Utilization Of Non-steroidal Anti-inflammatory Drugs Research Articles

526P A retrospective study on the protective effect of nonsteroidal anti-inflammatory drugs on panitumumab-related skin symptoms

Background An acneiform eruption, the most frequently observed adverse event due to anti-epidermal growth factor receptor (EGFR) antibodies, is reported due to local inhibition of EGFR. The utility of nonsteroidal anti-inflammatory drugs (NSAIDs) for the acneiform eruption due to erlotinib, an EGFR tyrosine kinase inhibitor, has been reported; thus, a protective effect of NSAIDs on an acneiform eruption has been expected. The objective of this study is to examine the protective effect of NSAIDs on the acneiform eruption due to panitumumab (Pmab). Methods This study comprised 104 patients with KRAS wild-type unresectable advanced/recurrent colorectal cancer who treated with either Pmab and concomitant NSAIDs (concomitant group) or Pmab alone (non-concomitant group) from April 2010 to March 2016. The protective effects of NSAIDs on Pmab-related skin symptoms were retrospectively and comparatively examined regarding age, sex, ECOG performance status, treatment line, treatment regimen, and incidence rate of acneiform eruption. The period of this study was limited to the first 6 cycles from initiation of Pmab treatment, because the acneiform eruption due to Pmab were frequently observed during this period. Patients treated with protective topical or oral steroids after the time that Pmab treatment was started were excluded from this study. Results Of the 104 patients, 37 were in the concomitant group and 67 in the non- concomitant group. The incidence of acneiform eruption in the concomitant group and non-concomitant group were 74.3% and 88.7% (P value = 0.0498), respectively; the numbers of patients with grade 0, 1, 2, 3, and 4 acneiform eruption in the concomitant group were 10, 20, 7, 0, and 0, and those who in the non-concomitant group were 7, 41, 18, 1, and 0 (P value = 0.0495), respectively. The significant differences in both incidence and severity of acneiform eruption were observed between the two groups. Conclusions The concomitant use of oral NSAIDs seemed to be useful for the prevention of acneiform eruption due to Pmab. Legal entity responsible for the study Shizuoka Cancer Center Funding Shizuoka Cancer Center Disclosure All authors have declared no conflicts of interest.

Bleeding Complications in Patients Undergoing Percutaneous Spinal Cord Stimulator Trials and Implantations.

Spinal cord stimulators (SCS) are indicated for the management of multiple pain states with strong evidence. Recent guidelines recommend discontinuing aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) for the described procedures. The goal of this investigation is to assess the rate of bleeding and neurologic sequelae in patients undergoing SCS trials and implantation. This is a retrospective review from 2005 through 2014 of all patients 18 years or older undergoing the following procedures: Percutaneous SCS implantations, SCS revisions, and SCS trials. Baseline characteristics, antiplatelet and anticoagulation medications, coagulation parameters, and procedural details were extracted. The primary outcome was the presence of a bleeding complication within 31 days of the procedure requiring emergency medicine, neurology, or neurosurgical evaluation. The neurological complication was independently categorized for its potential relationship to procedural bleeding, and periprocedural red blood cell transfusion requirements were analyzed as a secondary outcome. A total of 642 percutaneous SCS procedures were performed on 421 unique patients, including 346 SCS trials, 255 SCS implantations, and 41 revision surgeries. Patients had received aspirin or NSAIDs within 7 days of needle placement for 101 procedures (15.7%). There were no bleeding or neurological complications identified in this cohort. Although the incidence of epidural hematoma is low, the development of bleeding complications following SCS lead placement can be devastating. In the present investigation, we identified no cases of epidural hematoma following percutaneous SCS lead placement, including more than 100 patients receiving aspirin or NSAIDs. Future investigations with larger numbers are needed to better define the relationships between periprocedural aspirin and NSAID utilization and bleeding complications.

Nonsteroidal Anti-Inflammatory Drugs and Bone-Healing: A Systematic Review of Research Quality.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are often avoided by orthopaedic surgeons because of their possible influence on bone-healing. This belief stems from multiple studies, in particular animal studies, that show delayed bone-healing or nonunions associated with NSAID exposure. The purpose of this review was to critically analyze the quality of published literature that evaluates the impact of NSAIDs on clinical bone-healing. A MEDLINE and Embase search was conducted to identify all articles relating to bone and fracture-healing and the utilization of NSAIDs. All human studies, including review articles, were identified for further analysis. Non-English-language manuscripts and in vitro and animal studies were excluded. A total of twelve clinical articles and twenty-four literature reviews were selected for analysis. The quality of the clinical studies was assessed with a modified Coleman Methodology Score with emphasis on the NSAID utilization. Review articles were analyzed with regard to variability in the cited literature and final conclusions. The mean modified Coleman Methodology Score (and standard deviation) was significantly lower (p = 0.032) in clinical studies that demonstrated a negative effect of NSAIDs on bone-healing (40.0 ± 14.3 points) compared with those that concluded that NSAIDs were safe (58.8 ± 10.3 points). Review articles also demonstrated substantial variability in the number of cited clinical studies and overall conclusions. There were only two meta-analyses and twenty-two narrative reviews. The mean number (and standard deviation) of clinical studies cited was significantly greater (p = 0.008) for reviews that concluded that NSAIDs were safe (8.0 ± 4.8) compared with those that recommended avoiding them (2.1 ± 2.1). Unanimously, all reviews admitted to the need for prospective randomized controlled trials to help clarify the effects of NSAIDs on bone-healing. This systematic literature review highlights the great variability in the interpretation of the literature addressing the impact of NSAIDs on bone-healing. Unfortunately, there is no consensus regarding the safety of NSAIDs following orthopaedic procedures, and future studies should aim for appropriate methodological designs to help to clarify existing discrepancies to improve the quality of care for orthopaedic patients. This systematic review highlights the limitations in the current understanding of the effects of NSAIDs on bone healing. Thus, withholding these medications does not have any proven scientific benefit to patients and may even cause harm by increasing narcotic requirements in cases in which they could be beneficial for pain management. This review should encourage further basic-science and clinical studies to clarify the risks and benefits of anti-inflammatory medications in the postoperative period, with the aim of improving patient outcomes.

Effects of non-selective (piroxicam) and selective (meloxicam) cyclo-oxygenase inhibitors on the intestinal contractility of rabbits

Background: To shed some light on full characterization and utilization of non-steroidal anti-inflammatory drugs (NSAIDs) in veterinary medicine, this study, therefore, was designed to clarify the pharmacological effects of two NSAIDs (one selective, that is meloxicam, and the other is non-selective, that is piroxicam) on intestinal contractility of rabbit as a farm animal species. Methods: Rabbits were humanely slaughtered, and segments from different parts of intestinal tracts were dissected out and an intestinal segment of about 2 cm long was fixed in an organ bath containing warm oxygenated Tyrode’s solution at 37°C. The tissue was subjected to a resting tension of 2 g and allowed to equilibrate for 30 min and then the effects of graded increased concentrations of piroxicam and meloxicam were demonstrated on the normal rhythmic motility of the isolated intestinal segments. The sites of action of piroxicam and meloxicam were tried. Results: Piroxicam and meloxicam exhibited concentration-dependent relaxations of intestinal smooth muscle segments with minimal and maximal effects of more potency by prioxicam than meloxicam. Calculated inhibitory concentration 50% were 15.45 and 23.10 μg/ml bath for piroxicam and meloxicam, respectively. Effects of either piroxicam or meloxicam did not involve cholinergic, adrenergic, histaminergic, nitrergic, or purinergic pathways as the application of the corresponding agonists/antagonists did not affect the inhibitory response of piroxicam and meloxicam. It was assumed that the effects of the drugs were attributed to the direct effects of the drugs on the intestines in addition to inhibiting endogenous prostaglandin synthesis activity via their cyclo-oxygenase inhibiting properties. Conclusions: Data of the present study may indicate that piroxicam and meloxicam could be used effectively and safely in rabbits for their anti-inflammatory actions in small therapeutic doses. However, in large doses, they (particularly, piroxicam) may produce depressant effects on gastrointestinal tract motility that should be taken in consideration in the case of introducing these drugs in therapy with larger doses.

Lornoxicam Side Effects May Lead to Surgical Mismanagement, in Case of Postoperative Intra-Abdominal Collection: A Case Report and Literature Review.

Postoperative collection is a known complication of abdominal surgery, especially after major surgery; however, minor surgical procedures may also be associated with this phenomenon. Utilization of nonsteroidal anti-inflammatory drugs, such as lornoxicam, and the adverse effects thereof, may affect the surgeon's judgment regarding the need for, and extent of, draining of these collections. Here I report the case of a 25-year-old male who presented with perforated acute retrocaecal subhepatic appendicitis complicated by pleural effusion and a small abdominal collection. The pleural effusion resolved almost completely over time. However, the patient showed incomplete recovery, as demonstrated by nausea, vomiting, and mood disturbance along with abdominal pain, tachycardia, and a persistent small abdominal collection. We initially suspected infection caused by a highly virulent type of bacteria and planned to perform percutaneous drainage. However, owing to skin erythematic changes, administration of lornoxicam was ceased, which resulted in complete recovery of the symptoms and consequently in avoidance of unnecessary invasive intervention to drain the abdominal collection. These findings suggest that the utilization and adverse effects of some painkillers for postoperative pain, such as lornoxicam, may affect the surgeon's judgment regarding the most appropriate surgical workup in cases of postoperative fluid collection.

Clinical implications of prescribing nonsteroidal anti-inflammatory drugs in oral health care—a review

Nonsteroidal anti-inflammatory drugs (NSAIDs), including both the traditional nonselective NSAIDs and the selective cyclooxygenase (COX)-2 inhibitors, are widely used for their anti-inflammatory and analgesic effects. They are routinely prescribed in dental practice for the management of pain and swelling. Their use in treating acute dental pain and chronic orofacial pain, as adjuncts to the treatment of periodontal disease, and to minimize edema following surgical procedures is well documented. However, long-term utilization of nonselective NSAIDs could increase the risk of gastrointestinal symptoms, ranging from mild (e.g., dyspepsia, nausea, or vomiting) to serious gastric problems (e.g., gastric bleeding or perforation). Therefore, selective COX-2 inhibitors have been developed with fewer GI side effects but the recently identified cardiovascular adverse reactions limit their routine use in dental practice. Another major concern for oral physicians is NSAID-induced mucosal lesions and prolongation of bleeding time during invasive dental procedures. This article reviews therapeutic and analgesic uses of NSAIDs in dentistry. The various issues surrounding NSAID-induced adverse reactions and their implications in dentistry are also discussed.

Aspirin and Other NSAIDs as Chemoprevention Agents in Melanoma

Melanoma incidence is increasing and, despite recent therapeutic advances, the prognosis for patients with metastatic disease remains poor. Thus, early detection and chemoprevention are promising strategies for improving patient outcomes. Aspirin (acetylsalicylic acid) and other nonsteroidal anti-inflammatory drugs (NSAID) have demonstrated chemoprotective activity in several other cancers, and have been proposed as chemopreventive agents for melanoma. Throughout the last decade, however, a number of case-control, prospective, and interventional studies of NSAIDs and melanoma risk have yielded conflicting results. These inconsistent findings have led to uncertainty about the clinical utility of NSAIDs for melanoma chemoprevention. This mini-review highlights current knowledge of NSAID mechanisms of action and rationale for use in melanoma, provides a comparative review of outcomes and limitations of prior studies, and discusses the future challenges in demonstrating that these drugs are effective agents for mitigating melanoma risk.

Population-based analysis of non-steroidal anti-inflammatory drug use among children in four European countries in the SOS project: what size of data platforms and which study designs do we need to assess safety issues?

BackgroundData on utilization patterns and safety of non-steroidal anti-inflammatory drugs (NSAIDs) in children are scarce. The purpose of this study was to investigate the utilization of NSAIDs among children in four European countries as part of the Safety Of non-Steroidal anti-inflammatory drugs (SOS) project.MethodsWe used longitudinal patient data from seven databases (GePaRD, IPCI, OSSIFF, Pedianet, PHARMO, SISR, and THIN) to calculate prevalence rates of NSAID use among children (0–18 years of age) from Germany, Italy, Netherlands, and United Kingdom. All databases contained a representative population sample and recorded demographics, diagnoses, and drug prescriptions. Prevalence rates of NSAID use were stratified by age, sex, and calendar time. The person-time of NSAID exposure was calculated by using the duration of the prescription supply. We calculated incidence rates for serious adverse events of interest. For these adverse events of interest, sample size calculations were conducted (alpha = 0.05; 1-beta = 0.8) to determine the amount of NSAID exposure time that would be required for safety studies in children.ResultsThe source population comprised 7.7 million children with a total of 29.6 million person-years of observation. Of those, 1.3 million children were exposed to at least one of 45 NSAIDs during observation time. Overall prevalence rates of NSAID use in children differed across countries, ranging from 4.4 (Italy) to 197 (Germany) per 1000 person-years in 2007. For Germany, United Kingdom, and Italian pediatricians, we observed high rates of NSAID use among children aged one to four years. For all four countries, NSAID use increased with older age categories for children older than 11. In this analysis, only for ibuprofen (the most frequently used NSAID), enough exposure was available to detect a weak association (relative risk of 2) between exposure and asthma exacerbation (the most common serious adverse event of interest).ConclusionsPatterns of NSAID use in children were heterogeneous across four European countries. The SOS project platform captures data on more than 1.3 million children who were exposed to NSAIDs. Even larger data platforms and the use of advanced versions of case-only study designs may be needed to conclusively assess the safety of these drugs in children.

Nonsteroidal Anti-Inflammatory Drug Use in Collegiate Football Players

To determine prevalence of nonsteroidal anti-inflammatory drug (NSAID) use in college football players and whether positions sustaining the most contact would use NSAIDs more frequently. Prospective cross-sectional study. American college football programs. An anonymous survey was given to 211 college football players before the season. Use of NSAIDs. The dependent variables are the different patterns in NSAID usage among positions and the frequency of NSAID use before and after the season. Of the athletes surveyed, 95.7% had or were using NSAIDs. Athletes first used NSAIDs in junior high school (45.6%), high school (48.5%), or college (5.8%). Athletes were separated into high (daily or weekly) or low (monthly or rarely) utilizers of NSAIDs. High utilization of NSAIDs was more frequent during the season (50.0%) than in the off-season (14.6%), P < 0.001. High NSAID utilization among all players was more prevalent after than before games (32.7% vs 10.9%, P = 0.002). Players with a higher body mass index (BMI; >28) were significantly higher utilizers of NSAIDs, reporting higher rates of use in season compared with other players (57.4% vs 39.5%, P = 0.011, OR = 2.06). Use of NSAIDs in collegiate football players is common. It is concerning that those athletes with the highest cardiovascular risk (ie, elevated body mass index) use greater amounts of NSAIDs. Further investigation is needed to delineate the short-term and long-term consequences of NSAID utilization in young athletes.

OP0203-PC New Data, New Problem; Assessing the Prevalence of Nsaid Prescribing in Primary Care in Those with a Background of Ischaemic Heart Disease (IHD) or Risk Factors for IHD

BackgroundNonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed in the treatment of patients in primary care with rheumatic problems (1). The side effect profile and safety of NSAID use has been...

AB0810-PC Even short term treatment with nsaids may be unsafe: the feasibility of replacing the nsaid prescription with regular paracetemol

BackgroundThe NSAID prescription is prevalent in patients seen in primary care with rheumatic and musculoskeletal problems (1). New evidence suggests that there is a significant increase in the risk of...

Use of Nonsteroidal Anti-Inflammatory Drugs among Healthy People and Specific Cerebrovascular Safety

Nonsteroidal anti-inflammatory drugs can increase bleeding and thrombosis, but little is known about the cerebrovascular safety of these drugs, especially among healthy people. The aim of this study was to examine the risk of ischemic and hemorrhagic stroke associated with the use of nonsteroidal anti-inflammatory drugs in healthy people. By individual-level linkage of nationwide administrative registers in Denmark, information on hospital admissions, prescription claims, vital status, and cause of death were obtained. A cohort of healthy people without hospital admissions for five-years and no important prescription claims for two-years was selected. Case crossover and Cox proportional hazard models were used to analyze the relationship between nonsteroidal anti-inflammatory drug utilization and specific cerebrovascular risk (fatal or non-fatal ischemic or hemorrhagic stroke). We selected 1,028,437 healthy individuals (median age 39 years). At least one nonsteroidal anti-inflammatory drug was claimed by 44·7% of the study population, and the drugs were generally used for a short period of time and in low doses. High-dose ibuprofen and diclofenac were associated with increased risk of ischemic stroke [hazard ratio 2·15 (95% confidence interval 1·66-2·79) and 2·37 (confidence interval 1·99-2·81), respectively]. Diclofenac was also associated with increased risk of hemorrhagic stroke and so was naproxen [hazard ratio 2·15 (confidence interval 1·35-3·42)]. In healthy individuals, use of commonly available nonsteroidal anti-inflammatory drugs such as ibuprofen, diclofenac, and naproxen was associated with increased risk of stroke.

Utilization of non-steroidal anti-inflammatory drugs in General and Endocrine Surgery Ward at Clinical Center 'Kragujevac' in Kragujevac

Objective. The aim of this study is to determine and analyze the trend of consumption of NSAIDs on the Department of General and Endocrine Surgery, Clinical Center 'Kragujevac' for the five-year period (2005-2009.). Method. The utilization study was conducted for determining and monitoring the drug consumption in inpatient medical institution according to the adopted methodology of the World Health Organization based on the expression of drug consumption in accordance with the number of defined daily doses/1000 patients/day (DDD/1000 pat/day). Results. The results of this study indicated a relatively high rate of NSAIDs consumption in surgical department of the institution which performs health practice at the secondary and tertiary levels. According to the number of DDD/1000 pat/day, the following NSAIDs were within the DU 90% (drug utilization 90%): diclofenac and ketorolac. Ibuprofen was the least applied NSAIDs for the entire period of observation. The results are in accordance with the global trend of increased consumption of NSAIDs. Conclusion. Studies on inpatients utilization of NSAIDs in our country are necessary to establish their safety and quality of drug prescription.

Outpatient utilization of non-steroidal anti-inflammatory drugs in three largest municipalities in South Backa district

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used in the treatment of musculoskeletal system diseases (MSD) and are associated with numerous adverse effects. To determine the amount and structure of outpatient consumption of NSAIDs and its correlation with musculoskeletal system diseases in three municipalities in South Backa district with different levels of health care. To examine whether the cost of drugs and the level of health care influence the choice of drugs. Data on the quarterly consumption of NSAIDs have been collected from all pharmacies in Novi Sad, Vrbas and Backa Palanka. Data are presented by the number of defined daily dosage (DDD) per 1000 inhabitants. Cost (in RSD)/DDD was also calculated. The drug utilization 90% (DU90%) methodology was used. Data on the incidence of MSD from the three municipalities were obtained from the Institute of Public Health of Vojvodina and were presented as the number of patients/1000 inhabitants. The highest total outpatient consumption of NSAIDs was recorded in Backa Palanka, a municipality with the highest prevalence of MSD. The lowest NSAIDs consumption and the lowest number of patients were observed in Vrbas. Diclofenac was NSAID with the highest consummation in all three municipalities, while ibuprofen, meloxicam and nimesulide were dispensed in much smaller amounts. The cheapest NSAIDs were found to be piroxicam and naproxen, diclofenac was the third in terms of price/DDD, while ibuprofen was the sixth. In order to improve prescription practice and the profile of drug usage in the population, it is important to educate health care professionals, and to inform general population about the risks of inappropriate drug use.

Bone Marrow Niche Attenuation by Non-Steroidal Anti-Inflammatory Drugs Mobilizes Hematopoietic Stem and Progenitor Cells by Differing Mechanisms

Abstract 724Hematopoeitic stem (HSC) and progenitor cells (HPC) are localized in niches contained within the bone marrow (BM) microenvironment. To facilitate acquisition of HSC/HPC for hematopoietic transplantation, donors can be treated with granulocyte-colony stimulating factor (G-CSF) to “mobilize” HSC/HPC from the BM niche to the peripheral system. Our laboratory has recently discovered that short term administration of non-steroidal anti-inflammatory drugs (NSAIDs) also mobilizes HSC/HPC and works in synergy with G-CSF. To understand the mechanisms underlying this novel therapeutic utility of NSAIDs we analyzed the BM niche post-NSAID and G-CSF treatment.Femurs of mice were analyzed after a 4 day regimen of the NSAID Meloxicam (3mg/kg, bid) and compared to control or G-CSF treated mice. Gross histological analysis showed a remarkable osteoblast (OB) “flattening” similar to that seen with G-CSF. Goldners trichrome staining revealed significantly reduced osteoid bone surfaces, with ∼3-fold increase in quiescent surfaces. Similarly, dynamic bone formation analysis using calcein/tetracycline labeling demonstrated reductions in mineral apposition rate and bone formation rate. There were no significant alterations in trabecular bone as determined by MicroCT. TRAP+ osteoclasts (OCs) were slightly elevated in both Meloxicam and G-CSF treated groups. To further assess the role of OCs, mice were mobilized with or without zoledronic acid (ZA) treatment, which inhibits OC activity. Similar to a recent report (Winkler, Blood, 2010), ZA resulted in an increase in HSC/HPC mobilization by both Meloxicam and G-CSF, suggesting that increased OC activity is not a mitigating mechanism for NSAID-mediated mobilization. Immunohistochemical (IHC) staining showed marked reductions in osteopontin (OPN), stromal-derived factor-1 (SDF-1) and N-cadherin expression by Meloxicam and G-CSF treated mice. In a separate set of experiments, OBs and mesenchymal stem cells (MSCs) were sorted by flow cytometry and gene expression assessed by Taq-Man assay. Similar to IHC analysis, Meloxicam treatment resulted in reduced SDF-1, OPN, Jagged-1, Runx2 and VCAM-1 gene expression.While the interaction of SDF-1 with its hematopoietically expressed receptor CXCR4 is a well known mediator of niche retention, both HSC and HPC were significantly mobilized by Meloxicam in CXCR4 knockout (KO) mice, suggesting that while reduced SDF-1 expression may concurrently play a role in NSAID mediated mobilization, it is not the definitive mechanism. In contrast, when OPN KO mice were mobilized with Meloxicam or G-CSF, Meloxicam unexpectedly increased mobilization of HPC only, and not HSC, while both HPC and HSC were mobilized by G-CSF. This surprising result indicates that NSAID-mediated OPN reduction is specifically responsible for the observed HSC mobilization, while HPC mobilization appears to be mediated by another mechanism(s).Recently, it has been reported that G-CSF reduces resident F4/80+ monocytes/macrophages (MOs), which normally support niche OBs and MSCs, and this reduction is at least partially responsible for niche attenuation and hematopoietic mobilization. However, in contrast to G-CSF, IHC analysis showed no reduction in F4/80+ cells after Meloxicam treatment, nor was there a reduction in CD169+ BM macrophages as assessed by flow cytometry. Therefore, while NSAIDs and G-CSF attenuate the niche microenvironment similarly, these agents function through independent mechanisms, perhaps explaining the synergistic mobilization seen by the two.In conclusion, NSAID treatment results in significant attenuation of the BM niche, including the niche components SDF-1, OPN, and N-cadherin. NSAID-mediated mobilization is independent of reduced SDF-1/CXCR4 signaling, as CXCR4 KO mice can be mobilized by NSAID. OPN KO specifically blocks the NSAID mobilization of HSC, but not HPC, suggesting differing mechanisms, or possibly multiple niche locations for these two populations; an intriguing finding suggesting that other mobilization strategies may be able to specifically target HSC or HPC. While G-CSF treatment results in reduced MOs, NSAIDs do not alter BM levels of these supportive cells. These results define not only a novel strategy for mobilization of HSC/HPC, but also suggest a possible strategy for targeted niche attenuation for other therapeutic applications, such as reduced conditioning regimens. Disclosures:Hoggatt:Fate Therapeutics: Consultancy. Pelus:Fate Therapeutics: Consultancy.

The outpatient utilization of non-steroidal anti-inflammatory drugs in South Bačka District, Serbia

To evaluate the utilization of non-steroidal anti-inflammatory drugs (NSAIDs) in South Bačka District (SBD), Serbia. State-owned and private pharmacies in SBD, a northern district of Serbia, with 605,720 inhabitants (according to the 2008 census). Data on the number of packages, size of packages, and retail price of NSAIDs (Anatomical Therapeutic Chemical (ATC) group M01A) from 1 January to 31 March 2008 were obtained from all state-owned and private pharmacies in SBD. This included NSAIDs bought without prescription and those issued by prescription (on the Health Insurance Companies List for Reimbursement). The number of defined daily doses/1000 inhabitants/day (DDD/1000 inh/day) was calculated. Within the DU90% (drug utilization 90%) segment, the proportion of high-, medium- and low-risk NSAIDs with respect to the risk of gastrointestinal (GI) bleeding was determined. Price/DDD was also calculated. Consumption of drugs expressed as DDD/1000 inh/day. The total consumption of NSAIDs over a 3-month period was 48.31 DDD/1000 inh/day. Only four drugs were within DU90%: diclofenac, ibuprofen, nimesulide and meloxicam (62.14, 19.87, 5.77, and 5.73% of total NSAID consumption, respectively). All dispensed NSAIDs within the DU90% segment except nimesulide (which was exclusively purchased without prescription) were nearly equally purchased without prescription and issued by prescription. The average price per DDD within the DU90% segment was 0.17 Euro/DDD, whereas it was 0.30 Euro/DDD for NSAIDs beyond the DU90% segment. The pattern of use of NSAIDs according to their GI risk showed that medium-risk diclofenac accounted for 66.45%, whereas low-risk ibuprofen was estimated to be 21.25% within the DU90% segment. Factors other than evidence-based medicine (such as poor health education in the past that led to long-lasting consequences on the cultural behaviour of the general population as well as on the prescribing habits of physicians) have a dominating impact on the use of NSAIDs in SBD. Targeted education from independent sources in the prescribing, dispensing and use of drugs is required to improve the quality of prescription and use of NSAIDs in Serbia.

Zinc protects against indomethacin-induced damage in the rat small intestine

The clinical utility of nonsteroidal anti-inflammatory drugs (NSAIDs) is often limited by the adverse effects that they produce in the small intestine. Alterations in the composition and functions of the glycocalyx and brush border membranes of the rat small intestine have been shown to occur in response to indomethacin, an NSAID often used in the study of adverse effects of these drugs. The micronutrient, zinc, has been documented to have cytoprotective effects in the gastrointestinal tract. The aim of this study was to evaluate the potential of zinc to reduce indomethacin-induced small intestinal damage. We pre-treated rats with zinc sulphate (50mg/kg body weight) 2h before administration of indomethacin (20mg/kg body weight) and sacrificed the rats 1, 12 or 24h after indomethacin. The extent of small intestinal mucosal damage and the content of lipids and sugars in the mucosa were determined. Bacterial counts in the intestinal lumen and the mucosa were ascertained. Activities of matrix metalloproteinases (MMPs) and levels of metallothionein in the mucosa were also measured. Pre-treatment with zinc sulphate was found to reduce the extent of indomethacin-induced mucosal damage. It also prevented drug-induced changes in the content of lipids and sugars in the mucosa. Drug-induced increases in activities of the MMPs and bacterial counts in the intestine were also attenuated by zinc. Metallothionein levels were significantly higher in animals pre-treated with zinc. We conclude that zinc was effective in protecting against indomethacin-induced small intestinal damage and suggest that it may do so by induction of metallothionein.

Zinc prevents indomethacin-induced renal damage in rats by ameliorating oxidative stress and mitochondrial dysfunction

The clinical utility of non-steroidal anti-inflammatory drugs (NSAIDs) is limited by their gastrointestinal and renal toxicities. Indomethacin (an NSAID commonly used in toxicity studies) has been shown to induce significant oxidative stress and mitochondrial dysfunction in the rat kidney. The current study was designed to assess the potential of zinc, a known antioxidant, to protect the kidney against these drug-induced effects. Male Wistar rats were pre-treated with zinc sulphate (50 mg/kg) and dosed with indomethacin (20 mg/kg) by oral gavage. Rats were sacrificed 24 h after the dose of indomethacin. Parameters of oxidative stress, mitochondrial function and lipid content of the mitochondrial membranes were measured in the kidneys of these animals. It was found that zinc significantly attenuated indomethacin-induced oxidative stress, mitochondrial dysfunction and changes in the lipids in mitochondrial membranes in the kidney. The content of metallothionein, a cysteine-rich zinc-binding protein, was also determined in the tissue. There was no significant induction of metallothionein in the kidney in zinc-treated animals. Estimation of serum creatinine showed that zinc seemed to hasten functional recovery of the kidney following indomethacin administration. We conclude that pretreatment with zinc is effective in protecting against indomethacin-induced changes in the rat kidney. This protective effect does not appear to be mediated by metallothionein.

Utilization of non-steroidal anti-inflammatory drugs in patients attending clinics in a tertiary hospital in Nigeria

Non-steroidal anti-inflammatory drugs are widely prescribed worldwide. In Nigeria there is unrestricted access to these useful, yet potentially harmful drugs. We set out to assess the utilization of non-steroidal anti-inflammatory drugs in outpatients attending clinics in a Teaching Hospital in Nigeria. Consecutive patients were interviewed using a structured questionnaire until 200 respondents were obtained. Data were analyzed using the Microsoft Excel and SPSS software. All patients had taken traditional (non-selective) non-steroidal drugs. Piroxicam was the most frequently used non-steroidal anti-inflammatory drug. 15.5% of patients had experienced adverse drug reactions, chiefly abdominal pain/discomfort. 20% of patients had used two or more non-steroidal anti-inflammatory drugs concurrently. Community drug outlets were the preferred sources of purchase with significantly more patients with primary or no education purchasing their drugs from these sources (p=0.05). Patients who purchased their drugs from community outlets took non-steroidal anti-inflammatory drugs in combination significantly more than those who purchased from hospital outlets (p=0.032). Age above 60 years was associated with a preference for prescription non-steroidal anti-inflammatory drugs rather than self-dosing or prescriptions from unqualified persons (p=0.004). Interventions to improve the utilization of non-steroidal anti-inflammatory drugs should include regulation to limit the number of drugs available over-the-counter. Other interventions should focus on community drug outlets which contribute significantly to ‘prescriptions' for and sourcing of non-steroidal anti-inflammatory drugs. Keywords : Non-steroidal anti-inflammatory drugs, drug utilization West African Journal of Pharmacology and Drug Research Vol. 21 (1&2) 2005: pp. 22-30

Cyclooxygenase 2 Expression in Colorectal Cancer with DNA Mismatch Repair Deficiency

Cyclooxygenase 2 (COX-2) overexpression is a frequent but not universal event in colorectal cancer. It has been suggested that COX-2 protein expression is reduced in colorectal cancer with a defective mismatch repair (MMR) system, a phenomenon commonly associated with hereditary nonpolyposis colorectal cancer (HNPCC) but also present in up to 15% of sporadic tumors. To assess COX-2 expression in a large series of fully characterized colorectal cancer patients with respect to the MMR system and to dissect the mechanisms responsible for altered COX-2 expression in this setting. MMR-deficient colorectal cancer were identified in a nationwide, prospective, multicenter study (EPICOLON project). Control MMR-proficient colorectal cancer patients were randomly selected. COX-2 expression was evaluated by immunohistochemistry. Personal and familial characteristics, as well as MSH2/MLH1 expression and germ line mutations, were evaluated. One hundred fifty-three patients, 46 with MMR deficiency and 107 with MMR proficiency, were included in the analysis. Overall, tumor COX-2 overexpression was observed in 107 patients (70%). COX-2 overexpression was observed in 85 patients (79%) with a MMR-proficient system, but only in 22 patients (48%) with a MMR-deficient colorectal cancer (P < 0.001). The lack of COX-2 overexpression was independently associated with a MMR-deficient system (odds ratio, 3.89; 95% confidence interval, 1.78-8.51; P = 0.001) and a poor degree of differentiation (OR, 3.83; 95% CI, 1.30-11.31; P = 0.015). In the subset of patients with a MMR-deficient colorectal cancer, lack of COX-2 overexpression correlated with a poor degree of differentiation, no fulfillment of Amsterdam II criteria, absence of MSH2/MLH1 germ line mutations, presence of tumor MSH2 expression, and lack of tumor MLH1 expression. CpG island promoter hypermethylation of COX2 was observed in 6 of 18 (33%) tumors lacking COX-2 expression in comparison with 2 of 28 (7%) tumors expressing this protein (P = 0.04). Up to half of MMR-deficient colorectal cancer do not show COX-2 overexpression, a fact observed almost exclusively in patients with sporadic forms. COX2 hypermethylation seems to be responsible for gene silencing in one third of them. These results suggest the potential utility of nonsteroidal anti-inflammatory drugs in HNPCC chemoprevention and may explain the lack of response of this approach in some sporadic tumors.