Effects of cytokine-suppressive anti-inflammatory drugs on inflammatory activation in ex vivo human and ovine fetal membranes

Intrauterine infection and inflammation are responsible for the majority of early (<32 weeks) spontaneous preterm births (PTBs). Anti-inflammatory agents, delivered intra-amniotically together with antibiotics, may be an effective strategy for preventing PTB. In this study, the effects of four cytokine-suppressive anti-inflammatory drugs (CSAIDs:N-acetyl cysteine (NAC), SB239063, TPCA-1 and NEMO binding domain inhibitor (NBDI)) were assessed on human and ovine gestational membrane inflammation. Full-thickness membranes were collected from healthy, term, human placentas delivered by Caesarean section (n=5). Using a Transwell model, they were stimulatedex vivowith γ-irradiation-killedEscherichia coliapplied to the amniotic face. Membranes from near-term, ovine placentas were stimulatedin uterowith lipopolysaccharide,Ureaplasma parvumor saline control and subjected to explant culture. The effects of treatment with CSAIDs or vehicle (1% DMSO) on accumulation of PGE2and cytokines (human interleukin 6 (IL6), IL10 and TNFα; ovine IL8 (oIL8)) were assessed in conditioned media at various time points (3–20 h). In human membranes, the IKKβ inhibitor TPCA-1 (7 μM) and p38 MAPK inhibitor SB239063 (20 μM) administered to the amniotic compartment were the most effective in inhibiting accumulation of cytokines and PGE2in the fetal compartment. NAC (10 mM) inhibited accumulation of PGE2and IL10 only; NBDI (10 μM) had no significant effect. In addition to the fetal compartment, SB239063 also exerted consistent and significant inhibitory effects in the maternal compartment. TPCA-1 and SB239063 suppressed oIL8 production, while all CSAIDs tested suppressed ovine PGE2production. These results support the further investigation of intra-amniotically delivered CSAIDs for the prevention of inflammation-mediated PTB.

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In Vitro Chondrotoxicity of Nonsteroidal Anti-inflammatory Drugs and Opioid Medications

The American Journal of Sports Medicine ◽

10.1177/0363546517724423 ◽

2017 ◽

Vol 45 (14) ◽

pp. 3345-3350 ◽

Cited By ~ 7

Author(s):

Geoffrey D. Abrams ◽

Wenteh Chang ◽

Jason L. Dragoo

Keyword(s):

Cell Death ◽

Single Dose ◽

Joint Surface ◽

Saline Control ◽

Type I ◽

Dose Equivalent ◽

Inflammatory Drugs ◽

Anti Inflammatory ◽

Opioid Medications

Background: A variety of medications are administered to the intra-articular space for the relief of joint pain. While amide-type local anesthetics have been extensively studied, there is minimal information regarding the potential chondrotoxicity of nonsteroidal anti-inflammatory drugs (NSAIDs) and opioid medications. Purpose: To investigate the in vitro chondrotoxicity of single-dose equivalent concentrations of ketorolac, morphine, meperidine, and fentanyl on human chondrocytes. Study Design: Controlled laboratory study. Methods: Human cartilage was arthroscopically harvested from the intercondylar notch and expanded in vitro. Gene expression of cultured chondrocytes before treatment was performed with quantitative polymerase chain reaction for type I collagen, type II collagen, aggrecan, and SOX9. Chondrocytes were then exposed to 0.01%, 0.02%, and 0.04% morphine sulfate; 0.3% and 0.6% ketorolac tromethamine; 0.5%, 1.0%, and 1.5% meperidine hydrochloride; 0.0005% and 0.001% fentanyl citrate; and saline. A custom bioreactor was used to constantly deliver medications, with the dosage of each medication and the duration of exposure based on standard dose equivalents, medication half-lives, and differences in the surface area between the 6-well plates and the native joint surface. After treatment, a live/dead assay was used to assess chondrocyte viability and if minimal cell death was detected. A subset of samples after treatment was maintained to analyze for possible delayed cell death. Results: All tested concentrations of ketorolac and meperidine caused significantly increased cell death versus the saline control, demonstrating a dose-response relationship. The morphine and fentanyl groups did not show increased chondrotoxicity compared with the saline group, even after 2 weeks of additional culture. Conclusion: In vitro exposure of chondrocytes to single-dose equivalent concentrations of either ketorolac or meperidine demonstrated significant chondrotoxicity, while exposure to morphine or fentanyl did not lead to increased cell death.

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Anti-nociceptive and anti-inflammatory activity of synthesized novel benzoxazole derivatives

Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry ◽

10.2174/1871523020666210203103433 ◽

2021 ◽

Vol 20 ◽

Author(s):

Mansi L. Patil ◽

Swati S. Gaikwad ◽

Naresh J. Gaikwad

Keyword(s):

Cytotoxic Activity ◽

Research Study ◽

Ex Vivo ◽

Immunological Response ◽

Inflammatory Activity ◽

Inflammatory Drugs ◽

Anti Inflammatory ◽

Inflammatory Effect

Introduction: Pain is an immunological response to any infection or inflammation and long term use of pain management therapy includes use of Nonsteroidal anti-inflammatory drugs which is associated with occurrence of toxicity as well as gastrointestinal bleeding. Therefore, the investigation of new analgesic and anti-inflammatory agents remains a major challenge. Aims: The objective of this research study is to undergo the pharmacological evaluation of newly synthesized benzoxazole derivatives. These novel derivatives were evaluated for anti-nociceptive, anti-inflammatory and cytotoxic activity using various in-vivo and ex-vivo methods. Methods: The study was carried out using swiss mice (adult male) weighing between 20gm to 30gm and were divided into groups containing (n=6) six animals in each group for treatment. The anti-nociceptive activity was performed by using 0.1ml of 0.6% v/v acetic acid as nociception inducer and evaluated by the diminished number of abdominal writhes. The anti-inflammatory activity was done using 0.1 ml of 2% w/v Carrageenan induced paw edema method was observed which was evaluated by calculating the percent maximum possible effect. Histopathological evaluation and cytotoxic activity of the compounds was carried out. Results: The results of this research study revealed that synthesized derivatives (a, b, c, d and e) showed promising anti-nociceptive and anti-inflammatory effect along significantly higher cytotoxic activity in MCF-7 cell lines. Conclusion: It can be concluded that synthesized derivatives (a, b, c, d and e) have potential anti-nociceptive and anti-inflammatory effect along with cytotoxic activity and certain modification in structure may result in potent activity.

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Cervical epithelial damage promotes Ureaplasma parvum ascending infection, intrauterine inflammation and preterm birth induction in mice

Nature Communications ◽

10.1038/s41467-019-14089-y ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 7

Author(s):

Ioannis Pavlidis ◽

Owen B. Spiller ◽

Gabriella Sammut Demarco ◽

Heather MacPherson ◽

Sarah E. M. Howie ◽

...

Keyword(s):

Preterm Birth ◽

Mouse Model ◽

Bacterial Load ◽

Preterm Births ◽

Intrauterine Infection ◽

Cervical Injury ◽

Epithelial Damage ◽

Ureaplasma Parvum ◽

Non Invasive ◽

Ascending Infection

AbstractAround 40% of preterm births are attributed to ascending intrauterine infection, and Ureaplasma parvum (UP) is commonly isolated in these cases. Here we present a mouse model of ascending UP infection that resembles human disease, using vaginal inoculation combined with mild cervical injury induced by a common spermicide (Nonoxynol-9, as a surrogate for any mechanism of cervical epithelial damage). We measure bacterial load in a non-invasive manner using a luciferase-expressing UP strain, and post-mortem by qPCR and bacterial titration. Cervical exposure to Nonoxynol-9, 24 h pre-inoculation, facilitates intrauterine UP infection, upregulates pro-inflammatory cytokines, and increases preterm birth rates from 13 to 28%. Our results highlight the crucial role of the cervical epithelium as a barrier against ascending infection. In addition, we expect the mouse model will facilitate further research on the potential links between UP infection and preterm birth.

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Clinical Outcomes of Aspirin Interaction with Other Non-Steroidal Anti-Inflammatory Drugs: A Systematic Review

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/jpps29854 ◽

2018 ◽

Vol 21 (1s) ◽

pp. 48s-73s ◽

Cited By ~ 2

Author(s):

Zuhair Alqahtani ◽

Fakhreddin Jamali

Keyword(s):

Clinical Trials ◽

Platelet Aggregation ◽

Clinical Outcomes ◽

Randomized Clinical Trials ◽

Ex Vivo ◽

Biologically Active ◽

Cardioprotective Effect ◽

Inflammatory Drugs ◽

Anti Inflammatory ◽

Aggregation Level

Purpose: Concomitant use of some non-Aspirin nonsteroidal anti-inflammatory drugs (NANSAIDs) reduces the extent of platelet aggregation of Aspirin (acetylsalicylic acid). This is while many observational studies and clinical trials suggest that Aspirin reduces cardiovascular (CV) risk attributed to the use of NANSAIDs. Thus, the therapeutic outcome of the interaction needs to be assessed. Methods: We searched various databases up to October 2017 for molecular interaction studies between the drugs and long-term clinical outcomes based on randomized clinical trials and epidemiological observations that reported the effect estimates of CV risks (OR, RR or HR; 95% CI) of the interacting drugs alone or in combinations. Comparisons were made between outcomes after Aspirin alone, NANSAIDs alone and Aspirin with naproxen, ibuprofen, celecoxib, meloxicam, diclofenac or rofecoxib. Results: In total, 32 eligible studies (20 molecular interactions studies and 12 observational trials) were found. Conflicting in vitro/in vivo/ex vivo platelet aggregation data were found for ibuprofen, naproxen and celecoxib. Nevertheless, for naproxen, the interaction at the aggregation level did not amount to a loss of cardioprotective effects of Aspirin. Similarly, for ibuprofen, the results overwhelmingly suggest no negative clinical CV outcomes following the combination therapy. Meloxicam and rofecoxib neither interacted with Aspirin at the level of platelet aggregation nor altered clinical outcomes. The clinical outcomes data for celecoxib and diclofenac are in conflict. Conclusion: Aspirin appears to maintain its cardioprotective effect in the presence of naproxen, ibuprofen, meloxicam and rofecoxib. The limited available data suggest that the effect of interaction at the platelet aggregation level may dissipate shortly, or the reduced platelet aggregation yielded by the interaction may be sufficient for cardioprotection; i.e., no need for near complete aggregation. In addition, cardioprotective effect of Aspirin, despite reduced platelet aggregation caused by NANSAIDs, may be through its involvement in other mechanisms such as the renin-angiotensin system and/or metabolism of arachidonic acid to biologically active compounds mediated by cytochrome P450. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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In vitro and ex vivo pharmacodynamics of selected non-steroidal anti-inflammatory drugs in equine whole blood

The Veterinary Journal ◽

10.1016/j.tvjl.2011.03.016 ◽

2012 ◽

Vol 191 (3) ◽

pp. 327-333 ◽

Cited By ~ 15

Author(s):

B. Cuniberti ◽

R. Odore ◽

R. Barbero ◽

P. Cagnardi ◽

P. Badino ◽

...

Keyword(s):

Whole Blood ◽

Ex Vivo ◽

Inflammatory Drugs ◽

Anti Inflammatory

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Imidazolium-Based Ionic Liquid-Assisted Preparation of Nano-Spheres Loaded with Bio-Active Peptides to Decrease Inflammation in an Osteoarthritis Model: Ex Vivo Evaluations

Journal of Biomedical Nanotechnology ◽

10.1166/jbn.2021.3069 ◽

2021 ◽

Vol 17 (5) ◽

pp. 859-872

Author(s):

Yingzhuo Song ◽

Tao Zhang ◽

Huiguang Cheng ◽

Wei Jiang ◽

Pu Li ◽

...

Keyword(s):

Electron Microscopy ◽

Drug Delivery ◽

Drug Delivery System ◽

Delivery System ◽

Ex Vivo ◽

Cartilage Explants ◽

Therapeutic Drug ◽

Therapeutic Peptides ◽

Inflammatory Drugs ◽

Anti Inflammatory

Osteoarthritis is one of the most prevalent chronic diseases. Cartilage inflammation in osteoarthritis results from pain in articular joints. Anti-inflammatory drugs provide relief by hindering the production of pro-inflammatory cytokines and interleukin-6. Targeted delivery of anti-inflammatory drugs is very effective in the treatment of osteoarthritis. This approach reduces the usage of therapeutic drug dosages and unwanted side effects. Here, we fabricated a non-invasive and efficient targeted drug delivery system to reduce persistent inflammation in an osteoarthritis model. Temperature-sensitive hollow dextran/poly(N-isopropyl acrylamide) nanoparticles were synthesized by the destruction of N,N’-bis(acryloyl)cystamine crosslinked cores in imidazolium-based ionic liquids. The copolymerized 2-acrylamido-2-methylpropane sulfonic acid created sulfur functionalities that increase the loading of therapeutic KAFAK peptides. The chemical structure of the polymer nanoparticles was analyzed with UV-Visible, Fourier transform infrared, and X-ray photoelectron spectroscopy. The thermal responsive characteristics of the nanoparticles were determined with dynamic light scattering, scanning electron microscopy, and transmission electron microscopy analyses. Moreover, the synthesized nanoparticles were used as drug carriers to reduce inflammation in an Ex Vivo osteoarthritis model. The KAFAK-loaded hollow dextran/PNIPAM nanoparticles effectively delivered therapeutic peptides in cartilage explants to suppress inflammation. These thermoresponsive nanoparticles could be an effective drug delivery system to deliver anti-inflammatory therapeutic peptides in a highly osteoarthritic environment.

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