Conventional Nonsteroidal Anti-inflammatory Drugs Research Articles

Anti-inflammatory Activity of Polyphenols from Labisia pumila Leaves Extract

Non-Steroidal Anti-inflammatory Drugs (NSAIDs) represent a class of pharmaceutical agents that are frequently misused and misconstrued within the medical landscape. While demonstrably efficacious in providing transient pain relief, NSAIDs do not effectively address the fundamental etiology of pain and are associated with a spectrum of potential adverse effects. Labisia pumila var alata also known as "Kacip Fatimah" has been traditionally used which is attributed to its antioxidant properties. Nonetheless, little attempt has been made to examine its antioxidant and anti-inflammatory characteristics. This study determined the molecular interactions and inhibitory activity profiles of L. pumila methanolic extract (LPE) against the corresponding enzymes via in chemico and in silico approaches. In chemico analysis was done on antioxidant activity and anti-inflammatory properties of L. pumila. The findings indicated that LPE exhibit the potent anti-inflammatory activity. Through high-performance liquid chromatography, it was shown that LPE had the highest gallic acid concentration at 10.74 ± 2.23 mg/mL. LPE did not exhibit cytotoxicity up to 100 µg/mL and displayed optimal protective against UVB-irradiation at 50 µg/mL towards HSF1184 Fibroblast cell line. LPE exhibited potent anti-inflammatory activity as it inhibited elastase and COX-2. Molecular docking studies indicated that gallic acid has a good affinity for collagenase (˗5.68 kcal/mol), elastase (˗4.88 kcal/mol) and COX 2 (˗4.91 kcal/mol). These findings collectively suggested that L. pumila extract has significant potential for the formulation of the natural anti-inflammatory remedies which offer a safer alternative treatment for pain relief, especially for long-term use replacing the conventional NSAIDs medicines.

Comparison of the efficacy of aescin and diclofenac sodium in the management of postoperative sequelae and their effect on salivary Prostaglandin E2 and serum C–reactive protein levels after surgical removal of impacted mandibular third molar: a randomized, double-blind, controlled clinical trial.

Introduction Surgical removal of an impacted third molar is one of the most common oral surgical procedures performed in dental offices. The postoperative phase is often associated with severe inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) are usually prescribed to manage postoperative discomfort. NSAIDs have been associated with gastrointestinal bleeding, renal function disturbances, and platelet count reductions. Thus, the present study demonstrates the utility of aescin in managing postoperative discomfort after the surgical removal of impacted mandibular third molars. This study aimed to correlate salivary PGE2 levels and serum C-reactive protein levels with subjective and objective symptoms after surgical extraction of the mandibular third molar and their relationship with drug therapy. Methods The planned study is a single-center, double-blind, randomized, parallel, prospective clinical trial. Each patient will be prescribed either diclofenac sodium 150 mg/day or aescin (escin) 120 mg/day to be taken orally in divided doses for five days after surgically removing the impacted mandibular third molar. Pain will be assessed using a visual analog scale. Facial swelling and mouth opening will be recorded using a metric scale with standardized reference points. ELISA (enzyme-linked immunosorbent assay (ELISA) will be employed to measure salivary Prostaglandin E2 and serum C–reactive protein levels. All parameters will be recorded preoperatively (T0) on the second postoperative day (T1) and fifth postoperative day (T2). Conclusion The proposed study is expected to show a favorable response to the administration of aescin for the management of postoperative discomfort compared to diclofenac sodium after third molar surgery. The proposed study is expected to positively manipulate the levels of salivary Prostaglandin E2 and serum C–reactive protein, which are reliable inflammatory markers. The outcome of this study may provide an efficacious and safe alternative to conventional nonsteroidal anti-inflammatory drugs for managing postoperative discomfort following third molar surgery.

Increased risk of malignancy in HLA-B27-positive patients with ankylosing spondylitis requiring biologics for sustained inflammation: A long-term, single-center retrospective study.

To assess the link between the administration of biologic disease-modifying antirheumatic drugs (bDMARDs) and the risk of malignancy in human leukocyte antigen B27 (HLA-B27)-positive patients with ankylosing spondylitis (AS) experiencing sustained inflammation. Between 2006 and 2021, 1445 HLA-B27-positive patients with AS were retrospectively evaluated. Among them, 112 patients required bDMARD therapy. The study compared conventional therapy with bDMARDs and investigated the risk factors for developing malignancies. During 8253 patient-years of follow-up, 38 (2.6%) patients developed various malignancies, including lung, liver, breast, and colon cancer. The risk of malignancy was significantly higher in the bDMARD-treated group compared to PS-matched groups receiving conventional synthetic DMARDs (csDMARD) and non-steroidal anti-inflammatory drugs. The cumulative risk of malignancies increased significantly after 6 years of follow-up. All patients who developed malignancy after bDMARD therapy received tumor necrosis factor-α inhibitors. Requiring bDMARD therapy, requiring bDMARDs in combination with csDMARD therapy, and being diagnosed with AS after 30 years of age were independent risk factors for developing malignancy. HLA-B27-positive AS patients with sustained inflammation requiring biologic therapy, particularly if diagnosed after age 30, may have an increased risk of malignancy. Regular cancer screenings are advisable for these patients while undergoing biologic treatment.

Risk of infections in psoriatic arthritis or axial spondyloarthritis patients treated with targeted therapies: A meta-analysis of randomized controlled trials

ObjectiveTo evaluate the risk of global infections in patients with psoriatic arthritis (PsA) and axial spondyloarthritis encompassing ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA) treated with targeted therapies. MethodsMedline and Cochrane databases were systematically searched up to March 2021 for randomized controlled trials (RCTs) performed in patients with PsA or axial spondyloarthritis treated with biologic or targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs). Global infections (any infections reported, including bacterial, viral and fungal infections, except serious infections) were the primary outcome. Secondary outcomes included serious infections defined as life-threatening infections or any infection requiring intravenous antibiotics or hospitalization. The relative risk of infections was determined by meta-analysis of RCTs. ResultsA total of 60 RCTs were included (20,418 patients), encompassing 17 b/tsDMARDs, compared with placebo, conventional synthetic drugs (csDMARDs) or non-steroidal anti-inflammatory drugs (NSAIDs). An increased risk of any infection for patients exposed to these drugs was found (RR 1.15, 95% CI [1.06–1.25]), mainly with high doses and longer duration of treatment. Most infections were respiratory tract or ear, nose, and throat (ENT) infections. Subgroup analyses showed a statistically significant increased risk of infections for axial spondyloarthritis patients (RR 1.32, 95% CI [1.14–1.52]), but not for PsA patients (RR 1.05, 95% CI [0.97–1.14]). Infection risk was highest with TNF inhibitors (RR 1.23, 95% CI [1.11–1.37]) and IL-17 inhibitors (RR 1.30, 95% CI [1.07–1.59]). No increased risk of serious infections was shown. ConclusionIn contrast to serious infections, the risk of global infections is moderately increased with b/tsDMARDs in spondyloarthritis, and is associated in particular with use of TNF and IL-17 inhibitors.

A comparative study of oral diacerein and transdermal diacerein as Novasomal gel in a model of MIA induced Osteoarthritis in rats

Background: Osteoarthritis is a chronic pathology of the joints causing disability and morbidity. Diacerein is a disease-modifying agent indicated for osteoarthritis management with enhanced performance and have much lower side effects profile than conventional non-steroidal anti-inflammatory drugs. Oral administration of Diacerein is associated with a laxative effect , thus causing treatment discontinuation. Aim: This study aimed to evaluate the activity of Diacerein novasome-based transdermal gel compared with standard oral treatment in the management of induced osteoarthritis in a rat model. Materials and methods: A single intra-articular injection of monosodium iodoacetate was administered to the left knee joint, resulting in the development of Osteoarthritis. Disease progression and the effect of both routes of Diacerein treatment were evaluated by morphological, biochemical, histological, and radiological studies. Results: Osteoarthritis was successfully induced in rats’ knee joints. Morphological studies revealed that both Diacerein treatments significantly reduced joint swelling as compared to the untreated group. The serum TNF-α and IL-1β levels were significantly lower in both Diacerein treatment groups as compared to the untreated group throughout the course of the study. Histological and radiological findings confirmed that transdermal Diacerein treatment protects against cartilage degradation like oral treatment. Conclusion: Novasomal technology proved its efficacy as a carrier for the transdermal delivery of Diacerein. The in-vivo study on an animal model of osteoarthritis showed that Diacerein transdermal gels provided sufficient pharmacological activity for the attenuation of the disease. This finding could support its use as an alternative to the standard oral treatment to avoid side effects.

Streptococcus Salivarius K12 Probiotic in Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis syndrome

Background and Objectives: Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is the most common syndrome in children. This complication is characterized by the sudden onset of fever, aphthous stomatitis, pharyngitis, and cervical adenitis, as well as less common signs, such as headache, rash, and changes in the digestive system. This study aimed to investigate the effectiveness of the probiotic Streptococcus Salivarius K12 in patients with PFAPA. Materials and Methods: This randomized clinical trial included PFAPA patients divided into intervention and control groups. The intervention group, along with the conventional treatments, received Lactogum containing Probiotic Streptococcus Salivarius K12 for four months. The control group, however, received conventional treatments, including acetaminophen and non-steroidal anti-inflammatory drugs (prednisolone), along with a placebo. Results: This study investigated 40 PFAPA patients. The mean ages of the patients in the control and intervention groups were 6.94±2.21 and 5.71±2.59 years, respectively. The highest fever temperature of the children in the control and intervention groups upon admission to the clinic were 38.88±0.53ºC and 39.96±0.85ºC, respectively. According to the results, in the first month, the mean number of days suffering from fever was fewer in the intervention group, compared to the control group. Moreover, the mean number of pharyngitis days in the first and second months was fewer in the intervention group than that in the control group. In the fourth month, the disease symptom percentages were reduced in the intervention group, compared to the control group. Conclusion: The results show that the use of probiotics (Streptococcus Salivarius K12) can be effective in reducing the consumption of corticosteroids and minimizing the complications caused by conventional treatments. 

From the Bush to the Brain: Preclinical Stages of Ethnobotanical Anti-Inflammatory and Neuroprotective Drug Discovery—An Australian Example

The Australian rainforest is a rich source of medicinal plants that have evolved in the face of dramatic environmental challenges over a million years due to its prolonged geographical isolation from other continents. The rainforest consists of an inherent richness of plant secondary metabolites that are the most intense in the rainforest. The search for more potent and more bioavailable compounds from other plant sources is ongoing, and our short review will outline the pathways from the discovery of bioactive plants to the structural identification of active compounds, testing for potency, and then neuroprotection in a triculture system, and finally, the validation in an appropriate neuro-inflammatory mouse model, using some examples from our current research. We will focus on neuroinflammation as a potential treatment target for neurodegenerative diseases including multiple sclerosis (MS), Parkinson’s (PD), and Alzheimer’s disease (AD) for these plant-derived, anti-inflammatory molecules and highlight cytokine suppressive anti-inflammatory drugs (CSAIDs) as a better alternative to conventional nonsteroidal anti-inflammatory drugs (NSAIDs) to treat neuroinflammatory disorders.

The effect of guselkumab on inhibiting radiographic progression in patients with active psoriatic arthritis: study protocol for APEX, a Phase 3b, multicenter, randomized, double-blind, placebo-controlled trial

BackgroundGuselkumab, a fully human monoclonal antibody targeting the interleukin (IL)-23p19 subunit, is approved to treat adults with active psoriatic arthritis (PsA). In the Phase 3 DISCOVER-2 trial of 739 bilogico-naïve patients with active PsA, guselkumab 100 mg resulted in less radiographic progression, assessed via change from baseline in PsA-modified van der Heijde-Sharp (vdH-S) score, compared with placebo at week (W) 24 when given at W0, W4, and then every 4 weeks (Q4W) or Q8W. The least squares mean differences from placebo were -0.66 for guselkumab Q4W (p=0.011) and -0.43 for guselkumab Q8W (p=0.072). Reports suggest baseline C-reactive protein (CRP) and joint erosions are strongly prognostic of poor outcomes, especially radiographic progression, in PsA patients. We designed a trial (APEX) to further assess the effect of guselkumab on radiographic progression in patients with active PsA and risk factors for radiographic progression.MethodsPatients are eligible for APEX if they have had PsA for ≥6 months and active disease (≥3 swollen and ≥3 tender joints, CRP ≥0.3 mg/dL) despite prior therapy with conventional synthetic disease-modifying antirheumatic drugs, apremilast, and/or nonsteroidal anti-inflammatory drugs, with ≥2 joints with erosions on baseline radiographs (hands and feet). The primary and major secondary endpoints are the proportion of patients achieving ≥20% improvement in American College of Rheumatology response criteria (ACR20) response at W24 and change from baseline at W24 in PsA-modified vdH-S score, respectively. Sample sizes of 350/250/350 for guselkumab Q8W/guselkumab Q4W/placebo are expected to provide >99% power to detect significant differences in W24 ACR20 response rates for each guselkumab group vs placebo, as well as ≥90% (Q4W vs placebo) and ≥80% (Q8W vs placebo) power to detect a significant difference in PsA-modified vdH-S score change at W24. A Cochran-Mantel-Haenszel test and analysis of covariance will compare treatment efficacy for the primary and major secondary endpoints, respectively.DiscussionDISCOVER-2 findings informed the design of APEX, a Phase 3b study intended to further evaluate the impact of guselkumab in patients with active PsA and known risk factors for radiographic progression.Trial registrationThis trial was registered at ClinicalTrials.gov, NCT04882098. Registered on 11 May 2021.

Possible synergic action of non-steroidal anti-inflammatory drugs and glucosamine sulfate for the treatment of knee osteoarthritis: a scoping review

BackgroundSeveral studies have reported that glucosamine sulfate (GS) can improve knee osteoarthritis (OA) symptomatology. In parallel, the disease-modifying effects of non-steroidal anti-inflammatory drugs (NSAIDs) in knee OA have also been investigated. However, limited literature has reported the combined effect of GS and NSAIDs. The aim of this scoping review is to describe the scope and volume of the literature investigating the potential benefits and synergistic effect of a combination of GS and NSAIDs in patients with knee OA.MethodsPubMed and Embase were searched for studies published from inception through April 2022, evaluating the effects of the combination of GS and NSAIDs in OA patients, versus either treatment alone. Data are reported narratively.ResultsFive studies were included in this review; 4 were randomized control trials and one was a prospective observational study. The duration of combination treatment was 6 to 12 weeks. The combination was compared to celecoxib in 2 studies, meloxicam in 1, etoricoxib in 1, and a conventional NSAID in 1 (ibuprofen or piroxicam). All 5 studies reported that in patients with knee OA, the combination of GS plus NSAID yielded a significantly greater benefit than single-agent therapy, in terms of outcomes including pain reduction, function, joint stiffness, and markers of inflammatory activity and cartilage degradation.ConclusionThe 5 studies included in this scoping review all report a significantly greater clinical benefit with a combination of GS plus NSAID compared to either treatment alone. The evidence supports efficacy in reducing pain, improving function, and possibly regulating joint damage. However, further randomized trials with larger sample sizes are warranted to confirm these findings.

Potent Analgesic Action of 2-acetoxy-5-(2-4 (trifluoromethyl)-phenethylamino)-benzoic Acid (Flusalazine) in Experimental Mice.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase (COX)-2 selective inhibitors are the most widely used drugs to treat pain. Conventional NSAIDs and COX-2 selective inhibitors, however, cause several side effects such as gastric damage, kidney damage, and cardiovascular problems. Our previous study showed that 2-acetoxy-5-(2-4-(trifluoromethyl)-phenethylamino)-benzoic acid ie, flusalazine (also known as ND-07), which exerts dual actions by serving both as an anti-inflammatory agent and a free radical scavenger, is an effective and safe treatment for severe inflammatory diseases in mice. The goal of the present study was to examine the potential analgesic action and safety of flusalazine in mice models of pain. Flusalazine showed a significant analgesic effect in an acetic acid-induced abdominal constriction model. Likewise, total paw licking was reduced significantly in neurogenic (early stage) and inflammatory (late stage) pain induced by formalin in flusalazine-treated mice. In the tail immersion test, flusalazine significantly increased tail withdrawal time at 2 h after its administration. Also, the formation of paw edema in the flusalazine-treated group was significantly inhibited in a carrageenan-induced inflammatory pain model. Gastric damage was not induced by flusalazine even up to 1000 mg/kg, while aspirin and indomethacin caused critical gastric bleeding. These findings suggest that flusalazine's safety profile and analgesic effects have high translational potential for the clinical treatment of patients experiencing pain.

Cardiovascular risk associated with the use of selective COX-2 inhibitors: a systematic review

Introduction: Selective inhibitors of the enzyme cyclooxygenase-2 were developed to reduce the gastrointestinal toxicity of conventional nonsteroidal anti-inflammatory drugs. However, this class of drugs decreases prostacyclin production and can disrupt endothelial homeostatic balance, leading to a prothrombotic state that offsets potential gastrointestinal benefits.Methods: A systematic review of all study publications linking cyclooxygenase-2 inhibitor nonsteroidal anti-inflammatory drugs and related cardiovascular events was performed.Results: The highest overall risks were seen with rofecoxib, 1.45 (95% CI 1.33 to 1.59), and diclofenac, 1.40 (1.27 to 1.55). The lowest risks recorded were with ibuprofen, 1.18 (1.11, 1.25), and naproxen, 1.09 (1.02, 1.16). The risk of VTE increased with diclofenac [OR 1.63 (95% CI: 1.53, 1.74)], ibuprofen [OR = 1.49 (95% CI: 1.38, 1.62)], meloxicam [OR = 1.29 (95% CI: 1.11, 1.50)] and coxibs [celecoxib, OR= 1.30 (95% CI: 1.11, 1.51); rofecoxib, OR= 1.44 (95% CI: 1.18, 1.76)]. Naproxen did not increase the risk of VTE [OR = 1.00 (95% CI: 0.89, 1.12)]. Furthermore, there is a significant association with atrial fibrillation for etoricoxib (HR 1.35; 95% CI 1.19–1.54). Conclusion: This review suggests that the risk of these adverse effects is greater in patients with an earlier history of cardiovascular disease or at considerable risk for developing it. Evidence shows that among the widely used NSAIDs, low-dose naproxen and ibuprofen are less likely to increase cardiovascular risk. Data for etoricoxib were sparse, but in pairwise comparisons this drug had a significantly higher relative risk than either naproxen or ibuprofen. Indomethacin is an older drug that is also toxic to the gastrointestinal system, and evidence of cardiovascular risk casts doubt on its continued clinical use.

Comparison of efficacy and safety in the combination therapies of duloxetine and S-flurbiprofen plaster, and of duloxetine and conventional NSAIDs for chronic pain in patients with osteoarthritis (OASIS DUAL study).

The purpose of this study is to compare the efficacy and safety of pharmacotherapies for chronic pain due to osteoarthritis (OA) between a group with duloxetine (DLX) and S-flurbiprofen plaster (SFPP) (the SFPP group) and a group with DLX and conventional non-steroidal anti-inflammatory drugs (NSAIDs) (the control group). The subjects were 49 patients (17 men and 32 women). The evaluation of factors associated with treatment termination due to symptoms improvement showed that significantly more women terminated treatment than did men, and significantly more members of the SFPP group terminated treatment than did members of the control group. The visual analogue scale (VAS) score in the SFPP group was significantly improved from 6.6 ± 1.7 before treatment to 3.6 ± 2.1 one month later and showed significant difference until nine months later. The VAS score in the control group was significantly improved from 6.7 ± 1.9 to 4.1 ± 2.8 one month later. The VAS score improvement rate was significantly higher in the SFPP group than in the control group, suggesting that the DLX-SFPP combination had higher efficacy than the DLX-conventional NSAIDs combination. The incidence of adverse drug reactions was 55% in the SFPP group, which is not significantly different from 50% incidence in the control group. The treatment discontinuation rate due to adverse drug reactions, however, was 60% in the control group and 19% in the SFPP group. It was suggested that the efficacy and safety of the DLX-SFPP combination for chronic pain due to OA are equal to or higher than that of the DLX-conventional NSAIDs combination.

Polyarthritis presented in a patient with untreated chronic hepatitis B infection.

Hepatitis B virus (HBV) infection can cause arthritis, but it is rarely reported. In the current report, we present a case of chronic polyarthritis in a patient with untreated HBV infection. A 63-year-old woman suffering from polyarthritis in her fingers visited our institution. She had experienced exacerbations and remissions of polyarthritis for more than 20 years. She had been diagnosed with rheumatoid arthritis and had been treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and nonsteroidal anti-inflammatory drugs by her primary care doctor, but the csDMARDs were discontinued at the request of the patient 10 years before the first visit to our hospital. The blood test showed negative for rheumatoid factor and anticyclic citrullinated peptides antibody but positive for hepatitis B surface antigen. Hepatitis B surface antigen and HBV-Deoxyribo Nucleic Acid (DNA) were increased to 312.6 (IU/ml) and 4.6 (log copies/ml), respectively. Based on the results of abdominal computed tomography and echography, she was diagnosed with liver cirrhosis. Treatment for HBV infection was begun with oral tenofovir at 25 mg/day. The polyarthritis in her fingers gradually disappeared and has not relapsed for 6 months after the initiation of treatment for HBV infection. When polyarthritis is diagnosed, the possibility that chronic HBV infection can be one of the causes of polyarthritis should be considered.

In silico investigation of bioactive compounds from Ginkgo biloba as alternatives to non-steroidal anti-inflammatory drugs

Non-steroidal Anti-inflammatory Drugs (NSAIDs) are common over-the-counter drugs that are used for numerous inflammation-associated ailments. Despite their widespread consumption, these synthetic drugs are not without side effects. Adversities caused by NSAIDs range from simple nausea and vomiting to fatal conditions such as hypertension, gastrointestinal bleeding and diminished renal function. There is thus a need to develop novel alternatives to these drugs which possess comparable efficacies. Phytocompounds are attractive alternatives for a plethora of medicines used for various disorders and diseases as they are readily available in nature and have negligible side effects. In an attempt to identify safe alternatives to NSAIDs, we tested six bioactive compounds from Ginkgo biloba (Ginkgolide A, Amentoflavone, Bilobetin, Ginkgetin, Quercetin, and Bilobalide) for their abilities to inhibit Cyclooxygenase-1, Cyclooxygenase-2 and 5-Lipoxygenase which are inflammation-causing enzymes. Molecular docking experiments using Autodock Vina resulted in binding energy values between -6.6 and -11.9 kcal/mol, comparable to that of control drugs, which indicated that the tested phytocompounds were able to bind strongly to the active sites of the three proteins. Analyses of receptor-ligand interactions using Discovery Studio Visualizer revealed that all the tested compounds formed numerous non-covalent interactions with the surrounding amino acid residues, which confirmed their binding stabilities. Finally, evaluation of their drug likeness based on Lipinski’s rule of five showed that the tested G. biloba compounds possess the potential to be taken as oral drugs to replace conventional NSAIDs.

Synthesis, in vitro and in silico studies on novel 3-aryloxymethyl-5-[(2-oxo-2-arylethyl)sulfanyl]-1,2,4-triazoles and their oxime derivatives as potent inhibitors of mPGES-1

Human microsomal prostaglandin E synthase (mPGES)-1 is a glutathione-dependent membrane-bound enzyme which is involved in the terminal stage of prostaglandin E2 (PGE2) synthesis. It has been well reported as a key target for the discovery of new anti-inflammatory and anti-cancer drugs. Specific inhibitors of mPGES-1 are anticipated to selectively restrain the generation of PGE2 induced by the inflammatory stimuli, without obstructing of the regular biosynthesis of other homeostatic prostanoids. Therefore, the design of mPGES-1 inhibitors can represent a better choice to take control of PGE2 associated diseases, compared with conventional non-steroidal anti-inflammatory drugs and cyclooxygenase (COX) inhibitors, which are known for their serious side effects. Although there is an intensive effort for the identification of mPGES-1 inhibitors, none of the unveiled molecules so far have reached the clinical market. Therefore, the development of novel mPGES-1 inhibitors with proper drug-like properties is still an unmet medical need. As a continuation of our research for the identification of new chemotypes which might inhibit this enzyme, we now report the design and synthesis of 3-aryloxymethyl-5-[(2-oxo-2-arylethyl)sulfanyl]-1,2,4-triazoles and their oxime derivatives as inhibitors of human mPGES-1. All synthesized compounds were characterized by FTIR, 1H NMR, 13C NMR (for compounds 12, 14, 15, 26, 27), HMBC (for compounds 6, 7, 8, 16, 19, 23, 28), and MS data. Twenty-four target compounds 7–30 were screened for their mPGES-1/COX-2 inhibitory activities as well as their cytotoxicity. Of these compounds, 20 and 24 showed potent mPGES-1 inhibition by IC50 values of 0.224±0.070 µM and 1.08±0.35 µM, respectively. These two compounds have also been observed to inhibit angiogenesis in matrigel tube formation assay with no toxicity toward HUVEC cells. In silico studies were also held to understand inhibition mechanisms of the most active compounds using molecular docking, molecular dynamics calculations and ADMET predictions.

The serum immunoglobulin G titres against Porphyromonas gingivalis as a predictor of clinical response to 1-year treatment with biological disease-modifying antirheumatic drugs in rheumatoid arthritis patients: A retrospective cohort study.

The aim is to evaluate the relevance of serum immunoglobulin G (IgG) titres against periodontopathic bacteria to predict the clinical response to 1-year treatment with biological disease-modifying antirheumatic drugs (bDMARDs) in rheumatoid arthritis (RA) patients. Data were collected from 50 RA patients who had received conventional synthetic DMARDs, corticosteroids, or non-steroidal anti-inflammatory drugs before (baseline) and after 1-year treatment with bDMARDs in a retrospective cohort study. Changes in rheumatologic conditions were compared between the two groups for low and high baseline IgG titres against Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans according to their median measurements. Twenty-five patients with low anti-P. gingivalis IgG titres showed significantly greater decreases in changes in the Clinical Disease Activity Index and swollen joint count than 25 patients with high anti-P. gingivalis IgG titres (p = .04 for both). Bivariate and multivariate analyses revealed a significantly positive association of baseline anti-P. gingivalis IgG titres with Clinical Disease Activity Index changes (p = .02 and p = .002). However, post-treatment rheumatologic conditions were comparable between 25 patients each in the low and high baseline anti-A. actinomycetemcomitans IgG titre groups. Baseline serum anti-P. gingivalis IgG titres are predictive of the clinical response to 1-year treatment with bDMARDs in RA patients.

Naproxen sodium nanoparticles are less toxic and gastroprotective agents than the conventional NSAID drug naproxen sodium in Balb/c mice

Use of non-steroidal anti-inflammatory drugs (NSAIDs) is one of the leading causes of gastric ulcers. Excellent therapeutic properties have made the use of NSAIDs widespread. Nano-drug delivery to reduce systemic toxicity through modulating drug pharmacokinetics may be a better choice. Presently, we investigated if naproxen nanoformulation (PVA capped NPRS-MgO NPs) is less toxic to be used as an alternative drug. Groups of mice were assigned to control, NPRS-treated, CNF-treated, UNF-treated, and MgO NPs-treated groups. Analyses included gross examination of gastric mucosa, calculation of ulcer and inhibition indices, determination of tissue levels of reactive oxygen species (ROS), malondialdehyde (MDA), catalase (CAT), peroxidase (POD), superoxide dismutase (SOD), and reduced glutathione (GSH), histological and immunohistochemical assessment of i-NOS, COX-2, and caspase-3 of stomach mucosa, q-PCR for the detection of mRNA expression of IL-1β, IL-6, and TNF-α. Results were compared statistically at P < 0.05. Compared to NPRS-treated mice which developed multiple ulcers, had elevated MDA and ROS levels, and deceased CAT, POD, SOD, and GSH levels, significantly increased expression of IL-1β, IL-6, and TNF-α mRNA, damaged surface epithelium with disrupted glandular architecture and leucocyte infiltration of lamina propria with a marked increase in mucosal COX-2, i-NOS, and caspase-3 expression, oral administration of coated and uncoated naproxen nanoformulations prevented the gross mucosal damage by a restoration of all biochemical, histological, and immunohistochemical alterations to near control levels. The present study demonstrates that naproxen sodium nanoformulation has a gastroprotective action and in the clinical setting can be a better alternative to conventional naproxen.

The Sensitivity to Change of the ASAS Health Index in an Observational Real-Life Cohort Study.

The Assessment of Spondyloarthritis international Society Health Index (ASAS HI) measures global functioning and health in patients with axial spondyloarthritis (axSpA) covering domains of physical, emotional, and social functioning. The main aim of this study was to investigate the sensitivity to change of ASAS HI in comparison with established variables of disease activity, function, and mental health. Patients with axSpA from the disease register RABBIT-SpA with follow-up time of at least 12 months and available ASAS HI questionnaires were included. Patients received questionnaires addressing disease activity (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI], Ankylosing Spondylitis Disease Activity Score [ASDAS]), physical function (Bath Ankylosing Spondylitis Functional Index [BASFI]), mental health (5-item World Health Organization Well-Being Index [WHO-5]), and global functioning (ASAS HI). Standardized response means (SRMs) were calculated to compare the sensitivity to change of different variables. Six hundred and sixty-seven patients were included, 552 treated with biologic disease-modifying antirheumatic drugs (bDMARDs) and 115 with conventional synthetic DMARDs and/or nonsteroidal antiinflammatory drugs (control group). Between baseline and month 12, the mean ASAS HI declined from 6.9 to 5.1 in the bDMARD group and from 5.9 to 5.6 in the conventionally treated group. In the bDMARD group, the SRM of ASAS HI was 0.52, compared to 0.59 for BASFI, 0.65 for WHO-5, 0.73 for BASDAI, and 0.90 for ASDAS. The following ASAS HI domains were most frequently affected: pain (78% agreed), maintaining body position (75%), and energy/drive (73%). In the patients receiving bDMARDs, there was an improvement in all items. In the control group, the largest improvement was seen in pain. As expected, ASDAS and BASDAI as disease activity scores showed high sensitivity to change, whereas changes in physical function (BASFI), mental health (WHO-5), and the broader concept of functioning and health (ASAS HI) were moderate.

Efficacy of Preoperative Piroxicam, Diclofenac, Paracetamol With Tramadol and Placebo Tablets for Relief of Postoperative Pain After the Removal of Impacted Mandibular Third Molars: A Randomised Controlled Trial.

AimWe aimed to analyze the influence of preoperative piroxicam, diclofenac, paracetamol, tramadol, and placebo tablets as measured in the time required for rescue analgesia for postoperative pain relief after the extraction of impacted mandibular third molar.Materials & methodsForty-four patients who needed extraction of impacted mandibular third molar were arbitrarily categorized into four groups namely, piroxicam, diclofenac, paracetamol with tramadol, and placebo. The test medicine was given one hour preoperatively before the surgical removal. The pain was assessed using visual analog scale (VAS) and verbal rating scale (VRS) scores preoperatively and at the third and 24th hours. The time required for escape analgesia was measured. ResultsThe mean VAS and VRS scores showed significant differences across the groups after 24 hours. The mean score was lowest for the patients taking piroxicam (1.30+1.95) and highest for patients taking tramadol + paracetamol (4.50+2.59). As far as escape analgesia is concerned piroxicam group was by far superior.ConclusionThe pain scores and the rescue analgesic requirement suggested that piroxicam analgesic significantly reduced pain; moreover, it is a safe as well as an efficacious substitute to the conventional non-steroidal anti-inflammatory drugs (NSAIDs) for mandibular third molar impactions.

Efficacy and Safety of Tramadol Hydrochloride Twice-Daily Sustained-Release Bilayer Tablets with an Immediate-Release Component for Chronic Pain Associated with Knee Osteoarthritis: A Randomized, Double-Blind, Placebo-Controlled, Treatment-Withdrawal Study.

Background and ObjectivesKnee osteoarthritis pain is a chronic form of pain for which conventional non-steroidal anti-inflammatory drugs may provide insufficient analgesia. Twice-daily tramadol hydrochloride (65% sustained-release/35% immediate-release) bilayer tablets are a novel formulation of tramadol developed for managing chronic pain. The objectives of this study were to examine the effectiveness and safety of this formulation in patients with chronic knee osteoarthritis pain.MethodsThis was a multicenter, randomized, placebo-controlled, double-blind, parallel-group, treatment-withdrawal study. Patients with a reduction in Numeric Rating Scale (NRS) for pain of ≥2 points during a 1–3-week, open-label, tramadol dose-escalation period (100–300 mg/day) were randomized to continue tramadol or switched to placebo for 4 weeks (double-blind period). Patients with inadequate efficacy (increase in NRS ≥2 points/patient request) were withdrawn. Outcomes included the time to inadequate analgesic efficacy from randomization (primary endpoint), the cumulative retention rate, and safety.ResultsOverall, 249 and 160 patients entered the dose-escalation and double-blind periods, respectively (tramadol 79; placebo 81). Kaplan–Meier analysis revealed superiority of tramadol (log-rank p = 0.042), and a hazard ratio of 0.50 (95% confidence interval [CI] 0.25–0.99). Documentation of an inadequate analgesic effect was less frequent in the tramadol group (15.4%, 95% CI 8.2–25.3% vs. 30.9%, 95% CI 21.1–42.1%). The cumulative retention rate was greater in the tramadol group (83.7% vs. 69.0%). Adverse events occurred in 80.6% (200/248) of patients in the open-label period, and in 38.5% (30/78) and 13.6% (11/81) of patients in the tramadol and placebo groups, respectively, in the double-blind period. Opioid-associated adverse events, such as nausea, vomiting, constipation, somnolence, and dizziness, were the most frequent events.ConclusionThis study demonstrated the analgesic efficacy and safety of sustained-release tramadol tablets with an immediate-release component for chronic knee osteoarthritis pain.Trial registrationJapicCTI-132103 (Japan Pharmaceutical Information Center; registration date February 25, 2015)Supplementary InformationThe online version contains supplementary material available at 10.1007/s40261-022-01139-5.