24 weeks after stopping treatment was seen in all (100%) patients. Asthenia and fatigue were the most common adverse events (11.2%). No patients reported on-treatment virologic failure or discontinuation of treatment because of adverse events. The prevalence of HCV infection in this population was 14.1%, and treatment of HCV infection using sofosbuvir-velpatasvir or sofosbuvir-daclatasvir regimens was well tolerated and effective.

Development and Validation of a UHPLC-MS/MS-Based Method to Quantify Cenobamate in Human Plasma Samples.

Cenobamate (CNB) is the newest antiseizure medication (ASM) approved by the FDA in 2019 to reduce uncontrolled partial-onset seizures in adult patients. Marketed as Xcopri in the USA or Ontozry in the EU (tablets), its mechanism of action has not been fully understood yet; however, it is known that it inhibits voltage-gated sodium channels and positively modulates the aminobutyric acid (GABA) ion channel. CNB shows 88% of oral bioavailability and is responsible for modifying the plasma concentrations of other co-administered ASMs, such as lamotrigine, carbamazepine, phenytoin, phenobarbital and the active metabolite of clobazam. It also interferes with CYP2B6 and CYP3A substrates. Nowadays, few methods are reported in the literature to quantify CNB in human plasma. The aim of this study was to develop and validate, according to the most recent guidelines, an analytical method using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) to evaluate CNB dosage in plasma samples. Furthermore, we provided a preliminary clinical application of our methodology by evaluating the pharmacokinetic parameters of CNB in two non-adult patients. Plasma levels were monitored for two months. Preliminary data showed a linear increase in plasma CNB concentrations, in both patients, in agreement with the increase in CNB dosage. A seizure-free state was reported for both patients at the dose of 150 mg per day.