Inhibitory Effect Of Non-steroidal Anti-inflammatory Drugs Research Articles

The Inhibitory Effect of NSAIDs and Opioids on Spinal Fusion: An Animal Model.

Translational research. To evaluate the relative effects of NSAIDs, opioids, and a combination of the two on spinal fusion inhibition in a rodent model. Nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids are common postoperative analgesic agents. Since NSAIDs inhibit the cyclooxygenase (COX) pathway, they are seldom prescribed following spinal fusion. Opioids may be given instead, but recent evidence suggests opioids also adversely affect spinal fusion quality and success. Eighty male Sprague-Dawley rats underwent L4-5 posterior lumbar fusion and were given one of the following analgesia regimens: saline, morphine (6mg/kg), ketorolac (4mg/kg), or morphine (3mg/kg) and ketorolac (2mg/kg). Serum samples were drawn to evaluate systemic pro-osteoblastic cytokines and vascular endothelial growth factor-A (VEGF-A) levels, which were measured through enzyme-linked immunosorbent assays (ELISA). After six weeks, the rats were sacrificed, and the operated spinal segments underwent manual palpation, microCT, and histologic analysis. Manual palpation scores were significantly diminished in the opioid, NSAID, and multimodal groups when compared with control ( P <0.001). MicroCT fusion scores ( P <0.001) and fusion rates (control: 75% vs . NSAID: 35% vs . opioid: 0% vs . combination: 15%, P <0.001) were significantly diminished in the treatment groups. The bone volume (BV) to tissue volume (TV) ratio (BV/TV) ( P <0.001) and bone mineral density (BMD) ( P <0.001) were all lower in the treatment groups, with the opioid and combined groups having the lowest BMD. Although statistically insignificant ( P <0.09), the concentration of VEGF-A was greater in the control group compared with opioids, NSAIDs, and the combined group. Opioids and NSAIDs, both independently and combined, inhibited spinal fusion and caused inferior bony callus. Administration of opioids resulted in the lowest rate of spinal fusion. We propose this may be due to the inhibition of VEGF-A, which limits angiogenesis to the burgeoning fusion mass.

Insights into the acute effect of anti-inflammatory drugs on activated sludge systems with high solids retention time

ABSTRACT The increase in the occurrence of the pharmaceuticals in the environmental compartments is becoming emerging concern as it reflects their inefficient treatment in the wastewater treatment plants which are the main sources of these micropollutants. Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly prescribed and frequently detected pain medications in wastewater treatment plants. A lab scale sequencing batch reactor (SBR) was operated for seven months and acute inhibitory effect of NSAIDs on activated sludge was tested with respirometry. Culture amendment with different concentrations of NSAIDs in the presence as well as absence of nitrification inhibitor resulted in considerable variation in the oxygen uptake rate (OUR) profiles. The decrease in OUR and nitrate production rate governed with reduced heterotrophic and nitrification activity. The kinetics of half saturation for growth and maximum autotrophic growth rates are determined to be affected negatively by the acute impact of anti-inflammatory pharmaceuticals even at the environmentally relevant concentrations. High removal of tested NSAIDs was observed even for the first time introduce with these compounds.

Inhibitory Effect of Meclofenamate Sodium on Proteasome Activity in the Cardiac Cells and Reversal of its Effect by Antioxidants

Objective: Prolonged use of nonsteroidal anti-inflammatory drugs (NSAIDs) is reported to increase the occurrences of cardiovascular diseases (CVD). Significant proteasome inhibition is also associated with increased incidences of CVD. Hence, the effect of the NSAIDs meclofenamate sodium (MS) and naproxen sodium (NAP) on the proteasome system was investigated in H9c2 rat cardiac cells. Methods: 26S proteasome activity assays, cell viability assays, reactive oxygen species (ROS) assays, and MV151 fluorescent labelling of proteasome active sites were utilized. Results: Decreased 26S β5 chymotrypsin-like proteasome activity (30%) and β1 caspase-like activity (20%) was seen in H9c2 cells treated with 100µM MS for 24h compared to the cells treated with 500 µM NAP or vehicle. Rat heart lysates showed significant decreases in β5 activity in the presence of 50-500 µM MS. Purified proteasomes also showed decreased β5 activity in the presence of 100 µM MS. MV-151 labeling showed that this decrease in activity was not due to direct interaction between MS and the proteasome active sites. Both NSAIDs caused increased ROS levels in H9c2 cells but the rate of ROS formation was significantly higher in cells treated with 100 µM MS than 500 µM NAP after 2hrs. MS (100 µM) but not NAP (500 µM) significantly decreased cell viability. Pretreatment of the cells with antioxidants, 200 µM ascorbic acid and 100 µM tempol, completely reversed the effect of MS on the proteasome and cell viability. Conclusion Our results suggest for the first time that NSAIDs may have an implication in CVD through the direct inhibition of the proteasome system. Interestingly, this inhibitory effect of NSAIDs could be reversed by using antioxidants.

Perioperative use of non-steroidal anti-inflammatory drugs might impair dental implant osseointegration.

To appraise whether adverse biological events following oral implant placement may be associated with perioperative use of non-steroidal anti-inflammatory drugs (NSAIDs). All patients treated in a university faculty postgraduate dental clinic between 1979 and 2012 that had experienced a failing and surgically removed dental implant (292 implants in 168 patients) were contacted to solicit additional information about their present dental and medical status and frequency of current and past use of NSAIDs. Potential associations between perioperative NSAIDs use and the occurrence of adverse biological events were explored by the use of 2×2 tables and two-tailed Fisher's exact tests. One hundred and four patients with initially 468 implants had experienced 238 implant failures, of which 197 were due to failing osseointegration (42%). Sixty of the participants, initially with 273 implants, had used NSAIDs perioperatively and experienced 44% implant failures, versus 38% in the non-NSAID cohort. The NSAID cohort experienced 3.2 times more cases of radiographic bone loss greater than 30% of the vertical height of their remaining implants and 1.9 times more cases of cluster failures, defined as failure of 50% or more of the implant(s) placed. Notwithstanding that a retrospective study design is open to potential bias, the current data indicate that dental implant osseointegration may be affected negatively by an inhibitory effect of NSAIDs on bone healing in vulnerable patients. Future and better clinical studies than the current should be designed to appraise more precisely the potential effects of NSAIDs on implant osseointegration in study populations that are not limited by stringent medical inclusion and exclusion criteria.

In Silico Screening of Nonsteroidal Anti-Inflammatory Drugs and Their Combined Action on Prostaglandin H Synthase-1.

The detailed kinetic model of Prostaglandin H Synthase-1 (PGHS-1) was applied to in silico screening of dose-dependencies for the different types of nonsteroidal anti-inflammatory drugs (NSAIDs), such as: reversible/irreversible, nonselective/selective to PGHS-1/PGHS-2 and time dependent/independent inhibitors (aspirin, ibuprofen, celecoxib, etc.) The computational screening has shown a significant variability in the IC50s of the same drug, depending on different in vitro and in vivo experimental conditions. To study this high heterogeneity in the inhibitory effects of NSAIDs, we have developed an in silico approach to evaluate NSAID action on targets under different PGHS-1 microenvironmental conditions, such as arachidonic acid, reducing cofactor, and peroxide concentrations. The designed technique permits translating the drug IC50, obtained in one experimental setting to another, and predicts in vivo inhibitory effects based on the relevant in vitro data. For the aspirin case, we elucidated the mechanism underlying the enhancement and reduction (aspirin resistance) of its efficacy, depending on PGHS-1 microenvironment in in vitro/in vivo experimental settings. We also present the results of the in silico screening of the combined action of sets of two NSAIDs (aspirin with ibuprofen, aspirin with celecoxib), and study the mechanism of the experimentally observed effect of the suppression of aspirin-mediated PGHS-1 inhibition by selective and nonselective NSAIDs. Furthermore, we discuss the applications of the obtained results to the problems of standardization of NSAID test assay, dependence of the NSAID efficacy on cellular environment of PGHS-1, drug resistance, and NSAID combination therapy.

Apoptotic Effect of Tolfenamic Acid in KB Human Oral Cancer Cells: Possible Involvement of the p38 MAPK Pathway

Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to inhibit cancer growth by inhibiting the activity of cyclooxygenase (COX). However, there is increasing evidence that the COX-independent pathway may be also involved in the inhibitory effect of NSAIDs against tumor progression. Tolfenamic acid is a NSAID that exhibits anticancer activity in pancreatic and colorectal cancer models. In the present study, the anti-tumor effect of tolfenamic acid in KB human oral cancer cells is investigated. The results showed that tolfenamic acid does not alter the expression of the COX proteins, but it inhibits cell growth and induces apoptosis as evidenced by the annexin V positivity, sub-G1 population, nuclear fragmentation and the cleavage of poly ADP-ribose polymerase. In addition, tolfenamic acid also leads to a loss of the mitochondrial membrane potential in KB cells. These effects are related to the activation of p38 mitogen-activated protein kinase (MAPK) pathway. These results suggest that tolfenamic acid-induced apoptotic cell death inhibits cancer growth by activating the p38 MAPK pathway for cancer prevention.

A Role for HSP70 in Protecting against Indomethacin-induced Gastric Lesions

A major clinical problem encountered with the use of nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, is gastrointestinal complications. Both NSAID-dependent cyclooxygenase inhibition and gastric mucosal apoptosis are involved in NSAID-produced gastric lesions, and this apoptosis is mediated by the endoplasmic reticulum stress response and resulting activation of Bax. Heat shock proteins (HSPs) have been suggested to protect gastric mucosa from NSAID-induced lesions; here we have tested this idea genetically. The severity of gastric lesions produced by indomethacin was worse in mice lacking heat shock factor 1 (HSF1), a transcription factor for hsp genes, than in control mice. Indomethacin administration up-regulated the expression of gastric mucosal HSP70. Indomethacin-induced gastric lesions were ameliorated in transgenic mice expressing HSP70. After indomethacin administration, fewer apoptotic cells were observed in the gastric mucosa of transgenic mice expressing HSP70 than in wild-type mice, whereas the gastric levels of prostaglandin E(2) for the two were indistinguishable. This suggests that expression of HSP70 ameliorates indomethacin-induced gastric lesions by affecting mucosal apoptosis. Suppression of HSP70 expression in vitro stimulated indomethacin-induced apoptosis and activation of Bax but not the endoplasmic reticulum stress response. Geranylgeranylacetone induced HSP70 at gastric mucosa in an HSF1-dependent manner and suppressed the formation of indomethacin-induced gastric lesions in wild-type mice but not in HSF1-null mice. The results of this study provide direct genetic evidence that expression of HSP70 confers gastric protection against indomethacin-induced lesions by inhibiting the activation of Bax. The HSP inducing activity of geranylgeranylacetone seems to contribute to its gastroprotective activity against indomethacin.

Cancer Prevention: A New Era beyond Cyclooxygenase-2

The seminal epidemiological observation that nonsteroidal anti-inflammatory drugs (NSAIDs) prevent colon and possibly other cancers has spurred novel approaches to cancer prevention. The known inhibitory effect of NSAIDs on the eicosanoid pathway prompted studies focusing on cyclooxygenase (COX) and its products. The increased prostaglandin E2 levels and the overexpression of COX-2 in colon and many other cancers provided the rationale for clinical trials with COX-2 inhibitors for cancer prevention or treatment. Their efficacy in the prevention of sporadic colon and other cancers remains unknown; one COX-2 inhibitor has been withdrawn because of side effects, and there are concerns about whether these effects are class-specific. There is evidence to suggest that COX-2 may not be the only or ideal eicosanoid pathway target for cancer prevention. Six sets of observations support this notion: the relatively late induction of COX-2 during carcinogenesis; the finding that NSAIDs may not require inhibition of COX-2 for their effect; the modest effect of coxibs in cancer prevention; that currently available coxibs have multiple non-COX-2 effects that may account for at least some of their efficacy; the possibility that concurrent inhibition of COX-2 in non-neoplastic cells may be harmful; and the possibility that COX-2 inhibition may modulate alternative eicosanoid pathways in a way that promotes carcinogenesis. Given the limitations of COX-2-specific inhibitors and the biological evidence mentioned above, we suggest that targets other than COX-2 should be pursued as alternative or complementary approaches to cancer prevention.

Minimizing complications from nonsteroidal anti-inflammatory drugs: the cost-effectiveness of competing strategies in varying risk groups

The decisive epidemiological observation that non-steroidal anti-inflammatory drugs (NSAIDs) prevent colon and possibly other cancers as well has spurred novel approaches to cancer chemoprevention. The known inhibitory effect of NSAIDs on the prostaglandin production prompted studies focusing on cyclooxygenase (COX) and its products. The increased prostaglandin E2 levels and the over-expression of COX-2 in colon and many other cancers provided the rationale for clinical trials with COX-2 inhibitors for cancer chemoprevention. However, their modest efficacy in the prevention of sporadic colon and other cancers, and the recent withdrawal of Rofecoxib, a COX-2 specific inhibitor (coxib), because of its side effects are causes of concern about this class. There is evidence to suggest that COX-2 may not be the only or ideal target in the eicosanoid pathway for cancer chemoprevention. Various observations like the relatively late induction of COX-2 in carcinogenesis, the modest clinical efficacy of coxibs in comparison to traditional NSAIDs (tNSAIDs) in cancer prevention trials, the finding that NSAIDs may not require inhibition of COX-2 for their effect, that currently available coxibs have multiple non-COX-2 effects, the possibility that concurrent inhibition of COX-2 in non-malignant cells may be harmful and the possibility that COX-2 inhibition may modulate alternative eicosanoid pathways in a way that promote carcinogenesis support this concept. Given the limitations of COX-2-specific inhibitors and the biological evidence for the existence of other potential targets, we suggest that targets other than COX-2 should be explored as unconventional or paired approaches to cancer prevention.

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.

Peroxisome Proliferator-activated Receptor δ Activation Promotes Cell Survival following Hypertonic Stress

COX2-selective non-steroidal anti-inflammatory drugs (NSAIDs) cause selective apoptosis of renal medullary interstitial cells (RMIC) in vivo and reduce their ability to tolerate hypertonic stress in vitro. To determine the mechanism by which COX2 activity promotes RMIC viability, we examined the capacity of COX2-derived prostanoids to promote RMIC survival. Although RMICs synthesize prostaglandin E2 (PGE2) PGI2 > PGF2a > TxA2, only PGI2 enhanced RMIC viability following hypertonic stress. RMICs do not express the prostacyclin receptor, but they do express the prostacyclin responsive nuclear transcription factor peroxisome proliferator-activated receptor delta (PPARdelta). Hypertonic stress increased PGI2 synthesis 330% above base line and also activated a PPARdelta specific reporter (delta response element (DRE)) by 90% above base line. Conversely DRE activity was only inhibited by the COX2-selective inhibitor SC236 but not by a COX1-selective NSAID (SC560). Overexpression of PPARdelta using an adenovirus not only drove DRE activity but also prevented RMIC death due to COX2 inhibition. These studies are consistent with a model whereby hypertonicity activates COX2-derived prostaglandin production, which promotes RMIC viability through PPARdelta. Inhibition of PPARdelta activity may contribute to the renal papillary necrosis associated with analgesic and/or NSAID use.

Inhibition of inducible nitric oxide synthase gene expression by indomethacin or ibuprofen in β-amyloid protein-stimulated J774 cells

Recent studies show that a mononuclear phagocyte lineage, including microglia, plays a possible role in the pathogenesis of Alzheimer's disease through nitric oxide (NO)-mediated neurotoxicity. Epidemiological studies show that nonsteroidal anti-inflammatory drugs (NSAIDs) have a protective effect against Alzheimer's disease. Based on these observations, it has been hypothesized that an anti-Alzheimer's disease effect of NSAIDs could result from the inhibition of NO synthesis. We report here that indomethacin or ibuprofen dose-dependently reduce β-amyloid protein and interferon-γ-induced NO production, accompanied by an inhibition of inducible nitric oxide synthase mRNA expression in J774 cells, a murine macrophage cell line. Aspirin, however, does not produce such an effect, suggesting that the cyclooxygenases pathway is not involved in the inhibitory effects of NSAIDs on β-amyloid protein and interferon-γ-induced NO production in J774 cells.

Cyclooxygenase-1 and Cyclooxygenase-2 Selectivity of Widely Used Nonsteroidal Anti-Inflammatory Drugs

Purpose: Both isoforms of cyclo-oxygenase, COX-1 and COX-2, are inhibited to varying degrees by all of the available nonsteroidal anti-inflammatory drugs (NSAIDs). Because inhibition of COX-1 by NSAIDs is linked to gastrointestinal ulcer formation, those drugs that selectively inhibit COX-2 may have less gastrointestinal toxicity. We measured the extent to which NSAIDs and other anti-inflammatory or analgesic drugs inhibit COX-1 and COX-2 in humans. Subjects and Methods: Aliquots of whole blood from 16 healthy volunteers were incubated ex vivo with 25 antiinflammatory or analgesic drugs at six concentrations ranging from 0 (control) to 100 μM (n = 5 for each). Blood was assayed for serum-generated thromboxane B 2 synthesis (COX-1 assay) and for lipopolysaccharide-stimulated prostaglandin E 2 synthesis (COX-2 assay). In addition, gastric biopsies from the same volunteers were incubated with each drug ex vivo and mucosal prostaglandin E 2 synthesis measured. Results: Inhibitory potency and selectivity of NSAIDs for COX-1 and COX-2 activity in blood varied greatly. Some NSAIDs (eg, flurbiprofen, ketoprofen) were COX-1 selective, some (eg, ibuprofen, naproxen) were essentially nonselective, while others (eg, diclofenac, mefenamic acid) were COX-2 selective. Inhibitory effects of NSAIDs on gastric prostaglandin E 2 synthesis correlated with COX-1 inhibitory potency in blood ( P <0.001) and with COX-1 selectivity ( P <0.01), but not with COX-2 inhibitory potency. Even COX-2 “selective” NSAIDs still had sufficient COX-1 activity to cause potent inhibitory effects on gastric prostaglandin E 2 synthesis at concentrations achieved in vivo. Conclusion: No currently marketed NSAID, even those that are COX-2 selective, spare gastric COX activity at therapeutic concentrations. Thus, all NSAIDs should be used cautiously until safer agents are developed.

The effects of non-steroidal anti-inflammatory drugs on cholinergic and histamine-induced contractions of guinea-pig isolated ileum.

1 Eleven non-steroidal anti-inflammatory drugs (NSAID) reversibly inhibited contractions of the longitudinal muscle of the guinea pig isolated ileum induced by acetylcholine, histamine, electrical transmural stimulation and nicotine in this order of increasing potency. 2. After the addition of prostaglandins E1, E2 or F2alpha, with partially effective concentrations of NSAID (but not with higher concentrations which almost totally prevented the responses) the inhibitory effects of NSAID were reversibly lost, except for electrically induced contractions and prostaglandin F2alpha. 3 The effects of NSAID may be due to actions on biological membranes or on distribution of ions in addition to their inhibitory effect on prostaglandin synthesis. Prostaglandins may reverse the inhibition by non-selective sensitization of smooth muscle to various agonists.