2-(3-Indolyl)acetamides and their oxazoline analogues: Anticancer SAR study.

We previously studied 2-aryl-2-(3-indolyl)acetohydroxamates as potential agents against melanoma. These compounds were ineffective in a mouse melanoma xenograft model, most likely due to unfavorable metabolic properties, specifically due to glucuronidation of the N-hydroxyl of the hydoxamic moiety. In the present work, we prepared a series of analogues, 2-aryl-2-(3-indolyl)acetamides and their oxazoline derivatives, which do not contain the N-hydroxyl group. We investigated the structure-activity relationship in both series of compounds and found that the 2-naphthyl is a preferred group at C-2 of the indole in the amide series, whereas the tetralin moiety is favorable in the same location in the oxazoline series. Overall, three compounds in the amide series have GI50 values as low as 0.2-0.3 µM and the results clearly indicate that the N-hydroxyl group is not necessary for high potency in vitro.

Repurposed drug agomelatine is therapeutic against collagen-induced arthritis via iNOS targeting.

BACKGROUND: The most promising biologics tumor necrosis factor α (TNFα) inhibitors are effective in treating rheumatoid arthritis (RA) in only 50-70 % of the cases; thus, new drugs targeting TNFα-mediated inflammation are required. METHODS: Firstly, the drugs that could inhibit FLS proliferation and TNFα induced inflammatory cytokine production were screened. Secondly, treatment effects of the identified drugs were screened in collagen-induced arthritis (CIA) mouse model. Thirdly, the inhibitory effect of the identified drug, agomelatine (AOM), on TNFα induced inflammatory cytokine production and NF-κB activity were confirmed. Fourthly, bioinformatics was applied to predict the binding target of AOM and the binding was confirmed, and the already known inhibitor of target was used to test the treatment effect for CIA mouse model. Finally, the effect of AOM on signaling pathway was tested and on TNFα induced inflammatory cytokine production was observed after inhibiting the target. RESULTS: AOM effectively inhibited TNFα-induced NF-κB activation, NF-κB p65 translocation, and inflammatory cytokines production in vitro and was therapeutic against CIA. The mechanistic study indicated inducible nitric oxide synthase (iNOS) as the binding target of AOM. 1400 W, a known inhibitor of iNOS, could effectively treat CIA by decreasing iNOS activity and the levels of inflammatory cytokines. The inhibitory effect of AOM on TNFα-induced inflammation was further elucidated by 1400 W, or NF-κB p65 inhibitor JSH-23, indicating that AOM is therapeutic against CIA via iNOS/ERK/p65 signaling pathway after binding with iNOS. CONCLUSIONS: AOM is therapeutic against CIA via inhibition of the iNOS/ERK/p65 signaling pathway after binding with iNOS.

The effectiveness of agomelatine on headache severity and frequency in episodic migraine without aura; a parallel randomized controlled trial study.

BACKGROUND: Migraine is a headache disorder that affects public health and reduces the patient's quality of life. Preventive medication is necessary to prevent acute attacks and medication overuse headaches (MOH). Agomelatine is a melatonin antagonist. AIMS: This study aimed to determine the effectiveness of agomelatine on the severity and frequency of migraine attacks. METHODS: The study is a parallel randomized controlled trial with two groups of intervention and control. 400 patients were evaluated. Eligible individuals, including those with episodic migraine headaches without aura between the ages of 18 and 60 years who did not receive preventive treatment beforehand, were enrolled. Also, patients did not receive any specific medications for other diseases. Among these, 100 people met the inclusion criteria and entered the study. These subjects were randomly assigned to one of the two groups. The intervention group received 25 mg of agomelatine daily and the control group received B1. In this study, the effect of agomelatine on the frequency and severity of attacks, mean monthly migraine days (MMD), and migraine disability assessment (MIDAS), were assessed. The study was triple-blind and after three months, a post-test was performed. Data were analyzed using SPSS software. RESULTS: A total of 100 patients were randomly assigned to either intervention or control groups. The prescriber physician and the data collector did not know about the allocation of patients to groups. Before the intervention, there was no significant difference in the headache frequency per month (t=-0.182, df = 98, p = 0.85), mean MMD (p = 0.17), headache severity (p = 0.076), and MIDAS (p = 0.091). After the study, there was a significant difference between the two groups in terms of the headache frequency per month (p = 0.009), and mean of MMD (p = 0.025). There was also a significant difference between pretest and posttest in two groups in the headache severity (p < 0.001) and MIDAS (p < 0.001). CONCLUSION: Agomelatine can be used as a preventive medication for migraine without aura. It is suggested that agomelatine be studied in comparison with other preventive drugs for patients with migraine. TRIAL RETROSPECTIVELY REGISTRATION: Trial Retrospectively registration= IRCT20230303057599N1. Date: 2023-5-24 The present study is a residency thesis approved by the Tehran University of Medical Sciences.

Potential biomarkers and therapeutic targets for obsessive compulsive disorder: Evidences from clinical studies.

Obsessive compulsive disorder (OCD) is a prevalent behavioral disorder with a complex etiology. However, the underlying pathogenic molecular pathways and the associated risk factors are largely obscure. This has hindered both the identification of relevant prognostic biomarkers and the development of effective treatment strategies. Because of the diverse range of clinical manifestations, not all patients benefit from therapies currently practiced in the clinical setting. Nevertheless, several lines of evidence indicate that neurotrophic, neurotransmitter, and oxidative signaling are involved in the pathophysiology of OCD. Based upon evidences from clinical (and pre-clinical studies), the present review paper sets out to decipher the utilities of three parameters (i.e. brain-derived neurotrophic factor; BDNF, noradrenalin-synthesizing enzyme dopamine beta-hydroxylase; DBH; and oxidative damage marker malondialdehyde; MDA) as diagnostic peripheral biomarkers as well as bio-targets for therapeutic strategies. While the data indicates promising results, there is necessitation for future studies to further confirm and establish these. Further, based again on the available clinical data, we investigated the possibilities of exploiting the etiological links between disruptions in the sleep-wake cycle and insulin signaling, and OCD for the identification of potential anti-OCD ameliorative agents with the ability to elicit multimodal effects, including attenuation of the alterations in BDNF, noradrenergic and redox pathways. In this respect, agomelatine and metformin may represent particularly interesting candidates; however, further clinical studies are warranted to establish these as singular or complementary medications in OCD subjects.

Use of sertraline and agomelatine in hemodialysis patients: A case series report.

OBJECTIVE: Major depressive disorder (MDD) is one of the most common psychiatric issues in hemodialysis population. However, the research on proper diagnostic tools and its treatment is still insufficient. The study was performed to investigate the safety and effectiveness of sertraline and agomelatine in a group of hemodialysis patients. PATIENTS AND METHODS: 78 adult patients from one dialysis centre in Poland were included into the study. The Beck Depression Inventory II (BDI-II) was used to screen for depressive symptoms and was followed by the clinical interview with the psychiatrist. Nine patients diagnosed with major depressive disorder received antidepressant treatment with sertraline or agomelatine, according to the best clinical practice. The additional treatment with vortioxetine was used if the initial one was not effective. The time of observation was 24 weeks. The psychiatric follow up as well as the laboratory data were obtained during the course of observation. RESULTS: All patients receiving sertraline achieved remission of depressive symptoms. In patients receiving agomelatine no remission was observed despite dose augmentation. The side effects of antidepressants were mild and did not result in treatment discontinuation. No abnormalities in liver enzymes levels were observed. In five cases the significant decrease of haemoglobin level was noticed, with no cases of bleeding reported. CONCLUSION: In patients receiving sertraline the antidepressant effect was satisfactory. No remission of depressive symptoms was observed in patients taking agomelatine. The side effects of antidepressants were mild and transient. Further research on depression treatment in hemodialysis patients is needed, including newer medications.

Prolonged use of linezolid in bone and joint infections: a retrospective analysis of adverse effects.

OBJECTIVES: Antibiotic treatment for bone and joint infections generally lasts for 6 weeks or longer. Linezolid may be a good option for treating bone and joint infections, but there is an increased risk of potential serious adverse drug events (ADEs) when used for more than 28 days. The aim of this study was to obtain detailed information on the type and time to occurrence of the patient-reported ADEs, the dynamics of haematopoiesis over time, and the reasons for early discontinuation of linezolid when used for an intended maximum duration of 12 weeks. METHODS: This single-centre retrospective study was conducted at the Sint Maartenskliniek in The Netherlands. Patients were included if they were planned to use linezolid for more than 28 days. The main reason for discontinuation of linezolid, the ADE according to the Naranjo score, and the time to occurrence of ADEs were analysed. RESULTS: Among 78 patients, drug toxicity led to early discontinuation of linezolid in 11 (14%) patients before and nine (12%) after 28 days of therapy. The median treatment duration was 42 days. Gastrointestinal intolerance (42%) and malaise (32%) were the most common ADEs. In 75% of the cases the ADE occurred within 28 days of therapy. Sixty-seven patients were able to continue linezolid beyond 28 days, 87% of whom completed therapy as scheduled. Severe cytopenia, according to the Common Terminology Criteria for Adverse events (CTCA), was observed in four patients and was reversible after discontinuation of linezolid. One patient suffered optic neuropathy related to linezolid use. CONCLUSIONS: Linezolid could be considered an alternative option to the current standard of IV glycopeptides for the treatment of bone and joint infection for up to 12 weeks. If patients pass the first 28 days of therapy, the likelihood of successful completion of therapy is high with a low risk of serious ADEs.

Agomelatine on cisplatin-induced nephrotoxicity via oxidative stress and apoptosis.

Drug-induced nephrotoxicity is the greatest deterrent to the use of cisplatin, which is a frequently used chemotherapeutic with proven effectiveness in cancer therapy. Agomelatine, which is used in the treatment of sleep disorders and depression, has gained attention in recent years with its antioxidative and anti-inflammatory effects. In this study, the effects of the synthetic melatonin agonist agomelatine on nephrotoxicity were investigated in a rat model of cisplatin-induced nephrotoxicity using biochemical, histological, and immunohistochemical methods. Thirty-two male rats were divided into 4 groups: 1. control group, 2. agomelatine group, 3. cisplatin group, 4. cisplatin + agomelatine group. In the cisplatin group, there were widespread atypical glomerular structures and vacuolization in tubular epithelial cells, necrotic tubules, deterioration of brush border structure in proximal tubules, and fibrotic areas characterized by diffuse polymorphonuclear leukocyte (PNL) and extensive collagen deposition in the interstitial spaces. However, in the cisplatin + agomelatine group, we observed a reduction in glomeruli of atypical structure and necrotic tubules, in PNL infiltration in interstitial spaces, and fibrotic areas compared to the cisplatin group. The cisplatin + agomelatine group showed lower malondialdehyde (MDA) serum creatinine, serum urea levels, and higher glutathione (GSH) levels compared to the cisplatin group. Immunohistochemical analyses revealed that the elevated NF-kß/p65, 8-OHdG, and cleaved caspase-3 positivity in the cisplatin group had significantly decreased in the cisplatin + agomelatine group. In conclusion, agomelatine showed a nephroprotective effect against cisplatin-induced nephrotoxicity.

Discovery, SAR and mechanistic studies of quinazolinone-based acetamide derivatives in experimental visceral leishmaniasis.

Towards identification of novel therapeutic candidates, a series of quinazolinone-based acetamide derivatives were synthesized and assessed for their anti-leishmanial efficacy. Amongst synthesized derivatives, compounds F12, F27 and F30 demonstrated remarkable activity towards intracellular L. donovani amastigotes in vitro, with IC50 values of 5.76 ± 0.84 µM, 3.39 ± 0.85 µM and 8.26 ± 1.23 µM against promastigotes, and 6.02 µM ± 0.52, 3.55 ± 0.22 µM and 6.23 ± 0.13 µM against amastigotes, respectively. Oral administration of compounds F12 and F27 entailed >85% reduction in organ parasite burden in L. donovani-infected BALB/c mice and hamsters, by promoting host-protective Th1 cytokine response. In host J774 macrophages, mechanistic studies revealed inhibition of PI3K/Akt/CREB axis, resulting in a decrease of IL-10 versus IL-12 release upon F27 treatment. In silico docking studies conducted with lead compound, F27 demonstrated plausible inhibition of Leishmania prolyl-tRNA synthetase, which was validated via detection of decreased proline levels in parasites and induction of amino acid starvation, leading to G1 cell cycle arrest and autophagy-mediated programmed cell death of L. donovani promastigotes. Structure-activity analysis and study of pharmacokinetic and physicochemical parameters suggest oral availability and underscore F27 as a promising lead for anti-leishmanial drug development.

Effect of different doses of almorexant on learning and memory in 8-month-old APP/PS1 (AD) mice.

OBJECTIVE: To explore the effects of different doses of almorexant (an dual orexin receptor antagonist) on learning and memory in Alzheimer's disease (AD) mice. METHODS: Forty-four APP/PS1 (model of Alzheimer's disease; AD) mice were randomly divided into 4 groups: the control group (CON) and those that received 10 mg/kg almorexant (low dose; LOW), 30 mg/kg almorexant (medium dose; MED) and 60 mg/kg almorexant (high dose; HIGH). During the 28-day intervention period, mice received an intraperitoneal injection at the beginning of the light period (6:00 am). The effects of different doses of almorexant on learning and memory and 24-hour sleep-wake behaviour were assessed by immunohistochemical staining. The above continuous variables are expressed as the mean ± standard deviation (SD), and then univariate regression analysis and generalized estimating equations were performed to compare the groups; these results are expressed as the mean difference (MD) and 95% confidence interval (CI). The statistical software used STATA 17.0 MP. RESULTS: Forty-one mice completed the experiment (3 died: 2 mice in the HIGH group and 1 mouse in the CON group). Compared with the CON group, the LOW group (MD=6803 s, 95% CI: 4470 to 9137 s), MED group (MD=14,473 s, 95% CI: 12,140-16,806 s) and the HIGH group (MD=24,505 s, 95% CI: 22,052-26,959 s) had significantly longer sleep durations. The Y maze results showed that LOW group (MD=0.14,95%CI: 0.078-0.20) and MED group (MD=0.14,95%CI = 0.074-0.20) mice compared to the CON group, and the low-medium dose of Almorexant did not damage the short-term learning and memory performance of APP / PS1 (AD) mice.Compared with the CON, LOW, and MED groups, the HIGH group exhibited a significant decrease in the Aß plaque-positive area in the cortex (MD= -0.030, 95% CI: -0.035 to -0.025; MD=-0.049, 95% CI: -0.054 to -0.044; and MD=-0.07, 95% CI: -0.076 to -0.066, respectively). CONCLUSION: The moderate dose of almorexant (30 mg/kg) prolonged the sleep duration of APP/PS1 (AD) mice to a greater extent than the low dose (10 mg/kg) without altering learning and memory. The MED mice showed a good sleep response and a small residual effect on the next day. High-dose (60 mg / kg) almorexant impaired behavioral learning and memory performance in mice.Compared to the CON group and the LOW group, the MED group exhibited improved working memory. Thus, treatment with almorexant may reduce ß-amyloid deposition in AD, slowing neurodegeneration. Additional studies are needed to determine the mechanism of action.

Quantum evaluation and therapeutic activity of (E)-N-(4-methoxyphenyl)-2-(4-(3-oxo-3-phenylprop-1-en-1-yl) phenoxy)acetamide and its modified derivatives against EGFR and VEGFR-2 in the treatment of triple-negative cancer via in silico approach.

The most dangerous subtype of breast cancer, triple-negative breast cancer (TNBC), accounts for 25% of all breast cancer-related deaths and 15% of all breast cancer cases. TNBC is distinguished by the lack of immunohistochemical expression of HER2, progesterone receptors, or oestrogen receptors. Although it has been reported that upregulation of EGFR and VEGFR-2 is associated with TNBC progression, no proven effective targeted therapy exists at this time. We used structural bioinformatics methods, including density functional theory, molecular docking, molecular dynamic simulation, pharmacokinetic and drug-likeness models, to identify promising EGFR/VEGFR-2 inhibitors from N-(4-methoxyphenyl)-2-[4-(3-oxo-3-phenylprop-1-en-1-yl) phenoxy] acetamide and six of its modified derivatives in light of the lack of effective targets inhibitor Version 14 of Spartan software was used to analyse density functional theory. The Schrodinger software suite 2018's Maestro interface was used for the molecular docking analysis, and the admetSAR and swissADME servers were used for drug-likeness and absorption, distribution, metabolism, excretion, and toxicity. All of the compounds showed strong electronic characteristics. Additionally, all of the tested compounds met the ADMET and drug-likeness requirements without a single instance of Lipinski's rule of five violations. Additionally, the molecules' levels of affinity for the target proteins varied. The highest binding affinities were demonstrated by the MOLb-VEGFR-2 complex (- 9.925 kcal/mol) and the MOLg-EGFR complex (- 5.032 kcal/mol). The interaction of the molecules in the domain of the EGFR and VEGFR-2 receptors was also better understood through molecular dynamic simulation of the complex.

Synthesis and biological evaluation of substituted acetamide derivatives as potential butyrylcholinestrase inhibitors.

Alzheimer's disease (AD) is the most common type of age-related dementia. Inhibition of butyrylcholinesterase (BChE) emerge as an effective therapeutic target for AD. A series of new substituted acetamide derivatives were designed, synthesized and evaluated for their ability to inhibit BChE. The bioassay results revealed that several compounds displayed attractive inhibition against BChE). Among them, compound 8c exhibited the highest BChE inhibition with IC50 values of 3.94 µM. Lineweaver Burk plot indicated that 8c acted as a mixed-type BChE inhibitor. In addition, docking studies confirmed the results obtained through in vitro experiments, and showed that 8c bound to the catalytic anionic site (CAS) and peripheral anionic site (PAS) of BChE active site. Meanwhile, its ADME parameters were approximated using in silico method. Molecular dynamics simulation studies on the complex of 8c-BChE were performed, RMSD, RMSF, Rg, SASA, and the number of hydrogen bonds were calculated as well. These results implied that 8c could serve as appropriate lead molecule for the development of BChE inhibitor.

Evaluating the Effects of Agomelatine on Polysomnography Parameters in Patients with Obstructive Sleep Apnea.

PURPOSE: Obstructive sleep apnea (OSA) is a common serious sleep disorder. Melatonin-based drugs such as agomelatine may have beneficial effects on patients with sleep disorders. This study aimed to evaluate agomelatine effects on polysomnography parameters in patients with OSA. METHODS: In this randomized, parallel, and single-blind study, seventy patients 18 years of age or older with obstructive sleep apnea who were referred to the sleep clinic were evaluated. The patients were randomly assigned into agomelatine and control groups. Patients in the agomelatine group received 50 mg agomelatine, one hour before sleep, for three consecutive nights prior to the polysomnography test, while the patients in the control group did not receive agomelatine. Sleep test parameters were compared between the two groups. RESULTS: Three parameters in the agomelatine versus control group showed significant differences. They were the median and interquartile range of the total sleep time, 397 [326.5-437.4] vs. 287.5 [184-393.1; p, 0.004] minuets, sleep efficiency percentage, 75.6 [71-87.4] vs. 65.1 [50.8-80.1; p, 0.005] and the wakening percentage, 7.5 [12.01-27.6] vs. 8.8[18.3-49; p, 0.004] agomelatine vs. control group. Other polysomnography parameters revealed no significant differences between the two groups. CONCLUSIONS: Agomelatine administration in patients with OSA may improve total sleep time, sleep efficiency percentage and the percentage of patients' awakening.

The effect of lacosamide monotherapy on sleep architecture in patients with epilepsy: a preliminary evidence.

Lacosamide (LCM) is a third-generation antiseizure medication (ASM), and its effect on sleep architecture was supported by a few studies in patients with drug-resistant epilepsy in which LCM was used as an add-on treatment. To gather knowledge on ASMs effects on sleep, this study aimed at evaluating the effects of LCM monotherapy on sleep in patients with focal epilepsy. Ten patients diagnosed with epilepsy (mean age 58.00 ± 14.77, 60.0% female, mean monthly seizure frequency 1.20 ± 2.48) starting LCM as monotherapy were included. Sleep architecture was assessed through polysomnography at baseline and at the 6-month follow-up visit. A significant decrease was observed in seizure frequency (p = 0.004), being all patients seizure-free at follow-up. At baseline, eight patients had poor sleep efficiency (< 85%). Sleep efficiency increased at follow-up, with only three patients having an index < 85% (p = 0.022). From baseline to follow-up, a significant decrease was observed in sleep latency (p = 0.022) and wakefulness after sleep onset (p = 0.047). Moreover, a significant decrease was observed in the percentage of stage 1 (Md = 6.70 vs Md = 3.85, p = 0.005) and stage 3 (Md = 27.70 vs Md = 22.35, p = 0.01) of Non-REM sleep. This study suggests that LCM monotherapy may positively impact sleep architecture in patients with epilepsy. The sleep efficiency improvement and the decrease of sleep latency and wakefulness after sleep onset observed at follow-up highlight better sleep stability and continuity in patients treated with LCM. Notably, all patients were seizure-free at follow-up, and seizure freedom may also concur to sleep structure improvement.

Vortioxetine in patients with major depressive disorder and high levels of anxiety symptoms: An updated analysis of efficacy and tolerability.

BACKGROUND: Patients with major depressive disorder (MDD) often experience comorbid anxiety symptoms. Vortioxetine has demonstrated efficacy in treating anxiety symptoms in patients with MDD; however, efficacy and tolerability have not been assessed across the entire approved dosage range. METHODS: The efficacy and tolerability of vortioxetine 5-20 mg/day were assessed in patients with MDD and high levels of anxiety symptoms (Hamilton Anxiety Rating Scale [HAM-A] total score ≥ 20) using pooled data from four randomized, fixed-dose, placebo-controlled studies (n = 842). Data from a randomized, double-blind study of vortioxetine 10-20 mg/day versus agomelatine 25-50 mg/day in patients with an inadequate response to prior therapy (n = 299) were analyzed separately. Mean changes from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS), HAM-A, and Sheehan Disability Scale (SDS) total scores were analyzed by vortioxetine dosage. RESULTS: The pooled analysis of fixed-dose studies demonstrated a clear dose-response relationship for vortioxetine 5-20 mg/day for improvements in MADRS, HAM-A, and SDS total scores. Vortioxetine 20 mg/day demonstrated significant effects versus placebo from week 4 onwards. In the post-hoc analysis of the active-controlled study in patients with an inadequate response to prior therapy, vortioxetine 10-20 mg/day was superior to agomelatine across all outcome measures from week 4 onwards. Up-titration of vortioxetine to 20 mg/day was not associated with an increase in adverse events. LIMITATIONS: Short-term trials. CONCLUSIONS: Vortioxetine is efficacious and well tolerated in patients with MDD and high levels of anxiety symptoms, including those with an inadequate response to prior therapy. The greatest therapeutic benefits were observed with vortioxetine 20 mg/day. TRIAL REGISTRATION: NCT01140906, NCT01153009, NCT01163266, NCT01255787, NCT01488071.

Structural Determinants of Indole-2-carboxamides: Identification of Lead Acetamides with Pan Antimycobacterial Activity.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), is one of the leading causes of death in developing countries. Non-tuberculous mycobacteria (NTM) infections are rising and prey upon patients with structural lung diseases such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis. All mycobacterial infections require lengthy treatment regimens with undesirable side effects. Therefore, new antimycobacterial compounds with novel mechanisms of action are urgently needed. Published indole-2-carboxamides (IC) with suggested inhibition of the essential transporter MmpL3 showed good potency against whole-cell M.tb, yet had poor aqueous solubility. This project focused on retaining the required MmpL3 inhibitory pharmacophore and increasing the molecular heteroatom percentage by reducing lipophilic atoms. We evaluated pyrrole, mandelic acid, imidazole, and acetamide functional groups coupled to lipophilic head groups, where lead acetamide-based compounds maintained high potency against mycobacterial pathogens, had improved in vitro ADME profiles over their indole-2-carboxamide analogs, were non-cytotoxic, and were determined to be MmpL3 inhibitors.

Therapeutic Drug Monitoring of Lacosamide in Chinese Pediatric Patients with Epilepsy: Efficacy and Factors Influencing the Plasma Concentration.

BACKGROUND AND OBJECTIVE: The impact of individual patient variables on drug metabolism is particularly important for antiseizure medication, and lacosamide has not been studied in Chinese pediatric patients with epilepsy. This study evaluated the effects of dose, age, sex, medication time, seizure type, and concomitant enzyme-inducing antiseizure medications (EIASMs) on the plasma concentration of lacosamide. METHODS: A total of 500 pediatric patients from two hospitals in China were enrolled in this study. Lacosamide plasma concentration was processed using an ultra-performance liquid chromatography assay. Efficacy was evaluated based on the four-grade therapeutic effect criteria developed by the first National Epilepsy Academic Conference of the Chinese Medical Association. RESULTS: The responder rate to lacosamide therapy was 72.2% (361/500). There was a weaker relationship between the lacosamide daily dose and lacosamide plasma concentration (r = 0.238). Lacosamide plasma concentrations of patients ranged from 1.5 to 19.7 µg/mL, with a mean of 6.9 ± 3.2 µg/mL. The study results showed a significant contribution of age, body mass index, epilepsy duration, medication time, and EIASMs to the lacosamide plasma concentration (p < 0.05). Patients taking concomitant EIASMs with lacosamide had a significantly lower mean lacosamide plasma concentration (5.9 ± 2.6 µg/mL) than patients taking concomitant non-EIASMs (7.5 ± 3.5 µg/mL, p < 0.001). CONCLUSION: To ensure the clinical efficacy and safety of lacosamide therapy in pediatric patients, it is necessary to monitor the plasma concentration.

Selexipag in Patients With Pulmonary Hypertension: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Despite the availability of treatments for all subgroups of pulmonary hypertension (PH), the prognosis for PH remains poor. This systematic review and meta-analysis aimed to determine the efficacy and safety of selexipag in patients with PH. A systematic search was made of PubMed, Embase, Cochrane Library, and clinicaltrials.gov, without language restrictions. Randomized controlled trials (RCTs) on treatment of PH with selexipag, compared with placebo or blank, were reviewed. Studies were pooled to weighted mean differences (WMDs) and risk ratios (RRs), with 95% confidence intervals (CIs). Selexipag was safe and significantly improved hospitalization for worsening of PH, WHO FC, mPAP, NT-proBNP, and cardiac index in patients with PH. Selexipag should be considered in patients with pulmonary arterial hypertension or chronic thromboembolic PH.

Synthesis and biological evaluation of N-(benzene sulfonyl)acetamide derivatives as anti-inflammatory and analgesic agents with COX-2/5-LOX/TRPV1 multifunctional inhibitory activity.

In this study, a series of structurally novel N-(benzene sulfonyl) acetamide derivatives were designed, synthesized, and biologically evaluated as COX-2/5-LOX/TRPV1 multitarget inhibitors for anti-inflammatory and analgesic therapy. Among them, 9a and 9b displayed favorable COX-2 (9a IC50 = 0.011 µM, 9b IC50 = 0.023 µM), 5-LOX (9a IC50 = 0.046 µM, 9b IC50 = 0.31 µM) and TRPV1 (9a IC50 = 0.008 µM, 9b IC50 = 0.14 µM) inhibitory activities. The pharmacokinetic (PK) study of 9a in SD rats at the dosage of 10 mg/kg demonstrated a high oral exposure, an acceptable clearance and a favorable bioavailability (Cmax = 5807.18 ± 2657.83 ng/mL, CL = 3.24 ± 1.47 mL/min/kg, F = 96.8 %). Further in vivo efficacy studies illustrated that 9a was capable of ameliorating formalin-induced pain and inhibiting capsaicin-induced ear edema.

Use of lacosamide in children: experience of a tertiary medical care center in Brazil.

BACKGROUND: Lacosamide (LCM) is a third-generation anti-seizure drug approved in Europe and the United States, either as a monotherapy or adjunctive therapy, to treat partial-onset seizures in adults, adolescents, and children. In Brazil, LCM is licensed for treatment only in patients older than 16 years of age. OBJECTIVE: To evaluate a cohort of children presenting with refractory epilepsy who received LCM as an add-on therapy and observe the response and tolerability to the LCM treatment. METHODS: A retrospective cohort study conducted in a tertiary health care facility, which included 26 children, aged up to 16 years, who presented with refractory epilepsy and received LCM as an add-on treatment. The follow-up visits were scheduled every 3 months until 9 months of treatment with LCM. RESULTS: After 3 months of LCM administration, in 73.1% of the children, there was a reduction of > 50% in the frequency of seizures, and this clinical improvement was maintained in most patients (73.9%) for the following 9 months. Mild (such as, somnolence and behavioral changes) or severe (seizure worsening) adverse effects were observed in two and three children respectively. Among responders to LCM, there was a higher prevalence of males, fewer concomitant anti-seizure drugs, and lower percentage of patients using sodium channel blockers. CONCLUSIONS: Lacosamide should be considered as an early treatment option in pediatric patients with refractory epilepsy, mainly focal seizures.

ANTECEDENTES: Lacosamida (LCM) é um fármaco anticrise de terceira geração aprovado na Europa e nos Estados Unidos, utilizado como monoterapia ou terapia adjuvante para tratar crises epilépticas focais em adultos, adolescentes e crianças. No Brasil, a LCM só é aprovada para tratamento em pacientes com mais de 16 anos de idade. OBJETIVO: Avaliar uma coorte de crianças com epilepsia refratária que receberam LCM como terapia adjuvante e observar a resposta e tolerabilidade ao tratamento. MéTODOS: Um estudo de coorte retrospectivo conduzido em uma unidade terciária de saúde, que incluiu 26 crianças de até 16 anos de idade que apresentavam epilepsia refratária e receberam um tratamento complementar com LCM. As visitas de acompanhamento foram agendadas a cada 3 meses, até 9 meses de tratamento com LCM. RESULTADOS: Após 3 meses de administração de LCM, em 73,1% das crianças, a frequência das crises teve uma redução maior do que 50%, e essa melhora clínica foi mantida na maioria dos pacientes (73,9%) pelos 9 meses seguintes. Efeitos adversos leves (como, sonolência e alterações comportamentais) ou graves (agravamento das crises) foram observados em duas e três crianças, respectivamente. Entre as crianças que responderam ao tratamento com LCM, houve uma maior prevalência do sexo masculino, o uso de um menor número de medicações anticrise associadas e o uso de bloqueadores dos canais de sódio. CONCLUSõES: A LCM deve ser considerada uma opção de tratamento precoce em pacientes pediátricos com epilepsia refratária, principalmente aqueles que apresentam crises focais.