Mechanism Of Nonsteroidal Anti-inflammatory Drugs Research Articles

Adsorption of azo dyes and Naproxen by few-layer MXene immobilized with dialdehyde starch nanoparticles: Adsorption properties and statistical physics modeling

Novel Eco-friendly composite materials (DSP-M) were organized by combining few-layer MXene with the hydrophilic biomaterial dialdehyde starch nanoparticles (DASNP) and immobilizing DASNP on the surface of few-layer MXene by the dialdehyde-based cross-linking method. In addition to the study on the adsorption performance and mechanism of prohibited dyes (Rhodamine B, RB and Congo Red, CR) in food industry, the removal and mechanism of non-steroidal anti-inflammatory drug (Naproxen, NPX) residues in pharmaceutical field were also investigated. DSP-M was physiochemically characterized via series of analytical techniques and the dye adsorption isotherms at three temperatures were quantified. The results show that DSP-M exhibited excellent adsorption performance for all three selected adsorbates, and the Langmuir maximum monolayer adsorption capacity were 678.19 mg/L for RB, 754.41 mg/L for CR and 166.71 mg/L for NPX, respectively, and it agreed well with the Langmuir, pseudo–second order and intraparticle diffusion models. The statistical physics model was employed to further explore the adsorptive mechanism. The characteristics of DSP-M after adsorption and the simulation results indicate that the removal of RB, CR and NPX by DSP-M was mainly a physical adsorption process involved with hydrogen bonding, electrostatic force and van der Waals force.

Inhibitory effects of NSAID-conjugated SN-38 on the viability of A549 Non-small cell lung cancer cells

The goal of this paper was to look into the anti-tumor mechanism of Non-Steroidal Anti-Inflammatory Drug (NSAID)-conjugated SN-38 Prodrug in A549 lung cancer cells. We found that Indomethacine–SN–38 (IndoSN-38) and Naproxen–SN–38(NaproSN-38) as a theranostic prodrug targeting cyclooxygenase-2(COX-2) in cancer cells inhibited A549 cell viability in a dose-dependent fashion. IndoSN-38 and NaproSN-38 inhibited A549 cell viability in a dose-dependent fashion. The suppression of A549 cell viability was due to induction of the cell apoptosis by enhancing the activities of Caspase 3 and Caspase 8. The cell cycle arrest of sub-G1 was found in the cells treated with IndoSN-38 or NaproSN-38. Collectively, these data suggested that the anti-proliferative activities of the NSAID-conjugated SN-38 prodrugs were due to promotion of cell death and arresting the cell cycle which was similar with those of SN-38.

The Role of Organic Small Molecules in Pain Management.

In this review, a timeline starting at the willow bark and ending in the latest discoveries of analgesic and anti-inflammatory drugs will be discussed. Furthermore, the chemical features of the different small organic molecules that have been used in pain management will be studied. Then, the mechanism of different types of pain will be assessed, including neuropathic pain, inflammatory pain, and the relationship found between oxidative stress and pain. This will include obtaining insights into the cyclooxygenase action mechanism of nonsteroidal anti-inflammatory drugs (NSAID) such as ibuprofen and etoricoxib and the structural difference between the two cyclooxygenase isoforms leading to a selective inhibition, the action mechanism of pregabalin and its use in chronic neuropathic pain, new theories and studies on the analgesic action mechanism of paracetamol and how changes in its structure can lead to better characteristics of this drug, and cannabinoid action mechanism in managing pain through a cannabinoid receptor mechanism. Finally, an overview of the different approaches science is taking to develop more efficient molecules for pain treatment will be presented.

The gastroprotective effect of alpinia officinarum extract on indomethacin-induced topical injuries in RGM-1 Cells: Involvement of H+/K+-ATPase- and mitochondrial-mediated apoptosis

Background: Topical effects are essential mechanisms of nonsteroidal anti-inflammatory drugs (NSAIDs)-induced gastric damage. Our previous study showed that the extract of Alpinia officinarum (AOE) may have some protective effects against the topical effects of indomethacin (INDO). The aim of this study was to elucidate the protective effects and mechanisms of A. officinarum against INDO-induced topical injuries to gastric mucosa. Materials and Methods: 0.5 mM INDO was used to cause topical effects to rat gastric epithelial cells (RGM-1). Meanwhile, AOE (2.5 μg/mL) and galangin (GAL) (0.05 mM) were added, respectively, to explore their protective effects. The cell proliferation, mitochondrial viability, and mitochondrial-mediated apoptosis were assessed by flow cytometry, inverted fluorescence microscope, or microplate reader. Pro- and cleaved-caspase-3 were detected by Western blot method. Results: AOE and GAL could significantly protect INDO-damaged RGM-1 cells by promoting cell proliferation, upregulating mitochondrial viability, inhibiting mitochondrial cytochrome c release into cytoplasm, inhibiting lipid peroxidation and caspase-3 activity, and suppressing H+/K+-ATPase activity. Conclusion: The gastroprotective effects of AOE and GAL were closely associated with suppressing the gastric acid secretion and restraining mitochondrial-mediated apoptosis. These data provided new perceptions into interpreting the underlying mechanisms of gastroprotective effects of A. officinarum and showed a promising clinical use in treating gastric mucosal injury induced by NSAIDs.

Berberine ameliorates non-steroidal anti-inflammatory drugs-induced intestinal injury by the repair of enteric nervous system.

The study was to detect the role of GDNF, PGP9.5 (a neuronal marker), and GFAP (EGCs' marker) in the mechanism of non-steroidal anti-inflammatory drugs (NSAIDs) related to intestinal injury and to clarify the protective effect of berberine in the treatment of NSAID-induced small intestinal disease. Forty male SD rats were divided randomly into five groups (A-E): Group A: control group; Group B: model group received diclofenac sodium 7.5mg/(kg*day) for 5days; Group C-E: berberine low, medium and high dose groups were treated by 7.5mg/(kg*day) diclofenac sodium for 5days then received berberine 25mg/(kg*day), 50mg/(kg*day), and 75mg/(kg*day), respectively, between the sixth and eighth day. Intestinal mucosa was taken on the ninth day to observe the general, histological injuries, and to measure the intestinal epithelial thickness. Then, immunohistochemistry was performed to detect the expression of PGP9.5 and GFAP, and Western blot was performed to detect GDNF expression. The histological score and the general score in the model group were, respectively, 5.75±1.04 and 4.83±0.92. Scores in berberine medium and high berberine group were lower compared with the model group (P<0.05). The intestinal epithelial thickness in the model group was lower than in the control group and the berberine groups (P<0.05). PGP9.5, GFAP, and GDNF content in the model group and the three berberine groups were significantly lower than in the control groups (P<0.05). PGP9.5, GFAP, and GDNF content in the control group and the three berberine groups were higher compared with the model groups (P<0.05). Berberine can protect the intestinal mucosa of NSAID users, and the mechanism is associated with the reparation of the enteric nervous system via upregulating the expression of PGP9.5, GFAP, and GDNF.

The Mechanism of Mica on Protecting NSAIDs Induced Small Intestinal Mucosal Barrier Injury via ncRuPAR-PAR2 Pathway

Objective: The study was to detect the role of ncRuPAR and Protease activated receptor (PAR)2 in the mechanism of Non-steroidal anti-inflammatory drugs(NSAIDs) induced small intestinal mucosal barrier injury. And to clarify the possible mechanism of mica in treatment NSAIDs induced small intestinal disease. Methods: Caco-2 cells were cultured and divided into 6 groups: control group, diclofenac sodium group, control RNAa group, ncRuPAR RNA activation (RNAa) group, diclofenac sodium + mica group, diclofenac sodium + FSLLRY-NH2 group. 40 μmol/L diclofenac sodium treatment for 24 hours to establish NSAIDs induced small intestinal epithelial cell injury model, 10% mica-containing serum treatment for 24h, 100uM PAR2 blocker FSLLRY-NH2 treatment for 24h. Blank vector or ncRuPAR overexpression vector were transfected into cells for 72h. Then Transwell assay were performed to detect cell permeability, qPCR were used to detect RNA expression of PAR2 and ncRuPAR, and western blot were performed to detect PAR2, occludin and claudin-1 expression. Result: NSAIDs-induced small intestinal epithelial cell injury model was successfully built. Compared with the control group, ncRuPAR and PAR2 were up-regulated, occludin and claudin-1 were down-regulated, cell permeability were increased in diclofenac sodium group (P 0.05). Compared with the control RNAa group, overexpression of ncRuPAR significantly up-regulated the expression of ncRuPAR and PAR2, down-regulated the expression of occludin and claudin-1, and increased cell permeability (P<0.01). Conclusion: When NSAIDs induced small intestinal injury occurs, ncRuPAR activation could up-regulate PAR2, causing the destruction of intestinal epithelial cell tight junction and the increase of intestinal epithelial cells permeability. Mica-containing serum has a similar effect as PAR2 blocker, which could antagonize the above-mentioned damage process and play a role in protecting the mechanical barrier function of the intestinal mucosa. Funding Statement: This research was supported by funding from Zhejiang Provincial Natural Science Foundation of China under Grant No.LY18H030001； the Medicine and Health Science and Technology Plan Projects in Zhejiang province(2017KY413), Traditional Chinese Medicine Science and Technology Plan of Zhejiang Province(2017ZA089, 2016ZB071, 2015ZZ012, 2014ZA030); National Natural Science Foundation of China (81573760);Medical Health Platform Plan Projects of Zhejiang Province (2015RCA020); Zhejiang Provincial Natural Science Foundation of China (LY16H030010). Declaration of Interests: The authors state: There is no conflict of interest. Ethics Approval Statement: Not required.

Phenylbutazone induces equine glandular gastric disease without decreasing prostaglandin E2 concentrations.

In equids, phenylbutazone at high doses induces gastric disease, primarily in the glandular portion of the stomach. However, the mechanism of nonsteroidal anti-inflammatory drug (NSAID)-induced gastric disease in horses has yet to be determined. While phenylbutazone-associated ulceration is often attributed to a decrease in basal gastric prostaglandins, this has not been demonstrated in the horse. Twelve horses were randomly assigned to treatment (n=6; 4.4mg/kg phenylbutazone PO in 20ml molasses q 12hr for 7days) or placebo (n=6; 20ml molasses PO q 12hr for 7days) groups. Before treatment and 3 and 7days after initiation of treatment, gastroscopy was performed and glandular gastric biopsies were collected and frozen at -80°C. Glandular disease was assessed on a scale of 0-4. Prostaglandin E2 concentrations in biopsies were measured using a commercially available enzyme-linked immunosorbent assay. All phenylbutazone-treated horses developed grade ≥2 glandular disease. Prostaglandin concentrations increased over time (p=.0017), but there was no effect of treatment (p=.49). These findings indicate that despite induction of glandular disease grade ≥2, phenylbutazone did not decrease basal glandular gastric prostaglandin E2 concentration.

INFLAMMATION AS A THERAPEUTIC TARGET IN THE COMPLEX TREATMENT OF MALIGNANT TUMORS

In this review, we analyzed the role of inflammation in carcinogenesis, tumor development, and metastasis. In addition, the mechanisms of non-steroidal anti-inflammatory drugs (NSAIDs) and the reasons of their contradictory influence on cancers were discussed. We summarized the numerous data about effectiveness of anti-inflammatory drugs for the prevention and additional therapy of tumor diseases. In particular, divergent effects of NSAIDs may be due to the peculiarities of immune-inflammatory responses that are realized in carcinogenesis and tumor development that have yet to be studied. We also discussed the selectivity of NSAID effects on different cancers and opposite effects of anticancer drugs with similar mechanisms of action. Apparently, the unsuccessful use of NSAIDs in cancer prevention and therapy are more specific for squamous cell carcinomas. Based on the literature, we provided significant clinical findings regarding the need of NSAID use in the current therapy of certain cancers and the determination of molecular predictors of the drug effect. In fact, anti-inflammatory therapy could eliminate the factors that contribute to the appearance of invasive and metastatic tumor cells, cancer and premetastatic niches and thus prevent metastasis and recurrence. At present, some non-selective (aspirin) and selective (celecoxib) NSAIDs are highly promising in the therapy of solid tumors.

Therapeutic mechanisms of ibuprofen, prednisone and betamethasone in osteoarthritis.

The present study aimed to investigate the therapeutic mechanisms of nonsteroidal anti-inflammatory drugs (NSAIDs) and steroids in osteoarthritis (OA). The CHON‑002 human chondrocyte cell line was used in the study. The levels of the cytokines, interleukin (IL)‑1β, IL‑6, IL‑8 and IL‑10, released by cells treated with tumor necrosis factor‑α (TNF‑α) were determined by ELISA. Levels of collagen I, aggrecan, matrix metalloproteinase (MMP)‑1, MMP‑13, signal transducer and activator of transcription (STAT) 3, nuclear factor‑κB (NF‑κB) subunit p65 and inhibitory subunit of NF‑κB (IκB) following treatment with IL‑1β, IL‑6, IL‑8 or IL‑10 were assessed by western blot. Levels of IL‑6 and IL‑8 were measured by ELISA following administration of TNF‑α combined with certain drugs. In addition, these parameters were evaluated by western blot following incubation with drugs in combination with IL‑6 or IL‑8 and after knockdown of STAT3, by addition of small interfering RNA (siRNA)‑STAT3 (siSTAT3), an inhibitor of the proteasome (MG132) or both. IL‑1β, IL‑6, IL‑8 and IL-10 were upregulated by TNF‑α. Addition of IL‑6 or IL‑8 led to increased collagenI, MMP‑1 and MMP‑13 protein levels, and also promoted STAT3 phosphorylation and increased the expression of NF‑κB subunit p65, but had no effect on aggrecan protein levels. When siSTAT3 and MG132 treatment was combined, levels of collagen I, MMP‑1 and MMP‑13 were reduced. Additionally, levels of IL‑6 and IL‑8 were significantly decreased by prednisone, ibuprofen and betamethasone. However, no significant differences were observed following treatment with piroxicam or indomethacin. In combination with IL‑6 or IL‑8, prednisone, ibuprofen and betamethasone significantly reduced the levels of collagen I, MMP‑1 and MMP‑13, and inactivated NF‑κB and STAT3 pathways. In conclusion, prednisone, ibuprofen and betamethasone may prevent OA by suppressing the expression of IL‑6 and IL‑8, subsequently inactivating NF‑κB and STAT3 pathways, and ultimately, leading to decreased levels of collagen I, MMP‑1, and MMP‑13.

Impact and mechanism of non-steroidal anti-inflammatory drugs combined with chemotherapeutic drugs on human lung cancer-nude mouse transplanted tumors.

The present study aimed to investigate the impact of indomethacin treatment combined with oxaliplatin treatment on the expression of cluster of differentiation 44 variant 6 (CD44v6), matrix metalloproteinase-2 (MMP-2) and survivin in human lung cancer-nude mouse transplanted tumors. The human lung adenocarcinoma (A549)-nude mouse transplanted tumor model was established, and the mice were divided into a control group, an indomethacin treatment group, an oxaliplatin treatment group and an indomethacin-oxaliplatin combination treatment group. The tumor inhibition rate was calculated following sacrificing of the mice. Immunohistochemical staining and fluorescence reverse transcription-quantitative polymerase chain reaction were utilized to detect the protein and messenger (m)RNA expression of CD44v6, MMP-2 and survivin. The tumor inhibition rates of the indomethacin group, the oxaliplatin group and the combination group were 26.67, 47.70 and 68.88%, respectively. The protein and mRNA expression levels of CD44v6, MMP-2 and survivin in the transplanted tumors of each treatment group were reduced compared with the control group (P<0.05), and those of the combination group were lower compared with the single-drug treatment groups (P<0.05). Survivin and MMP-2, MMP-2 and CD44v6, and MMP-2 and CD44v6 all exhibited linear positive correlation. The present study provides evidence that the administration of indomethacin alone, or in combination with oxaliplatin, may significantly inhibit the growth of lung cancer-nude mouse transplanted tumors and the expression of CD44v6, MMP-2 and survivin inside the tumor. The combination of non-steroidal anti-inflammatory drugs with chemotherapeutic drugs may improve the antitumor effects.

Pathogenesis of NSAID-induced gastric damage: Importance of cyclooxygenase inhibition and gastric hypermotility

This article reviews the pathogenic mechanism of non-steroidal anti-inflammatory drug (NSAID)-induced gastric damage, focusing on the relation between cyclooxygenase (COX) inhibition and various functional events. NSAIDs, such as indomethacin, at a dose that inhibits prostaglandin (PG) production, enhance gastric motility, resulting in an increase in mucosal permeability, neutrophil infiltration and oxyradical production, and eventually producing gastric lesions. These lesions are prevented by pretreatment with PGE₂ and antisecretory drugs, and also via an atropine-sensitive mechanism, not related to antisecretory action. Although neither rofecoxib (a selective COX-2 inhibitor) nor SC-560 (a selective COX-1 inhibitor) alone damages the stomach, the combined administration of these drugs provokes gastric lesions. SC-560, but not rofecoxib, decreases prostaglandin E₂ (PGE₂) production and causes gastric hypermotility and an increase in mucosal permeability. COX-2 mRNA is expressed in the stomach after administration of indomethacin and SC-560 but not rofecoxib. The up-regulation of indomethacin-induced COX-2 expression is prevented by atropine at a dose that inhibits gastric hypermotility. In addition, selective COX-2 inhibitors have deleterious influences on the stomach when COX-2 is overexpressed under various conditions, including adrenalectomy, arthritis, and Helicobacter pylori-infection. In summary, gastric hypermotility plays a primary role in the pathogenesis of NSAID-induced gastric damage, and the response, causally related with PG deficiency due to COX-1 inhibition, occurs prior to other pathogenic events such as increased mucosal permeability; and the ulcerogenic properties of NSAIDs require the inhibition of both COX-1 and COX-2, the inhibition of COX-1 upregulates COX-2 expression in association with gastric hypermotility, and PGs produced by COX-2 counteract the deleterious effect of COX-1 inhibition.

Depigmenting mechanism of NSAIDs on B16F1 melanoma cells

The aim of the present work was to clarify the anti-melanogenic mechanism of non-steroidal anti-inflammatory drugs (NSAIDs). Mefenamic acid, diclofenac, and nimesulide were used in this study, and these drugs inhibit melanin synthesis in B16F1 melanoma cells. To elucidate the anti-melanogenic mechanism of NSAIDs, we performed western blotting analysis for melanogenic proteins, such as tyrosinase, TRP-1, and TRP-2. All NSAIDs used in this study inhibited tyrosinase protein level. Semi-quantitative RT-PCR analysis showed that the depigmentation effect of mefenamic acid and nimesulide might be due to the inhibition of tyrosinase gene transcription. These results indicate that NSAIDs inhibit α-MSH-enhanced melanin synthesis, and are candidate anti-melanogenic agents since they might be effective in hyperpigmentation disorders.

Indirect role of β2-adrenergic receptors in the mechanism of analgesic action of nonsteroidal antiinflammatory drugs

Adrenal gland hormones have been shown to have a role in the antiinflammatory effect mechanism of nonsteroidal antiinflammatory drugs. This study investigates whether the analgesic effects of indomethacin, diclofenac sodium, aspirin, and nimesulide (IDAN; upper case letters of the four drugs we used) are also related to adrenal gland hormones. The analgesic effects of IDAN were studied in the carrageenan-induced inflammatory pain model using both intact and adrenalectomized rats. Paw withdrawal tests were performed in adrenalectomized rats that had been pretreated with phenoxybenzamine, propranolol, and metoprolol. This study was performed in Pharmacology and Biochemistry Laboratories of Faculty of Medicine. A total of 306 (114 intact and 192 adrenalectomized) male Albino Wistar rats were used. Adrernalectomy, drug administrations, pain model induction and pain threshold measurements were performed during the study. Although the analgesic effects of nonsteroidal antiinflammatory drugs were lost in adrenalectomized rats, they exerted significant analgesia in adrenalectomized rats that had been pretreated with prednisolone and adrenalin. All these drugs were found to decrease serum adrenalin concentration but did not change serum cortisole (corticosterone in rats) concentration. Prednisolone and adrenalin inhibited carrageenan-induced hyperalgesia in adrenalectomized rat groups pretreated with metoprolol or phenoxybenzamine, but not in rats given propranolol. Propranolol also negated the analgesic effects of IDAN in intact rats. The analgesic effects provided by either prednisolone or adrenalin could not be inhibited by the alpha1, alpha2, or beta1 blockers but disappeared when beta2 receptors were blocked. The analgesic effects of nonsteroidal antiinflammatory drugs appear to be related to endogenous adrenalin and cortisole. We have demonstrated that adrenalin and prednisolone play important roles in the analgesic effect mechanism of IDAN. Prednisolone and adrenalin produce analgesic effects through beta2-adrenergic receptors, suggesting an indirect role for beta2-adrenergic receptors in the analgesic effect mechanism of the nonsteroidal antiinflammatory drugs mentioned.

Role of monocarboxylic acid transporters in the cellular uptake of NSAIDs

The present study investigated the cellular uptake mechanism of non-steroidal anti-inflammatory drugs (NSAIDs) in Caco-2 cells. Diflunisal, diclofenac, ketoprofen and naproxen exhibited a strong inhibition effect on the cellular uptake of [14C]-benzoic acid in Caco-2 cells with IC50 values of 0.05-0.44 mM. The inhibition of naproxen and ketoprofen against the membrane transport of [14C]-benzoic acid appeared to be competitive, with Ki values of 0.22 and 0.38 mM, respectively. The membrane permeability of naproxen and ketoprofen was concentration dependent, implying that the cellular uptake pathway of ketoprofen and naproxen was saturable at the higher concentration. Furthermore, the cellular accumulation of ketoprofen was significantly reduced in the presence of benzoic acid and L-lactic acid, two known substrates of monocarboxylic acid transporter 1 (MCT1). These results suggest that MCT1 contributes at least in part to the carrier-mediated transport of NSAIDs containing a carboxylic acid moiety across the apical membrane in Caco-2 cells.

Inhibitory Mechanism of Non-steroidal Anti-inflammatory Drugs on Osteoclast Differentiation and Activation

Inhibitory Mechanism of Non-steroidal Anti-inflammatory Drugs on Osteoclast Differentiation and Activation

MP-20.03: Molecular mechanisms of nonsteroidal anti-inflammatory drugs induced apoptosis

MP-20.03: Molecular mechanisms of nonsteroidal anti-inflammatory drugs induced apoptosis

The cytoprotective effect of a nitric oxide donor drug on gastric mucous membrane of rats treated with ketoprofen, a non-steroidal anti-inflammatory drug

Non-steroidal anti-inflammatory drugs are considered today a very important group of medication, with a wide variety of therapeutic use, in different areas of modern medicine. Despite their beneficial effects on the patient, these drugs show a high incidence of side effects, mainly in the gastrointestinal tract. The physiopathological mechanisms of non-steroidal anti-inflammatory drugs induced lesions and the gastric mucosa defense mechanism became an important source for medical research, especially those which try to evaluate the role of nitric oxide as a cytoprotective agent. To define a possible cytoprotective effect of a nitric oxide donor, isosorbide dinitrate, on the gastric mucous of rats submitted to non-steroidal anti-inflammatory drugs ketoprofen treatment. Adult male Wistar rats, previously submitted to starvation for 24 hours and divided in three groups: group I (standard): animals that received isotonic saline solution intragastric by gavage and intravenous. Group II (control-ketoprofen): animals that received isotonic saline solution intragastric by gavage and ketoprofen intravenous. Group III (nitrate/ketoprofen): animals that received 2mM solution of isosorbide dinitrate intragastric by gavage and ketoprofen intravenous. Later on, these animals were sacrificed and had their stomach removed and submitted to macroscopical, microscopical and biochemical studies. The evaluated parameters were: a) gastric lesion index; b) gastric mucous layer thickness; c) gastric tissue nitrate/nitrite (NOx) concentration and d) gastric tissue malondialdehyde concentration. a) Gastric lesion index evaluation showed a smaller statistically significant incidence on the animals of group III; b) group III showed a thicker mucous layer, which also was statistically significant, when compared to group II; c) the variation on tissue nitrate/nitrite concentration was similar in all three groups, without statistical significance when compared to each other. Isosorbide dinitrate has a cytoprotective activity on the gastric mucosa of rats submitted to ketoprofen action.

Efficacy of a selective COX-2 inhibitor for controlling irregular uterine bleeding in DMPA users

Purpose This double-blind, placebo-controlled study was conducted to evaluate the efficacy of valdecoxib and placebo for controlling irregular uterine bleeding in depot-medroxyprogesterone acetate (DMPA) users. Method A total of 51 DMPA users were enrolled. All subjects in the study had abnormal bleeding and were randomly divided into two groups. One group totaling 22 received valdecoxib, 40 mg, once a day for 5 days, and placebos were given to another 24 in the same manner; 5 subjects dropped out from the study. Analysis of the number of treatment days required for stopping the bleeding episode, percentage of women whose bleeding was stopped in 7 days, total number of bleeding-free days and length of the bleeding-free interval after the initial treatment was determined in the first and the fourth weeks. Results The percentage of the subjects whose bleeding was stopped during the first week after the initial treatment and the mean value of the bleeding-free days during the 28 days of the follow-up period were significantly higher in the valdecoxib group than in the placebo group (77.3% vs. 33.3%, p<.01; and 17.8 days vs. 11.5 days, p<.05, respectively). The mean duration of treatment days required for stopping the bleeding episode in the valdecoxib-treated group was 1.7 days, and the mean duration of the bleeding-free interval in valdecoxib-treated group was 18.6 days. Conclusion Valdecoxib was more effective than placebo in the short-term control of irregular bleeding in DMPA users. The mechanism of nonsteroidal anti-inflammatory drugs (NSAIDs) for the reduction of endometrial bleeding is likely from COX-2 inhibition.

Non-steroidal Anti-inflammatory Drugs Inhibit Nitric Oxide-induced Apoptosis and Dedifferentiation of Articular Chondrocytes Independent of Cyclooxygenase Activity

Nitric oxide (NO) causes apoptosis and dedifferentiation of articular chondrocytes by the modulation of extracellular signal-regulated kinase (ERK), p38 kinase, and protein kinase C (PKC) alpha and -zeta. In this study, we investigated the effects and mechanisms of non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, ketoprofen, ibuprofen, sulindac sulfide, and flurbiprofen, in NO-induced apoptosis and dedifferentiation of articular chondrocytes. We found that all of the examined NSAIDs inhibited apoptosis and dedifferentiation. NO production in chondrocytes caused activation of ERK-1/2 and p38 kinase, which oppositely regulate apoptosis and dedifferentiation. NO production also caused inhibition of PKCalpha and -zeta independent of and dependent on, respectively, p38 kinase, which is required for apoptosis and dedifferentiation. Among the signaling molecules modulated by NO, NSAIDs blocked NO-induced activation of p38 kinase, potentiated ERK activation, and blocked inhibition of PKCalpha and -zeta. NSAIDs also inhibited some of the apoptotic signaling that is downstream of p38 kinase and PKC, such as NFkappaB activation, p53 accumulation, and caspase-3 activation. The inhibitory effects of NSAIDs on apoptosis and dedifferentiation were independent of the inhibition of cyclooxygenase (COX)-2 and prostaglandin E(2) (PGE(2)) production, as evidenced by the observation that specific inhibition of COX-2 activity and PGE(2) production or exogenous PGE(2) did not affect NO-induced apoptosis and dedifferentiation. Taken together, our results indicate that NSAIDs block NO-induced apoptosis and dedifferentiation of articular chondrocytes by the modulation of ERK, p38 kinase, and PKCalpha and -zeta in a manner independent of their ability to inhibit COX-2 and PGE(2) production.

LTC4-synthase A-444C polymorphism: lack of association with NSAID-induced isolated periorbital angioedema in a Spanish population

The mechanism of nonsteroidal anti-inflammatory drug (NSAID)-induced reactions is unknown. However, strong evidence supports the hypothesis of an enhanced production of cysteinyl-leukotrienes. The existence of a polymorphism (A-444C) in the promoter region of the leukotriene (LT)C4-synthase gene (the terminal enzyme in the LTC4 production pathway) has been reported. This polymorphism has yielded contradictory results on its association with aspirin-induced asthma. The present study was designed to investigate the possible genetic association of C(-444) allele and a specific clinical phenotype of NSAID sensitivity, the NSAID-induced isolated periorbital angioedema, via a case/control study. The polymorphism A-444C was analyzed in 58 patients with NSAID-induced periorbital angioedema and 61 control subjects, who had undergone single-blind, placebo-controlled oral challenge. Genotype was determined by polymerase chain reaction-restriction fragment length polymorphism. We have not found an association of C(-444), allele with NSAID-induced isolated periorbital angioedema. Further studies are needed to determine whether polymorphisms in the LTC4-synthase gene or other leukotriene-forming enzymes are involved in the pathogenesis of the different subsets of NSAID sensitivity.