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Indian Journal of Pharmacology Mar 2024Ixora coccinea leaves possess antioxidant, anti-inflammatory, antinociceptive, antimutagenic, and gastroprotective properties. On this background, its antiarthritic...
CONTEXT
Ixora coccinea leaves possess antioxidant, anti-inflammatory, antinociceptive, antimutagenic, and gastroprotective properties. On this background, its antiarthritic potential was evaluated.
AIMS
The objective is to evaluate the effect of Ethanolic extract of Ixora coccinea leaves (EEICL) on complete Freund's adjuvant-induced arthritis in rats.
SETTINGS AND STUDY DESIGN
PG research laboratory, Pharmacology Department, MKCG Medical College, Berhampur, Odisha.
SUBJECTS AND METHODS
Thirty-six Wistar albino rats were randomly distributed into sixgroups (n = 6) as follows: Gr 1 (normal control)-DW p.o, Gr-2 (disease control [DC] - Tween 80 p.o), Gr-3 (piroxicam 0.9 mg/kg p.o), Gr-4 (EEICL-1 g/kg, p.o, Gr 4-EEICL-1.5 g/kg p.o, Gr 5-ED50 (0.82 g/kg) + piroxicam (0.45 mg/kg) p.o. After induction of arthritis, drugs, and vehicles were administered daily from 5th to 25th day. On 0, 5th, 10th, 15th, and 25th day, parameters like body weight, rotarod fall time, paw volume displacement, and arthritis index were measured. On the last day, Erythrocyte sedimentation rate (ESR), tissue malondialdehyde (MDA), and histopathological analysis were done.
STATISTICAL ANALYSIS USED
Analysis of parametric data was done by one-way ANOVA and nonparametric data by Kruskal-Wallis test using graph pad prism 7.0. P < 0.05 was considered statistically significant.
RESULTS
EEICL (1.5 mg/kg) showed anti-arthritic effect compared with DC. Rotarod fall-off time 137.5 ± 2.5 sec and body weight (139 ± 12.74 g) were increased significantly. The percentage inhibition of paw volume was increased(52%) whereas arthritic score(0.33), ESR(3.51mm/hr), synovial tissue MDA level (0.62±0.13µmol/gm) and Mankin score(2) were reduced significantly as compared to disease control.
CONCLUSIONS
EEICL has anti-arthritic potential in rat model.
Topics: Animals; Plant Extracts; Plant Leaves; Rats, Wistar; Arthritis, Experimental; Freund's Adjuvant; Rats; Ethanol; Male; Anti-Inflammatory Agents; Phytotherapy
PubMed: 38687315
DOI: 10.4103/ijp.ijp_210_23 -
World Journal of Clinical Cases Apr 2024Various non-steroidal anti-inflammatory drugs (NSAIDs) have been used for juvenile idiopathic arthritis (JIA). However, the optimal method for JIA has not yet been...
BACKGROUND
Various non-steroidal anti-inflammatory drugs (NSAIDs) have been used for juvenile idiopathic arthritis (JIA). However, the optimal method for JIA has not yet been developed.
AIM
To perform a systematic review and network meta-analysis to determine the optimal instructions.
METHODS
We searched for randomized controlled trials (RCTs) from PubMed, EMBASE, Google Scholar, CNKI, and Wanfang without restriction for publication date or language at August, 2023. Any RCTs that comparing the effectiveness of NSAIDs with each other or placebo for JIA were included in this network meta-analysis. The surface under the cumulative ranking curve (SUCRA) analysis was used to rank the treatments. value less than 0.05 was identified as statistically significant.
RESULTS
We included 8 RCTs (1127 patients) comparing 8 different instructions including meloxicam (0.125 qd and 0.250 qd), Celecoxib (3 mg/kg bid and 6 mg/kg bid), piroxicam, Naproxen (5.0 mg/kg/d, 7.5 mg/kg/d and 12.5 mg/kg/d), inuprofen (30-40 mg/kg/d), Aspirin (60-80 mg/kg/d, 75 mg/kg/d, and 55 mg/kg/d), Tolmetin (15 mg/kg/d), Rofecoxib, and placebo. There were no significant differences between any two NSAIDs regarding ACR Pedi 30 response. The SUCRA shows that celecoxib (6 mg/kg bid) ranked first (SUCRA, 88.9%), rofecoxib ranked second (SUCRA, 68.1%), Celecoxib (3 mg/kg bid) ranked third (SUCRA, 51.0%). There were no significant differences between any two NSAIDs regarding adverse events. The SUCRA shows that placebo ranked first (SUCRA, 88.2%), piroxicam ranked second (SUCRA, 60.5%), rofecoxib (0.6 mg/kg qd) ranked third (SUCRA, 56.1%), meloxicam (0.125 mg/kg qd) ranked fourth (SUCRA, 56.1%), and rofecoxib (0.3 mg/kg qd) ranked fifth (SUCRA, 56.1%).
CONCLUSION
In summary, celecoxib (6 mg/kg bid) was found to be the most effective NSAID for treating JIA. Rofecoxib, piroxicam, and meloxicam may be safer options, but further research is needed to confirm these findings in larger trials with higher quality studies.
PubMed: 38680254
DOI: 10.12998/wjcc.v12.i12.2056 -
Micromachines Apr 2024Non-steroidal anti-inflammatory piroxicam (PRX) is a poorly water-soluble drug that provides relief in different arthritides. Reducing the particle size of PRX increases...
Non-steroidal anti-inflammatory piroxicam (PRX) is a poorly water-soluble drug that provides relief in different arthritides. Reducing the particle size of PRX increases its bioavailability. For pediatric, geriatric, and dysphagic patients, oral dispersible systems ease administration. Moreover, fast disintegration followed by drug release and absorption through the oral mucosa can induce rapid systemic effects. We aimed to produce an orodispersible lyophilizate (OL) consisting of nanosized PRX. PRX was solved in ethyl acetate and then sonicated into a poloxamer-188 solution to perform spray-ultrasound-assisted solvent diffusion-based nanoprecipitation. The solid form was formulated via freeze drying in blister sockets. Mannitol and sodium alginate were applied as excipients. Dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA) were used to determine the particle size. The morphology was characterized by scanning electron microscopy (SEM). To establish the crystallinity, X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) were used. A disintegration and in vitro dissolution test were performed. DLS and NTA presented a nanosized PRX diameter. The SEM pictures showed a porous structure. PRX became amorphous according to the XRPD and DSC curves. The disintegration time was less than 1 min and the dissolution profile improved. The final product was an innovative anti-inflammatory drug delivery system.
PubMed: 38675343
DOI: 10.3390/mi15040532 -
Pharmaceutics Apr 2024Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most prescribed drugs to treat pain or fever. However, oral administration of NSAIDs is frequently...
Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most prescribed drugs to treat pain or fever. However, oral administration of NSAIDs is frequently associated with adverse effects due to their inhibitory effect on the constitutively expressed cyclooxygenase enzyme 1 (COX-1) in, for instance, the gastrointestinal tract. A systemic delivery, such as a buccal delivery, of NSAIDs would be beneficial and additionally has the advantage of a non-invasive administration route, especially favourable for children or the elderly. To investigate the transport of NSAIDs across the buccal mucosa and determine their potential for buccal therapeutic usage, celecoxib, diclofenac, ibuprofen and piroxicam were tested using an established oral mucosa Transwell model based on human cell line TR146. Carboxyfluorescein and diazepam were applied as internal paracellular and transcellular marker molecule, respectively. Calculated permeability coefficients revealed a transport ranking of ibuprofen > piroxicam > diclofenac > celecoxib. Transporter protein inhibitor verapamil increased the permeability for ibuprofen, piroxicam and celecoxib, whereas probenecid increased the permeability for all tested NSAIDs. Furthermore, influence of local inflammation of the buccal mucosa on the transport of NSAIDs was mimicked by treating cells with a cytokine mixture of TNF-α, IL-1ß and IFN-γ followed by transport studies with ibuprofen (+ probenecid). Cellular response to pro-inflammatory stimuli was confirmed by upregulation of cytokine targets at the mRNA level, increased secreted cytokine levels and a significant decrease in the paracellular barrier. Permeability of ibuprofen was increased across cell layers treated with cytokines, while addition of probenecid increased permeability of ibuprofen in controls, but not across cell layers treated with cytokines. In summary, the suitability of the in vitro oral mucosa model to measure NSAID transport rankings was demonstrated, and the involvement of transporter proteins was confirmed; an inflammation model was established, and increased NSAID transport upon inflammation was measured.
PubMed: 38675204
DOI: 10.3390/pharmaceutics16040543 -
PloS One 2024Mathematical models of epidermal and dermal transport are essential for optimization and development of products for percutaneous delivery both for local and systemic...
Mathematical models of epidermal and dermal transport are essential for optimization and development of products for percutaneous delivery both for local and systemic indication and for evaluation of dermal exposure to chemicals for assessing their toxicity. These models often help directly by providing information on the rate of drug penetration through the skin and thus on the dermal or systemic concentration of drugs which is the base of their pharmacological effect. The simulations are also helpful in analyzing experimental data, reducing the number of experiments and translating the in vitro investigations to an in-vivo setting. In this study skin penetration of topically administered caffeine cream was investigated in a skin-on-a-chip microfluidic diffusion chamber at room temperature and at 32°C. Also the transdermal penetration of caffeine in healthy and diseased conditions was compared in mouse skins from intact, psoriatic and allergic animals. In the last experimental setup dexamethasone, indomethacin, piroxicam and diclofenac were examined as a cream formulation for absorption across the dermal barrier. All the measured data were used for making mathematical simulation in a three-compartmental model. The calculated and measured results showed a good match, which findings indicate that our mathematical model might be applied for prediction of drug delivery through the skin under different circumstances and for various drugs in the novel, miniaturized diffusion chamber.
Topics: Animals; Mice; Skin Absorption; Caffeine; Drug Compounding; Microfluidics; Administration, Cutaneous; Skin; Models, Theoretical
PubMed: 38603673
DOI: 10.1371/journal.pone.0299501 -
BioRxiv : the Preprint Server For... Mar 2024Mitochondrial (Mito) dysfunction in IBD reduces mucosal O2 consumption and increases O2 delivery to the microbiome. Increased enteric O2 promotes blooms of facultative...
BACKGROUND
Mitochondrial (Mito) dysfunction in IBD reduces mucosal O2 consumption and increases O2 delivery to the microbiome. Increased enteric O2 promotes blooms of facultative anaerobes (eg. ) and restricts obligate anaerobes (eg. ). Dysbiotic metabolites negatively affect host metabolism and immunity. Our novel compound (AuPhos) upregulates intestinal epithelial cell (IEC) mito function, attenuates colitis and corrects dysbiosis in humanized mice. We posit that AuPhos corrects IBD-associated dysbiotic metabolism.
METHODS
Primary effect of AuPhos on mucosal Mito respiration and healing process was studied in ex vivo treated human colonic biopsies and piroxicam-accelerated (Px) mice. Secondary effect on microbiome was tested in DSS-colitis WT B6 and germ-free 129.SvEv WT or mice reconstituted with human IBD stool (Hu- ). Mice were treated orally with AuPhos (10- or 25- mg/kg; q3d) or vehicle, stool samples collected for fecal lipocalin-2 (f-LCN2) assay and microbiome analyses using 16S rRNA sequencing. AuPhos effect on microbial metabolites was determined using untargeted global metabolomics. AuPhos-induced hypoxia in IECs was assessed by Hypoxyprobe-1 staining in sections from pimonidazole HCl-infused DSS-mice. Effect of AuPhos on enteric oxygenation was assessed by (aerobic respiration-proficient) and mutant (aerobic respiration-deficient).
RESULTS
Metagenomic (16S) analysis revealed AuPhos reduced relative abundances of and increased blooms of in uninflamed B6 WT, DSS-colitis, Hu-WT and Hu- mice. AuPhos also increased hypoxyprobe-1 staining in surface IECs suggesting enhanced O2 utilization. AuPhos-induced anaerobiosis was confirmed by a significant increase in cydA mutant compared to WT (O2-utlizing) . Ex vivo treatment of human biopsies with AuPhos showed significant increase in Mito mass, and complexes I and IV. Further, gene expression analysis of AuPhos-treated biopsies showed increase in stem cell markers (Lgr4, Lgr5, Lrig1), with concomitant decreases in pro-inflammatory markers (IL1β,MCP1, RankL). Histological investigation of AuPhos-fed Px- mice showed significantly decreased colitis score in AuPhos-treated Px- mice, with decrease in mRNA of pro-inflammatory cytokines and increase in Mito complexes ( , ). AuPhos significantly altered microbial metabolites associated with SCFA synthesis, FAO, TCA cycle, tryptophan and polyamine biosynthesis pathways. AuPhos increased pyruvate, 4-hydroxybutyrate, 2-hydroxyglutarate and succinate, suggesting an upregulation of pyruvate and glutarate pathways of butyrate production. AuPhos reduced IBD-associated primary bile acids (BA) with concomitant increase in secondary BA (SBA). AuPhos treatment significantly decreased acylcarnitines and increased L-carnitine reflective of enhanced FAO. AuPhos increases TCA cycle intermediates and creatine, energy reservoir substrates indicating enhanced OxPHOS. Besides, AuPhos also upregulates tryptophan metabolism, decreases Kynurenine and its derivatives, and increases polyamine biosynthesis pathway (Putresceine and Spermine).
CONCLUSION
These findings indicate that AuPhos-enhanced IEC mitochondrial function reduces enteric O2 delivery, which corrects disease-associated metabolomics by restoring short-chain fatty acids, SBA, AA and IEC energy metabolism.
PubMed: 38559035
DOI: 10.1101/2024.03.14.584471 -
Frontiers in Pharmacology 2023Current therapies for RA have limitations and side effects, leading to a growing need for safer treatment options. Natural compounds from plants are gaining attention...
Current therapies for RA have limitations and side effects, leading to a growing need for safer treatment options. Natural compounds from plants are gaining attention for their therapeutic benefits and fewer side effects. One such compound is the campesterol derivative, a steroid derivative occurring in plants. Studies have shown that this derivative has anti-inflammatory properties and can impact the expression of pro-inflammatory factors. The primary objective of this study was to explore and assess the potential therapeutic effects of Campesterol Ester Derivatives (CED) utilizing a rat model of arthritis induced by Complete Freund's Adjuvant (CFA). The rats were divided into specific experimental groups and treated with either CED or piroxicam (as a positive control) for a duration of 28 days. We determined the effects of CED on various parameters including paw edema, thermal hyperalgesia, and mechanical allodynia at different time points. Furthermore, serum levels of inflammatory cytokines, oxidative stress markers and histological analyses were performed. Additionally, mRNA expression levels of inflammatory markers, both pro-inflammatory (such as TNF-α, NF-κB, IL-6, COX-1, COX-2, and IL-4) and anti-inflammatory were analyzed. In the arthritic rat model, CED exhibited significant anti-inflammatory effects and resulted in a notable reduction in paw edema levels compared to the control group. Histopathological examination of the treated rats' paws confirmed a decrease in inflammation and tissue damage, including reduced pannus formation and bone erosion. Importantly, there were no observable signs of damage to the liver and kidneys following CED treatment, indicating its safety profile and potential for organ protection. At the molecular level, CED treatment downregulated mRNA expression levels of pro-inflammatory markers, indicating its ability to suppress inflammation. Conversely, certain anti-inflammatory markers were upregulated following CED treatment, suggesting a positive influence on the immune response. The positive effects of CED were not limited to joint inflammation; it also showed systemic benefits by positively influencing hematological and biochemical parameters. CED demonstrated promising therapeutic potential as an anti-inflammatory intervention for arthritis in the experimental rat model. Its ability to reduce inflammation, protect tissues, and improve organ function indicates its multifaceted benefits.
PubMed: 38322703
DOI: 10.3389/fphar.2023.1346054 -
Heliyon Jan 2024Traditional non-steroidal anti-inflammatory drugs (NSAIDs) show serious adverse effects during clinical use, which limits their usage. Oxicams (e.g., piroxicam,...
Traditional non-steroidal anti-inflammatory drugs (NSAIDs) show serious adverse effects during clinical use, which limits their usage. Oxicams (e.g., piroxicam, meloxicam) are widely used as NSAIDs. However, selectivity to cyclooxygenase (COX) 2 may cause cardiovascular problems considering the long-term use of the drugs. Therefore, it is important to develop new non-steroidal compounds as anti-inflammatory drugs. In the present study, we evaluated the anti-inflammatory activity of a newly developed nonsteroidal drug XK01. Our data showed that XK01 reduced the contents of nitric oxide (NO) and reactive oxygen species (ROS)and inhibited the transcription levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β in a dose-dependent manner in lipopolysaccharide (LPS)-stimulated mouse RAW264.7 macrophages. XK01 showed no significant inhibitory effect on COX-1, but inhibited the expression of COX-2. At molecular level, XK01 prevented the translocation of p65 protein from the cytoplasm to the nucleus and inhibited the phosphorylation of p65, IκB, and MAPKs proteins. And high concentration of XK01 also inhibited the phosphorylation of JNK, p38 and ERK, showing stronger effect than that of meloxicam. In addition, the anti-inflammatory activity of XK01 was further validated in Xylene-induced mouse ear swelling model. Thus, this study verified that XK01 inhibits the expression of inflammatory mediators and COX-2, and exhibits potential anti-inflammatory effects via suppressing the NF-κB and MAPK pathway.
PubMed: 38312593
DOI: 10.1016/j.heliyon.2024.e24004 -
BMC Pharmacology & Toxicology Feb 2024Methotrexate (MTX) is the cornerstone of rheumatoid arthritis (RA) treatment and is highly effective with low-dose intermittent administration. MTX is occasionally used...
Drug-drug interaction assessment based on a large-scale spontaneous reporting system for hepato- and renal-toxicity, and thrombocytopenia with concomitant low-dose methotrexate and analgesics use.
BACKGROUND
Methotrexate (MTX) is the cornerstone of rheumatoid arthritis (RA) treatment and is highly effective with low-dose intermittent administration. MTX is occasionally used in combination with non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (APAP)/paracetamol for pain or inflammation control. With MTX treatment, the side effects, such as hepatotoxicity, renal failure, and myelosuppression should be considered. These are also seen with analgesics treatment.
METHODS
We used a large spontaneously reported adverse event database (FAERS [JAPIC AERS]) to analyze whether the reporting of adverse events increased upon MTX and analgesic therapy in patients with RA.
RESULTS
After identifying RA cases, the crude reporting odds ratios (cRORs) for hepatotoxicity, renal failure, and thrombocytopenia associated with the use of MTX, APAP, or NSAIDs were calculated by disproportionality analysis, which revealed significantly higher cRORs for these events. No analgesics showed consistent positive signals for drug-drug interaction (DDI) with concomitant low-dose MTX analyzed using four algorithms for DDI interaction (the Ω shrinkage measure, additive or multiplicative, and combination risk ratio models). However, in renal failure and thrombocytopenia, loxoprofen (Ω = 0.08) and piroxicam (Ω = 0.46), and ibuprofen (Ω = 0.74) and ketorolac (Ω = 3.52), respectively, showed positive signals in the Ω shrinkage measure model, and no consistency was found among adverse events or NSAIDs.
CONCLUSIONS
Studies using spontaneous reporting systems have limitations such as reporting bias or lack of patient background; however, the results of our comprehensive analysis support the results of previous clinical or epidemiological studies. This study also demonstrated the usefulness of FAERS for DDI assessment.
Topics: Humans; Methotrexate; Antirheumatic Agents; Acetaminophen; Anti-Inflammatory Agents, Non-Steroidal; Analgesics; Arthritis, Rheumatoid; Thrombocytopenia; Drug Interactions; Chemical and Drug Induced Liver Injury; Renal Insufficiency
PubMed: 38303016
DOI: 10.1186/s40360-024-00738-6 -
JMIR Public Health and Surveillance Jan 2024Drug-induced suicide (DIS) is a severe adverse drug reaction (ADR). Although clinical trials have provided evidence on DIS, limited investigations have been performed on... (Review)
Review
BACKGROUND
Drug-induced suicide (DIS) is a severe adverse drug reaction (ADR). Although clinical trials have provided evidence on DIS, limited investigations have been performed on rare ADRs, such as suicide.
OBJECTIVE
We aimed to systematically review case reports on DIS to provide evidence-based drug information.
METHODS
We searched PubMed to obtain case reports regarding DIS published until July 2021. Cases resulting from drugs that are no longer used or are nonapproved, substance use, and suicidal intentions were excluded. The quality of each case report was assessed using the CASE (Case Reports) checklist. We extracted data regarding demographics, medication history, suicide symptoms, and symptom improvement and evaluated the causality of DIS using the Naranjo score. Furthermore, to identify the potential suicidal risk of the unknown drugs, we compared the results of the causality assessment with those of the approved drug labels.
RESULTS
In 83 articles, we identified 152 cases involving 61 drugs. Antidepressants were reported as the most frequent causative drugs of DIS followed by immunostimulants. The causality assessment revealed 61 cases having possible, 89 cases having probable, and 2 cases having definite relationships with DIS. For approximately 85% of suspected drugs, the risk of suicidal ADRs was indicated on the approved label; however, the approved labels for 9 drugs, including lumacaftor/ivacaftor, doxycycline, clozapine, dextromethorphan, adalimumab, infliximab, piroxicam, paclitaxel, and formoterol, did not provide information about these risks.
CONCLUSIONS
We found several case reports involving drugs without suicide risk information on the drug label. Our findings might provide valuable insights into drugs that may cause suicidal ADRs.
Topics: Humans; Doxycycline; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Suicidal Ideation; Suicide; Case Reports as Topic
PubMed: 38289650
DOI: 10.2196/49755