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Neuropathy is a disturbance of function or a pathological change in nerves causing poor health and quality of life. A proportion of chronic pain patients in the community suffer persistent neuropathic pain symptoms because current drug therapies may be suboptimal so there is a need for new therapeutic modalities. This study investigated the neuroprotective flavonoid, 6-methoxyflavone (6MF), as a potential therapeutic agent and gabapentin as the standard comparator, against neuropathic models. Thus, neuropathic-like states were induced in Sprague-Dawley rats using sciatic nerve chronic constriction injury (CCI) mononeuropathy and systemic administration of streptozotocin (STZ) to induce polyneuropathy. Subsequent behaviors reflecting allodynia, hyperalgesia, and vulvodynia were assessed and any possible motoric side-effects were evaluated including locomotor activity, as well as rotarod discoordination and gait disruption. 6MF (25-75 mg/kg) antagonized neuropathic-like nociceptive behaviors including static- (pressure) and dynamic- (light brushing) hindpaw allodynia plus heat/cold and pressure hyperalgesia in the CCI and STZ models. 6MF also reduced static and dynamic components of vulvodynia in the STZ induced polyneuropathy model. Additionally, 6MF reversed CCI and STZ suppression of locomotor activity and rotarod discoordination, suggesting a beneficial activity on motor side effects, in contrast to gabapentin. Hence, 6MF possesses anti-neuropathic-like activity not only against different nociceptive modalities but also impairment of motoric side effects., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

We purposed to explore the consequences of the use quercetin and fisetin alone and in combination with pregabalin and gabapentin, which are used in the management of neuropathic pain, and on neuropathic pain in general. The anti-allodynic effect of various doses (5, 10, and 20 mg/kg) of quercetin and fisetin, both singly and in combination with pregabalin and gabapentin, was evaluated by developing a neuropathic pain model induced by chronic constrictive nerve damage in rats. The effectiveness of these flavonoids was investigated by combining them with gabapentin (50 mg/kg) and pregabalin (15 mg/kg), choosing the effectual dose of 10 mg/kg and the dose of 5 mg/kg, which did not show significant antiallodynic effects. In groups combined with gabapentin and pregabalin, it was determined that they showed a significant antiallodynic effect compared with 50 mg/kg gabapentin and 15 mg/kg pregabalin. In conclusion, in our combination studies, it was observed that the effectiveness of gabapentin and pregabalin, was increased and the duration of effect was prolonged when used with lower doses of flavonoids. Based on these findings; it is possible to say that quercetin and fisetin are potential agents that can be used alone or in combination with other effective treatments to alleviate neuropathic pain., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: A single administration of the opioid receptor antagonist methocinnamox (MCAM) antagonizes the antinociceptive effects of µ-opioid receptor agonists for 2 weeks or longer. Such a long duration of antagonism could necessitate the use of nonopioid drugs for treating pain in patients receiving MCAM for opioid use disorder (OUD)., Methods: The antinociceptive effects of fentanyl and nonopioid drugs were assessed in 24 male Sprague Dawley rats using a complete Freund's adjuvant (CFA) model of inflammatory pain. Twelve rats received 10mg/kg MCAM and 12 received vehicle; half (n=6) of the animals from each treatment group were treated (intraplantar) with CFA or saline. Hypersensitivity to mechanical stimulation was measured using a von Frey anesthesiometer. Fentanyl (0.01-0.1mg/kg), ketamine (17.8-56mg/kg), gabapentin (32-100mg/kg), meloxicam (3.2-10mg/kg), and ∆ 9 -tetrahydrocannabinol (THC, 1-10mg/kg) were administered intraperitoneally and tested every 3 days in a pseudorandom order. Next, the same drugs were studied for effects on motor performance using a rotarod apparatus., Results: CFA-induced hypersensitivity was attenuated by fentanyl in vehicle- but not MCAM-treated rats. THC, ketamine, and gabapentin attenuated (up to 82, 66, and 46 %, respectively) CFA-evoked mechanical hypersensitivity in both MCAM- and vehicle-treated rats. Meloxicam failed to alter CFA-evoked mechanical hypersensitivity in either group. Fentanyl, THC, gabapentin, and meloxicam did not affect motor performance in either group whereas ketamine impaired motor performance in both groups (up to 71 % reduction in latency to fall)., Conclusions: These data suggest that ketamine, gabapentin, and THC could be effective for treating inflammatory pain under conditions of long term µ-opioid receptor antagonism., Competing Interests: Declaration of Competing Interest CPF is co-holder of a US Patent for methocinnamox (MCAM). Other authors have no declarations of interest, (Copyright © 2024 Elsevier B.V. All rights reserved.)

We examine the cost-effectiveness of treating epilepsy with anti-epileptic medicines in autistic children, looking at impacts on healthcare providers (in England, Ireland, Italy and Spain) and children's families (in Ireland). We find carbamazepine to be the most cost-effective drug to try first in children with newly diagnosed focal seizures. For England and Spain, oxcarbazepine is the most cost-effective treatment when taken as additional treatment for those children whose response to monotherapy is suboptimal. In Ireland and Italy, gabapentin is the most cost-effective option. Our additional scenario analysis presents the aggregate cost to families with autistic children who are being treated for epilepsy: this cost is considerably higher than healthcare provider expenditure., (© 2023. The Author(s).)

Background: Gabapentin supplementation may have some potential in pain control after lumbar laminectomy and discectomy, and this meta-analysis aims to explore the impact of gabapentin supplementation on postoperative pain management for lumbar laminectomy and discectomy., Methods: PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases were systematically searched, and we included randomized controlled trials assessing the effect of gabapentin supplementation on the pain control of lumbar laminectomy and discectomy., Results: Five randomized controlled trials were finally included in the meta-analysis. Overall, compared with control intervention for lumbar laminectomy and discectomy, gabapentin supplementation was associated with significantly lower pain scores at 2 hours (MD = -2.75; 95% CI = -3.09 to -2.41; P < .00001), pain scores at 4 hours (MD = -2.28; 95% CI = -3.36 to -1.20; P < .0001), pain scores at 24 hours (MD = -0.70; 95% CI = -0.86 to -0.55; P < .00001) and anxiety score compared to control intervention (MD = -1.32; 95% CI = -1.53 to -1.11; P < .00001), but showed no obvious impact on pain scores at 12 hours (MD = -0.58; 95% CI = -1.39 to 0.22; P = .16). In addition, gabapentin supplementation could significantly decrease the incidence of vomiting in relative to control intervention (OR = 0.31; 95% CI = 0.12-0.81; P = .02), but they had similar incidence of nausea (OR = 0.51; 95% CI = 0.15-1.73; P = .28)., Conclusions: Gabapentin supplementation benefits to pain control after lumbar laminectomy and discectomy., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: Neuropathic corneal pain (NCP) is a new and ill-defined disease characterized by pain, discomfort, aching, burning sensation, irritation, dryness, and grittiness. However, the mechanism underlying NCP remain unclear. Here, we reported a novel rat model of primary NCP induced by long ciliary nerve (LCN) ligation. After sustained LCN ligation, the rats developed increased corneal mechanical and chemical sensitivity, spontaneous blinking, and photophobia, which were ameliorated by intraperitoneal injection of morphine or gabapentin. However, neither tear reduction nor corneal injury was observed in LCN-ligated rats. Furthermore, after LCN ligation, the rats displayed a significant reduction in corneal nerve density, as well as increased tortuosity and beading nerve ending. Long ciliary nerve ligation also notably elevated corneal responsiveness under resting or menthol-stimulated conditions. At a cellular level, we observed that LCN ligation increased calcitonin gene-related peptide (neuropeptide)-positive cells in the trigeminal ganglion (TG). At a molecular level, upregulated mRNA levels of ion channels Piezo2, TRPM8, and TRPV1, as well as inflammatory factors TNF-α, IL-1β, and IL-6, were also detected in the TG after LCN ligation. Meanwhile, consecutive oral gabapentin attenuated LCN ligation-induced corneal hyperalgesia and increased levels of ion channels and inflammation factors in TG. This study provides a reliable primary NCP model induced by LCN ligation in rats using a simple, minimally invasive surgery technique, which may help shed light on the underlying cellular and molecular bases of NCP and aid in developing a new treatment for the disease., (Copyright © 2024 International Association for the Study of Pain.)

Background: The purpose of this study was to assess the quality of evidence informing on common pharmacologic modalities used in upper extremity complex regional pain syndrome (CRPS)., Methods: A literature search was performed for primary prospective trials that reported on the pharmacologic treatment of CRPS type I and II specific to the upper extremity. Thirty-one trials were included and evaluated by 2 independent reviewers according to the Oxford Levels of Evidence (LOE), modified Coleman Methodology Score, and the revised Consolidated Standards of Reporting Trials (CONSORT) score. Cohen's kappa coefficient was calculated to measure interrater reliability., Results: Twenty-two Oxford LOE I and 9 level II trials met the inclusion criteria. Overall, there was high interrater reliability in the Oxford LOE (100% agreement), modified Coleman Methodology Score (87% agreement), and CONSORT score (94% agreement). The pharmacologic interventions with the highest quality of evidence supporting use in treatment of upper extremity CRPS were bisphosphonates and ketamine. Interventions that lack high-quality evidence are tricyclic antidepressants (TCAs) and topical dimethyl sulfoxide (DMSO). Pharmacologic agents that remain inconclusive are calcitonin, gabapentin, mycophenolate, probiotics, steroids, nonsteroidal anti-inflammatory drugs, vitamin C, and N -acetylcysteine. Agents with limited benefit are mannitol, isosorbide dinitrate, guanethidine, and morphine., Conclusions: Based on the evidence evaluated in this study, bisphosphonates should be considered as a first-line medication in the treatment of CRPS. In patients presenting with chronic or refractory CRPS, strong consideration should be given for the use of ketamine. Adjunct treatment in the acute setting should include TCAs and/or topical DMSO., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aim: Bile acid sequestrants are cholesterol-lowering drugs, which also improve glycaemic control in people with type 2 diabetes. The mechanism behind the glucose-lowering effect is unknown but has been proposed to be mediated by increased glucagon-like peptide-1 (GLP-1) secretion. Here, we investigated the glucose-lowering effects of sevelamer including any contribution from GLP-1 in people with type 2 diabetes., Materials and Methods: In a randomized, double-blind, placebo-controlled, crossover study, 15 people with type 2 diabetes on metformin monotherapy underwent two 17-day treatment periods with the bile acid sequestrant sevelamer and placebo, respectively, in a randomized order and with an interposed wash-out period of minimum 6 weeks. On days 15 and 17 of each treatment period, participants underwent experimental days with 4-h liquid meal tests and application of concomitant infusion of exendin(9-39)NH 2 or saline., Results: Compared with placebo, sevelamer improved insulin sensitivity (assessed by homeostatic model assessment of insulin resistance) and beta-cell sensitivity to glucose and lowered fasting and postprandial plasma glucose concentrations. In both treatment periods, exendin(9-39)NH 2 increased postprandial glucose excursions compared with saline but without absolute or relative difference between the two treatment periods. In contrast, exendin(9-39)NH 2 abolished the sevelamer-induced improvement in beta-cell glucose sensitivity., Conclusions: The bile acid sequestrant sevelamer improved insulin sensitivity and beta-cell sensitivity to glucose, but using the GLP-1 receptor antagonist exendin(9-39)NH 2 we were not able to detect a GLP-1-mediated glucose-lowering effect of sevelamer in individuals with type 2 diabetes. Nevertheless, the sevelamer-induced improvement of beta-cell sensitivity to glucose was shown to be GLP-1-dependent., (© 2023 John Wiley & Sons Ltd.)

Methicillin-resistant Staphylococcus aureus (MRSA) is a widespread pathogen causing clinical infections and is multi-resistant to many antibiotics, making it urgent need to develop novel antibacterials to combat MRSA. Here, a series of novel isoxanthohumol-amine conjugates were synthesized as antibacterials. After bioactivity evaluation, a compound E2 was obtained, which showed excellent antibacterial activity against S. aureus and clinical MRSA isolates (MICs = 0.25-1 μg/mL), superior to vancomycin, and with negligible hemolysis and good membrane selectivity. Additionally, E2 exhibited fast bacterial killing, less susceptible to resistance, relatively low cytotoxicity, and good plasma stability. Mechanism investigation revealed that E2 can disrupt bacterial membranes by specifically binding to phosphatidylglycerol on the bacterial membrane, thus causing elevated intracellular ROS and leakage of DNA and proteins, and ultimately killing bacteria. Noticeably, E2 displayed a good in vivo safety profile and better in vivo therapeutic efficacy than the same dose of vancomycin, allowing it to be a potential antibacterial to conquer MRSA infections., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Objective: Gabapentin is commonly used to treat pain in children receiving pediatric palliative care. This study describes the real-world use of gabapentin and the associated benefits and adverse effects/events (AEs)., Methods: A prospective, multicenter cohort of standardized data collection after a clinical decision was made to use gabapentin for managing neuropathic or nociplastic pain in children attended on by a pediatric palliative care service. It was conducted across 11 sites in seven countries including hospital, inpatient, and outpatient services. Clinical outcomes were graded using pain scales validated for age and cognitive ability and the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) at baseline, 14 days, 28 days, six weeks and 12 weeks after initiation of gabapentin. Ad-hoc safety reporting continued throughout the study., Results: Data were collected from 127 children with a median age of 4.7 years (IQR 0.1-17.9); 61% had a neurological disorder, 21% advanced cancer and the cohort had a high level of disability (Lansky/Karnofsky performance score 37.1). Gabapentin was prescribed at standard pediatric doses. On average, 76% of children had a reduction in pain and 42% experienced a potential AE. The mean pain score decreased from 6.0 (SD 2.6) at baseline to 3.3 (SD 2.4) at 14 days and 1.8 (SD 1.8) after 12-weeks of gabapentin therapy. Ten percent had increased pain at each time point. AEs did not increase when individual changes over time were accounted for except for somnolence (7%). Serious AEs attributable to gabapentin were possible or probable in 3% of children., Conclusions: Gabapentin prescribed at standard doses for advanced cancer and severe neurological injury in children under a pediatric palliative care service was associated with generally improved pain intensity at previously described levels of adverse effects., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Nuclear factor- κ B (NF- κ B) plays a central role in inflammatory responses, and its physiologic functions are essential for cell survival and proliferation. Currently, drugs targeting NF- κ B inhibition have not yet been applied in clinical practice. We investigated the physiologic effect of a novel NF- κ B inhibitory compound, 1 H -pyrazolo[3,4- d ]pyrimidin-4-amine derivative (INH #1), on three inflammatory animal models. The pharmacokinetics were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. Acute hepatitis was induced by administrating lipopolysaccharide (LPS) and D-(+)-galactosamine hydrochloride followed by the analysis of survival time and inflammatory mediators. Collagen-induced arthritis (CIA) was induced by immunization with type II collagen (CII), and serum-transfer arthritis (STA) was caused by injecting K/BxN mice serum. Clinical and histologic scores were evaluated in both arthritis models. Immune cell subset analysis, CII-induced interferon-gamma (IFN- γ ) production and proliferation, and measurement of anti-CII IgG antibodies were performed in the CIA model. In the acute hepatitis model, INH #1 suppressed tumor necrosis factor- α (TNF- α ) production and prevented early death in a dose-dependent manner. INH #1 significantly attenuated arthritis scores and joint inflammation in both arthritis models. Additionally, in the CIA model, dendritic cells (DCs) in the regional lymph nodes were decreased in the treated mice and antigen-induced IFN- γ production and cell proliferation in splenocytes were inhibited, whereas the titers of anti-CII IgG antibodies were comparable regardless of the treatment. Here we revealed that INH #1 exerted anti-inflammatory effects in vivo via inhibition of inflammatory mediators and suppression of cellular immune responses. This compound could be a novel candidate for inhibition of NF- κ B in certain inflammatory diseases. SIGNIFICANCE STATEMENT: A novel nuclear factor- κ B (NF- κ B) inhibitory compound, 1 H -pyrazolo[3,4- d ]pyrimidin-4-amine derivative (INH #1), which retains physiologically essential NF- κ B bioactivity, suppressed inflammation in three different mouse models: the acute hepatitis model, the collagen-induced arthritis model, and the K/BxN serum-transfer arthritis model. These results suggest that this compound could be a novel and potent anti-inflammatory agent., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Major depressive disorder (MDD) is a leading cause of suicide in the world. Monoamine-based antidepressant drugs are a primary line of treatment for this mental disorder, although the delayed response and incomplete efficacy in some patients highlight the need for improved therapeutic approaches. Over the past two decades, ketamine has shown rapid onset with sustained (up to several days) antidepressant effects in patients whose MDD has not responded to conventional antidepressant drugs. Recent preclinical studies have started to elucidate the underlying mechanisms of ketamine's antidepressant properties. Herein, we describe and compare recent clinical and preclinical findings to provide a broad perspective of the relevant mechanisms for the antidepressant action of ketamine.

Background: Methylmercury (MeHg), the causative agent of Minamata disease, damages the cranial nervous system and causes specific sensory disturbances, especially hypoesthesia, in the extremities. However, recent reports demonstrate that patients with chronic Minamata disease conversely develop neuropathic pain in the lower extremities. Studies on our established Minamata disease model rats showed that MeHg-mediated neurodegeneration might induce neuropathic pain by over time through inducing rewiring with neuronal activation in the somatosensory cortex via microglial activation in the spinal dorsal horn., Methods: In this study, the effects of gabapentin, a potentially effective treatment for neuropathic pain, was evaluated using this Minamata disease model rats. To further elucidate the mechanism of its medicinal effects, histochemical and biochemical analyses of the nervous system of Minamata disease model rats were conducted., Results: Gabapentin treatment restored the reduction in the pain threshold caused by MeHg exposure in rats. Histochemical and biochemical analyses revealed that gabapentin showed no effect on MeHg-induced neurodegeneration in entire nervous system and microglial activation in the spinal dorsal horn. However, it was shown that gabapentin may reduce excessive synaptogenesis through its antagonist action on the alpha2-delta-1 subunit of calcium channels in the somatosensory cortex., Conclusions: These results indicate that gabapentin may alleviated neuropathic pain in MeHg poisoning, as typified by Minamata disease, by reversibly modulation synaptic rewiring in the somatosensory cortex.

Background/aims: Fexuprazan is a novel potassium-competitive acid blocker that could be of benefit to patients with gastric mucosal injury. The aim of this study was to assess the 2-week efficacy and safety of fexuprazan in patients with acute or chronic gastritis., Methods: In this study, 327 patients with acute or chronic gastritis who had one or more gastric erosions on endoscopy and subjective symptoms were randomized into three groups receiving fexuprazan 20 mg once a day (q.d.), fexuprazan 10 mg twice a day (b.i.d.), or placebo for 2 weeks. The posttreatment assessments were the primary endpoint (erosion improvement rate), secondary endpoints (cure rates of erosion and edema and improvement rates of redness, hemorrhage, and subjective symptoms), and drug-related adverse events., Results: Among the patients, 57.8% (59/102), 65.7% (67/102), and 40.6% (39/96) showed erosion improvement 2 weeks after receiving fexuprazan 20 mg q.d., fexuprazan 10 mg b.i.d., and placebo, respectively. Both fexuprazan 20 mg q.d. and 10 mg b.i.d. showed superior efficacy to the placebo (p=0.017 and p<0.001, respectively). Likewise, both fexuprazan 20 mg q.d. and 10 mg b.i.d. also showed higher erosion healing rates than the placebo (p=0.033 and p=0.010, respectively). No difference was noted in the edema healing rate and the improvement rates for redness, hemorrhage, and subjective symptoms between the fexuprazan and placebo groups. No significant difference was noted in the incidence of adverse drug reactions., Conclusions: Fexuprazan 20 mg q.d. and 10 mg b.i.d. for 2 weeks showed therapeutic efficacy superior to that of placebo in patients with acute or chronic gastritis (ClinicalTrials.gov identifier NCT04341454).

Background: Peripheral neuropathy is not only the most prevalent consequence of diabetes but also the main reason for foot ulceration, disability, and amputation. Therefore, the current study aims to determine the effectiveness of oral clonidine and gabapentin on peripheral neuropathy in diabetic patients., Methods: This 12-week, randomized, and parallel-group trial was conducted to compare the efficacy of oral clonidine and gabapentin with gabapentin alone in diabetic patients in southwest Iran during the first half of 2021. Thirty patients with type 2 diabetes with peripheral neuropathy as assessed by a visual analog scale (VAS) and divided into two groups of 15 patients, treated for up to three months. The data were analyzed using SPSS-21 software. In order to report the results, descriptive indices, independent t-test, one-way analysis of covariance (ANCOVA) and analysis of variance with repeated measures were used., Results: The mean and standard deviation of the age of the participants in the clonidine + gabapentin group was equal to 50.20 ± 7.44, and in the gabapentin group was equal to 50.47 ± 7.57 (t = 0.10, P-value = 0.923). This research showed a significant difference between the clonidine + gabapentin group and with gabapentin group in terms of neuropathic pain and the severity of neuropathic pain (P < 0.001)., Conclusions: According to this research results, clonidine + gabapentin can reduce neuropathic pain and the severity of neuropathic pain in diabetic patients. Therefore, it is recommended that healthcare professionals with diabetes expertise prescribe these medications to reduce neuropathic pain and its severity., Trial Registration: This study was registered in the Iranian Clinical Trials System with the ID (IRCT20211106052983N1) on 14/01/2022., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Two statements from national organizations outline recommended minimum effective doses of gabapentin and pregabalin for the treatment of diabetic peripheral neuropathy (DPN). However, studies of real-world gabapentinoid dosing demonstrate that the recommended dose targets are frequently not met and do not consider renal insufficiency. This study aimed to characterize gabapentinoid prescribing patterns in patients receiving primary care at two internal medicine clinics within an academic medical center. This retrospective chart review included adult outpatients who were newly initiated on gabapentin or pregabalin between October 1, 2017 and October 1, 2020 and reviewed for 12 months. A total of 1,221 patients were included in the study with 1,079 (88.4%) prescribed gabapentin and 142 (11.6%) prescribed pregabalin. Only 22.4% of patients prescribed gabapentin and 33.3% of patients prescribed pregabalin with adequate renal function met the minimum effective dosing of gabapentin 1800 mg per day and pregabalin 300 mg per day provided by the American Diabetes Association (ADA) and American Academy of Neurology (AAN). This study supports the need for optimization of gabapentinoid dosing to ensure an adequate trial at the minimum effective dose is completed.

Purpose: This review was designed to compile the currently available evidence on the prophylactic use of gabapentin in the head and neck cancer patient population., Methods: A systematic search was conducted of PubMed, Web of Science, and Google Scholar to identify articles related to the use of prophylactic gabapentin in patients undergoing head and neck cancer therapy. Candidate studies were screened for inclusion and a subsequent bias assessment was conducted by multiple reviewers. Meta-analysis was conducted in cases in which the studies used compatible outcome measures., Results: Ten studies were identified that met the inclusion criteria and were assessed for bias. Among the four small studies that examined pain prevention, 2 were positive and 2 were inconclusive. Three of the four studies examiniRDng opioid use noted less need for opioids in the treatment arm. Meta-analysis of the pertinent studies showed no difference in feeding tube placement (RD = 0.64%, 95%CI: (- 25.8%, 27.1%), p = 0.962) but substantially less weight loss among those in the treatment arm (p = 0.047)., Conclusion: Prophylactic gabapentin appears to be a promising treatment option for preventing pain, reducing opioids, and reducing weight loss in patients undergoing head and neck cancer therapy. However, the studies on the treatment to date are small and several have a substantial risk of bias., (© 2023. The Author(s).)

Background: First symptoms of narcolepsy mostly present during childhood. Pharmacological management options in children are limited, also due to approval status. Pitolisant is an inverse histamine 3 receptor agonist and has been approved for the treatment of adult narcolepsy with or without cataplexy by EMA and FDA. Clinical experience indicates for a beneficial use also in children and adolescents. Our goal was to evaluate the effects and tolerability of pitolisant in narcolepsy children/adolescents in a real-world setting., Methods: This multicentre retrospective observational study included 55 patients with narcolepsy from three international narcolepsy centers (Germany, France and Italy) who were treated with pitolisant. Patients were eligible if they were at least 6 years old and diagnosed with narcolepsy type 1 or 2. Demographic and clinical characteristics, questionnaires, sleep medicine and laboratory data were collected., Results: 55 children/adolescents (25 girls, 45.45%, 30 boys, 54.55%) aged 6-18 years, with narcolepsy (type 1 = 92.7%, type 2 = 7.3%), were treated with pitolisant. The mean pitolisant dose was 34.1 mg/d. Treatment was effective for excessive daytime sleepiness (EDS) and cataplexy: the pediatric Epworth Sleepiness Scale (ESS) score decreased from 19 to 13.5 (p < 0.001) and the weekly cataplexy frequency improved from 7.9 at baseline to 5.2 (p < 0.001). Treatment with pitolisant was well tolerated. Side effects were mild and mostly short-term. Insomnia was reported most frequently (5.5%)., Conclusion: First real-world results suggest that pitolisant treatment is effective in improving EDS and cataplexy in children with narcolepsy, and also is well tolerated., Competing Interests: Declaration of competing interest UK reports receiving research grants from Bioprojet Pharma, Jazz Pharmaceuticals, and serving as a consultant or advisory board member for AOP Orphan Pharmaceuticals, Bioprojet Pharma, Harmony Biosciences, Jazz Pharmaceuticals, Takeda Pharmaceutical Co., Ltd., and UCB Pharma. ML reports serving as a consultant and participating in advisory boards for NLS Pharma, Jazz Pharmaceuticals, UCB Pharma, and Bioprojet; and receiving grant support from Shire. APdL reports no conflict of interest. LL reports no conflict of interest. GP reports participating in advisory boards for UCB, Jazz Pharmaceuticals, and Bioprojet. FP received fee from Jazz for symposia, support for attending congress from Bioprojet, and participated to advisory board for Takeda. RR reports no conflict of interest. AT reports no conflict of interest. SV reports no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aims: This study aimed to compare the efficacy of gabapentin, dexamethasone, and gabapentin + dexamethasone for pain control after septoplasty., Materials and Methods: This prospective randomized trial included 120 patients that underwent septoplasty and were randomly divided into 4 groups: group G (preoperative gabapentin 600 mg p.o.); group D (intraoperative dexamethasone 8 mg i.v.); group GD (preoperative gabapentin 600 mg p.o. + intraoperative dexamethasone 8 mg i.v.); group C (placebo control)., Results: The median VAS score was significantly lower in groups G and GD at 1, 2, 4, 6, 12, and 24 hours postsurgery than in group C ( P  < .008 for all). The median VAS score was significantly lower in group D than in group C at 1, 2, and 4 hours postsurgery ( P  < .008 for all). There weren't any significant differences in the VAS score between groups D, G, and GD at any time point. Groups G, D, and GD had a significantly lower frequency of rescue analgesic use than group C; however, there were no differences between groups G, GD, and C ( P  < .001 and P  = .108, respectively)., Conclusion: Gabapentin, dexamethasone, and gabapentin + dexamethasone are equally more effective analgesics during the first 4 hours postsurgery than placebo. The addition of dexamethasone to gabapentin does not provide extra analgesia. Both gabapentin and gabapentin + dexamethasone have a more prolonged analgesic effect than dexamethasone alone.

Gabapentin and pregabalin both exert high affinity to the α2δ subunit of the voltage-gated calcium channels which inhibits excitatory neurotransmitter release. The synergistic mechanism was described in rats given combinations of gabapentin and pregabalin. In this case series, we described 2 cases which may illustrate the synergistic effect of gabapentin and pregabalin in treatment resistant neuropathic pain. Low dose pregabalin was added to therapeutic gabapentin to achieve appreciable pain reduction in one case and improved quality of life in another case. Further research with more enrollment and longer study duration may help elucidate the appropriate dosing and potential associated side effects.

Early applications of positron emission tomography (PET) in psychiatry sought to identify derangements of cerebral blood flow and metabolism. The need for more specific neurochemical imaging probes was soon evident, and these probes initially targeted the sites of action of neuroleptic (dopamine D 2 receptors) and psychoactive (serotonin receptors) drugs. For nearly 30 years, the centrality of monoamine dysfunction in psychiatric disorders drove the development of an armamentarium of monoaminergic PET radiopharmaceuticals and imaging methodologies. However, continued investments in monoamine-enhancing drug development realized only modest gains in efficacy and tolerability. As patent protection for many widely prescribed and profitable psychiatric drugs lapsed, drug development pipelines shifted away from monoamines in search of novel targets with the promises of improved efficacy, or abandoned altogether. Over this period, PET radiopharmaceutical development activities closely parallelled drug development priorities, resulting in the development of new PET imaging agents for non-monoamine targets. In part two of this review, we survey clinical research studies using the novel targets and radiotracers described in part one across major psychiatric application areas such as substance use disorders, anxiety disorders, eating disorders, personality disorders, mood disorders, and schizophrenia. Important limitations of the studies described are discussed, as well as key methodologic issues, challenges to the field, and the status of clinical trials seeking to exploit these targets for novel therapeutics., (© 2022 International Society for Neurochemistry.)

To discover the best-in-class Bruton's Tyrosine Kinase (BTK) inhibitors, for th treatment of autoimmune disorders like cancer (B-Cell Lymphoma (BCL)) and rheumatoid arthritis (RA), in the present investigation, novel structural optimizations were carried out. Introduction of novel bicyclic amine linkers and aromatic backbone led to series of compounds 9a-h and 14a-u. Compound 14b was found to be potent, orally bioavailable, selective and irreversible BTK inhibitor. In vitro, 14b showed IC 50 of 1.0 nM and 0.8 nM, in BTK and TMD8 assays, respectively. In vivo,14b displayed robust efficacy in collagen-induced arthritis (CIA) and TMD8 xenograft models, which could be correlated with its improved oral bioavailability. In the repeated dose acute toxicity study, 14b showed no adverse changes, indicating that the BTK inhibitor 14b could be viable therapeutic option for the treatment of autoimmune disorders., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation of the joints, leading to pain, swelling, and joint deformity. Effective management of RA involves the use of disease-modifying drugs that can slow down disease progression and alleviate symptoms. Among the potential targets for RA treatment is Bruton's tyrosine kinase (BTK), which plays a crucial role in B-cell signalling and contributes to the pathogenesis of RA., Aims: QSARINS (QSAR-INSUBRIA) is software used for the development and validation of Quantitative Structure-Activity Relationship (QSAR) analysis. In the present work, this software was explored for pharmacophore optimization of the pyrrolo-pyrimidine nucleus for anti-rheumatoid activity., Methods: A series of pyrrolo-pyrimidine derivatives were used to build the QSAR models. These models were generated to identify structural features that correlate significantly with the activity. We followed the assessment of statistical parameters to ensure thorough validation of all the QSAR models. The QSAR models demonstrating better statistical performance were selected, and descriptors of these models were analysed., Results: The results showed that the QSAR models were highly statistically robust and exhibited a strong external predictive ability. Their structural features were also deduced., Conclusion: This QSAR study provided crucial information about the specific molecular features that can be used for the optimization of the pharmacophores. This research provides valuable insights into the structural features essential for BTK inhibition and paves the way for the design and development of novel anti-rheumatic agents targeting BTK in RA., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: The aim: To investigate the in!uence of prescribing a complex of amino acids in pathogenetic therapy in patients with pulmonary tuberculosis on liver function., Patients and Methods: Materials and methods: The study included 50 patients with drug susceptible TB and 50 patients with drug-resistant TB (multidrug-resistant and extensively drug-resistant)., Results: Results: The study included 50 patients with drug susceptible tuberculosis (TB) and 50 patients with drug-resistant TB. When comparing biochemical pa-rameters characterizing liver function in patients with drug-susceptible TB after 1 month of anti-tuberculosis therapy, it was found that patients receiving additional therapy with a complex of amino acids had a lower level of bilirubin, p <0.05. After 60 doses, patients receiving additional therapy with amino acids had significantly lower bilirubin levels alanine aminotransferase (ALT) and aspartate aminotransferase (AST), p <0.05. When comparing the biochemical parameters characterizing liver function in patients with drug-resistant tuberculosis after a month of anti-tuberculosis therapy, significantly higher protein level was found in the groups of patients receiving additional therapy with amino acids, as well as significantly lower ALT level, AST and creatinine p <0.05., Conclusion: Conclusions: The additional appointment of the complex of amino acids in the pathogenetic therapy of patients with pulmonary tuberculosis makes it possible to reduce the severity of hepatotoxic reactions manifested by the main parameters (AST, ALT, total bilirubin) and to increase the protein-synthetic function of the liver, which allows us to recommend their appointment to improve the tolerance of anti-tuberculosis therapy.

Background: Gabapentin is a recommended first-line agent for treating neuropathic pain; however, its efficacy rate is reportedly low, and the risk of adverse events is high. A plausible explanation for this lies with its wide range of actions, the entirety of which have yet to be fully elucidated., Methods: A review of the literature was conducted on gabapentin's known and proposed analgesic mechanisms of action, as well as potentially opposing or detrimental actions., Results: Gabapentin's classical analgesic mechanisms involve direct attenuation of excitatory neurotransmission in the spinal cord via inhibition of neuronal ion channels, while indirect mechanisms include descending inhibition and block of injury-evoked synaptogenesis. Glial effects have also been reported; however, whether they are neuroprotective or detrimental is unknown. Furthermore, data from animal models do not reflect clinical outcomes., Conclusions: Gabapentin's clinical use should be reconsidered according to the net effects of its numerous assumed actions, including the tripartite synapse and oligodendrocyte effects. Whether it is doing more harm than good, especially in the scenarios of incomplete or loss of response, warrants consideration when prescribing gabapentin., (© 2022 The Authors. Pain Practice published by Wiley Periodicals LLC on behalf of World Institute of Pain.)

Butyrylcholinesterase (BChE) is recently regarded as a biomarker in progressed Alzheimer's disease (AD), the development of selective BChE inhibitors has attracted a great deal of interest and may be a viable therapeutic strategy for AD. Previously, an aromatic tertiary amine derivative (S17-1001) was screened and validated as a selective BChE inhibitor. Structured-based molecular modification guided the synthesis of 43 analogs. Biological test of cholinesterase inhibition, in vitro blood brain barrier permeation assay, neurotoxicity assay and neuroprotective effects assay indicated two optimal compounds 17c and 19c. Both compounds showed selective BChE inhibitory (hBChE < 20 nM, eeAChE > 10 μM), good BBB permeation and primary cell safety. Besides, 17c can dose-response protect cell from Aβ 1-42 induced damage. It also demonstrated that 17c and 19c were able to restore cognitive impairment in vivo test. These data suggest that 17c and 19c represent promising candidate for follow-up in the drug-discovery process against AD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Severe side effects of chemotherapy agents on vital organs are the major causes of cancer-related mortality, not merely cancer disease. Encapsulating chemotherapeutic molecules in nanocarriers is a justifiable solution in decreasing the risk of their side effects and boosting the efficiency of treatment. The present study has developed the doxorubicin (DOX)-loaded AS1411 (anti-nucleolin) aptamer surface-functionalized exosome (DOX-Apt-Exo) to treat colorectal cancer in both in-vitro and in-vivo experimental models. HEK293-derived exosomes were loaded with DOX through the incubation method with a nearly 13% encapsulation efficiency. Afterwards, the 5-terminal carboxyl group of AS1411-aptamer was converted into amine-reactive NHS esters with EDC/NHS amide coupling chemistry before being conjugated to the amine groups on the exosome surface. DLS and TEM estimated the designed formulation (DOX-Apt-Exo) size of about 200 nm. Aptamer-binding affinity and cellular uptake of DOX-Apt-Exo by nucleolin-overexpressing cancer cells were depicted through fluorescence microscopy. Comparing the in-vitro cytotoxicity impact of DOX-loaded exosomes, either targeted or non-targeted by MTT assay, clearly verified a high effectiveness of ligand-receptor mediated target therapy. Subsequently, in-vivo experiments which were conducted on four groups of ectopic mouse models of colon cancer (5 in each group) demonstrated the tumor growth suppression through professional long-term accumulation and retention of DOX-Apt-Exo at the tumor site by ligand-receptor interaction. The results suggested that AS1411 aptamer-functionalized exosomes can be recommended as a safe and effective system to site-specific drug delivery in possible clinical applications of colon cancer., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Triple-negative breast cancers (TNBCs) are highly aggressive and metastatic. To date, finding efficacious targeted therapy molecules might be the only window of hope to cure cancer. Fibromodulin (FMOD), is ectopically highly expressed on the surface of Chronic Lymphocytic Leukemia (CLL) and bladder carcinoma cells; thus, it could be a promising molecule for targeted therapy of cancer. The objective of this study was to evaluate cell surface expression of FMOD in two TNBC cell lines and develop an antibody-drug conjugate (ADC) to target FMOD positive TNBC in vitro and in vivo., Materials and Methods: Two TNBC-derived cell lines 4T1 and MDA-MB-231 were used in this study. The specific binding of anti-FMOD monoclonal antibody (mAb) was evaluated by flow cytometry and its internalization was verified using phAb amine reactive dye. A microtubulin inhibitor Mertansine (DM1) was used for conjugation to anti-FMOD mAb. The binding efficacy of FMOD-ADC was assessed by immunocytochemistry technique. The anti-FMOD mAb and FMOD-ADC apoptosis induction were measured using Annexin V-FITC and flow cytometry. Tumor growth inhibition of anti-FMOD mAb and FMOD-ADC was evaluated using BALB/c mice injected with 4T1 cells., Results: Our results indicate that both anti-FMOD mAb and FMOD-ADC recognize cell surface FMOD molecules. FMOD-ADC could induce apoptosis in 4T1 and MDA-MB-231 cells in vitro. In vivo tumor growth inhibition was observed using FMOD-ADC in 4T1 inoculated BALB/c mice., Conclusion: Our results suggests high cell surface FMOD expression could be a novel bio-marker TNBCs. Furthermore, FMOD-ADC could be a promising candidate for targeting TNBCs., (© 2022. The Author(s), under exclusive licence to The Japanese Breast Cancer Society.)

Inflammation is a natural response of the organism to an infection, trauma, or cellular stress. Pain is the first symptom of acute and chronic inflammation. The standard class of medication to treat inflammatory pain is the nonsteroidal anti-inflammatory drug (NSAID). These drugs are associated with severe side effects such as gastric ulcers, gastritis, or internal bleeding. One of NSAIDs, Dipyrone® (metamizole) is largely used in many European and South American countries despite its dubious effectivity and its withdrawal from the market of several countries. Here, aiming to identify a new anti-inflammatory drug prototype based on Dipyrone® structure, a set of 27 molecules were virtually screened, and 4 compounds containing the active metabolite 4-aminoantipyrine and 1,4-dioxo-2-butenyl fragment were selected for docking, synthesis, and biological evaluation. The selection was based on the number of H-bonds and π- π stacking interactions between the inhibitor and the amino acids within the binding site of the enzyme. Carrageenan-induced paw edema, acetic acid-induced writhing, and formalin assays were used to evaluate inflammation and pain response. The selected compounds 1-4 inhibited the involvement of biogenic amines in the formation of paw edema. Compounds 1-4 also reduced pain in the inflammatory response phase. It has to be noted that 4-AA may cause agranulocytosis, which should be borne in mind when developing drug candidates of similar structure. Our new drug prototypes based on 4-aminoantipyrine and 1,4-dioxo-2-butenyl moieties open a gate for developing a prototype of nonsteroidal anti-inflammatory drugs., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The application of non-planar scaffolds in drug design allows for the enlargement of the chemical space, and for the construction of molecules that have more effective target-ligand interactions or are less prone to the development of resistance. Among the works of the last decade, a literature search revealed spirothiazamenthane, which has served as a lead in the development of derivatives active against resistant viral strains. In this work, we studied the novel molecular scaffold, which resembles spirothiazamenthane, but combines isoxazoline as a heterocycle and cyclooctane ring as a hydrophobic part of the structure. The synthesis of new 3-nitro- and 3-aminoisoxazolines containing spiro-fused or 1,2-annelated cyclooctane fragments was achieved by employing 1,3-dipolar cycloaddition of 3-nitro-4,5-dihydroisoxazol-4-ol 2-oxide or tetranitromethane-derived alkyl nitronates with non-activated alkenes. A series of spiro-sulfonamides was obtained by the reaction of 3-aminoisoxazoline containing a spiro-fused cyclooctane residue with sulfonyl chlorides. Preliminary screening of the compounds for antiviral, antibacterial, antifungal and antiproliferative properties in vitro revealed 1-oxa-2-azaspiro[4.7]dodec-2-en-3-amine and 3a,4,5,6,7,8,9,9a-octahydrocycloocta[d]isoxazol-3-amine with activity against the influenza A/Puerto Rico/8/34 (H1N1) virus in the submicromolar range, and high values of selectivity index. Further study of the mechanism of the antiviral action of these compounds, and the synthesis of their analogues, is likely to identify new agents against resistant viral strains.

Introduction and Hypothesis: Chronic pelvic pain (CPP) affects 2.1-24% of women, causing physical and psychological damage to women around the world. Based on the efficacy of gabapentin in the treatment of chronic pain, we conducted this study to evaluate the efficacy and safety of gabapentin in reducing pain in women with CPP., Methods: Systematic searches were performed in the electronic databases of PubMed, Embase, Web of Science, Scopus, Cochrane, and Clinicalkey databases. Studies focused on comparing the efficacy of gabapentin and placebo in the treatment of female CPP patients were included. RevMan 5.4 was used to analyze the results and risk of bias. Two investigators independently selected eligible studies and extracted related pain scores and side effects for meta-analysis., Results: In total, 4 RCTs were enrolled in the meta-analysis, totaling 425 patients. Among patients receiving gabapentin, the average pain scores in 3 and 6 months were significantly lower than those in the placebo group(p < 0.00001). The results showed that there was no statistical difference between gabapentin and placebo in the reduction of pain scores from baseline(p = 0.41). The incidence of side effects in the gabapentin group was significantly higher than that in the placebo group (p < 0.00001)., Conclusion: This systematic review and meta-analysis demonstrated that for women with CPP, gabapentin was significantly different from placebo in average pain scores at 3 and 6 months. However, the two drugs did not differ in the reduction in pain scores from baseline. Gabapentin can bring more significant side effects, whether they are common side effects or serious side effects., (© 2021. The International Urogynecological Association.)

The cancer drug delivery process involves a series of biological barriers, which require the nanomedicine to exhibit different, even opposite properties for high therapeutic efficacy. The prevailing design philosophy, i.e., integrating these properties within one nanomedicine via on-demand property transitions such as PEGylation/dePEGylation, complicates nanomedicines' composition and thus impedes clinical translation. Here, polyzwitterionic micelles of poly(tertiary amine-oxide)-block-poly(ε-caprolactone) (PTAO-PCL) amphiphiles that enable all the required functions are presented. The zwitterionic nature and unique cell membrane affinity confer the PTAO micelles long blood circulation, efficient tumor accumulation and penetration, and fast cellular internalization. The mitochondrial targeting capability allows drug delivery into the mitochondria to induce mitochondrial dysfunction and overcome tumor multidrug resistance. As a result, the PTAO/drug micelles exhibit potent anticancer efficacy. This simple yet multipotent carrier system holds great promise as a generic platform for potential clinical translation., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Overexpression and frequent mutations in FMS-like tyrosine kinase-3 (FLT3) are considered risk factors for severe acute myeloid leukemia (AML). Hyperactive FLT3 induces premature activation of multiple intracellular signaling pathways, resulting in cell proliferation and anti-apoptosis. We conducted the computational modeling studies of 40 pyrimidine-4,6-diamine-based compounds by integrating docking, molecular dynamics, and three-dimensional structure-activity relationship (3D-QSAR). Molecular docking showed that K644, C694, F691, E692, N701, D829, and F830 are critical residues for the binding of ligands at the hydrophobic active site. Molecular dynamics (MD), together with Molecular Mechanics Poison-Boltzmann/Generalized Born Surface Area, i.e., MM-PB(GB)SA, and linear interaction energy (LIE) estimation, provided critical information on the stability and binding affinity of the selected docked compounds. The MD study suggested that the mutation in the gatekeeper residue F691 exhibited a lower binding affinity to the ligand. Although, the mutation in D835 in the activation loop did not exhibit any significant change in the binding energy to the most active compound. We developed the ligand-based comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models. CoMFA ( q 2 = 0.802, r 2 = 0.983, and QF32 = 0.698) and CoMSIA ( q 2 = 0.725, r 2 = 0.965 and QF32 = 0.668) established the structure-activity relationship (SAR) and showed a reasonable external predictive power. The contour maps from the CoMFA and CoMSIA models could explain valuable information about the favorable and unfavorable positions for chemical group substitution, which can increase or decrease the inhibitory activity of the compounds. In addition, we designed 30 novel compounds, and their predicted pIC 50 values were assessed with the CoMSIA model, followed by the assessment of their physicochemical properties, bioavailability, and free energy calculation. The overall outcome could provide valuable information for designing and synthesizing more potent FLT3 inhibitors.

For patients with osteoarthritis (OA) of the knee, pain is the most debilitating symptom. Although it has been proposed that the chronic phase of the monoiodoacetate (MIA)-induced rodent model of knee joint pain may be superior to other chronic or acute OA models for assessing the analgesic efficacy of novel molecules, relatively few pharmacological studies have been conducted in the chronic phase of this model. Hence, this study was designed to use pharmacological methods to characterize the chronic phase of the MIA-induced rat model of knee joint OA pain. Rats received a single intraarticular injection of MIA at 2.5 mg or vehicle (saline) into the left (ipsilateral) knee joint. Pain behaviour was assessed by measuring paw withdrawal thresholds (PWTs) in the hindpaws pre-MIA injection and twice-weekly until study completion on day 42. Mechanical allodynia was fully developed in the ipsilateral hindpaws (PWTs ≤6 g) from day 7 and it persisted until day 42. MIA-injected rats with PWTs ≤6 g in the ipsilateral hindpaws received single doses of one of four clinically available drugs that represent four distinct pharmacological classes, viz gabapentin, amitriptyline, meloxicam and morphine, according to a 'washout' protocol with at least 48 hours between successive doses. Gabapentin evoked dose-dependent anti-allodynia as did morphine whereas amitriptyline and meloxicam were inactive. Our findings are aligned with clinical data showing that gabapentin and morphine alleviated OA pain in the knee. The lack of efficacy of amitriptyline is consistent with the loss of descending diffuse noxious inhibitory controls reported by others in this model., (© 2021 John Wiley & Sons Australia, Ltd.)

Background: Storm phobia in companion dogs is a common disorder that significantly impacts dogs' welfare. Gabapentin, the action of which is only partially understood, is widely used for its antiepileptic and analgesic properties. Only recently, the veterinary community began to use gabapentin to address phobia and anxiety in dogs. This study tested gabapentin to lower fear responses of dogs during a thunderstorm event., Methods: Eighteen dogs suffering from storm phobia completed our double-blind, placebo-controlled crossover trial. Each dog's behaviour was evaluated twice by his owner: once under placebo, once under gabapentin. The treatment was orally administered at least 90 min before the exposure. Gabapentin was given at a dose ranging from 25 to 30 mg/kg., Results: Our results indicate a significant reduction of the fear responses of dogs under gabapentin. The adverse effects were rare, and the most frequent amongst them was ataxia., Conclusion: In this trial, gabapentin appears to be an efficient and safe molecule that should be considered as part of the treatment plan of storm phobia in dogs., (© 2021 British Veterinary Association.)

Introduction: Gabapentin (Neurontin) is prescribed widely for conditions for which it has not been approved by regulators, including certain neuropathic pain conditions. There is limited evidence that gabapentin is safe and effective for the treatment of neuropathic pain. Published trial reports, and systematic reviews based on published trial reports, mislead patients and providers because information about gabapentin's harms has been published only partly. We confirmed that trials conducted by the drug developer have been abandoned, and we plan to conduct a restoration with support from the Restoring Invisible and Abandoned Trials Support Centre (https://restoringtrials.org/)., Methods and Analysis: In this study, we will analyse and report the harms that were observed in six trials of gabapentin, which have not been reported publicly (eg, in journal articles). We will use clinical study reports and individual participant data to identify and report the harms observed in each individual trial and to summarise the harms observed across all six trials. We will report all adverse events observed in the included trials by sharing deidentified data and summary tables on the Open Science Framework (https://osf.io/w8puv/). Additionally, we will produce a summary report that describes differences between the randomised groups in each trial and across trials for prespecified harms outcomes., Ethics and Dissemination: We will use secondary data. This study was determined to be exempt from Institutional Review Board (IRB) review (protocol #1910607198)., Competing Interests: Competing interests: EM-W and TL previously received support for research about gabapentin from the Patient Centred Outcomes Research Institute (PCORI)., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

A novel series of dimethylamino chalcone-O-alkylamines derivatives was designed and synthesized as multifunctional agents for the treatment of AD. All the target compounds exhibited significant abilities to inhibit and disaggregate Aβ aggregation, and acted as potential selective AChE inhibitors, biometal chelators and selective MAO-B inhibitors. Among these compounds, compound TM-6 showed the greatest inhibitory activity against self-induced Aβ aggregation (IC50 = 0.88 μM) and well disaggregation ability toward self-induced Aβ aggregation (95.1%, 25 μM), the TEM images, molecular docking study and molecular dynamics simulations provided reasonable explanation for its high efficiency, and it was also found to be a remarkable antioxidant (ORAC-FL values of 2.1eq.), the best AChE inhibitor (IC50 = 0.13 μM) and MAO-B inhibitor (IC50 = 1.0 μM), as well as a good neuroprotectant. UV-visual spectrometry and ThT fluorescence assay revealed that compound TM-6 was not only a good biometal chelator by inhibiting Cu2+-induced Aβ aggregation (95.3%, 25 μM) but also could disassemble the well-structured Aβ fibrils (88.1%, 25 μM). Further, TM-6 could cross the blood-brain barrier (BBB) in vitro. More importantly, compound TM-6 did not show any acute toxicity in mice at doses of up to 1000 mg/kg and improved scopolamine-induced memory impairment. Taken together, these data indicated that TM-6, an excellent balanced multifunctional inhibitor, was a potential lead compound for the treatment of AD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

We performed a comparative analysis of infarction-limiting activity of analogues of opioid receptor agonist U-50488 under conditions of heart reperfusion in rats. Derivatives of amide N-methyl-2-(pyrrolidin-1-yl)cyclohexyl-1-amine were administered 5 min before reperfusion in a dose of 1 mg/kg, derivative II (opicor) was additionally used in a dose of 2 mg/kg. In a dose of 1 mg/kg, all derivatives of opioid U-50488 were ineffective and produced no infarction-limiting effect. Opicor in a dose of 2 mg/kg reduced the infarction size/area at risk ratio and improved the contractility parameters of the isolated heart. Opioid receptor antagonist naltrexone (5 mg/kg) abolished the infarction-limiting effect of opicor. Hence, the infarction-reducing effect of opicor is associated with activation of opioid receptors. We also demonstrated that the opioid (opicor) can improve cardiac contractility during the reperfusion period.

We identified (5R)-6-methyl-5-phenyl-1,3,4,5,6,7-hexahydro-2,5-methano-2,6-benzodiazonine (DS21980956: 4-(R)) as a novel [5.2.1]bicyclic basic compound. The scaffold was inspired by fentanyl or pethidine, which possess potent analgesic activities. DS21980956 had potent analgesic activity in the mouse acetic acid writhing test or tail flick test without agonistic activity at the µ opioid receptor (MOR). The mechanism of analgesic action of DS21980956 was considered to differ from a biased ligand, for example, TRV-130 (3, oliceridine)., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depressive disorder (MDD), yet their mechanisms of action are not fully understood and their therapeutic benefit varies among individuals. We used a targeted metabolomics approach utilizing a panel of 180 metabolites to gain insights into mechanisms of action and response to citalopram/escitalopram. Plasma samples from 136 participants with MDD enrolled into the Mayo Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) were profiled at baseline and after 8 weeks of treatment. After treatment, we saw increased levels of short-chain acylcarnitines and decreased levels of medium-chain and long-chain acylcarnitines, suggesting an SSRI effect on β-oxidation and mitochondrial function. Amines-including arginine, proline, and methionine sulfoxide-were upregulated while serotonin and sarcosine were downregulated, suggesting an SSRI effect on urea cycle, one-carbon metabolism, and serotonin uptake. Eighteen lipids within the phosphatidylcholine (PC aa and ae) classes were upregulated. Changes in several lipid and amine levels correlated with changes in 17-item Hamilton Rating Scale for Depression scores (HRSD 17 ). Differences in metabolic profiles at baseline and post-treatment were noted between participants who remitted (HRSD 17  ≤ 7) and those who gained no meaningful benefits (<30% reduction in HRSD 17 ). Remitters exhibited (a) higher baseline levels of C3, C5, alpha-aminoadipic acid, sarcosine, and serotonin; and (b) higher week-8 levels of PC aa C34:1, PC aa C34:2, PC aa C36:2, and PC aa C36:4. These findings suggest that mitochondrial energetics-including acylcarnitine metabolism, transport, and its link to β-oxidation-and lipid membrane remodeling may play roles in SSRI treatment response.

Background: Similar anticonvulsants, such as gabapentin and pregabalin are recommended in neuropathic pain management, however little is known about their clinical differences in cases of low back pain. This paper aims to highlight some of the possible clinical differences between gabapentin and pregabalin in low back pain., Methods: Patients with moderate to severe low back pain were recruited. Eligible patients were randomised to receive either pregabalin (300 mg/day)or gabapentin (800 mg/day) for six weeks. The primary outcome measure was pain intensity according to the Visual Analogue Score (VAS) at baseline and at six weeks. The secondary outcome measures were: anxiety, insomnia, fatigue and the self-rated (GCI), measured at baseline, second, fourth, and the sixth week., Results: A total of 64 patients, pregabalin group (n=28), gabapentin group (n=36) completed the study. While pregabalin group showed a significantly lower pain score (p=0.039). The gabapentin group showed significant improvement in anxiety (p=0.001), insomnia (p=0.001), general fatigue (p=0.009), physical fatigue (p=0.001), reduce activity (p=0.001), and mental fatigue (p=0.014) higher than that of pregabalin. No difference in (GCI) was seen at six weeks., Conclusion: This is the first trial aimed at comparing gabapentin with pregabalin in NLBP. Although the results are preliminary, in our pilot study pregabalin was found to be superior in pain reduction, gabapentin demonstrated better effect on anxiety, insomnia and fatigue symptoms. The results are preliminary and studies with a larger sample size are still required., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Carbapenem-resistant Enterobacteriaceae (CRE) are multidrug-resistant pathogens for which new treatments are desperately needed. Carbapenemases and other types of antibiotic resistance genes are carried almost exclusively on large, low-copy-number plasmids (pCRE). Accordingly, small molecules that efficiently evict pCRE plasmids should restore much-needed treatment options. We therefore designed a high-throughput screen to identify such compounds. A synthetic plasmid was constructed containing the plasmid replication machinery from a representative Escherichia coli CRE isolate as well as a fluorescent reporter gene to easily monitor plasmid maintenance. The synthetic plasmid was then introduced into an E. coli K12 tolC host. We used this screening strain to test a library of over 12,000 known bioactive agents for molecules that selectively reduce plasmid levels relative to effects on bacterial growth. From 366 screen hits we further validated the antiplasmid activity of kasugamycin, an aminoglycoside; CGS 15943, a nucleoside analog; and Ro 90-7501, a bibenzimidazole. All three compounds exhibited significant antiplasmid activity including up to complete suppression of plasmid replication and/or plasmid eviction in multiple orthogonal readouts and potentiated activity of the carbapenem, meropenem, against a strain carrying the large, pCRE plasmid from which we constructed the synthetic screening plasmid. Additionally, we found kasugamycin and CGS 15943 blocked plasmid replication, respectively, by inhibiting expression or function of the plasmid replication initiation protein, RepE. In summary, we validated our approach to identify compounds that alter plasmid maintenance, confer resensitization to antimicrobials, and have specific mechanisms of action., Competing Interests: Competing interest statement: The authors declare a competing interest (as defined by PNAS policy). This work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number R33AI119114 to J.E.K. K.E.Z. was supported in part by a National Institute of Allergy and Infectious Diseases training grant (T32AI007061). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The HP D300 digital dispenser and TECAN M1000 were provided for our use by TECAN (Morrisville, NC). Tecan had no role in study design, data collection/interpretation, manuscript preparation, or decision to publish.

Objective: To determine whether the use of perioperative gabapentin reduces postoperative pain and anxiety, decreases ropivacaine consumption and side effects, and improves patient satisfaction., Design: Randomized, placebo-controlled, phase 4 trial., Blinding: Participants, care providers, investigators, data analysts., Setting: Department of Thoracic Surgery of the Institute of Tuberculosis and Lung Disease, Rabka Zdrój Branch, Poland., Subjects: Forty patients undergoing the Ravitch procedure., Methods: Patients aged nine to 17 years were randomized into a gabapentin (preoperative 15 mg/kg, treatment) or placebo group. Postoperative analgesia included gabapentin (7.5 mg/kg) or placebo two times per day for three days, epidural ropivacaine + fentanyl, paracetamol, nonsteroidal anti-inflammatory drugs, and metamizol as a "rescue drug." Pain, anxiety, analgesic consumption, side effects, and patient satisfaction were recorded., Results: There was no statistically significant difference in median pain scores (numerical rating scale < 1/10) or incidence of adverse side effects between the gabapentin group (N = 20) and the placebo group (N = 20). Postoperative anxiety scores were significantly lower than before surgery in the gabapentin group (6 [4-8] vs 7 [6-8.5], P < 0.01) and remained unchanged in the placebo group (6 [5-6.5] vs 6 [5-7], P = 0.07). Gabapentin-treated patients received a lower number of doses of ondansetron when compared with the placebo group (6 [5-6] vs 7 [6-9], P = 0.02). A significant negative association was found between patient satisfaction and postoperative state anxiety in the gabapentin group (R = -0.51, P = 0.02)., Conclusions: Perioperative administration of gabapentin resulted in a decrease of postoperative anxiety in pediatric patients undergoing the Ravitch procedure., (© 2019 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Bacterial infections induced by drug-resistant strains have become a global crisis. A membrane-disrupted mechanism is considered as an effective way to kill bacteria with little chance to trigger drug resistance. It is necessary to explore and develop new materials based on the membrane-disrupted mechanism to combat bacterial resistance. Here we report the design of organic nanoparticles based on a polymer (PDCP) as highly effective inhibition and bactericidal reagents. The PDCP is devised to have a hydrophobic skeleton and hydrophilic side chain modified with protonated primary amines, which could self-assemble to form organic nanoparticles (PDCP-NPs). By taking advantage of the large surface to volume ratio of nanoparticles, the synthesized PDCP-NPs have enriched positive charges and multiple membrane-binding sites. Research results display that PDCP-NPs have highly potent antibacterial activity in vitro and vivo, especially for Gram-negative bacteria with low toxicity against mammalian cells. This work design will inspire researchers to develop more membrane-disrupted bactericide and advance the applications of organic nanoparticles in the antibacterial area.