CNS Side Effects Research Articles

The Emergent Role of Low-Dose Naltrexone in the Symptomatic Management of Chronic Musculoskeletal and Neuropathic Pain

As a result of the intricate mechanisms of pain transmission, traditional analgesics used alone, as well as concomitantly, often do not provide consistent and/or adequate pain relief for patients suffering with chronic pain conditions. Many analgesics, as well as antineuropathic and antispastic drugs, demonstrate synergistic CNS side effects, increasing the risk of respiratory depression and overdose when used in combination. Given the steady rise of opioid-related overdose deaths in the USA, pursuit of novel treatment options, such as low dose naltrexone (LDN) regimens, are of particular interest to researchers. Although multiple reliable studies exist which demonstrate the potential for LDN in pain management, large-scale, high-quality studies are lacking, or are in progress. This review article aims to analyze the currently available literature regarding low dose naltrexone therapy in order to evaluate its potential role in the management of chronic inflammatory, neuropathic, and generalized pain symptoms. Although promising, available data is limited in its utility, warranting further research and development regarding the clinical role and place in therapy of LDN in chronic pain management.

Role of MRI in Assessment of Central Nervous System Lesions and Post Treatment Complications in Pediatric Patents with Leukemia

Abstract Background In terms of pediatric oncology, leukemia is one of the most frequent deadly illnesses. Early CNS problem identification and appropriate therapy were enhanced by MRI. Aim Describe the MRI results brought on by leukemia's involvement in CNS structures and treatment-related CNS side effects, and evaluate their efficacy for early therapy and preventing long-term adverse effects. Patients and Methods A prospective observational study included 52 children with leukemia. All patients undergone MR examination including conventional MRI, MR diffusion imaging and MR venography (MRV). Results Regarding MRI finding of CNS, leukemic infiltration was found in 57.7%, sub volimic changes in mild manner in 50% and about 26% in a moderate manner while absent in 23.1%, PRES was present in 19.2%, venous thrombosis present in 30.8% and post treatment complications were found in 7.7%. Conclusion Diffusion-weighted MRI proved very helpful in the early diagnosis and distinction of various CNS lesions seen in young patients with leukemia and post-treatment CNS sequelae. These techniques included conventional, post- contrast, MR venography, and diffusion-weighted MRI.

Design and Synthesis of Quinoxaline Hybrids as Modulators of HIF-1a, VEGF, and p21 for Halting Colorectal Cancer.

A library of 16 3-benzyl-N 1-substituted quinoxalin-2-ones was synthesized as N 1-substituted quinoxalines and quinoxaline-triazole hybrids via click reaction. These compounds were tested for their anticancer activity via MTT assay on HCT-116 and normal colonocyte cell lines to assess their cytotoxic potentials and safety profiles. Overall, compounds 6, 9, 14, and 20 were found to be promising anticolorectal cancer agents; they exhibited remarkable cytotoxicity (IC50 0.05-0.07 μM) against HCT-116 cells within their safe doses (EC100) on normal colon cells. Their pronounced anticancer activities were observed as severe morphological alterations and shrinkage of the treated cancer cells. Besides, qRT-PCR analysis was conducted showing the potential of the promising hits to downregulate HIF-1a, VEGF, and BCL-2 as well as their ability to enhance the expression of proapoptotic genes p21, p53, and BAX in HCT-116 cells. In silico prediction revealed that most of our compounds agree with Lipinski and Veber parameters of rules, in addition to remarkable medicinal chemistry and drug-likeness parameters with no CNS side effects. Interestingly, docking studies of the compounds in the VEGFR-2' active site showed significant affinity toward the essential amino acids, which supported the biological results.

Combination administration of alprazolam and N-Ethylmaleimide synergistically enhances sleep behaviors in mice with no potential CNS side effects.

N-Ethylmaleimide (NEM), an agonist of the potassium chloride cotransporters 2 (KCC2) receptor, has been correlated with neurosuppressive outcomes, including decreased pain perception and the prevention of epileptic seizures. Nevertheless, its relationship with sleep-inducing effects remains unreported. The present study aimed to investigate the potential enhancement of NEM on the sleep-inducing properties of alprazolam (Alp). The test of the righting reflex was used to identify the appropriate concentrations of Alp and NEM for inducing sleep-promoting effects in mice. Total sleep duration and sleep quality were evaluated through EEG/EMG analysis. The neural mechanism underlying the sleep-promoting effect was examined through c-fos immunoreactivity in the brain using immunofluorescence. Furthermore, potential CNS-side effects of the combination Alp and NEM were assessed using LABORAS automated home-cage behavioral phenotyping. Combination administration of Alp (1.84 mg/kg) and NEM (1.0 mg/kg) significantly decreased sleep latency and increased sleep duration in comparison to administering 1.84 mg/kg Alp alone. This effect was characterized by a notable increase in REM duration. The findings from c-fos immunoreactivity indicated that NEM significantly suppressed neuron activation in brain regions associated with wakefulness. Additionally, combination administration of Alp and NEM showed no effects on mouse neural behaviors during automated home cage monitoring. This study is the first to propose and demonstrate a combination therapy involving Alp and NEM that not only enhances the hypnotic effect but also mitigates potential CNS side effects, suggesting its potential application in treating insomnia.

Safety of prolonged use of metoclopramide and domperidone as treatment for chronic gastrointestinal dysmotility disorders in patients with systemic sclerosis

BackgroundMetoclopramide and domperidone are prokinetic agents commonly used to treat gastrointestinal dysmotility disorders. This study aimed to evaluate the safety and associated side effects of prolonged-use metoclopramide and domperidone as treatment for chronic gastrointestinal dysmotility disorders in patients with systemic sclerosis (SSc). MethodsA quantitative observational survey was conducted by interview questionnaire in rheumatology outpatients at a tertiary teaching hospital in Riyadh, Saudi Arabia. The study included all patients aged 25–80 years diagnosed with SSc. All patients were on metoclopramide or domperidone for the treatment of chronic gastrointestinal dysmotility symptoms over at least 12 weeks. ResultsEighteen eligible patients were included. Most study participants were diagnosed with SSc complicated by interstitial lung disease (n = 13; 72.2 %). The most frequently reported side effect that occurred while taking prokinetic drugs was shortness of breath (n = 12; 66.7 %). None of the participants reported experiencing depression, galactorrhea, or syncope. CNS side effects were reported in 5.6 %. There were no differences in side effects based on the type and dosage of prokinetic drug used. ConclusionsUse of metoclopramide and domperidone for the treatment of chronic gastrointestinal dysmotility in SSc patients for 12 weeks or longer was not associated with any troublesome side effects. Further studies with more participants are needed to confirm our findings.

KRM–II–81 suppresses epileptifom activity across the neural network of cortical tissue from a patient with pharmacoresistant epilepsy

A clinical case of a 19-year-old male patient with pharmacoresistant seizures occurring following parieto-occipital tumor-resection at age 6 is described. Seizure surgery work-up included prolonged video EEG monitoring and head CT without contrast. Seizure focus was localized to the left temporal lobe, and we felt that the patient was an excellent candidate for seizure surgery. The patient underwent a left frontotemporal craniotomy for removal of the seizure focus with intraoperative electrocorticography (ECoG) conducted pre and post resection. ECoG recordings pre- and post-resection confirmed resolution of seizure generation. Imaging obtained immediately postoperatively showed complete resection of the residual tumor with no evidence of recurrence in follow-ups. A year after the surgery the patient is seizure-free but remains on seizure medication. With the patient's consent the excised epileptogenic tissue was used for ex-vivo research studies. The microelectrode recordings confirmed epileptiform activity in the excised tissue incubated in excitatory artificial cerebrospinal fluid. The epileptiform activity in the epileptogenic tissue was suppressed by addition of KRM–II–81, a novel α2/3 subtype preferring GABAA receptor (GABAAR) potentiator with previously demonstrated antiepileptic efficacy in multiple animal models of epilepsy and with reduced potential for CNS side-effects compared to classical benzodiazepine GABAAR potentiators. These findings support the proposition that KRM–II–81 might reduce seizure burden in pharmacoresistant patients.

Fragment merging approach for design, synthesis, and biological assessment of urea/acetyl hydrazide clubbed thienopyrimidine derivatives as GSK-3β inhibitors

New thienopyrimidine derivatives were designed and synthesized as GSK-3β inhibitors based on the structure of active binding site of GSK-3β enzyme. In this study, compounds 6b and 6a were found to be moderate GSK-3β inhibitors with IC50s 10.2 and 17.3 μM, respectively. Molecular docking study was carried out by docking the targeted compounds in the binding site of the GSK-3β enzyme using the MOE program. Moreover, ADME study was performed to predict certain pharmacokinetic properties. The results showed that all synthesized compounds may not be able to penetrate the blood brain barrier; so, the chances of CNS side effects are predicted to be low. CYP1D6 is predicted to be inhibited by compounds (5a, 5d, 6a, 9a and 9b), So drug-drug interactions are expected upon administration of these compounds.Graphical

Introducing of novel class of pyrano[2,3-c]pyrazole-5-carbonitrile analogs with potent antimicrobial activity, DNA gyrase inhibition, and prominent pharmacokinetic and CNS toxicity profiles supported by molecular dynamic simulation

Microbiological DNA gyrase is recognized as an exceptional microbial target for the innovative development of low-resistant and more effective antimicrobial drugs. Hence, we introduced a one-pot facile synthesis of a novel pyranopyrazole scaffold bearing different functionalities; substituted aryl ring, nitrile, and hydroxyl groups. All new analogs were characterized with full spectroscopic data. The antimicrobial screening for all analogs was assessed against standard strains of Gm + ve and Gm-ve through in vitro considers. The screened compounds displayed very promising MIC/MBC values against some of the bacterial strains with broad or selective antibacterial effects. Of these, 4j biphenyl analog showed 0.5-2/2-8 µg/mL MIC/MBC for suppression and killing of Gm + ve and Gm-ve strains. Moreover, the antimicrobial screening was assessed for the most potent analogs against certain highly resistant microbial strains. Consequently, DNA gyrase supercoiling assay was done for all analogs using ciprofloxacin as reference positive control. Obviously, the results showed a different activity profile with potent analog 4j with IC50 value 6.29 µg/mL better than reference drug 10.2 µg/mL. Additionally, CNS toxicity testing was done using the HiB5 cell line for attenuation of GABA/NMDA expression to both 4j and ciprofloxacin compounds that revealed better neurotransmitter modulation by novel scaffold. Importantly, docking and dynamic simulations were performed for the most active 4j analog to investigate its interaction with DNA binding sites, which supported the in vitro observations and compound stability with binding pocket. Finally, a novel scaffold pyranopyrazole was introduced as a DNA gyrase inhibitor with prominent antibacterial efficacy and low CNS side effect toxicity better than quinolones. Communicated by Ramaswamy H. Sarma

431-P: Effects of CB1 Antagonist INV-202 in Patients with Metabolic Syndrome—A Randomized, Placebo-Controlled, Double-Blind Phase 1B Study

Cannabinoid blockers have been successful for the treatment of obesity. However, due to CNS side effects drug development programs were halted. We present data from INV-202, a peripherally acting next generation CB1 blocker with very low CNS penetration. This randomized, DB, PC, PG, 28day study (NCT05282446) enrolled subjects with metabolic syndrome. Subjects received INV-202 25 mg or placebo and assessed weekly by lipid profile, weight, waist, and biomarkers. Oral glucose tolerance test (OGTT) was performed at baseline and at the end of study. All statistical comparisons are post-hoc.37 subjects were enrolled (46% Fem, Age 55 years, HgbA1c 5.7%, TG 2.22 mmol/L, BMI 38.1) INV-202 exhibited a mean weight loss of 3.5 kg (3.3%) compared with placebo subjects who gained a mean of 0.6 kg (0.5%). All other biomarkers showed improvements. There were no discontinuations, no SAEs and all AEs were mild to moderate. (nausea, decreased appetite, and diarrhea) INV-202 was well tolerated over 28 days of treatment. Significant improvements were noted. Further studies on the long-term cardiometabolic effect of this novel CB1 blocker are warranted. Disclosure G.D.Crater: Employee; Inversago Pharma. F.Ravenelle: Employee; Inversago. K.Lalonde: Employee; Inversago. J.Després: Advisory Panel; Inversago Pharma Inc., Other Relationship; Rockpointe Corporation – Steering Committee.

Novel topical anandamide formulation for alleviating peripheral neuropathic pain

Peripheral neuropathy (PN) is a condition of peripheral nerve damage leading to severe pain. The first line therapies are associated with adverse psychotropic effects (PSE) and second line therapies are not efficient enough to relieve pain. There is an unmet drug need for relieving pain effectively without PSE in PN. Anandamide, an endocannabinoid activates cannabinoid receptors to relieve the pain due to peripheral neuropathy (PN). Anandamide has a very short biological half-life as they are extensively metabolized by fatty acid amide hydrolase enzyme (FAAH). Regional delivery of safe FAAH inhibitor (FI) with anandamide would be beneficial for PN without PSE. The objective of the study is to identify a safe FI and deliver the anandamide in combination with the FI topically for the management of PN. The FAAH inhibition potential of silymarin constituents was evaluated by molecular docking and in vitro studies. The topical gel formulation was developed to deliver anandamide and FI. The formulation was assessed in chemotherapeutic agent-induced PN rat models to relieve mechanical-allodynia and thermal-hyperalgesia. The molecular docking studies demonstrated that the Prime MM-GBSA free energy of silymarin constituents were in the order of silybin > isosilybin > silychristin > taxifolin > silydianin. In in vitro studies, silybin 20 µM inhibited > 61.8% of FAAH activity and increased the half-life of anandamide. The developed formulation increased permeation of anandamide and silybin across the porcine skin. Furthermore, on the application of anandamide and anandamide–silybin gel to rat paws, there was a significant increase in the pain threshold for allodynic and hyperalgesic stimulus up to 1 h and 4 h, respectively. The topical anandamide with silybin delivery approach could serve to alleviate PN efficiently and thus could minimize unwanted CNS side effects of synthetic or natural cannabinoids in patients.

Behavioral and transcriptomic effects of the cancer treatment tamoxifen in mice.

Tamoxifen is a common treatment for estrogen receptor-positive breast cancer. While tamoxifen treatment is generally accepted as safe, there are concerns about adverse effects on cognition. We used a mouse model of chronic tamoxifen exposure to examine the effects of tamoxifen on the brain. Female C57/BL6 mice were exposed to tamoxifen or vehicle control for six weeks; brains of 15 mice were analyzed for tamoxifen levels and transcriptomic changes, and an additional 32 mice were analyzed through a battery of behavioral tests. Tamoxifen and its metabolite 4-OH-tamoxifen were found at higher levels in the brain than in the plasma, demonstrating the facile entry of tamoxifen into the CNS. Behaviorally, tamoxifen-exposed mice showed no impairment in assays related to general health, exploration, motor function, sensorimotor gating, and spatial learning. Tamoxifen-treated mice showed a significantly increased freezing response in a fear conditioning paradigm, but no effects on anxiety measures in the absence of stressors. RNA sequencing analysis of whole hippocampi showed tamoxifen-induced reductions in gene pathways related to microtubule function, synapse regulation, and neurogenesis. These findings of the effects of tamoxifen exposure on fear conditioning and on gene expression related to neuronal connectivity suggest that there may be CNS side effects of this common breast cancer treatment.

Design, Synthesis, Biological Evaluation, and Molecular Dynamics Studies of Novel Lapatinib Derivatives.

Co-expression of the epidermal growth factor receptor (EGFR, also known as ErbB1) and human epidermal growth factor receptor 2 (HER2) has been identified as a diagnostic or prognostic sign in various tumors. Despite the fact that lapatinib (EGFR/HER2 dual inhibitor) has shown to be successful, many patients do not respond to it or develop resistance for a variety of reasons that are still unclear. As a result, new approaches and inhibitory small molecules are still needed for EGFR/HER2 inhibition. Herein, novel lapatinib derivatives possessing 4-anilinoquinazoline and imidazole scaffolds (6a-l) were developed and screened as EGFR/HER2 dual inhibitors. In vitro and in silico investigations revealed that compound 6j has a high affinity for the ATP-binding regions of EGFR and HER2. All of the designed candidates were predicted to not penetrate the BBB, raising the expectation for the absence of CNS side effects. At 10 µM, derivatives possessing 3-chloro-4-(pyridin-2-ylmethoxy)aniline moiety (6i-l) demonstrated outstanding ranges of percentage inhibition against EGFR (97.65-99.03%) and HER2 (87.16-96.73%). Compound 6j showed nanomolar IC50 values over both kinases (1.8 nM over EGFR and 87.8 nM over HER2). Over EGFR, compound 6j was found to be 50-fold more potent than staurosporine and 6-fold more potent than lapatinib. A kinase selectivity panel of compound 6j showed poor to weak inhibitory activity over CDK2/cyclin A, c-MET, FGFR1, KDR/VEGFR2, and P38a/MAPK14, respectively. Structure-activity relationship (SAR) that were obtained with different substitutions were justified. Additionally, molecular docking and molecular dynamics studies revealed insights into the binding mode of the target compounds. Thus, compound 6j was identified as a highly effective and dual EGFR/HER2 inhibitor worthy of further investigation.

Combination of curcumin and piperine synergistically improves pain-like behaviors in mouse models of pain with no potential CNS side effects

BackgroundCurcumin and piperine are major bioactive compounds of Curcuma longa and Piper nigrum, widely consumed as spices and flock medicine. The combinational use of these plants is a common practice in Southeast Asia. Synergism between curcumin and piperine has been found in several animal models but not in periodontal disease and diabetes, and the antinociceptive interaction is still unknown. Hence, the present study aimed to assess the interaction between curcumin and piperine in pain and its potential CNS side effect profile.MethodsFormalin test and in vitro LPS-stimulated RAW 264.7 macrophage cells were used to assess the synergistic interaction of curcumin and piperine in a mouse model of inflammatory pain. Tail-flick and cold plate tests were applied to determine the antinociceptive synergism between piperine and curcumin. The interaction was determined by applying isobolographic analysis. The potential CNS-side effects of the curcumin and piperine combination were also assessed using LABORAS automated home-cage behavioral analysis.ResultsCurcumin alone dose-dependently improved pain-like behaviors in the formalin, tail-flick, and cold plate tests with the ED50 of 71.4, 34.4, and 31.9 mg/kg, respectively. Additionally, piperine exhibited efficacy in the formalin, tail-flick, and cold plate tests with the ED50 of 18.4, 8.1, and 28.1 mg/kg, respectively. The combination of curcumin and piperine (1:1 ED50 ratio) produced synergistic interaction in the formalin, tail-flick, and cold plate tests as assessed significantly lower experimental ED50 values (5.9, 5.2, and 5.5 mg/kg) compared to theoretical ED50 values (44.9, 21.3, and 30.0 mg/kg), isobologram analysis, and interaction index values of 0.13, 0.24 and 0.18, respectively. The synergistic interaction of curcumin and piperine was further confirmed by the efficacy of the combination in LPS-stimulated RAW 264.7 macrophage cells. Curcumin and piperine interacted synergistically, reducing proinflammatory mediators. The combination also demonstrated better compatibility profiles with neuronal cells. Furthermore, the curcumin-piperine combination had no effects on mouse spontaneous locomotor behaviors in LABORAS automated home cage monitoring.ConclusionOverall, the present study demonstrates strong antinociceptive synergism between curcumin and piperine in mouse models with no potential CNS side effects, suggesting its possible use in clinical trials.

Artificial Intelligent Context-Aware Machine-Learning Tool to Detect Adverse Drug Events from Social Media Platforms.

Pharmacovigilance (PV) has proven to detect post-marketing adverse drug events (ADE). Previous research used the natural language processing (NLP) tool to extract unstructured texts relevant to ADEs. However, texts without context reduce the efficiency of such algorithms. Our objective was to develop and validate an innovative NLP tool, aTarantula, using a context-aware machine-learning algorithm to detect existing ADEs from social media using an aggregated lexicon. aTarantula utilized FastText embeddings and an aggregated lexicon to extract contextual data from three patient forums (i.e., MedHelp, MedsChat, and PatientInfo) taking warfarin. The lexicon used warfarin package inserts and synonyms of warfarin ADEs from UMLS and FAERS databases. Data was stored on SQLite and then refined and manually checked by three clinical pharmacists for validation. Multiple organ systems where the most frequent ADE were reported at 1.50%, followed by CNS side effects at 1.19%. Lymphatic system ADEs were the least common side effect reported at 0.09%. The overall Spearman rank correlation coefficient between patient-reported data from the forums and FAERS was 0.19. As determined by pharmacist validation, aTarantula had a sensitivity of 84.2% and a specificity of 98%. Three clinical pharmacists manually validated our results. Finally, we created an aggregated lexicon for mining ADEs from social media. We successfully developed aTarantula, a machine-learning algorithmn based on artificial intelligence to extract warfarin-related ADEs from online social discussion forums automatically. Our study shows that it is feasible to use aTarantula to detect ADEs. Future researchers can validate aTarantula on the diverse dataset.

Curcumin Diethyl γ-Aminobutyrate, a Prodrug of Curcumin, for Enhanced Treatment of Inflammatory Pain.

Curcumin is a naturally occurring polyphenol compound with potential analgesic effects. It has been shown to improve pain-like behaviors in numerous models of pain. Despite its potential, curcumin exhibits poor physicochemical and pharmacokinetic properties, which hinder its oral therapeutic efficacy. Curcumin diethyl γ-aminobutyrate (CUR-2GE), a carbamate prodrug of curcumin, was designed to overcome these limitations and demonstrated greater anti-neuroinflammatory effects compared to curcumin in vitro. Thus, this study evaluated the effect of CUR-2GE and its parent compound on pain-like behaviors in carrageenan- and LPS-induced mouse models. The possible side effects of CUR-2GE were also assessed by exploring its effects on motor coordination and spontaneous locomotor activity after acute and chronic treatments. The results showed that CUR-2GE improved mechanical and thermal hyperalgesia and locomotor activity to a greater extent than curcumin in carrageenan-induced mice. These results are in line with the ability of CUR-2GE to suppress peripheral inflammation in the paw tissue of carrageenan-induced mice, indicated by a significant decrease in TNF-α and IL-6 expression levels. Similarly, in LPS-induced mice, CUR-2GE improved sickness and pain-like behaviors (exploratory behaviors and long-term locomotor activity) to a greater extent than curcumin. Furthermore, CUR-2GE significantly reduced the level of proinflammatory cytokines in both the plasma and spinal cord tissue of LPS-induced mice, exhibiting significantly higher inhibition than curcumin. Moreover, the motor coordination, and locomotive behaviors of mice were not affected by both acute and chronic administration of CUR-2GE, indicating no potential CNS side effects. Thus, CUR-2GE demonstrated enhanced therapeutic efficacy in mouse models of inflammatory pain without any possible CNS side effects, suggesting its potential to be developed as an analgesic agent against inflammatory pain.

Nanogel-mediated drug delivery system for anticancer agent: pH stimuli responsive poly(ethylene glycol/acrylic acid) nanogel prepared by gamma irradiation

The popularity of nanogel as nano drug carrier lies in its adjustable physical properties, and the ability to encapsulate drug particles with improved properties is being developed to meet the diverse pH-sensitive nanogel for anticancer agent. Monitoring pH has been identified as an important diagnostic element during the treatment process. A pH-sensitive nanogel consisting of (PEG/PMAc) in the ratio of (50:50%) hasbeen cross-linkedby γ-irradiation techniques at an irradiation dose of 5 kGy. Compound 4 and its nanogel 5 were synthesized and assessed for their anticancer effects against HepG2, A549, MCF-7 and HCT-116 as dual VEGFR-2 and EGFR tyrosine kinases inhibitors. The molecular design was performed to investigate the binding mode of compound 4 with VEGFR-2 and EGFR receptors. Our compound 5 in nanogel showed enhanced anticancer activities against the four tested cancer cell lines and also showed higher inhibition activities against VEGFR-2 and EGFRT790M kinases than the derivative 4. Finally, our derivative 4 showed good in silico calculated ADMET profile. It was expected to show good GIT absorption in human, lower CNS side effects, no hepatotoxic actions and higher acute and oral chronic toxic doses in comparing to sorafenib and erlotinib. The obtained results showed that, our compound could be useful as a template for future design, optimization, adaptation and investigation to produce more potent and selective dual VEGFR-2/EGFRT790M inhibitors with higher anticancer activity.

Curcumin and metformin synergistically modulate peripheral and central immune mechanisms of pain

Metformin is a well-tolerated antidiabetic drug and has recently been repurposed for numerous diseases, including pain. However, a higher dose of metformin is required for effective analgesia, which can potentiate its dose-dependent gastrointestinal side effects. Curcumin is a natural polyphenol and has beneficial therapeutic effects on pain. Curcumin has been used as an analgesic adjuvant with several analgesic drugs, allowing synergistic antinociceptive effects. Nevertheless, whether curcumin can exert synergistic analgesia with metformin is still unknown. In the present study, the nature of curcumin-metformin anti-inflammatory interaction was evaluated in in vitro using lipopolysaccharide-induced RAW 264.7 macrophage and BV-2 microglia cells. In both macrophage and microglia, curcumin effectively potentiates the anti-inflammatory effects of metformin, indicating potential synergistic effects in both peripheral and central pathways of pain. The nature of the interaction between curcumin and metformin was further recapitulated using a mouse model of formalin-induced pain. Coadministration of curcumin and metformin at a 1:1 fixed ratio of their ED50 doses significantly reduced the dose required to produce a 50% effect compared to the theoretically required dose in phase II of the formalin test with a combination index value of 0.24. Besides, the synergistic interaction does not appear to involve severe CNS side effects indicated by no motor alterations, no alterations in short-term and long-term locomotive behaviors, and the general well-being of mice. Our findings suggest that curcumin exerts synergistic anti-inflammation with metformin with no potential CNS adverse effects.

Synthesis, docking study, and structure activity relationship of novel anti-tumor 1, 2, 4 triazole derivatives incorporating 2-(2, 3- dimethyl aminobenzoic acid) moiety

A series of 1,2,4 triazole derivatives (H7-12) have been synthesized by reacting an excess of hydrazine hydrate with carbothioamide derivatives (H1-6). The final compounds (HB1-HB6) were synthesized by reacting the triazole derivatives with mefenamic acid using DCC as a coupling agent. The chemical structures were confirmed by FT-IR,1H, and13C-NMR spectra, and some physicochemical properties were determined. The cytotoxicity of the different compounds (HB1-HB6) was evaluated by the MTT assay against two human epithelial cancer cell lines, A549 lung carcinoma and Hep G2 hepatocyte carcinoma, and one normal human cell line WI-38 lung fibroblasts. The mode of cell killing (apoptosis versus necrosis), as well as the effect on cell cycle phases were evaluated via flow cytometry. Additionally, EGFR tyrosine kinase inhibition assay was performed. The results presented in the current study indicate that the six tested compounds exhibited cytotoxicity against both cancer cell lines, and the lowest IC50was achieved with compound HB5 against Hep G2 cancer cells which was found to be highly selective against cancer cells. HB5-treated Hep G2 cells were arrested at the S and G2/M cell cycle phases. Compound HB5 caused cell killing via apoptosis rather than necrosis, and this was achieved by inhibiting EGFR tyrosine kinase activity needed for cell proliferation, and cell cycle progression. In silicopre-ADMET studies confirmed all final compounds don’t cause CNS side effects, with little liver dysfunction effect.

Novel Liposomal Rolipram Formulation for Clinical Application to Reduce Emesis.

IntroductionThe phosphodiesterase 4 (PDE4) inhibitor, rolipram, has beneficial effects on tissue inflammation, injury and fibrosis, including in the liver. Since rolipram elicits significant CNS side-effects in humans (ie, nausea and emesis), our group developed a fusogenic lipid vesicle (FLV) drug delivery system that targets the liver to avoid adverse events. We evaluated whether this novel liposomal rolipram formulation reduces emesis.MethodsC57Bl/6J male mice were used to compare the effect of three doses of free and FLV-delivered (FLVs-Rol) rolipram in a behavioral correlate model of rolipram-induced emesis. Tissue rolipram and rolipram metabolite levels were measured using LC-MS/MS. The effect of FLVs-Rol on brain and liver PDE4 activities was evaluated.ResultsLow and moderate doses of free rolipram significantly reduced anesthesia duration, while the same doses of FLVs-Rol had no effect. However, the onset and duration of adverse effects (shortening of anesthesia period) elicited by a high dose of rolipram was not ameliorated by FLVs-Rol. Post-mortem analysis of brain and liver tissues demonstrated that FLVs affected the rate of rolipram uptake by liver and brain. Lastly, administration of a moderate dose of FLVs-Rol attenuated endotoxin induced PDE4 activity in the liver with negligible effect on the brain.DiscussionThe findings that the low and moderate doses of FLVs-Rol did not shorten the anesthesia duration time suggest that FLV delivery prevented critical levels of drug from crossing the blood-brain barrier (BBB) to elicit CNS side-effects. However, the inability of high dose FLVs-Rol to prevent CNS side-effects indicates that there was sufficient unencapsulated rolipram to cross the BBB and shorten anesthesia duration. Notably, a moderate dose of FLVs-Rol was able to decrease PDE4 activity in the liver without affecting the brain. Taken together, FLVs-Rol has a strong potential for clinical application for the treatment of liver disease without side effects.

ZYKR1, a novel, potent, and peripherally selective kappa opioid receptor agonist reduces visceral pain and pruritus in animal models

Opioid receptor agonists are effective analgesic agents. Central activation of the mu and/or kappa opioid receptors (KOR) is associated with CNS side effects, which limits their effectiveness. Recent studies indicated that peripherally restricted, selective KOR agonists were potent analgesics and devoid of CNS-related side effects. To confirm this hypothesis, we designed a novel, potent, and peripherally restricted KOR-selective agonist, ZYKR1. The analgesic efficacy, brain penetration and safety of ZYKR1 were assessed in pre-clinical models. ZYKR1 showed KOR agonistic activity in the cAMP assay, with an EC50 of 0.061 nM and more than 105-fold selectivity over the mu and delta opioid receptors (EC50 > 10 μM). ZYKR1 was not found to bind mu, delta opioid, and NOP receptors in radioligand binding assays. ZYKR1 produced concentration-dependent inhibition of electrically evoked contractions in isolated mouse vas deferens with an IC50 of 1.6 nM ZYKR1 showed peripheral restriction and potent analgesic efficacy in various in-vivo animal models (acetic acid induced visceral pain mouse model, ED50: 0.025 mg/kg, IV; ovariohysterectomy induced postoperative pain rat model, ED50: 0.023 mg/kg, IV; and C48/80 induced pruritus mouse model, ED50: 0.063 mg/kg, IV). In addition, ZYKR1 was devoid of motor coordination, physical dependence, dysphoria, and respiratory depression at 30, 400, 10 and 10-fold of efficacy dose, respectively. In conclusion, ZYKR1 has potent antinociceptive action in visceral pain and pruritus with limited CNS side effects in preclinical models owing to its peripheral restriction.