Remission of organ failure in patients with predicted severe acute pancreatitis treated by somatostation, octreotide and cyclooxygenase-2 inhibitors.

BACKGROUND: /Objectives: Persistent organ failure (OF) in severe acute pancreatitis (SAP) is caused by activation of cytokine cascades, resulting in inflammatory injury. Anti-inflammation may be helpful in OF remission in early SAP. To assess the efficacy of anti-inflammatory regimens for OF prevention and remission in patients with predicted SAP and display clinical doctors' acceptance of these strategies, we conducted this retrospective study in the real world. METHODS: Clinical data of patients with predicted SAP from 2010 to 2017 were retrospectively reviewed. Cases were divided into conventional support (C), C+ somatostatin/octreotide (C + S/O), and C + S/O + Cyclooxygenase-2-inhibitors (C + S/O + COX-2-I). The occurrence of SAP, OF, changes of proportion for three strategies, length of hospital stay, meperidine injection, and cytokine levels were compared. The constituent ratios of the three schemes over eight years were evaluated. RESULTS: A total of 580 cases (C = 124, C + S/O = 290, C + S/O + COX-2-I = 166) were included. The occurrences of SAP in the C + S/O (28.3 %) and C + S/O + COX-2-I (18.1 %) groups were significantly lower than that in C group (60.5 %, P < 0.001), mainly by reducing persistent respiratory failure (P < 0.001) and renal failure (P = 0.002). C + S/O and C + S/O + COX-2-I regimens significantly decreased new onset OF and enhanced OF amelioration within 48 h when compared with C treatment (P < 0.001) in patients with OF score <2 and ≥ 2 on admission, respectively. C + S/O and C + S/O + COX-2-I as compared with C group significantly decrease OF occurrences in a multivariate logistic regression analysis (P < 0.05). CONCLUSIONS: Somatostatin or its analogs and cyclooxygenase-2 inhibitors are promising for OF prevention and remission in patients with predicted SAP. The acceptance of combined strategies in the real world has increased, and the occurrence of SAP has decreased annually.

α-Conotoxins and α-Cobratoxin Promote, while Lipoxygenase and Cyclooxygenase Inhibitors Suppress the Proliferation of Glioma C6 Cells.

Among the brain tumors, glioma is the most common. In general, different biochemical mechanisms, involving nicotinic acetylcholine receptors (nAChRs) and the arachidonic acid cascade are involved in oncogenesis. Although the engagement of the latter in survival and proliferation of rat C6 glioma has been shown, there are practically no data about the presence and the role of nAChRs in C6 cells. In this work we studied the effects of nAChR antagonists, marine snail α-conotoxins and snake α-cobratoxin, on the survival and proliferation of C6 glioma cells. The effects of the lipoxygenase and cyclooxygenase inhibitors either alone or together with α-conotoxins and α-cobratoxin were studied in parallel. It was found that α-conotoxins and α-cobratoxin promoted the proliferation of C6 glioma cells, while nicotine had practically no effect at concentrations below 1 µL/mL. Nordihydroguaiaretic acid, a nonspecific lipoxygenase inhibitor, and baicalein, a 12-lipoxygenase inhibitor, exerted antiproliferative and cytotoxic effects on C6 cells. nAChR inhibitors weaken this effect after 24 h cultivation but produced no effects at longer times. Quantitative real-time polymerase chain reaction showed that mRNA for α4, α7, ß2 and ß4 subunits of nAChR were expressed in C6 glioma cells. This is the first indication for involvement of nAChRs in mechanisms of glioma cell proliferation.

Non-steroidal anti-inflammatory drugs on core body temperature during exercise: A systematic review.

BACKGROUND: Because of their anti-pyretic effects, some individuals prophylactically use non-steroidal anti-inflammatory drugs (NSAIDs) to blunt core temperature (Tc) increases during exercise, thus, potentially improving performance by preventing hyperthermia and/or exertional heat illness. However, NSAIDs induce gastrointestinal damage, alter renal function, and decrease cardiovascular function, which could compromise thermoregulation and increase Tc. The aim of this systematic review was to evaluate the effects of NSAIDs on Tc in exercising, adult humans. METHODS: We conducted searches in MEDLINE, PubMed, Cochrane Reviews, and Google Scholar for literature published up to November 2020. We conducted a quality assessment review using the Physiotherapy Evidence Database scale. Nine articles achieved a score ≥ seven to be included in the review. RESULTS: Seven studies found aspirin, ibuprofen, and naproxen had no effect (p > .05) on Tc during walking, running, or cycling for ≤ 90 min in moderate to hot environments. Two studies found significant Tc changes. In one investigation, 81 mg of aspirin for 7-10 days prior to exercise significantly increased Tc during cycling (p < .001); final Tc at the end of exercise = 38.3 ± 0.1 °C vs. control = 38.1 ± 0.1 °C. In contrast, participants administered 50 mg rofecoxib for 6 days experienced significantly lower Tc during 45 min of cycling compared to placebo (NSAID Tc range ≈ 36.7-37.2 °C vs control ≈ 37.3-37.8 °C, p < 0.05). CONCLUSIONS: There are limited quality studies examining NSAID effects on Tc during exercise in humans. The majority suggest taking non-selective NSAIDs (e.g., aspirin) 1-14 days before exercise does not significantly affect Tc during exercise. However, it remains unclear whether Tc increases, decreases, or does not change during exercise with other NSAID drug types (e.g., naproxen), higher dosages, chronic use, greater exercise intensity, and/or greater environmental temperatures.

Effect of Novel Pyrrolo[3,4-d]pyridazinone Derivatives on Lipopolysaccharide-Induced Neuroinflammation.

Neuroinflammation is considered to be one of the potential causes for the development of neurodegenerative diseases, including Alzheimer's disease. In this study, we evaluated the effect of four newly synthesized pyrrolo[3,4-d]pyridazinone derivatives on the neuron-like PC12 cells under simulated inflammation conditions by preincubation with lipopolysaccharide (LPS). Our novel derivatives are selective cyclooxygenase-2 (COX-2) inhibitors and have similar effects to nonsteroidal anti-inflammatory drugs (NSAIDs). We assessed viability (LDH assay), metabolic activity (MTT assay), DNA damage (number of double-strand breaks measured by fast halo assay), and the neuronal features of cells (average neurite length and neurite outgrowth measured spectrofluorimetrically). DCF-DA and Griess assays were also performed, which allowed determining the impact of the tested compounds on the level of oxygen free radicals and nitrites. LPS administration significantly negatively affected the results in all tests performed, and treatment with the tested derivatives in most cases significantly reduced this negative impact. Multiple-criteria decision analysis indicated that overall, the best results were observed for compounds 2a and 2b at a concentration of 10 µM. The new derivatives showed intense activity against free oxygen radicals and nitrites. Reduced reactive oxygen species level also correlated with a decrease in the number of DNA damage. The compounds improved neuronal features, such as neurite length and outgrowth, and they also increased cell viability and mitochondrial activity. Our results suggest that derivatives 2a and 2b may also act additionally on mechanisms other than 3a and 3b.

A Carrier-Free Nanostructure Based on Platinum(IV) Prodrug Enhances Cellular Uptake and Cytotoxicity.

Flurbiprofen, a hydrophobic COX inhibitor, was coordinated axially with oxoplatin to form a new conjugate, cis, cis, trans-[Pt(IV)(NH3)2Cl2(flurbiprofen)2]. The successful synthesis of this new conjugate was confirmed by 1H, 13C, and 195Pt NMR. The potential of this conjugate being reduced to cisplatin and subsequently exerting its DNA cross-linking ability was verified using cyclic voltammetry (CV), HPLC, and mass spectrometry (MS). This conjugate showed markedly higher cytotoxicity on many cancer cell lines than cisplatin, flurbiprofen, and their physical mixture (mole ratio, cisplatin:flurbiprofen = 1:2). This is consistent with the result of an apoptosis-inducing assay. This conjugate spontaneously assembles carrier-free nanoparticles in aqueous solution, which is confirmed by DLS, TEM, SEM, and AFM, and thus facilitates cellular uptake and markedly improves its cytotoxicity and apoptosis-inducing ability in vitro.

Discovery of selective RIO2 kinase small molecule ligand.

We report the discovery and initial optimization of diphenpyramide and several of its analogs as hRIO2 kinase ligands. One of these analogs is the most selective hRIO2 ligand reported to date. Diphenpyramide is a Cyclooxygenase 1 and 2 inhibitor that was used as an anti-inflammatory agent. The RIO2 kinase affinity of diphenpyramide was discovered by serendipity while profiling of 13 marketed drugs on a large 456 kinase assay panel. The inhibition values also suggested a relative selectivity of diphenpyramide for RIO2 against the other kinases in the panel. Subsequently three available and eight newly synthesized analogs were assayed, one of which showed a 10 fold increased hRIO2 binding affinity. Additionally, this compound shows significantly better selectivity over assayed kinases, when compared to currently known RIO2 inhibitors. As RIO2 is involved in the biosynthesis of the ribosome and cell cycle regulation, our selective ligand may be useful for the delineation of the biological role of this kinase. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases.

ATB-346, a novel hydrogen sulfide-releasing anti-inflammatory drug, induces apoptosis of human melanoma cells and inhibits melanoma development in vivo.

Inflammation plays a key role in tumor promotion and development. Indeed, cyclooxygenase-2 (COX-2) expression is strongly associated with different types of cancer. An emerging class of compounds with significant anti-inflammatory properties is the hydrogen sulfide-releasing non-steroidal anti-inflammatory drugs (H2S-NSAIDs). They consist of a traditional NSAID to which an H2S-releasing moiety is covalently attached. We have recently demonstrated that H2S donors inhibit melanoma cell proliferation. In the current study, we evaluated the potential beneficial effects of a new H2S-releasing derivative of naproxen, ATB-346 [2-(6-methoxynapthalen-2-yl)-propionic acid 4-thiocarbamoyl phenyl ester] which inhibits COX activity but also releases H2S. We used cell culture and a mouse melanoma model to evaluate the effect of ATB-346 on: i) in vitro growth of human melanoma cells; ii) in vivo melanoma development in mice. Cell culture studies demonstrated that ATB-346 reduced the in vitro proliferation of human melanoma cells and this effect was associated to induction of apoptosis and inhibition of NF-κB activation. Moreover, ATB-346 had novel Akt signaling inhibitory properties. Daily oral dosing of ATB-346 (43µmol/kg) significantly reduced melanoma development in vivo. This study shows that ATB-346, a novel H2S-NSAID, inhibits human melanoma cell proliferation by inhibiting pro-survival pathways associated with NF-κB and Akt activation. Furthermore, oral treatment with ATB-346 inhibits melanoma growth in mice. In conclusion, the combination of inhibition of cyclooxygenase and delivery of H2S by ATB-346 may offer a promising alternative to existing therapies for melanoma.

Proactive Diagnosis and Tailor-Made Treatment of Patent Ductus Arteriosus in Very Preterm Infants with Routine Echocardiography in Japan: A post hoc Analysis of the PLASE Study.

INTRODUCTION: A feature of the management of extremely preterm infants in Japan is proactive circulatory management using early routine echocardiography performed by neonatologists. METHODS: This study was a post hoc analysis of the Patent ductus arteriosus and Left Atrial Size Evaluation in preterm infants (PLASE) study, which is a prospective cohort study including preterm infants admitted to 34 tertiary neonatal intensive care units in Japan between October 2015 and December 2016. We described the details of the treatment strategy of patent ductus arteriosus (PDA) based on early routine echocardiography. RESULTS: In total, 613 preterm infants were included into the analysis. Twenty percent of infants with prophylactic indomethacin were switched to therapeutic cyclooxygenase inhibitor (COX-I) before the completion of the full prophylactic indomethacin course. Therapeutic COX-I was mostly administered based on echocardiographic findings before PDA became symptomatic or hemodynamically significant. Therapeutic COX-I was frequently discontinued after one or two doses before the full course (three doses) was completed. The proportion of infants requiring additional treatment (additional therapeutic COX-I course or surgical PDA closure) after discontinued COX-I courses (<3 doses) compared to infants after completed 3 doses course was significantly lower (after the first therapeutic COX-I course 46% vs. 68%, p < 0.001) or without a significant difference (after the second or third course). CONCLUSIONS: The clinical management of PDA in Japan featured (1) COX-I administration based on echocardiographic findings before symptomatic or hemodynamically significant PDA appeared and (2) frequent discontinuation of therapeutic COX-I before completing the standard three doses course.

Hybrids of carbonic anhydrase and cyclooxygenase inhibitors attenuate cardiac hypoxic inflammatory injuries.

Cardiac inflammation is easily accompanied by hypoxia, while hypoxia-induced injury and microenvironmental variations limit the efficacy of common anti-inflammatory drugs. In order to effectively attenuate myocardial injury caused by hypoxic and inflammatory injury, we designed and synthesized a kind of anti-inflammatory compounds by coupling cyclooxygenase (COX) and carbonic anhydrase (CA) inhibitors, and evaluated the activity and their mechanism in vitro and in vivo. It was found that these compounds were structurally stable and had two enzymatic inhibition activities. By inhibiting the activity of overexpressed CA under hypoxia, the acidic microenvironment can be regulated to inhibit the hypoxic injury, in which the pH-dependent primary drug resistance can be overcome to improve the anti-inflammatory effect of the COX inhibitor. Consequently, this study provides a new strategy for the treatment of cardiac inflammation accompanied by hypoxia.

The effect of celecoxib for treatment of preterm labor on fetuses during the second trimester of pregnancy: A pilot case series.

OBJECTIVE: Although cyclooxygenase inhibitors effectively suppress uterine contraction, constriction of the fetal ductus arteriosus (DA) and oligohydramnios are major concerns. Celecoxib, a selective cyclooxygenase 2 inhibitor, is a potential potent tocolytic agent, but there are no studies that have evaluated the beneficial or adverse effects of celecoxib use on fetuses for more than 48 hours in pregnant women. We therefore aimed to evaluate the effect of middle-long-term celecoxib administration on the fetus during the second trimester of pregnancy, particularly in terms of fetal DA and amniotic fluid volume. MATERIALS AND METHODS: We retrospectively extracted and reviewed data from patients with preterm labor who received celecoxib for tocolysis for more than 48 hours between 2016 and 2020. Celecoxib was used for tocolysis only when treatment of patients with conventional tocolytic agents was ineffective. Data on the peak systolic velocity in ductus arteriosus (PSV-DA) and the maximum vertical pocket (MVP) were collected. RESULTS: A total of 15 patients were eligible. The median gestational age at celecoxib introduction was 22.6 weeks, and the median period of administration was 9 days (range 3-40 days). The median gestational age at delivery was 27.1 weeks, and the median duration from initial celecoxib administration to delivery was 40 days. The Z scores of PSV-DA and MVP did not change significantly after celecoxib administration. During administration, PSV-DA exceeded the 95th percentile of the corresponding normal reference range in three cases, but the levels returned to normal after reduction or discontinuation of treatment. There was no oligohydramnios during the treatment. CONCLUSION: Celecoxib administration for more than 48 hours in the second trimester of pregnancy might be safe and tolerable in terms of fetal PSV-DA and amniotic fluid volume as long as careful ultrasound monitoring is performed. Celecoxib could be an alternative for preterm labor when conventional tocolysis is not effective.

Herb-Drug Interaction in Inflammatory Diseases: Review of Phytomedicine and Herbal Supplements.

Many people worldwide use plant preparations for medicinal purposes. Even in industrialized regions, such as Europe, where conventional therapies are accessible for the majority of patients, there is a growing interest in and usage of phytomedicine. Plant preparations are not only used as alternative treatment, but also combined with conventional drugs. These combinations deserve careful contemplation, as the complex mixtures of bioactive substances in plants show a potential for interactions. Induction of CYP enzymes and pGP by St John's wort may be the most famous example, but there is much more to consider. In this review, we shed light on what is known about the interactions between botanicals and drugs, in order to make practitioners aware of potential drug-related problems. The main focus of the article is the treatment of inflammatory diseases, accompanied by plant preparations used in Europe. Several of the drugs we discuss here, as basal medication in chronic inflammatory diseases (e.g., methotrexate, janus kinase inhibitors), are also used as oral tumor therapeutics.

Effect of cyclooxygenase inhibitor use on immunotherapy efficacy in non-small cell lung cancer.

BACKGROUND: A synergistic effect of cyclooxygenase inhibitors (COX-I) and immune checkpoint inhibitors (ICIs) has been suggested. However, the impact of COX-I on the efficacy of ICIs is unclear. Here, we aimed to evaluate the relationship between COX-I use and the efficacy of ICI in patients with non-small cell lung cancer (NSCLC). METHODS: We retrospectively reviewed NSCLC patients who received ICI monotherapy. We defined COX-I use as regular use of COX-I other than low-dose aspirin during the initiation of ICIs to the first evaluation of efficacy. The efficacy of ICIs was evaluated with response rate (RR), disease control rate (DCR), progression free survival (PFS), and overall survival (OS). Differences in baseline characteristics by COX-I use were controlled by using an inverse probability of treatment weighting (IPW) adjusted analysis. RESULTS: A total of 198 patients with NSCLC received ICIs; 128, 50, and 20 patients received nivolumab, pembrolizumab, and atezolizumab, respectively; there were 65 (32.8%) COX-I users. While there was no significant difference in RR (15.4% vs. 13.5%; p = 0.828), DCR (41.5% vs. 49.6%; p = 0.294), PFS (median, 2.69 vs. 3.68 months; 95% confidence intervals [CI], 1.77-5.19 vs. 2.20-4.60 months; p = 0.630), COX-I users had significantly shorter OS than non-COX-I users (median, 6.08 vs. 16.10 months; 95% CI: 3.78-11.66 vs. 9.49-19.68 months; p = 0.003). On IPW adjusted analysis, there was no significant difference in OS (median, 7.85 vs. 15.11 months; 95% CI: 5.03-14.92 vs. 9.49-19.32 months; p = 0.081). CONCLUSIONS: There was no additional or negative impact of COX-I use on the efficacy of ICIs in NSCLC.

Effects of Antiplatelet and Nonsteroidal Anti-inflammatory Medications on Platelet-Rich Plasma: A Systematic Review.

BACKGROUND: Platelet-rich plasma (PRP) has wide applications in orthopaedic care. Its beneficial effects are attributed to the growth factor profile from the platelet secretome. In theory, these effects would be diminished by medications that inhibit platelet activation and/or the subsequent release of growth factors. PURPOSE: To determine whether commonly used antiplatelets, nonsteroidal anti-inflammatory drugs (NSAIDs), or anticoagulant medications affect platelet growth factor release in PRP. STUDY DESIGN: Systematic review; Level of evidence, 2. METHOD: A systematic review of the literature related to antiplatelet, anti-inflammatory, and anticoagulant drugs was performed following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We used the Downs and Black objective quality scoring system. The literature search consisted of PubMed and Cochrane Library databases. Search terms consisted of 1 item selected from "platelet-rich plasma," "platelet-derived growth factor," and "platelet-rich plasma AND growth factor" combined with 1 item from "antiplatelet," "aspirin," "anticoagulant," and "NSAID." Only studies published within the past 25 years were included. RESULTS: A total of 15 studies met the inclusion criteria: 7 studies detected no significant decrease in growth factors or mitogenesis, whereas 6 detected a decrease with antiplatelet agents, 1 detected mixed results with an antiplatelet agent, and 1 had mixed results with an antiplatelet agent/vasodilator. In terms of PRP activation, all 3 studies assessing collagen, the 2 studies analyzing adenosine diphosphate alone, and the 1 study investigating arachidonic acid found a decrease in growth factor concentration. CONCLUSION: Antiplatelet medications may decrease the growth factor release profile in a cyclooxygenase 1- and cyclooxygenase 2-dependent manner. Eight of 15 studies found a decrease in growth factors or mitogenesis. However, more studies are needed to comprehensively understand antiplatelet effects on the PRP secretome.

Postoperative non-steroidal anti-inflammatory drugs and anastomotic leakage after gastrointestinal anastomoses: Systematic review and meta-analysis.

AIM: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to control postoperative pain; however, their postoperative use has been associated with anastomotic leakage after gastrointestinal surgery. This systematic review and meta-analysis aimed to determine the correlation between the use of NSAIDs and anastomotic leakage. METHODS: We conducted a comprehensive electronic literature search up to August 2018 to identify studies comparing anastomotic leakage in patients with and without postoperative NSAID use following gastrointestinal surgery. We then carried out a meta-analysis using random-effects models to calculate odds ratios (OR) with 95% confidence intervals (CI). RESULTS: Twenty-four studies were included in this meta-analysis, including a total of 31 877 patients. Meta-analysis showed a significant association between NSAID use and anastomotic leakage (OR 1.73; 95% CI = 1.31-2.29, P < .0001). Subgroup analyses showed that non-selective NSAIDs, but not selective cyclooxygenase-2 inhibitors, were significantly associated with anastomotic leakage. However there was no significant subgroup difference between selective and non-selective NSAIDs. CONCLUSION: Results of this meta-analysis indicate that postoperative NSAID use is associated with anastomotic leakage following gastrointestinal surgeries. Caution is warranted when using NSAIDs for postoperative analgesic control in patients with gastrointestinal anastomoses.

SCO-Spondin Defects and Neuroinflammation Are Conserved Mechanisms Driving Spinal Deformity across Genetic Models of Idiopathic Scoliosis.

Adolescent idiopathic scoliosis (AIS) affects 3% to 4% of children between the ages of 11 and 18 [1, 2]. This disorder, characterized by abnormal three-dimensional spinal curvatures that typically develop during periods of rapid growth, occurs in the absence of congenital vertebral malformations or neuromuscular defects [1]. Genetic heterogeneity [3] and a historical lack of appropriate animal models [4] have confounded basic understanding of AIS biology; thus, treatment options remain limited [5, 6]. Recently, genetic studies using zebrafish have linked idiopathic-like scoliosis to irregularities in motile cilia-mediated cerebrospinal fluid flow [7-9]. However, because loss of cilia motility in human primary ciliary dyskinesia patients is not fully associated with scoliosis [10, 11], other pathogenic mechanisms remain to be determined. Here, we demonstrate that zebrafish scospondin (sspo) mutants develop late-onset idiopathic-like spinal curvatures in the absence of obvious cilia motility defects. Sspo is a large secreted glycoprotein functionally associated with the subcommissural organ and Reissner's fiber [12]-ancient and enigmatic organs of the brain ventricular system reported to govern cerebrospinal fluid homeostasis [13, 14], neurogenesis [12, 15-18], and embryonic morphogenesis [19]. We demonstrate that irregular deposition of Sspo within brain ventricles is associated with idiopathic-like scoliosis across diverse genetic models. Furthermore, Sspo defects are sufficient to induce oxidative stress and neuroinflammatory responses implicated in AIS pathogenesis [9]. Through screening for chemical suppressors of sspo mutant phenotypes, we also identify potent agents capable of blocking severe juvenile spine deformity. Our work thus defines a new preclinical model of AIS and provides tools to realize novel therapeutic strategies.

[Evaluation of the neurotoxic effects of intrathecal administration of (S)-(+)-Ketoprofen on rat spinal cords: randomized controlled experimental study]. / Avaliação dos efeitos neurotóxicos da administração intratecal do (S)­(+)­cetoprofeno em medula espinhal de rato: estudo experimental randômico e controlado.

BACKGROUND AND OBJECTIVES: Intrathecal administration of non-steroidal anti-inflammatory drugs is more efficacious for post-operative pain management. Cyclooxygenase inhibiting non-steroidal anti-inflammatory drugs like (S)-(+)-Ketoprofen, may be effective at lower intrathecal doses than parenteral ones. Preclinical safety regarding possible neurotoxicity associated with the intrathecal (S)-(+)-Ketoprofen was not evaluated. Here we analysed the neurotoxicity of intrathecally administered (S)-(+)-Ketoprofen in rats. METHODS: A randomized placebo-controlled experimental study was conducted. Sprague-Dawley rats (250-300g) aged 12-16 weeks were randomly divided into 2 treatments [100 and 800µg (S)-(+)-Ketoprofen] and control (sterile water) groups. Intrathecal catheters were placed via the atlantoaxial space in anesthetized rats. Pinch-toe tests, motor function evaluations and histopathological examinations of the spinal cord and nerve roots were performed at days 3, 7 and 21. Spinal cord sections were evaluated by light microscopy for the dorsal axonal funiculus vacuolation, axonal myelin loss, neuronal chromatolysis, neuritis, meningeal inflammation, adhesions, and fibrosis. RESULTS: Rats in all the groups exhibited normal pinch-toe testing response (score=0) and normal gait at each observed time (motor function evaluation score=1). Neurotoxicity was higher with treatments on days 3 and 7 than that on day 21 (2, 3, 0, p=0.044; 2, 5, 0, p=0.029, respectively). On day 7, the total scores reflecting neuronal damage were higher in the 800µg group than those in the 100µg and Control Groups (5, 3, 0, p=0.048, respectively). CONCLUSION: Intrathecal (S)-(+)-Ketoprofen caused dose-dependent neurohistopathological changes in rats on days 3 and 7 after injection, suggesting that (S)-(+)-Ketoprofen should not be intrathecally administered.

[Determination of seven non-selective cyclooxygenase inhibitors in milk powder by ultra-performance liquid chromatography-tandem mass spectrometry with dispersive solid phase extraction].

An ultra-performance liquid chromatography-tandem mass spectrometry with dispersive solid phase extraction (dSPE-UPLC-MS/MS) method was developed to determine seven non-selective cyclooxygenase inhibitors in milk powder. The samples were extracted with 0.01 mol/L pH 2.5 ascorbic acid-acetonitrile-ethyl acetate solution (2:5:5, v/v/v), and then purified with a mixture of anhydrous sodium sulfate, octadecyl carbon silica gel (C18-N) sorbent and ethylenediamine-N-propyl carbon silica gel (NH2-PSA) sorbent. The analysis was performed using a UPLC-MS/MS system with Waters CORTECS UPLC C18 (100 mm×2.1 mm, 1.6 µm) column. The mobile phase consisted of 0.1% (v/v) formic acid aqueous solution and acetonitrile containing 0.1% (v/v) formic acid by gradient elution, and the multiple reaction monitoring (MRM) mode was used. Five linear calibration curves were obtained with correlation coefficients (r2) ≥ 0.9965. The recoveries were determined at three spiked levels and ranged from 76.4% to 89.8%. The limits of quantification (LOQs) were from 2 to 5 µg/kg. This method is suitable for the determination of seven non-selective cyclooxygenase inhibitors in milk powder.

Twice-Daily vs. Once-Daily Dosing with 0.075% Bromfenac in DuraSite: Outcomes from a 14-Day Phase 2 Study.

INTRODUCTION: Bromfenac is a well-known topical ophthalmic nonsteroidal anti-inflammatory drug (NSAID) that is commercialized in the USA and other regions of the world. A new formulation, 0.075% bromfenac in DuraSite®, was developed to treat postoperative inflammation and reduce pain in patients who have undergone cataract surgery. We hypothesized that efficacy and safety would be enhanced with twice-daily (BID) dosing compared to once-daily (QD) dosing. METHODS: This was a multicenter, double-masked, comparative study in which 40 and 45 subjects were randomized to groups receiving BID dosing and QD dosing, respectively. Subjects self-instilled the study drug for 14 days postoperative and were followed for an additional 2-week evaluation phase. The primary efficacy endpoint was the proportion of subjects with an anterior chamber cell (ACC) grade of 0 at day 15. RESULTS: A total of 45 subjects had cleared ACC (grade "0") at day 15, of whom 21 were in the BID group (52.5%) and 24 were in the QD group (53.5%). A secondary analysis found 7/40 (17.5%) subjects in the BID group and 10/45 (22.2%) subjects in the QD group achieved an ACC grade of 0 at day 8. There were more adverse events in the QD group (n = 16) than in the BID group (n = 12). CONCLUSION: Similar outcomes were observed for subjects using Bromfenac 0.075% in DuraSite® in the BID and QD dosing regimens for the treatment of post-cataract surgery inflammation. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01190878. FUNDING: InSite Vision (now a division of Sun Pharma).

The impact of aspirin and anticoagulant usage on outcomes after aneurysmal subarachnoid hemorrhage: a Nationwide Inpatient Sample analysis.

OBJECTIVE Although aspirin usage may be associated with a decreased risk of rupture of cerebral aneurysms, any potential therapeutic benefit from aspirin must be weighed against the theoretical risk of greater hemorrhage volume if subarachnoid hemorrhage (SAH) occurs. However, few studies have evaluated the association between prehemorrhage aspirin use and outcomes. This is the first nationwide analysis to evaluate the impact of long-term aspirin and anticoagulant use on outcomes after SAH. METHODS Data from the Nationwide Inpatient Sample (NIS; 2006-2011) were extracted. Patients with a primary diagnosis of SAH who underwent microsurgical or endovascular aneurysm repair were included; those with a diagnosis of an arteriovenous malformation were excluded. Multivariable logistic regression was performed to calculate the adjusted odds of in-hospital mortality, a nonroutine discharge (any discharge other than to home), or a poor outcome (death, discharge to institutional care, tracheostomy, or gastrostomy) for patients with long-term aspirin or anticoagulant use. Multivariable linear regression was used to evaluate length of hospital stay. Covariates included patient age, sex, comorbidities, primary payer, NIS-SAH severity scale, intracerebral hemorrhage, cerebral edema, herniation, modality of aneurysm repair, hospital bed size, and whether the hospital was a teaching hospital. Subgroup analyses exclusively evaluated patients treated surgically or endovascularly. RESULTS The study examined 11,549 hospital admissions. Both aspirin (2.1%, n = 245) and anticoagulant users (0.9%, n = 108) were significantly older and had a greater burden of comorbid disease (p < 0.001); severity of SAH was slightly lower in those with long-term aspirin use (p = 0.03). Neither in-hospital mortality (13.5% vs 12.6%) nor total complication rates (79.6% vs 80.0%) differed significantly by long-term aspirin use. Additionally, aspirin use was associated with decreased odds of a cardiac complication (OR 0.57, 95% CI 0.36%-0.91%, p = 0.02) or of venous thromboembolic events (OR 0.53, 95% CI 0.30%-0.94%, p = 0.03). Length of stay was significantly shorter (15 days vs 17 days [12.73%], 95% CI 5.22%-20.24%, p = 0.001), and the odds of a nonroutine discharge were lower (OR 0.63, 95% CI 0.48%-0.83%, p = 0.001) for aspirin users. In subgroup analyses, the benefits of aspirin were primarily noted in patients who underwent coil embolization; likewise, among patients treated endovascularly, the adjusted odds of a poor outcome were lower among long-term aspirin users (31.8% vs 37.4%, OR 0.63, 95% CI 0.42%-0.94%, p = 0.03). Although the crude rates of in-hospital mortality (19.4% vs 12.6%) and poor outcome (53.6% vs 37.6%) were higher for long-term anticoagulant users, in multivariable logistic regression models these variations were not significantly different (mortality: OR 1.36, 95% CI 0.89%-2.07%, p = 0.16; poor outcome: OR 1.09, 95% CI 0.69%-1.73%, p = 0.72). CONCLUSIONS In this nationwide study, neither long-term aspirin nor anticoagulant use were associated with differential mortality or complication rates after SAH. Aspirin use was associated with a shorter hospital stay and lower rates of nonroutine discharge, with these benefits primarily observed in patients treated endovascularly.

A randomized double-masked study to compare the ocular safety, tolerability, and efficacy of bromfenac 0.075% compared with vehicle in cataract surgery subjects.

PURPOSE: The aim of this study was to evaluate the safety, tolerability, and efficacy of a low-dose version of bromfenac 0.075% in DuraSite® (bromfenac 0.075%) compared with DuraSite® vehicle (vehicle) alone for the treatment of postoperative inflammation and ocular pain after cataract surgery. METHODS: A multicenter, double-masked, vehicle-controlled, parallel-group clinical trial of 240 subjects randomized in a 2:1 ratio to bromfenac 0.075% or vehicle was conducted. Subjects were dosed BID beginning 1 day before the cataract surgery, the day of surgery, and 14 days after surgery. A slit lamp biomicroscopy examination was performed to evaluate the signs of inflammation, including anterior chamber cells (ACC) and anterior chamber flare (ACF). The primary efficacy variable was the proportion of subjects with an ACC grade of 0 at Day 15. Secondary efficacy endpoints included the proportion of subjects who achieved a pain score of 0 at each postsurgical visual analog scale (VAS) assessment and the proportion of subjects with an ACF grade of 0 at Day 15. RESULTS: At Day 15, proportionally more subjects in the bromfenac 0.075% group than in the vehicle group had an ACC grade of 0 (57.1% vs 18.8%, respectively; P<0.001). At each of the postsurgical time points (Days 1, 8, 15, and 29), proportionally more bromfenac 0.075%-treated subjects (76.8%, 90.5%, 92.9%, and 85.1%, respectively) had no pain (a VAS score of 0) compared with the vehicle-treated subjects (48.2%, 38.8%, 42.4%, and 47.1%, respectively), and at each time point, these differences in proportions were statistically significant (P<0.001). More subjects in the bromfenac 0.075% group had complete ACF resolution (151/167; 90.4%) compared to those in the vehicle group (54/85; 63.5%). There were no new safety signals reported. CONCLUSION: Bromfenac 0.075% in DuraSite is safe, well tolerated, and effective at reducing inflammation and preventing pain associated with cataract surgery.