Co-administration Of Non-steroidal Anti-inflammatory Drugs Research Articles

Trends and hospital practice variation for analgesia for children with sickle cell disease with vaso-occlusive pain episodes: An 11-year analysis

This cross-sectional analysis of 86,111 visits for sickle cell disease and vaso-occlusive episodes (VOE) in U.S. pediatric emergency departments between 2013 and 2023 shows increased use of NSAIDs, ketamine, and acetaminophen, with unchanged opioid use. Hospitals with a higher volume of VOE visits more frequently administered opioids. BackgroundVaso-occlusive episodes (VOEs) are a hallmark of sickle cell disease (SCD), leading to frequent emergency department (ED) visits. Effective pain management is crucial, with guidelines recommending routine use of non-steroidal anti-inflammatory drugs (NSAIDs) with opioids, and emerging evidence supporting ketamine use. However, these recommendations are based on low-certainty evidence, and the impact of these guidelines on analgesia use over time remains unclear. ObjectiveThis study aimed to analyze trends in analgesia use over an 11-year period in pediatric SCD patients presenting to U.S. EDs with VOE and assess variations in treatment across hospitals. MethodsA cross-sectional study was conducted using data from the Pediatric Health Information System covering 34 U.S. children's hospitals from January 1, 2013, to December 31, 2023. The primary outcomes were the proportions of visits where opioids, NSAIDs, acetaminophen, and/or ketamine were administered on the first calendar day of the initial visit. Secondary outcomes included the co-administration of NSAIDs with opioids. Logistic and linear regression models were used to assess trends and hospital-level variations. ResultsA total of 86,111 ED visits for VOE were analyzed. Opioids were administered in 82 % of encounters, NSAIDs in 72 %, acetaminophen in 17 %, and ketamine in 1 %. Co-administration of NSAIDs with opioids occurred in 59 % of the visits. Among discharged patients, there was a positive trend for NSAID use (slope: 1.68 %/year, 95 % CI: 0.91 %, 2.45 %) and NSAID-opioid co-administration (slope: 1.03 %/year, 95 % CI: 0.37 %, 1.69 %) over time. Acetaminophen use also increased over the study period (slope: 0.99 %/year, 95 % CI: 0.80 %, 1.17 %). In hospitalized patients, there was a significant upward trend for acetaminophen (slope: 1.29 %/year, 95 % CI: 0.69 %, 1.89 %) and ketamine (slope: 0.36 %/year, 95 % CI: 0.27 %, 0.45 %), while opioid use remained unchanged. Significant hospital-level variations were observed, with larger hospitals more likely to administer opioids but less likely to co-administer NSAIDs with opioids compared to medium-volume hospitals. ConclusionOver the past decade, the use of NSAIDs, acetaminophen, and ketamine has increased in the management of VOE in pediatric SCD patients, while opioid use remains consistent. The co-administration of NSAIDs and opioids has also increased, reflecting guideline adherence. Variations in analgesia practices across hospitals underscore the need for standardizing pain management strategies in this population.

Damage-associated molecular patterns as a mechanism of sevoflurane-induced neuroinflammation in neonatal rodents.

General anesthesia is inevitable for pediatric patients undergoing surgery, though volatile anesthetic agents may cause neuroinflammation and neurodevelopmental impairment; however, the underlying pathophysiology remains unclear. We aimed to investigate the neuroinflammation mechanism in developing rat brains associated with sevoflurane exposure time, by identifying the specific damage-associated molecular patterns (DAMPs) pathway and evaluating the effects of non-steroidal anti-inflammatory drugs (NSAIDs) in alleviating neuroinflammation. A three-step experiment was conducted to investigate neuroinflammation induced by sevoflurane. First, the exposure time required for sevoflurane to cause neuroinflammation was determined. Next, the specific pathways of DAMPs involved in neuroinflammation by sevoflurane were identified. Finally, the effects of NSAIDs on sevoflurane-induced neuroinflammation were investigated. The expression of various molecules in the rat brain were assessed using immunohistochemistry, immunofluorescence, quantitative real-time polymerase chain reaction, western blot analysis, and enzyme-linked immunosorbent assay. In total, 112 rats (aged 7 days) were used, of which six rats expired during the experiment (mortality rate, 5.3%). Expression of CD68, HMGB-1, galectin-3, TLR4, TLR9, and phosphorylated NF-κB was significantly increased upon 6 h of sevoflurane exposure. Conversely, transcriptional levels of TNF-α and IL-6 significantly increased and IFN-γ significantly decreased after 6 h of sevoflurane exposure. Co-administration of NSAIDs with sevoflurane anesthesia significantly attenuated TNF-α and IL-6 levels and restored IFN-γ levels. In conclusion, 6 h of sevoflurane exposure induces neuroinflammation through the DAMPs pathway, HMGB-1, and galectin-3. Co-administration of ibuprofen reduced sevoflurane-induced neuroinflammation.

Histomorphological and biochemical alterations on the liver of Wistar rats following co-administration of NSAIDs (Piroxicam, Diclofenac and Ibuprofen)

Non-steroidal anti-inflammatory drugs (NSAIDs) are an important therapeutic class of drugs widely used to suppress acute or chronic pains and inflammatory diseases such as in rheumatoid arthritis (RA), osteoarthritis (OS) etc. The aim of this study was to investigate the random combination and individual effect of COX-2 inhibitors (NSAIDs) on the liver. This study was conducted using a total of 40 adults Wistar rats. The rats were divided into eight groups of 5 rats each. Group one was the control group, group 2 was given piroxicam (0.29mg/kg) daily, group 3 was given ibuprofen (5.71mg/kg) daily, and group 4 received diclofenac (1.42mg/kg) daily. Group 5 received piroxicam (0.29mg/kg bodyweight) plus ibuprofen (0.58mg/kg), group 6 received piroxicam (0.29mg/kg) plus diclofenac (1.42mg/kg) and group 7 received ibuprofen (0.58mg/kg) plus diclofenac (1.42mg/kg) respectively daily. Group 8 was given Piroxicam (0.29mg/kg bodyweight) plus Ibuprofen (5.71mg/kg) plus diclofenac (1.42mg/kg) daily. Intervention was over a period of 3days. Animals were sacrificed after 24 hours and the liver tissues were excised, some were fixed in 10% neutral buffered formalin for histological studies while others were placed in normal saline for biochemical analysis. The results revealed that there was no significant statistical difference in total bilirubin, ALT and AST when compared to the control. This suggests that NSAIDs may have no significant effects on the liver for this regimen. Histological changes observed were congested portal vein, haemorrhagic bile ducts, distortion of portal triad and sinusoids, and degeneration of hepatocytes. In conclusion, NSAIDs may have harmful effect on the cytoarchitecture of the liver which can lead to liver damage especially when given in high doses and in combination, but however it had no effect on liver function.

Suitability of Oral Rehydration Solution (ORS) for Use in the Cisplatin Short Hydration Method.

Short hydration is a method to change partial intravenous hydration to oral to administer cisplatin (CDDP); however, the most suitable form of oral hydration is unknown. This study aimed to determine whether oral rehydration solution (ORS) affects CDDP-induced nephrotoxicity (CIN) and electrolyte imbalance. Lung cancer patients (n=200) who had received CDDP-including regimens (CDDP dosage ≥75 mg/m2) were retrospectively evaluated. We used logistic analysis to evaluate whether ORS intake could be a preventive factor for CIN (≥grade 2 serum creatinine elevation). Moreover, incidence of CIN and electrolyte imbalance and the variation in serum creatinine and electrolyte levels were compared between ORS and non-ORS (control) patients. CIN occurred in 9.8% of ORS patients, and 7.5% of non-ORS patients (p=0.79). The variation in serum creatinine level was also similar in both groups. Multivariate analysis suggested that ORS intake does not affect CIN, although CIN was associated with the coadministration of non-steroidal anti-inflammatory drugs and the presence of diabetes mellitus. The variations in serum electrolyte levels did not differ, and incidence of hyponatremia, hypokalemia, and hypochloremia was also similar between the groups. Moreover, patients in ORS group experienced significantly more anorexia compared to controls, and approximately 40% of the patients were unable to continue ORS intake. ORS intake in CDDP short hydration regimens does not affect CIN and CDDP-induced electrolyte imbalance; however, its intake is associated with the incidence of anorexia suggesting that ORS should not be used for oral hydration.

Comparison of the nephroprotective effects of non-steroidal anti-inflammatory drugs on cisplatin-induced nephrotoxicity in vitro and in vivo

Cisplatin (CDDP) is an anticancer drug, often used in the treatment of several types of cancers. CDDP-induced nephrotoxicity (CIN) is one of the most severe adverse events associated with the use of CDDP. It has been suggested that the co-administration of non-steroidal anti-inflammatory drugs (NSAIDs) is a risk factor for CIN. However, the specific NSAIDs that affect CIN and the precise mechanisms underlying this interaction remain unclear. Hence, we aimed to evaluate the effect of NSAIDs on CDDP-induced cytotoxicity in vitro and confirmed the results in vivo. Using the epithelioid clone of the normal rat kidney cells (NRK-52E cells), we assessed the effects of 17 NSAIDs on CDDP-induced cytotoxicity all at once using the MTT assay. Furthermore, we evaluated two NSAIDs, which significantly attenuated or enhanced CDDP-induced cytotoxicity, in vivo. Wistar rats were treated with CDDP (5 mg/kg, i.p., day 1) and NSAIDs (p.o., day 1–4), and the kidneys were excised on day 5. Our results demonstrated that several NSAIDs attenuated, while others enhanced CDDP-induced cytotoxicity. Celecoxib significantly attenuated and flurbiprofen markedly enhanced cell dysfunction by CDDP. These results were reproduced in vivo as celecoxib decreased and flurbiprofen increased the expression of kidney injury molecule 1 (Kim-1) mRNA, a sensitive kidney injury marker, compared to the CDDP group. Moreover, celecoxib increased the antioxidant and autophagy markers quantified by qPCR in vitro and prevented a decrease in body weight induced by CDDP in vivo. In conclusion, we revealed that celecoxib significantly attenuated CIN in vitro and in vivo.

Detection of Signals of Convulsion-inducing Effect for Fluoroquinolone Antibiotics Alone and with Co-administration of Nonsteroidal Anti-inflammatory Drugs in Association with Aging Using Japanese Adverse Drug Event Reporting Database

Detection of Signals of Convulsion-inducing Effect for Fluoroquinolone Antibiotics Alone and with Co-administration of Nonsteroidal Anti-inflammatory Drugs in Association with Aging Using Japanese Adverse Drug Event Reporting Database

Effects of escitalopram and ibuprofen on a depression-like phenotype induced by chronic stress in rats

Clinical and preclinical studies have reported that co-administration of nonsteroidal anti-inflammatory drugs (NSAIDs) and antidepressant drugs are effective in patients with depression and in animal models of depression. However, several studies have suggested that NSAIDs inhibit the antidepressant effects of selective serotonin reuptake inhibitors in humans and mice. The present study investigated the effects of escitalopram (ESC) and ibuprofen (IBU), alone or in combination, on the stress-induced behavior and expression of brain-derived neurotrophic factor (BDNF) and p11, markers of depression and antidepressant action, in chronically stressed rats. Rats were subjected to chronic restraint stress (CRS) for 3 weeks and administered the following drugs: single administration of ESC or IBU or co-administration of ESC and IBU (ESC + IBU). Immobility time was measured by the forced swimming test (FST), and hippocampal BDNF and p11 levels were analyzed by quantitative real-time polymerase chain reaction and Western blotting. CRS increased immobility time on the FST. Administration of ESC, IBU, or ESC + IBU significantly attenuated the stress-induced increase in immobility time. CRS also significantly increased plasma corticosterone concentration by 169%. This effect was significantly recovered by administering ESC, IBU, or ESC + IBU. The levels of BDNF and p11 in the hippocampus decreased significantly in response to CRS. These decreases were prevented by administering ESC, IBU, or ESC + IBU. These findings suggest that both single and co-administration of ESC and IBU exerts antidepressant effects. These effects were associated with upregulation of BDNF and p11 expression.

Synergistic Interaction of Matricaria Chamomilla Extract with Diclofenac and Indomethacin on Carrageenan-Induced Paw Inflammation in Rats.

Preclinical Research The coadministration of non-steroidal anti-inflammatory drugs (NSAIDs) with medicinal plant extracts may increase anti-inflammatory activity, thus permitting the use of lower NSAID doses and limiting the side effects. The aim of this study was to explore the interactions between an ethanolic extract of M. chamomilla extract (MCE) with two NSAIDs, diclofenac and indomethacin on carrageenan-induced paw inflammation and gastric injury in rats. Diclofenac, indomethacin and MCE, or combinations with MCE produced an anti-inflammatory effect. Effective dose (ED) values were estimated for the individual drugs, and isobolograms were constructed. The final experimental ED values were 483.7 mg/kg for diclofenac + MCE combination, and 212.6 mg/kg for indomethacin + MCE. These values were lower (p < 0.05) than the theoretical ED values (1186.9 mg/kg for diclofenac + MCE combination, and 1183.8 mg/kg for indomethacin + MCE). These data suggest that the interactions between NSAIDs and MCE that mediate the anti-inflammatory effects at the systemic level are synergistic and may have therapeutic advantages for the clinical treatment of inflammatory processes. Drug Dev Res 78 : 360-367, 2017. © 2017 Wiley Periodicals, Inc.

Role of NADPHox/Rho-kinase signaling in the cyclosporine-NSAIDs interactions on blood pressure and baroreflexes in female rats

AimsThe hypertensive effect of the immunosuppressant drug cyclosporine (CSA) is paralleled, and probably triggered, by impaired arterial baroreceptor sensitivity (BRS). Here we asked if these effects of CSA are influenced by co-administration of nonsteroidal antiinflammatory drugs (NSAIDs) and if the oxidative NADPH-oxidase (NADPHox)/Rho-kinase (ROCK) pathway mediates this interaction. Materials and methodsFemale rats were treated for 10days with CSA (25mg/kg/day), diclofenac (DIC, COX-1/COX-2 inhibitor, 1mg/kg/day), celecoxib (COX-2 inhibitor, 10mg/kg/day), or their combinations. Baroreflex curves relating changes in heart rate (HR) to increases or decreases in blood pressure (BP) evoked by phenylephrine (PE) and sodium nitroprusside (SNP), respectively, were constructed and slopes of the curves were taken as measures of BRS. Key findingsCompared with control rats, CSA increased BP and reduced reflex chronotropic responses as indicated by the significantly smaller BRSPE and BRSSNP values. Similar effects were observed in rats treated with diclofenac alone or combined with CSA. Whereas CSA hypertension was maintained after selective COX-2 inhibition by celecoxib, the concomitant BRS reductions were largely eliminated. NADPHox inhibition by diphenyleneiodonium (DPI) blunted the CSA/DIC-evoked increases and decreases in BP and BRSPE, respectively. By contrast, fasudil (ROCK inhibitor) had no effect on CSA/DIC hypertension but reversed the associated reductions in both BRSPE and BRSSNP. SignificanceDepending on the nature of the cardiovascular response, NADPHox and ROCK contribute variably to the worsened cardiovascular profile in CSA/DIC-treated rats. Further, celecoxib rather than diclofenac could be a better choice as an add-on therapy to CSA in autoimmune arthritic conditions.

Prescription Pattern Analysis of Nonsteroidal Anti-inflammatory Drugs in the Northeastern Iranian Population.

Objective:Inappropriate nonsteroidal anti-inflammatory drugs (NSAIDs) therapy is a common cause of actual and potential adverse effects, such as bleeding and gastrointestinal ulceration, which exacerbates the patient's medical condition and might even be life threatening. We aimed to evaluate and analyze the prescription pattern of NSAIDs in Northeastern Iranian population and also provide suggestions for a more rational prescription behavior for such drugs.Methods:In this cross-sectional retrospective study, pattern of 1-year prescriptions was inspected based on 9.3 million prescriptions from two insurance companies. Type of NSAIDs, all dispensed doses and the number of NSAIDs ordered per prescription, and the route of administration for each patient were extracted from the databases. The prescription pattern of NSAIDs was analyzed seasonally.Findings:Out of 9,303,585 prescriptions, 19.3% contained at least one NSAID. Diclofenac was the most commonly prescribed NSAID (49.21%). At least two NSAIDs were simultaneously prescribed in 7% of prescriptions. General practitioners prescribed NSAIDs more frequently (67%) than specialists. Orthopedic surgeons and internists more frequently prescribed NSAIDs in comparison with other physicians (6% and 4%, respectively). Gastroprotective agents (GPAs) were coprescribed to only 7.62% of prescriptions.Conclusion:The frequency of NSAIDs prescription was relatively high in Northeast of Iran. A significant number of prescriptions were associated with irrational prescribing in both coadministration of NSAIDs and GPAs and NSAIDs combination. A strategy must be developed and implemented for prescribing and rational use of medications, e.g., continuing medical education regarding the potential risks of NSAIDs, importance of their appropriate and rational use, and necessity of appropriate prescription writing regarding both content and indication.

Effects of High Salt Intake on Blood Pressure and Cardiovascular Disease: The Role of COX Inhibitors.

Sodium has a bidirectional effect on blood pressure (BP) and cardiovascular disease (CVD). High sodium intake increases both BP and CVD, whereas low sodium intake decreases them. The significance of this association has been debated for years, mostly due to the inconsistency of data, but recently it has been revived due to new evidence about the harmful effects of sodium. Recent studies have indicated that high sodium intake was associated with an increase in BP and CVD, which in 2010 was estimated to have accounted for 1.65 million deaths worldwide. Based on this evidence, the American Heart Association has issued a Science Advisory statement regarding the significance of high sodium intake in relation to the incidence of hypertension and CVD. In addition to high sodium intake, experimental studies have shown that the coadministration of nonsteroidal anti-inflammatory drugs further aggravates the harmful effects of high sodium intake. The interrelationship of high sodium intake and nonsteroidal anti-inflammatory drugs will be discussed in this commentary.

Chemopreventive action of non-steroidal anti-inflammatory drugs on the inflammatory pathways in colon cancer.

Non-steroidal anti-inflammatory drugs (NSAIDs) are emerging as novel chemopreventive agents against a variety of cancers owing to their capability in blocking the tumor development by cellular proliferation and by promoting apoptosis. Inflammation is principal cause of colon carcinogenesis. A missing link between inflammation and cancer could be the activation of NF-κB, which is a hallmark of inflammatory response, and is commonly detected in malignant tumors. Therefore, targeting pro-inflammatory cyclooxygenase enzymes and transcription factors will be profitable as a mechanism to inhibit tumor growth. In the present study, we have studied the role of various pro-inflammatory enzymes and transcription factors in the development of the 1,2-dimethylhydrazine dihydrochloride (DMH)-induced colorectal cancer and also observed the role of three NSAIDs, viz., Celecoxib, Etoricoxib and Diclofenac. Carcinogenic changes were observed in morphological and histopathological studies, whereas protein regulations of various biomolecules were identified by immunofluorescence analysis. Apoptotic studies was done by TUNEL assay and Hoechst/PI co-staining of the isolated colonocytes. It was found that DMH-treated animals were having an over-expression of pro-inflammatory enzymes, aberrant nuclear localization of activated cell survival transcription factor, NF-κB and suppression of anti-inflammatory transcription factor PPAR-γ, thereby suggesting a marked role of inflammation in the tumor progression. However, co-administration of NSAIDs has significantly reduced the inflammatory potential of the growing neoplasm.

Exercise-induced Anaphylaxis: the Role of Cofactors.

Introduction:Anaphylaxis is a dramatic clinical emergency. It is a very severe, life-threatening generalized or systemic hypersensitivity reaction. Based on immunologic mechanism the anaphylaxis is divided in IgE, IgG, complement, or immune complexes-mediated vs non allergic anaphylaxis. There are a lot of etiologic factors of anaphylaxis, but the three principal immunologic triggers are drugs, insect stings, and foods. Regarding the clinical severity there are several proposed grading systems. The diagnosis of anaphylaxis is mainly clinical.Discussion:The anaphylaxis markers measured in clinical laboratories are total tryptase and histamine. There are some conditions that modulate the onset of anaphylaxis, acting as co- or augmentation factors, which significantly lower the allergen dose necessary for triggering anaphylaxis. The well-documented cofactors of anaphylaxis are physical exercise, alcohol consumption, some foods, co-administration of nonsteroidal anti-inflammatory drugs (NSAID), and concomitant infectious diseases. Development of anaphylaxis depends on the sensitization pattern, the proportion of the involved immunoglobulin classes, characteristics of the allergen, the proportion of the involved immunoglobulin classes, the avidity and affinity of immunoglobulins to bind an allergen, the route of allergen application, and, last but not least, the presence of cofactors of anaphylaxis.Conclusion:Anaphylaxis remains a continuous challenge for the diagnosis and treatment. The adequate management of anaphylaxis requires rapid diagnosis, implementation of primary and secondary prevention measures, and immediate administration of subcutaneous epinephrine.

About the role and underlying mechanisms of cofactors in anaphylaxis

Anaphylaxis is the systemic and most severe presentation of type I allergy. A number of conditions were identified that modulate the onset of anaphylaxis such as co- or augmentation factors, which significantly lower the allergen dose necessary for triggering anaphylaxis. Next to physical exercise or alcohol consumption, co-administration of nonsteroidal anti-inflammatory drugs (NSAID) or concomitant infectious diseases are well-documented cofactors of anaphylaxis. Registries for anaphylaxis document a role for cofactors in about 30% of anaphylactic reactions. Some disease entities such as 'wheat-dependent exercise-induced anaphylaxis' (WDEIA) are explicitly characterized by elicitation of anaphylaxis only in the presence of at least one such cofactor. Using WDEIA as a model disease, studies demonstrated that exercise increases skin prick test reactivity to and bioavailability of the allergen. Additional data indicate that alcohol consumption and NSAID administration display similar effects. Modulation of the cellular activation threshold is another mechanism underlying cofactor-induced anaphylaxis, most likely also functional when infectious diseases orchestrate elicitation of anaphylaxis. Cofactors are increasingly accepted to play a fundamental role in eliciting anaphylaxis. Consequently, to improve patient management modalities, a better understanding of the underlying mechanisms is warranted. This review aims to update clinicians and clinical scientists on recent developments.

Sulindac and Celecoxib Regulate Cell Cycle Progression by p53/p21 Up Regulation to Induce Apoptosis During Initial Stages of Experimental Colorectal Cancer

In the present study we have elaborated the putative mechanisms could be followed by the non-steroidal anti-inflammatory drugs (NSAIDs) viz. Sulindac and Celecoxib in the regulation of cell cycle checkpoints along with tumor suppressor proteins to achieve their chemopreventive effects in the initial stages of experimental colorectal cancer. Male Sprague-Dawley rats were administered with 1,2-dimethylhydrazine dihydrochloride (DMH) to produce early stages of colorectal carcinogenesis. The mRNA expression profiles of various target genes were analyzed by RT-PCR and validated by quantitative real-time PCR, whereas protein expression was analyzed by Western blotting. Nuclear localization of transcription factors or other nuclear proteins was analyzed by electrophoretic mobility shift assay and immunofluorescence. Flowcytometry was performed to analyze the differential apoptotic events and cell cycle regulation. Molecular docking studies with different target proteins were also performed to deduce the various putative mechanisms of action followed by Sulindac and Celecoxib. We observed that DMH administration has abruptly increased the proliferation of colonic cells which is macroscopically visible in the form of multiple plaque lesions and co-relates with the disturbed molecular mechanisms of cell cycle regulation. However, co-administration of NSAIDs has shown regulatory effects on cell cycle checkpoints via induction of various tumor suppressor proteins. We may conclude that Sulindac and Celecoxib could possibly follow p53/p21 mediated regulation of cell proliferation, where down regulation of NF-κB signaling and activation of PPARγ might serve as important additional events in vivo.

Influence of coadministration of antithrombotic medicines, warfarin, and NSAIDs on heparin safety: data from a prospective observational study.

Utilization of heparins has been increasing in the last decade, thus, in-depth analysis is needed to assess heparins safety monitoring patterns, incidence rates of adverse drug reactions (ADR), and frequency of coadministration with other medicines. To investigate the safety monitoring of heparin in hospitals and the influence of coadministration of nonsteroidal anti-inflammatory drugs (NSAIDs), antithrombotic medicines, and warfarin on heparin safety. We reviewed hospital records of 339 patients who had orders for heparin or low molecular weight heparin from May 2009 to May 2010. IBM SPSS Statistics version 18.0 was used to perform statistical analysis. Dalteparin (n=238, 70.21%) was the most frequently prescribed heparin. The most frequent indications given were for prophylaxis of venous thrombosis (n=135, 39.82%) and treatment of unstable coronary artery disease and myocardial infarction (n=166, 48.97%). ADRs were reported for 75 patients (22.12%), including coagulation abnormalities in 25 patients (7.37%), renal dysfunctions in 24 patients (7.08%), and thrombocytopenia in 10 patients (2.95%). 256 patients (75.52%) had relative contraindications. ADRs were associated with the previously reported relative contraindications (Spearman's rank correlation coefficient [rS] = 0.261, Pearson's chi-squared test [χ2]= 45.5, P less than 0.0005) and with prolonged treatment with heparins (rS=0.279 and χ2=74.7, P less than 0.0005). ADRs were not related to heparin use but indicated increased risk for negative treatment outcomes. Coadministration of heparin with warfarin, acetylsalicylic acid, clopidogrel, ketorolac, and NSAIDs was associated with the increased risk of adverse drug reactions. The relationship was low but statistically significant. The strongest relationship was with coadministration of aspirin (rS=0.283, χ2=21.42, P less than 0.0005), while the coadministration of NSAIDs showed only a very weak relationship to the development of ADRs (rS=0.133, χ2=21.01, P less than 0.0005). For the development of thrombocytopenia, the strongest risk was calculated for coadministration of warfarin (rS=0.248, χ2=28.14, P less than 0.0005), while coadministration of medicines from the list did not have a relationship with the risk of thrombocytosis. Safety monitoring of heparin orders is essential, especially for patients with relative contraindications during long-term treatment and in case of coadministration of oral anticoagulants, platelet inhibitors, and NSAIDs.

Drug utilization study of co-administration of nonsteroidal anti-inflammatory drugs and gastroprotective agents in an orthopaedics outpatients department of a tertiary care hospital in West Bengal

Background: Non steroidal anti-inflammatory drugs (NSAIDs) are the commonly prescribed analgesic in the orthopaedics department. NSAIDs are prescribed for a long period in both acute condition (like fracture of bones, muscle injury, postoperative procedures etc) or chronic conditions (osteoarthritis etc). However, they have many adverse effects, especially gastrointestinal toxicity when use regularly. For this reason NSAIDs are frequently co-prescribed with gastro protective agents. Common gastroprotective agents are proton pump inhibitors (PPI), H2 blockers, sucralfate, antacids and misoprostol (prostaglandin analogue). Methods: A cross-sectional, unicentric drug utilization study was conducted. Prescriptions were collected from patients attending the orthopaedic outpatients department. The prescription pattern of NSAIDs, gastroprotective agents or co-administration of NSAIDS and gastroprotective agents were analyzed. Results: A total of 977 prescriptions were studied; in which 928 prescriptions contained NSAIDs with gastroprotective agents (97.92%). The most common gastroprotective agents combined with NSAIDs was H2 receptor blockers (60.56%), followed by proton pump inhibitors (PPIs) (21.65%), while antacids are prescribed least (17.78%). Misoprostol or sucralfate were not used at all. Conclusions: NSAIDs are commonly co-prescribed with gastroprotective agents in high percentage.

Downregulation of NF-κB and PCNA in the regulatory pathways of apoptosis by cyclooxygenase-2 inhibitors in experimental lung cancer

Non-steroidal anti-inflammatory drugs (NSAIDs) are emerging as novel chemopreventive agents against a variety of cancers owing to their capability in blocking the tumor development by cellular proliferation, angiogenesis and by promoting apoptosis. The present study further explored the comparative role of a traditional NSAID, indomethacin and a newly developed coxib, etoricoxib against 9,10-dimethylbenz(a)anthracene (DMBA)-induced lung carcinogenesis in rats. Morphological and histological analysis revealed the occurrence of tumors and lesions along with constricted alveolar spaces in the DMBA treated animals which were largely corrected both by indomethacin and etoricoxib. COX-1 was found to be uniformly expressed in all the groups while COX-2 levels were raised prominently in the DMBA treated animals. Proliferation, as studied by PCNA expression was found to be markedly increased in the DMBA group as compared to the others. Increased NF-κB expression in the DMBA group was found to correct with the co-administration of NSAIDs. Also, fluorescent co-staining of the isolated lung cells revealed a significantly decreased apoptosis and altered mitochondrial membrane potential. In conclusion, these parameters indicate to the chemopreventive action of the two NSAIDs studied in lung cancer and as their mechanism of action suggests, can be achievable both by COX-dependent and COX-independent pathways.

Non-Steroidal Anti-Inflammatory Drugs and Imatinib; Drug Interactions That May Impact Efficacy,

Abstract 3501 Aim:The human organic cation transporter-1 (OCT-1) is the primary active influx protein for imatinib (IM) into target BCR-ABL-positive cells. The functional activity of the OCT-1 protein (OCT-1 activity; OA) is predictive of molecular response and event-free survival in de-novo chronic phase chronic myeloid leukemia (CP-CML) patients. Due to the common use of non-steroidal anti-inflammatory drugs (NSAIDs) among CML patients on IM to treat musculoskeletal pain, it is of particular interest to investigate the impact of NSAIDs on OCT-1 mediated IM uptake. Methods:12 NSAIDs were firstly examined for their impact on OA using the intracellular uptake and retention (IUR) assay and [14-C]-IM. The degree of in vitro kinase inhibition achieved was assessed using p-Crkl in the IC50imatinib assay. Viable cell numbers were determined by trypan blue exclusion method after 72 hours incubation with the co-administration of NSAIDs and IM. NSAIDs concentration was adjusted to median blood levels on standard doses. Results:The majority of NSAIDs (10 of 12) selected did not induce any significant change in OA in CML cell lines. Compared to control cells, increased OA were observed when K562 or KU812 cells were treated with diclofenac (10μM), and this resulted in a concomitant decrease in the IC50imatinib. In keeping with this, after 72 hours co-incubation with IM, diclofenac resulted in a significantly lower viable cell number compared with IM alone. In contrast, ibuprofen (130μM) led to a significant decrease in OA, resulting in an increased IC50imatinib and thus reduced the inhibition of IM on cell growth number (Table 1).Table 1The effect of diclofenac and ibuprofen on the OCT-1 activity, IC50imatinib and viable cell numbers in KU812 and HL60 cellsOCT-1 activity (percentage of vehicle control)IC50imatinib (μM, mean±SEM)viable cell number after 72 hours coincubation with IM (percentage of vehicle control; IM dose: 0.25μM in K562, 0.05μM in KU812)diclofenac (10 μM)ibuprofen (130 μM)no NSAIDsdiclofenac (10 μM)ibuprofen (130 μM)diclofenac (10 μM)ibuprofen (130 μM)K562127%, n=3*48%, n=4**5.7±0.8, n=33.7±0.7, n=3*8.1±0.5, n=3*71.4%, n=3*167%, n=3*KU812122%, n=6*59%, n=6**3.5±0.6, n=32.2±0.4, n=3*6.6±0.8, n=3*64.3%, n=3*145%, n=3*de-novo CP-CML MNC183%, n=50**59%, n=12**1.0±0.1, n=90.7±0.1, n=9*NANANAHealthy donors106%, n=1050%, n=6**NANANANANA*p<0.01,**p<0.001 compared with vehicle controlThe effects of diclofenac and ibuprofen on IM efficacy were then further investigated using primary samples. In keeping with the results observed in cell lines, diclofenac resulted in significant increases in OA, which translated to a significant decrease in IC50imatinib. Ibuprofen induced significant decreases in OA in all patients and healthy donors (Table 1). Conclusion:These finding provide strong evidence for interactions between some NSAIDs and IM which may substantially impact the response of CML patients to IM. While drugs such as diclofenac are likely to have a positive influence on IM efficacy, the findings observed with ibuprofen suggest caution when administrating NSAIDs to CML patients on IM treatment. Disclosures:Hughes:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ARIAD: Honoraria, Membership on an entity's Board of Directors or advisory committees. Osborn:Novartis: Research Funding. White:Novartis Pharmaceuticals: Research Funding; BMS: Research Funding.

Statistical identification of predictors for peripheral neuropathy associated with administration of bortezomib, taxanes, oxaliplatin or vincristine using ordered logistic regression analysis

Chemotherapy-induced peripheral neuropathy (CIPN) is a major drug-induced adverse reaction that becomes a dose-limiting toxicity. However, effective strategies for preventing or treating CIPN are lacking. Accordingly, this study aimed to statistically identify predictors for CIPN. Retrospective analysis was carried out for 190 patients who had been treated with bortezomib (n=28), taxanes (paclitaxel or docetaxel; n=58), oxaliplatin (n=52) or vincristine (n=52) at our hospital between April 2005 and December 2008. The severity of CIPN was assessed at the time of chemotherapy completion, graded as grade 0-5 in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. Multivariate ordered logistic regression analysis was used to investigate predictors for CIPN. Predictors for CIPN in patients that were administered bortezomib were no co-administration of dexamethasone [odds ratio (OR), 0.455; confidence interval (CI), 0.208-0.955; P=0.0376] and sex (male) (OR, 3.035; CI, 1.356-6.793; P=0.0069). For taxanes (paclitaxel or docetaxel), the predictor for CIPN was a large number of chemotherapy cycles (OR, 2.379; CI, 1.035-5.466; P=0.0412). For oxaliplatin, the predictors for CIPN were a large number of chemotherapy cycles (OR, 3.089; CI, 1.598-5.972; P=0.0008) and no co-administration of non-steroidal anti-inflammatory drugs (OR, 0.393; CI, 0.197-0.785; P=0.0082). For vincristine, predictors for CIPN were a large number of chemotherapy cycles (OR, 6.015; CI, 1.880-19.248; P=0.0025) and co-administration of an analgesic adjuvant (OR, 3.907; CI, 1.383-11.031; P=0.0101). In conclusion, our study indicates that CIPN will be alleviated by the co-administration of dexamethasone with bortezomib and non-steroidal anti-inflammatory drugs with oxaliplatin.