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Objective: We aimed to investigate whether ibuprofen use, compared with other non-selective non-steroidal anti-inflammatory drugs (ns-NSAIDs), cyclooxygenase-2 inhibitors (COX-2i) or paracetamol, increases the risk of coronavirus disease 2019 (COVID-19) diagnosis or hospitalisation. Design: A prevalent user and active comparator cohort study. Setting: Two US claims databases (Open Claims and PharMetrics Plus) mapped to the Observational Medical Outcomes Partnership Common Data Model. Participants: Insured patients with a history of osteoarthritis or back pain and receiving ibuprofen, other ns-NSAIDs, COX-2i or paracetamol between 1 November, 2019 and 31 January, 2020 (study enrolment window 1) or between 1 February, 2020 and 31 October, 2020 (study enrolment window 2). Main Outcome Measures: Large-scale propensity score matching and empirical calibration were used to minimise confounding. Incidence and hazard ratios of COVID-19 diagnosis and hospitalisation according to drug/s use were estimated and pooled in the same study period across data sources using a fixed-effects meta-analysis. Index treatment episode was the primary risk evaluation window, censored at the time of discontinuation. Results: A total of 633,562 and 1,063,960 participants were included in periods 1 and 2, respectively, for the ibuprofen versus ns-NSAIDs comparison, 311,669 and 524,470 for ibuprofen versus COX-2i, and 492,002 and 878,598 for ibuprofen versus paracetamol. Meta-analyses of empirically calibrated hazard ratios revealed no significantly differential risk of COVID-19 outcomes in users of ibuprofen versus any of the other studied analgesic classes: hazard ratios were 1.13 (0.96–1.33) for the ibuprofen-ns-NSAIDs comparison, 1.03 (0.83–1.28) for the ibuprofen-COX-2i comparison and 1.13 (0.74–1.73) for ibuprofen-paracetamol comparison on COVID-19 diagnosis in the February 2020–October 2020 window. Similar hazard ratios were found on COVID-19 hospitalisation and across both study periods. Conclusions: In patients with osteoarthritis or back pain, we found no differential risks of incident COVID-19 diagnosis or COVID-19 hospitalisation for ibuprofen users compared with other ns-NSAIDs, COX-2i or paracetamol. Our findings support regulatory recommendations that NSAIDs, including ibuprofen, should be prescribed as indicated in the same way as before the COVID-19 pandemic, especially for those who rely on ibuprofen or NSAIDs to manage chronic arthritis or musculoskeletal pain symptoms. [ABSTRACT FROM AUTHOR]

Background: Celecoxib‐tramadol co‐crystal (CTC) is a first‐in‐class analgesic co‐crystal of celecoxib and racemic tramadol with an improved pharmacologic profile, conferred by the co‐crystal structure, compared with its active constituents administered alone/concomitantly. Aim: We evaluated CTC in moderate‐to‐severe acute postoperative pain. Materials and Methods: This randomized, double‐blind, factorial, active‐ and placebo‐controlled phase 3 trial (NCT03108482) was conducted at 6 US clinical research centers. Adults with moderate‐to‐severe acute pain following bunionectomy with osteotomy were randomized to oral CTC (200 mg [112 mg celecoxib/88 mg rac‐tramadol hydrochloride] every 12 h), tramadol (50 mg every 6 h), celecoxib (100 mg every 12 h), or placebo for 48 h. Patients, investigators, and personnel were blinded to assignment. The primary endpoint was the 0–48 h sum of pain intensity differences (SPID0–48) in all randomized patients. Pain intensity was assessed on a 0–10 numerical rating scale (NRS). Safety was analyzed in patients who received study medication. Funded by ESTEVE Pharmaceuticals. Results: In 2017 (March to November), 1323 patients were screened and 637 randomized to CTC (n = 184), tramadol (n = 183), celecoxib (n = 181), or placebo (n = 89). Mean baseline NRS was 6.7 in all active groups. CTC had a significantly greater effect on SPID0–48 (least‐squares mean: −139.1 [95% confidence interval: −151.8, −126.5]) than tramadol (−109.1 [−121.7, −96.4]; p < 0.001), celecoxib (−103.7 [−116.4, −91.0]; p < 0.001), or placebo (−74.6 [−92.5, −56.6]; p < 0.001). Total treatment‐emergent adverse events (TEAEs) were 358 for CTC and 394 for tramadol. Drug‐related TEAEs occurred in 37.7% patients in the CTC group, compared with 48.6% in the tramadol group. There were no serious TEAEs/deaths. Conclusion: CTC provided greater analgesia than comparable daily doses of tramadol and celecoxib, with similar tolerability to tramadol. CTC is approved in the United States. [ABSTRACT FROM AUTHOR]

Objective To evaluate the risk of venous thromboembolism (VTE, i.e. deep vein thrombosis or pulmonary embolism, or both) following new use of NSAIDs in a long-term cohort of U.S. women. Methods We investigated initiation of coxibs and traditional NSAIDs (excluding aspirin) and incident VTE in 39 876 women enrolled in the Women's Health Study from 1993–95 and followed with yearly questionnaires until 2012. We defined initiation as the first reported use of NSAIDs for ≥4 days per month. Incident VTE was confirmed by an end point committee. We estimated hazard ratios (HRs) and risk differences (RDs, expressed as percentages) comparing NSAID initiation with non-initiation and acetaminophen initiation (active comparator) via standardization using a propensity score that incorporated age, BMI, calendar time, and relevant medical, behavioural, and socioeconomic variables updated over time. Results The HR (95% CI) for risk of VTE in the as treated analyses comparing initiation with non-initiation, was 1.5 (1.2, 1.8) for any NSAID, 1.3 (1.1, 1.7) for traditional NSAIDs, and 2.0 (1.3, 3.1) for coxibs, with 2-year RDs 0.11, 0.08 and 0.32, respectively. When comparing the risk of VTE after initiation of any NSAID with that after acetaminophen initiation, the HRs were 0.9 (0.6, 1.5), 0.9 (0.5, 1.5) and 1.4 (0.6, 3.4), with 2-year RDs 0.03, –0.01, and 0.13, respectively. Conclusion New use of NSAIDs was associated with increased VTE risk compared with non-use, but the association was null or diminished when compared with acetaminophen initiation. Elevated VTE risks associated with NSAID use in observational studies may in part reflect different baseline risks among individuals who need analgesics and may overstate the risk patients incur compared with pharmacologic alternatives. [ABSTRACT FROM AUTHOR]

The voluntary withdrawal of Vioxx (rofecoxib) from the market in 2004, as well as the 2005 and 2014 US FDA Advisory Committee meetings about non-steroidal anti-inflammatory drugs (NSAIDs) and cardiovascular risk, have raised questions surrounding the use of NSAIDs in at-risk populations. This paper discusses the cardiovascular safety profile of naproxen in the context of the NSAID class. The balance of evidence suggests that cardiovascular risk correlates with cyclooxygenase (COX)-2 selectivity, and the low COX-2 selectivity of naproxen results in a lower cardiovascular risk than that of other NSAIDs. The over-the-counter (OTC) use of naproxen is expected to pose minimal cardiovascular risk; however, the benefit-risk ratio and appropriate use should be considered at an individual patient level, particularly to assess underlying conditions that may increase the risk of events. Likewise, regulatory authorities should revisit label information periodically to ensure labeling reflects the current understanding of benefits and risks. [ABSTRACT FROM AUTHOR]

The article offers medical news brief as of March, 2017. Online palliative care course offered by Lancaster University in Great Britain for staff working in palliative care. Drugs buprenorphine/naloxone sublingual tablet, and Zubsolv was approved by the U.S. Food and Drug Administration (FDA) from the pharmaceutical firm Orexo. American Society for Regional Anesthesia and Pain Medicine (ASRA) announced the clinical usage of marijuana for intractable chronic pain.

BACKGROUND: Non-steroidal anti-inflammatory drugs are considered potentially harmful for patients with heart failure. OBJECTIVE: To determine the prevalence of in-hospital NSAID use their type, associated diagnosis and impact in clinical outcomes among patients with a diagnosis of heart failure. METHODS: The University Health System Consortium Database was used to identify all first hospitalizations with an International Classification of Diseases-9 discharge diagnosis code of systolic heart failure as the primary diagnosis between January 1, 2011 and December 31st 2014. RESULTS: Among 65,902 patients admitted for a primary diagnosis of SHF, 2675 (4.1%) were exposed to NSAID. The most frequent NSAID used was ibuprofen (51.63%), followed by ketorolac (29.38%) naproxen (8.07%) celecoxib (5.61%) and others. On multivariable analyses the length of stay of patients exposed to NSAID was longer compared to non-exposed (OR: 4.67, p < 0.001, 95% CI 4.10-5.25), but differences in mortality were not statistically different (OR: 0.90, p = 0.476, 95% CI 0.69-1.19). CONCLUSION: The use of NSAID in patients admitted with a primary diagnosis of systolic heart failure was low but was associated with longer length of stay. Further studies are needed to understand the impact of NSAID use in this patient population. [ABSTRACT FROM AUTHOR]

Objective. Little is known about the burgeoning Mexican American (MA) population's pain experience. Methods. Using 1999-2004 National Health and Nutrition Examination Survey (NHANES) data, prevalence of chronic pain, analgesic medication use, and substance use were examined among MA, non-Hispanic White (NHW), and non-Hispanic Black (NHB) respondents. Logistic and linear regression models examined racial/ethnic differences in: 1) chronic pain prevalence among all respondents, 2) location and number of pain sites among respondents with chronic pain, and 3) analgesic medication and substance use among respondents with chronic pain. Results. Compared to NHWs and NHBs, MAs were less likely to report any chronic pain. Among respondents with chronic pain, MAs had higher odds of reporting headache, abdominal pain, and a greater number of pain sites than NHWs. Compared to NHWs, MAs with chronic pain had lower odds of reporting past-month analgesic medication and COX-2 inhibitor use. MAs with chronic pain had lower odds of being a current cigarette smoker and heavy alcohol drinker but had similar street drug/ cocaine use relative to NHWs. Conclusions. Results suggest that: 1) MAs are less likely to develop chronic pain than NHWs, 2) MAs with chronic pain report greater headache and abdominal pain than NHWs, and 3) MAs with chronic pain are less likely to use analgesic medications and other substances compared to NHWs. These results suggest that providers should consider taking extra time to discuss analgesic medications with MAs. Future investigations should examine reasons underlying these racial/ethnic differences in chronic pain, as well as differences in the use of other substances, such as marijuana. [ABSTRACT FROM AUTHOR]

BACKGROUND: In this article, the authors examine the available scientific evidence regarding adverse effects of short-term use of nonsteroidal anti-inflammatory drugs (NSAIDs). Short-term use was defined as 10 days or fewer. METHODS: The authors reviewed randomized controlled clinical trials and cohort and case-controlled clinical studies published between 2001 and June 2015 in which the investigators reported on the safety of nonselective cyclooxygenase inhibitors and of cyclooxygenase-2 selective inhibitor NSAIDs. RESULTS: The systematic review process according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines allowed the authors to identify 40 studies that met the inclusion criteria. CONCLUSIONS: On the basis of the available scientific evidence, NSAIDs may be considered relatively safe drugs when prescribed at the most effective dose and for the shortest duration of time, which was defined to be 10 days or fewer. PRACTICAL IMPLICATIONS: Although the US Food and Drug Administration recommends the use of NSAIDs beyond 10 days to be accompanied by a consultation with a health care provider, the use of NSAIDs may be considered relatively safe when prescribed at the most effective dose and for the shortest duration of time, which was defined as 10 days or fewer. Exceptions would be for patients at risk of developing NSAID-exacerbated respiratory disease, patients with prior myocardial infarction who are receiving antithrombotic therapy, patients with asthma, and patients with a history of renal disease. [ABSTRACT FROM AUTHOR]

Rubus occidentalisis a black-fruited raspberry originating from North America. Its popularity and demand has been growing over the years, as studies outline its high anthocyanin and ellagitannin content and significance for human health. Interaction between chemical composition and pharmacological activity, mechanisms of action at cellular and molecular levels are all active areas of study. The vast majority of research concerning black raspberries is focused on chemoprevention and anticancer effects. This review summarizes the data on chemical composition and anticancer activity of black raspberry fruits throughout the years. [ABSTRACT FROM AUTHOR]

Background: Metabolic syndrome-associated osteoarthritis (MetS-OA) is a distinct osteoarthritis phenotype defined by the coexistence of MetS or its individual components. Despite the high prevalence of MetS-OA, its pathogenic mechanisms are unclear. The aim of this study was to determine the role of cellular senescence in the development of MetS-OA., Methods: Analysis of the human osteoarthritis initiative (OAI) dataset was conducted to investigate the MRI subchondral bone features of MetS-human OA participants. Joint phenotype and senescent cells were evaluated in two MetS-OA mouse models: high-fat diet (HFD)-challenged mice and STR/Ort mice. In addition, the molecular mechanisms by which preosteoclasts become senescent as well as how the senescent preosteoclasts impair subchondral bone microenvironment were characterized using in vitro preosteoclast culture system., Results: Humans and mice with MetS are more likely to develop osteoarthritis-related subchondral bone alterations than those without MetS. MetS-OA mice exhibited a rapid increase in joint subchondral bone plate and trabecular thickness before articular cartilage degeneration. Subchondral preosteoclasts undergo senescence at the pre- or early-osteoarthritis stage and acquire a unique secretome to stimulate osteoblast differentiation and inhibit osteoclast differentiation. Antagonizing preosteoclast senescence markedly mitigates pathological subchondral alterations and osteoarthritis progression in MetS-OA mice. At the molecular level, preosteoclast secretome activates COX2-PGE2, resulting in stimulated differentiation of osteoblast progenitors for subchondral bone formation. Administration of a selective COX2 inhibitor attenuated subchondral bone alteration and osteoarthritis progression in MetS-OA mice. Longitudinal analyses of the human Osteoarthritis Initiative (OAI) cohort dataset also revealed that COX2 inhibitor use, relative to non-selective nonsteroidal antiinflammatory drug use, is associated with less progression of osteoarthritis and subchondral bone marrow lesion worsening in participants with MetS-OA., Conclusions: Our findings suggest a central role of a senescent preosteoclast secretome-COX2/PGE2 axis in the pathogenesis of MetS-OA, in which selective COX2 inhibitors may have disease-modifying potential., Funding: This work was supported by the National Institutes of Health grant R01AG068226 and R01AG072090 to MW, R01AR079620 to SD, and P01AG066603 to XC., Competing Interests: WS, GL, BM, JW, AS, WZ, BL, PG, XC, SD No competing interests declared, AG received consultancy fees from Pfizer, Novartis, MerckSerono, TissueGene, AstraZeneca, and Regeneron. The author has no other competing interests to declare, MW Reviewing editor, eLife, (© 2022, Su, Liu, Mohajer et al.)

Despite well known complications, oral nonsteroidal anti-inflammatory drugs (NSAIDs) remain the most commonly prescribed medications in the US for musculoskeletal disorders such as osteoarthritis. Although there has been a recent focus on the cardiovascular and renal complications associated with these agents, NSAID gastropathy continues to be a particular concern in many patients, especially those at increased risk for serious adverse events, including the elderly. Complicating the diagnosis of NSAID gastropathy is its silent course, which, up to half of the time, is asymptomatic. Several strategies are currently employed by physicians to mitigate the risk of serious gastrointestinal events. These include either addition of a proton pump inhibitor to current nonselective NSAID therapy or the use of a cyclo-oxygenase- 2-selective NSAID. Although these agents are effective at mitigating the overall risk of gastrointestinal adverse events, they fail to address NSAID- related cardiovascular and renal risks. Due to their reduced systemic absorption, topical NSAIDs may present a viable option for patients at increased risk for serious NSAID-related adverse events, including gastropathy. [ABSTRACT FROM AUTHOR]

Abstract: Like in the adult population, nonsteroidal anti-inflammatory drugs (NSAIDS) are commonly used agents for their anti-inflammatory, anti-pyretic and analgesic effects in pediatrics. They are also used for some distinct indications in pediatrics such as Kawasaki disease, patent ductus arteriosus (PDA) closure, and Juvenile Idiopathic Arthritis (JIA). The primary mechanism thought to cause their therapeutic effects is the inhibition of prostaglandin synthesis. NSAIDs inhibit cyclooxygenase (COX) which is an enzyme that is necessary for the formation of prostaglandins. Unfortunately, this same mechanism, the inhibition of prostaglandins, is thought to be the most likely cause of gastrointestinal (GI) mucosal damage, because prostaglandins through multiple mechanisms assist in the preparation and maintenance of the protective barrier of the mucosal lining of the stomach. Similarly, prostaglandins in the kidney promote intrarenal plasma flow and electrolyte balance. The efficacy and safety of NSAIDs must be considered in prescribing these agents. The real conundrum of these therapies is determining the role of newer agents such as intravenous ibuprofen compared to existing alternatives. Available data for intravenous ibuprofen in adults is promising, but further studies are needed in pediatric patients to determine efficacy, place in therapy, and safety. [Copyright &y& Elsevier]

Background: South American camelids in the United States have rapidly developed into an important agricultural industry in need of veterinary services. Pain management is challenging in camelids because there are no drugs currently approved by the U.S. Food and Drug Administration for use in these species. Dosage regimens used for many therapeutic drugs have been extrapolated from other ruminants; however, the pharmacokinetics, in camelids, may differ from those of other species. Studies investigating the pharmacokinetics of cyclooxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drugs in camelids are deficient in the published literature. Six adult llamas (121-168 kg) were administered either a 1 mg/kg dose of oral or a 0.5 mg/kg dose of IV meloxicam in a randomized cross-over design with an 11 day washout period between treatments. Plasma samples collected up to 96 hours post-administration were analyzed by high pressure liquid chromatography and mass spectrometry detection (HPLC-MS) followed by non-compartmental pharmacokinetic analysis. Results: A mean peak plasma concentration (CMAX) of 1.314 μg/mL (Range: 0.826 – 1.776 μg/mL) was recorded at 21.4 hours (Range: 12.0 – 24.0 hours) with a half-life (T ½ λz) of 22.7 hours (Range: 18.0 – 30.8 hours) after oral meloxicam administration. In comparison, a half-life (T ½ λz) of 17.4 hours (Range: 16.2 – 20.7 hours) was demonstrated with IV meloxicam administration. The oral bioavailability (F) of meloxicam (dose normalized) was 76% (Range: 48 – 92%). No adverse effects associated with either treatment modality were observed in the llamas. Conclusions: The mean bioavailability (F) of oral meloxicam was 76% indicating a high degree of gastrointestinal absorption. Plasma meloxicam concentrations >0.2 μg/mL were maintained for up to 72 h after oral administration; >0.2 μg/mL is considered to be the concentration of meloxicam required for analgesic effects in other species such as the horse. These data suggest that a single dosage of oral meloxicam at 1 mg/kg could potentially maintain therapeutic concentrations in plasma for up to 3 days in adult llamas. [ABSTRACT FROM AUTHOR]

The article discusses the development of modern day antipsychotic drugs in 2011 and presents a discussion of whether the drugs which are being used in 2011 have had their safety and efficacy proven through evidence-based research. A discussion of research which has been conducted on several antipsychotic drugs, including Rofecoxib, Tegaserol and Cerivastatin, is presented.

Nonmelanoma skin cancer is one of the most frequently occurring cancers in the United States. Chronic exposure to UVB irradiation is a major cause of this cancer. Daidzein, along with genistein, is a major isoflavone found in soybeans; however, little is known about the chemopreventive effects of daidzein and its metabolites in UVB-induced skin cancer. Here, we found that 7,3',4'-trihydroxyisoflavone (THIF), a major metabolite of daidzein, effectively inhibits UVB-induced cyclooxygenase 2 (COX-2) expression through the inhibition of NF-κB transcription activity in mouse skin epidermal JB6 P+ cells. In contrast, daidzein had no effect on COX-2 expression levels. Data from Western blot and kinase assays showed that 7,3',4'-THIF inhibited Cot and MKK4 activity, thereby suppressing UVB-induced phosphorylation of mitogen-activated protein kinases. Pull-down assays indicated that 7,3',4'-THIF competed with ATP to inhibit Cot or MKK4 activity. Topical application of 7,3',4'-THIF clearly suppressed the incidence and multiplicity of UVB-induced tumors in hairless mouse skin. Hairless mouse skin results also showed that 7,3',4'-THIF inhibits Cot or MKK4 kinase activity directly, resulting in suppressed UVB-induced COX-2 expression. A docking study revealed that 7,3',4'-THIF, but not daidzein, easily docked to the ATP binding site of Cot and MKK4, which is located between the N- and C-lobes of the kinase domain. Collectively, these results provide insight into the biological actions of 7,3',4'-THIF, a potential skin cancer chemopreventive agent. [ABSTRACT FROM AUTHOR]

The article presents news on medications. On February 11, 2011 France's Health Products Safety Agency suspended the marketing authorization for medications containing buflomedil. The U.S. Food and Drug Administration has approved abiraterone acetate in combination with prednisone to treat prostate cancer. The U.S. Food and Drug Administration (FDA) has approved rituximab in combination with glucocorticoids to treat patients with Wegener granulomatosis and microscopic polyangiitis.

A biopsy procedure was developed to enable repeated sampling of a single equine corpus luteum (CL) over the course of an estrous cycle. The tissue collected was utilized in characterizing mRNA abundance for genes involved in luteal formation, function, and regression in the cyclic mare. Serial biopsies of CL in cyclic mares (2.7 to 27.5 mg per biopsy) were collected using an ultrasound-guided transvaginal technique. Biopsies were collected from each mare on d 2 and 5 (d 0 = ovulation) of the estrous cycle, and every other day from d 12 through luteolysis. Samples were obtained from 4 mares with normal estrous cycles and 1 mare with a retained CL. The biopsy procedure did not adversely affect luteal size or function, as measured by luteal area and serum concentrations of progesterone. Real-time reverse-transcription PCR was used to quantify steady state mRNA concentrations in each tissue sample obtained. Mean abundance of steroidogenic acute regulatory protein (StAR) mRNA was not different (P = 0.102 to 0.964) on any of the sampling dates, but a trend for mRNA encoding StAR to decrease between d 12 and 14 (P = 0.10) was observed. Values for mRNA encoding StAR were positively correlated to serum concentrations of progesterone on d 5 (R = 0.95; P = 0.05) and 14 (R > 0.99; P < 0.01). Steady-state abundance of mRNA for 313-hydroxysteroid dehydrogenase, z~ 5-~ 4 isomerase (313-HSD) declined between d 12 and 14 (P = 0.15). There were positive correlations between mRNA for 3β-HSD and concentrations of progesterone on d 5 (R = 0.94; P = 0.06) and 12 (R > 0.99; P = 0.05). No difference was detected in abundance of mRNA encoding cyclooxygenase-2 (cox-2; P = 0.340 to 0.840) or caspase-3 (P = 0.517 to 0.882) between any of the sampling dates. A successful luteal biopsy procedure was developed that did not negatively affect luteal function, and abundance of mRNA encoding StAR, 313-HSD, cox-2, and caspase-3 was characterized in luteal biopsy tissue collected on d 2, 5, 12, and 14 of the estrous cycle in the mare. [ABSTRACT FROM AUTHOR]

Abstract: Skin cancer is the most frequently diagnosed cancer in the United States. Ultraviolet B (UVB) rays (wavelength: 280–320nm) play a pivotal role in the development of skin cancer by inducing the expression of inflammatory proteins such as cyclooxygenase-2 (COX-2). Cyanidin, the most plentiful of the plant pigments known as anthocyanidins, is a potent chemopreventive agent. In the present study, we examined the molecular mechanisms underlying the chemopreventive activity of cyanidin and identified its molecular targets. Cyanidin inhibited UVB-induced COX-2 expression and prostaglandin E2 secretion in the epidermal skin cell line JB6 P+ by suppressing the transactivation of nuclear factor-κB and activator protein-1 which are well-known transcription factors regulated by mitogen-activated protein kinase. Cyanidin markedly inhibited the phosphorylation of JNK1/2, ERK1/2, and MEK1/2 than the of MKK4 and Raf-1, two upstream kinases of JNK1/2, ERK1/2, and MEK1/2. Cyanidin significantly suppressed the activities of MKK4, MEK1, and Raf-1 through direct binding. Transient transfection of a small interfering RNA specific for MKK4 inhibited the UVB-induced expression of COX-2 in JB6 P+ cells, as did the expression of a dominant-negative ERK2 mutant. We conclude that MKK4, MEK1, and Raf-1 are targets of cyanidin for the suppression of UVB-induced COX-2 expression. [Copyright &y& Elsevier]

The recent withdrawal of Cox-2 Inhibitors has generated debate on the role of information in drug diffusion: can the market learn the efficacy of new drugs, or does it depend solely on manufacturer advertising and FDA updates? In this study, we use a novel data set to study the role of learning in the diffusion of three Cox-2 Inhibitors—Celebrex, Vioxx and Bextra—before the Vioxx withdrawal. Our study has two unique features: first, we observe each patient’s reported satisfaction after consuming a drug. This patient level data set, together with market level data on FDA updates, media coverage, academic articles, and pharmaceutical advertising, allows us to model individual prescription decisions. Second, we distinguish across-patient learning of a drug’s general efficacy from the within-patient learning of the match between a drug and a patient. Our results suggest that prescription choice is sensitive to many sources of information. At the beginning of 2001 and upon Bextra entry in January 2002, doctors held a strong prior belief about the efficacy of Celebrex, Vioxx, and Bextra. As a result, the learning from patient satisfaction is gradual and more concentrated on drug-patient match than on across-patient spillovers. News articles are weakly beneficial for Cox-2 drug sales, but academic articles appear to be detrimental. The impact of FDA updates is close to zero once we control for academic articles, which suggests that FDA updates follow academic articles and therefore deliver little new information to doctors. Two counterfactual experiments are carried out to quantify the influence of information on market shares. [ABSTRACT FROM AUTHOR]

Background: Adjusting for large numbers of covariates ascertained from patients' health care claims data may improve control of confounding, as these variables may collectively be proxies for unobserved factors. Here, we develop and test an algorithm that empirically identifies candidate covariates, prioritizes covariates, and integrates them into a propensity-score-based confounder adjustment model.Methods: We developed a multistep algorithm to implement high-dimensional proxy adjustment in claims data. Steps include (1) identifying data dimensions, eg, diagnoses, procedures, and medications; (2) empirically identifying candidate covariates; (3) assessing recurrence of codes; (4) prioritizing covariates; (5) selecting covariates for adjustment; (6) estimating the exposure propensity score; and (7) estimating an outcome model. This algorithm was tested in Medicare claims data, including a study on the effect of Cox-2 inhibitors on reduced gastric toxicity compared with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs).Results: In a population of 49,653 new users of Cox-2 inhibitors or nonselective NSAIDs, a crude relative risk (RR) for upper GI toxicity (RR = 1.09 [95% confidence interval = 0.91-1.30]) was initially observed. Adjusting for 15 predefined covariates resulted in a possible gastroprotective effect (0.94 [0.78-1.12]). A gastroprotective effect became stronger when adjusting for an additional 500 algorithm-derived covariates (0.88 [0.73-1.06]). Results of a study on the effect of statin on reduced mortality were similar. Using the algorithm adjustment confirmed a null finding between influenza vaccination and hip fracture (1.02 [0.85-1.21]).Conclusions: In typical pharmacoepidemiologic studies, the proposed high-dimensional propensity score resulted in improved effect estimates compared with adjustment limited to predefined covariates, when benchmarked against results expected from randomized trials. [ABSTRACT FROM AUTHOR]

Background Our understanding of the benefits and risks of aspirin non steroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 (COX-2) selective NSAIDs and gastro-protective agents (GPAs) continues to expand. Aim To assess the perceptions and practices of US primary care physicians (PCPs) regarding the use of aspirin, NSAIDs, COX-2 selective NSAIDs and GPA. Methods A 34-question survey was administered to 1000 US PCPs via the internet. Questions addressed issues involving aspirin, NSAIDs, COX-2 selective NSAIDs, and GPAs. Around 491 of 1000 PCPs had participated in a similar survey conducted in 2003. Results Eighty-five per cent of PCPs reported that >25% of their patients were taking aspirin for preventive reasons. Nineteen per cent performed a risk calculation when deciding whether to start aspirin for cardioprotection. Fifty-four per cent recommended a proton pump inhibitor (PPI) for a patient with a recently healed ulcer who required ongoing aspirin. Thirty-one per cent reported prescribing NSAIDs more often and 52% were more likely to recommend a GPA with an NSAID than in 2003. Although PCPs were less likely to recommend a COX-2 selective NSAID compared to 2003, only 41% felt that rofecoxib increased cardiovascular risk. One-third felt that celecoxib and traditional NSAIDs were associated with increased cardiac risk. Conclusion This survey identified several areas of ongoing confusion regarding aspirin, NSAIDs, COX-2 selective NSAIDs and GPAs, which should help direct future educational efforts regarding the benefits, risks and appropriate use of these agents. [ABSTRACT FROM AUTHOR]

The article explores the gene expression of embryonic lethal abnormal vision (ELAV)-like protein HuR to identify patients with mesothelioma cell lines in the U.S. It notes that HuR is a messenger RNA-binding protein which controls the stability of cyclooxygenase 2 (COX-2) transcripts. Moreover, it highlights that HuR affects the tumor progression in mesothelioma.

The inhibition of cyclooxygenase (COX)-2 confers a small but absolute risk of cardiovascular events on patients taking nonsteroidal anti-inflammatory drugs (NSAIDs). This risk has been established by placebo-controlled trials of NSAIDs selective for COX-2; traditional NSAIDs seem to be heterogeneous with respect to cardiovascular risk. The American Heart Association (AHA) has proposed a ‘stepped-care’ approach to the use of NSAIDs in patients with cardiovascular disease, whereas the Food and Drug Administration (FDA) has failed to approve the COX-2-selective NSAID etoricoxib. In this article, these actions of the AHA and the FDA are interpreted in the light of current knowledge, prompting the formulation of scientific questions that might be addressed. [Copyright &y& Elsevier]

Purpose. A summary of the basic science underlying the current controversies regarding cyclooxygenase-2 (COX-2)-selective nonsteroidal antiinflammatory drugs (NSAIDs), including data on their cardiovascular safety, their gastrointestinal (GI) benefits, cost-effectiveness, physician-prescribing trends, and recommendations for prescribing these agents is presented. Summary. A number of randomized controlled trials (RCTs) have reported that COX-2-selective NSAIDs increase cardiovascular events, although there appear to be gradations of risks among the COX-2-selective NSAIDs. In addition, traditional NSAIDs may increase the risk for cardiovascular events, complicating the interpretation of RCTs that use traditional NSAIDs as comparators. Selective inhibitors of COX-2-selective NSAIDs are effective antiinflammatory and analgesic drugs with improved upper-GI safety compared to traditional NSAIDs. Data on the cost-effectiveness of COX-2-selective NSAIDs indicate that they should be limited to patients at high risk for upper-GI adverse effects. However, they had been increasingly used in patients with lower GI risks until recent events reversed that trend. Circumstances under which COX-2-selective NSAIDs may be appropriate are in patients at high GI risk and in patients who did not respond to multiple traditional NSAIDs. The national spotlight in the United States on NSAID-related adverse events and recent lawsuits against health care providers prescribing COX-2-selective NSAIDs further highlights the need for provider-patient communication and risk disclosure. The relative cardiovascular risks of NSAIDs are similar in magnitude to other currently prescribed therapies. Conclusion. Health care providers must consider the efficacy, GI and cardiovascular risks, concomitant medications, and costs when determining the appropriateness of COX-2-selective NSAID therapy. [ABSTRACT FROM AUTHOR]

Background: The cyclooxygenase-2 specific inhibitor valdecoxib has not been approved in the United States for treatment of acute pain. Hypothesis: Valdecoxib 20 mg twice daily or once daily (both with a 40-mg loading dose) is not clinically inferior to tramadol for treating the signs and symptoms of acute ankle pain. Study Design: Randomized, controlled clinical trial; Level of evidence, 1. Methods: Patients (N = 829) with acute first- or second-degree ankle sprain received 7 days' treatment with valdecoxib 20 mg either twice daily or once daily (both with 40-mg loading dose), tramadol 50 mg 4 times daily, or placebo. The primary end point was Patient's Assessment of Ankle Pain visual analog scale on day 4; a test of noninferiority compared valdecoxib with tramadol. Results: On day 4, both valdecoxib doses were significantly better versus placebo and were comparable with tramadol in relieving ankle pain. On day 7, valdecoxib, but not tramadol, significantly reduced pain versus placebo. On days 4 and 7, more patients resumed normal walking with valdecoxib (45%–47% and 73%–79%, respectively) than with placebo (35% and 64%, respectively) or tramadol (38% and 67%, respectively). In contrast to valdecoxib, the number of withdrawals due to adverse events was significantly higher in the tramadol group (12.2% vs 3.4%; P = .0005). Conclusions: Valdecoxib was comparable with tramadol and was significantly better than placebo in treating acute ankle sprain, and it enabled more patients to resume normal walking on days 4 and 7. Both valdecoxib and tramadol were well tolerated. [ABSTRACT FROM AUTHOR]

Inflammation and oxidative stress are associated with cancer, atherosclerosis, and other chronic diseases. Dietary flavonoids have been reported to possess antiinflammatory and antioxidant properties, but their mechanisms of action and structure-activity relations have not been fully investigated. We hypothesized that differences in antioxidant activity between the structurally similar flavones, luteolin and chrysin (differing only in B-ring hydroxylation patterns), would differentially affect inflammation-associated Cox-2 expression and PGE2 formation. Pretreatment of RAW 264.7 macrophage-like cells with 25, 50, or 100 micromol/L concentrations of luteolin inhibited lipopolysaccharide (LPS)-induced Cox-2 protein expression (P < 0.0001). Chrysin pretreatment did not reduce LPS-induced Cox-2 protein expression at any level tested. Conversely, both luteolin and chrysin completely suppressed LPS-induced PGE2 formation (P < 0.001). Luteolin, but not chrysin, inhibited xanthine/xanthine oxidase-generated superoxide formation at 100 micromol/L in a cell-free system (P < 0.001). Although both luteolin and chrysin reduced LPS-induced hydroxyl radical formation relative to the positive control (P < 0.001), luteolin was superior to chrysin (P = 0.003). In summary, luteolin and chrysin suppressed PGE2 formation equally well, despite differential effects on Cox-2 protein expression and on superoxide and hydroxyl radical scavenging. These data indicate that flavones may display similar antiinflammatory activity via different mechanisms. [ABSTRACT FROM AUTHOR]

BACKGROUND AND OBJECTIVE: The search for NSAIDs with less gastrointestinal toxicity led to the introduction of the selective cyclo-oxygenase-2 (COX-2) inhibitors. However, following their introduction into the market, concerns have developed regarding their safety, particularly their cardiovascular safety. The purpose of this study was to assess the cardiovascular risk (events included were myocardial infarction, stroke and myocardial infarction-related deaths) associated with long-term (>180 days of exposure) and short-term (≤180 days of exposure) use of non-selective NSAIDs, including ‘preferential COX-2 inhibitors’ (i.e. etodolac, nabumetone and salsalate), and selective COX-2 inhibitors. METHODS: A retrospective analysis of the Veterans Integrated Service Network 17 Veterans Affairs (VA) database was conducted. Medicare data and Texas Department of Health mortality data were incorporated to capture events occurring outside the VA healthcare network. Patients ≥35 years of age who received celecoxib, rofecoxib, ibuprofen, etodolac and naproxen from 1 January 1999 through 31 December 2001, were included. Multivariate Cox proportional hazard models were used to analyse the relationship between cardiovascular risk and NSAID use, including selective COX-2 inhibitor use, while adjusting for various risk factors. RESULTS: We identified 12 188 exposure periods (11 930 persons) and 146 cardiovascular events over the entire study period. Compared with long-term ibuprofen use, long-term use of celecoxib (adjusted hazard ratio [HR] 3.64; 95% CI 1.36, 9.70) and rofecoxib (adjusted HR 6.64; 95% CI 2.17, 20.28) was associated with a significant increase in cardiovascular risk. When restricted to patients ≥65 years of age, the cardiovascular risks associated with long-term celecoxib (adjusted HR 7.36; 95% CI 1.62, 33.48) and rofecoxib (adjusted HR 13.24; 95% CI 2.59, 67.68) use increased. Short-term use of celecoxib (adjusted HR 0.75; 95% CI 0.42, 1.35) and rofecoxib (adjusted HR 0.85; 95% CI 0.39, 1.86) was not associated with any significant change in cardiovascular risk when compared with short-term ibuprofen use. Neither long- nor short-term exposure to naproxen and etodolac was associated with cardionegative or cardioprotective effects when compared with ibuprofen use. CONCLUSIONS: The findings of this observational study, along with recent clinical trial results, suggest that prolonged exposure to selective COX-2 inhibitors may be associated with an increased risk of adverse cardiovascular outcomes. [ABSTRACT FROM AUTHOR]

This article focuses on acute and chronic pain,which characterize most conditions that sports medicine physicians treat. Though cyclooxygenase-2 (COX-2) inhibitors are no more effective for the treatment of pain and inflammation than other nonsteroidal anti-inflammatory drugs, their gastroprotective effects have made them an attractive option for patients who are at risk for gastrointestinal bleeding, particularly those who are on longterm pain medication for conditions such as osteoarthritis and rheumatoid arthritis. The US Food and Drug Administration approved the first COX-2 inhibitor in 1998, followed by rofecoxib and valdecoxib.

Background: Individuals with Barrett's esophagus, in which the normal squamous esophageal epithelium is replaced with a columnar mucosa, are at increased risk for esophageal adenocarcinoma. Mucosal injury may be involved in the progression to neoplasia via the synthesis of prostaglandins and other mediators of inflammation. Cyclooxygenase (COX)-2 is the rate-limiting enzyme involved in prostaglandin synthesis. We examined the effect of inhibiting COX-2 activity in Barrett's esophageal cells.Methods: Primary esophageal epithelial and fibroblast cell cultures were established from endoscopic biopsy specimens from 20 consecutive patients with Barrett's esophagus. COX-2 expression and activity were determined on pooled cell cultures by reverse transcription-polymerase chain reaction and prostaglandin E(2) (PGE(2)) enzyme immunoassay, respectively. Proliferation was measured by Ki-67 staining. PGE(2) levels were determined in supernatants from epithelial cells treated with the selective COX-2 inhibitor NS-398, proinflammatory cytokines (interleukin 1beta and tumor necrosis factor-alpha), and conditioned medium from fibroblast cultures (both unstimulated and stimulated with proinflammatory cytokines).Results: Esophageal epithelial cells and fibroblasts expressed COX-2 messenger RNA. Compared with control-treated cells, NS-398 decreased proliferation of Barrett's esophageal epithelial cells by 55% (95% confidence interval = 47.1% to 63.8%; P<.001) and decreased COX-2 activity. The addition of exogenous PGE(2) reversed the antiproliferative effect of NS-398 on Barrett's esophageal epithelial cells. Proinflammatory cytokines did not affect COX-2 activity in esophageal epithelial cells but stimulated COX-2 activity in fibroblasts. However, conditioned medium from unstimulated and stimulated fibroblasts increased COX-2 activity in esophageal epithelial cells.Conclusion: COX-2 is functionally active in Barrett's esophagus because treatment with the COX-2 inhibitor hinders proliferation of Barrett's esophageal epithelial cells in culture, but proliferation is restored by treatment with prostaglandin. These results raise the possibility that inhibition of COX-2 may have chemopreventive potential for Barrett's esophagus. [ABSTRACT FROM AUTHOR]

The article discusses the advantages and disadvantages of using oral and topical analgesics in patients with osteoarthritis, based on studies reviewed by the U.S. Agency for Healthcare Research and Quality (AHRQ). The review covered clinical trials and studies which examined the effectiveness of nonsteroidal anti-inflammatory drugs (NSAID), cyclooxygenase-2 inhibitors, acetaminophen and diclofenac. The cardiovascular and gastrointestinal (GI) adverse effects of NSAID are mentioned.

Presents news briefs related to science as of January 17, 2005. Details of a bribery case involving agrochemical firm Monsanto regarding studies of its genetically modified cotton; Return of the marketing rights to Bayer for its erectile dysfunction drug Levitra by GlaxoSmithKline; Advice of the U.S. Food and Drug Administration for physicians concerning cyclooxygenase-2 anti-inflammatory drugs.

Background: Breast cancer is a leading cause of cancer-related death for women in the USA. Thus, there is an increasing need to investigate novel prognostic markers and therapeutic methods. Inflammation raises challenges in treating and preventing the spread of breast cancer. Specifically, the nuclear factor kappa b (NFκB) pathway contributes to cancer progression by stimulating proliferation and preventing apoptosis. One target gene of this pathway is PTGS2, which encodes for cyclooxygenase 2 (COX-2) and is upregulated in 40% of human breast carcinomas. COX-2 is an enzyme involved in the production of prostaglandins, which mediate inflammation. Here, we investigate the effect of Singleminded-2s (SIM2s), a transcriptional tumor suppressor that is implicated in inhibition of tumor growth and metastasis, in regulating NFκB signaling and COX-2.Methods: For in vitro experiments, reporter luciferase assays were utilized in MCF7 cells to investigate promoter activity of NFκB and SIM2. Real-time PCR, immunoblotting, immunohistochemistry, and chromatin immunoprecipitation assays were performed in SUM159 and MCF7 cells. For in vivo experiments, MCF10DCIS.COM cells stably expressing SIM2s-FLAG or shPTGS2 were injected into SCID mice and subsequent tumors harvested for immunostaining and analysis.Results: Our results reveal that SIM2 attenuates the activation of NFκB as measured using NFκB-luciferase reporter assay. Furthermore, immunostaining of lysates from breast cancer cells overexpressing SIM2s showed reduction in various NFκB signaling proteins, as well as pAkt, whereas knockdown of SIM2 revealed increases in NFκB signaling proteins and pAkt. Additionally, we show that NFκB signaling can act in a reciprocal manner to decrease expression of SIM2s. Likewise, suppressing NFκB translocation in DCIS.COM cells increased SIM2s expression. We also found that NFκB/p65 represses SIM2 in a dose-dependent manner, and when NFκB is suppressed, the effect on the SIM2 is negated. Additionally, our ChIP analysis confirms that NFκB/p65 binds directly to SIM2 promoter site and that the NFκB sites in the SIM2 promoter are required for NFκB-mediated suppression of SIM2s. Finally, overexpression of SIM2s decreases PTGS2 in vitro, and COX-2 staining in vivo while decreasing PTGS2 and/or COX-2 activity results in re-expression of SIM2.Conclusion: Our findings identify a novel role for SIM2s in NFκB signaling and COX-2 expression. [ABSTRACT FROM AUTHOR]

The objective of the study was to conduct a review of the pharmacological regulation and pharmacokinetic parameters of firocoxib when administered orally or intravenously in horses. A search for literature was done in SCOPUS and PubMed for studies that had to evaluate the pharmacological regulation as well as the pharmacokinetic parameters of firocoxib when administered in horses. The nonsteroidal anti-inflammatory drugs have analgesic, anti-inflammatory, antipyretics, and antiendotoxic effects. The newly developed is selective to COX2 characterized by less adverse effects in veterinary patients when administered at the recommended doses and do not exceed the established prescribed time. Firocoxib is authorized by the Food and Drug Administration for the treatment of pain in horses, whereas for humans, there is still no approval. Controversy has arisen because the administration of the same pharmaceutical presentation in horses and dogs has pharmacokinetic differences between animal species. However, special attention must be paid to pharmacokinetic differences between species like in horses and dogs. In the case of the horse, the dosage is 0.1 mg/kg in single dose or up to 14 days in oral paste formulation and can keep maintained on the same concentration for a period of 7-14 days in oral tablet formulation. Thorough knowledge of pharmacological regulations and pharmacokinetic parameters, it allows the posology and effective application of firocoxib in pathologies associated with chronic pain, avoiding the indiscriminate use by owners and in some cases veterinarians, thus reducing the negative impacts on horse's health., (Copyright © 2019 Elsevier Inc. All rights reserved.)

This section offers news briefs on medicine. The U.S. Centers for Disease Control and Prevention (CDC) has found that the annual deaths from poisoning had increased by 62.5% from 12,186 in 1999 to 20,950 in 2004. The CDC also estimated that methicillin-resistant S. aureus (MRSA) infections were reported in 45 out of 1,000 dialysis patients in 2005. Meanwhile, the American Heart Association (AHA) has issued new guidelines regarding the increased risks associated with the use of nonsteroidal anti-inflammatory drugs (NSAID) and cyclooxygenase-2 (COX-2).

The article reports on the states and federal legislation related to clinical trials database in the United States. Public outcry over pharmaceutical companies' failure to report safety data from research on antidepressants and COX-2 inhibitors has exerted pressure on industry, researchers, and policy-makers to ensure transparent and unbiased reports of clinical trials results. One response receiving international attention is creation of clinical trials registries and results databases. Clinical trials registries provide a public record of the nature and eligibility criteria of newly initiated, ongoing, and closed trials. Results databases are public postings of all clinical trials findings, including potentially adverse side effects. The original intent of registries was to inform patients about clinical trials in which they might participate. The current legislative proposals call for posting and open access to all raw or summative clinical trials data from successful studies, as well as those that have failed or produced equivocal results or data contradictory to a report submitted for review. Legislative proposals seek to limit such negative consequences by requiring prominent display of a statement indicating when trials are assessing the safety, effectiveness, or benefit of a use not described in the approved labeling for the drug, biological product, or device.

Focuses on several studies which analyzed issues related to the administration of COX-2 and nonsteroidal anti-inflammatory drugs in the U.S. Significance of Medicaid prior-authorization plans in drug administration; Implications of the cost of COX-2 for insurance programs; Indications for COX-2 inhibitors.

The article looks at how the trials involving Merck & Co. Inc.'s drug Vioxx are changing drug regulation in the United States. The author reviews how Merck & Co. faces more than 6000 lawsuits involving the drug, a COX2 inhibitor rofecoxib. It is the author's view that, no matter how these legal battles are resolved, they are already impacting how the pharmaceutical industry and government regulators do business. Details regarding Vioxx trials that have already taken place are reviewed. The article includes comments on the issue from Jere Beasley, the attorney representing one of the plaintiffs. Also included are comments regarding the ongoing litigation from Bruce Kuhlik, Merck's vice president and associate general counsel.

Presents health-related news briefs as of August 2005. Agreement between U.S. biotechnology firms Biogen Idec Inc. and Protein Design Labs Inc. to develop and commercialize antibody products; Approval of the Celebrex cyclooxygenase 2 inhibitor from Pfizer Inc. by the U.S. Department of Food anf Drug Administration; Decline in the sale of Slim-Fast dietary products from Unilever PLC.

Presents the author's views on issues regarding drug safety and regulation worldwide. Review of how numerous medical journals have been publishing editorials and news items relating to drug safety and regulation; View that the single biggest issue regarding drug safety has been the withdrawal of rofecoxib (Vioxx) from the market and the controversy surrounding the safety of other COX 2 inhibitors; Summarization of how such high profile cases have resulted in regulatory bodies such as the United States Food and Drug Administration and the United Kingdom Medicines and Healthcare Products Regulatory Agency to come under fire; View that the whole safety system for drugs needs improvement, well beyond the process of regulation itself.

This article reports that despite unanimity in the belief that the COX-2 selective nonsteroidal anti-inflammatory drugs significantly increase cardiovascular risk, FDA's Arthritis and Drug Safety and Risk Management Advisory Committees have advised FDA that the risk/benefit profile of the previously approved COX-2 inhibitors support the marketing of these agents in the U.S. The committees stated that the cardiovascular risk posed by all of the COX-2 inhibitors warrants a "black box" warning and that rofecoxib in particular should be limited to a second or third line option, with its dose and duration of use being restricted.

Reports on the plan of the U.S. Food and Drug Administration Arthritis Drugs and Drug Safety and Risk Management Advisory committees to review the risk-benefit profile of COX-2. Gastrointestinal protective claims in COX-2 labeling; Pressure to review cardiovascular effect of COX-2.

Presents the outcome of patients diagnosed with esophageal adenocarcinoma in the U.S. Occurrence in the setting of Barret's esophagus; Increase of risk for developing esophageal adenocarcinoma; Implications of the treatment with COX-2 inhibitors.