Mechanism study of the protective effects of selective cyclooxygenase-2 enzyme inhibitors on the liver of rats with type 2 diabetes mellitus combined with nonalcoholic steatohepatitis via Rho/ROCK pathway / 中华肝脏病杂志

Objective: To investigate whether the selective cyclooxygenase-2 enzyme inhibitors celecoxib has protective effect on the liver of rats with type 2 diabetes mellitus (T2DM) combined with nonalcoholic steatohepatitis (NASH) via inhibiting the expression of Rho/ROCK pathway. Methods: Forty male SD rats were randomly divided into four groups: type 2 diabetes mellitus combined with nonalcoholic steatohepatitis (T2DM-NASH) group, T2DM-NASH + celecoxib group, control group, and control+celecoxib group. The T2DM-NASH and T2DM-NASH + celecoxib groups were fed with high-sugar and fat diet, and the control group and control + celecoxib group were fed with basal diet (25 kJ/kg). Four weeks later, streptozotocin (STZ, 30 mg/kg) was intraperitoneally injected into the NASH group and T2DM-NASH + celecoxib group to induce T2DM model, and the control group and control + celecoxib group were intraperitoneally injected with isovolumic citric acid-sodium citrate buffer. Four weeks after STZ injection, the T2DM-NASH + celecoxib group and the control + celecoxib group were gavaged with celecoxib (10 mg·kg·d) dissolved in normal saline for 4 weeks, and the remaining two groups of rats were gavaged with isovolumic normal saline for 4 weeks. Animals were sacrificed at the end of the 12- weeks, and the liver tissue was collected. Liver pathological changes were observed by HE staining. The expressions of RhoA, RhoA, ROCK1 and ROCK2 proteins in liver were detected by immunohistochemistry and western blot. The expressional condition of RhoA, ROCK1 and ROCK2 mRNA in liver were detected by real-time quantitative PCR. The differences were compared between protein and mRNA expression among the groups by analysis of variance and t-test. Results: Compared with the control group and the control + celecoxib group, the liver tissue of the T2DM-NASH group and the T2DM-NASH + celecoxib group had severe steatosis, and there was partial inflammatory cell infiltration under the light microscope. The expression levels of RhoA, ROCK1 and ROCK2 protein and mRNA were significantly increased (P < 0.05) in each liver tissue, while liver steatosis was reduced to certain extent in T2DM-NASH + celecoxib group than T2DM-NASH group, and the expression levels of RhoA, ROCK1 and ROCK2 protein and mRNA were decreased in each liver tissue of T2DM-NASH group (P < 0.05). Conclusion: The selective cyclooxygenase-2 enzyme inhibitors celecoxib has a protective effect on the liver of rats with T2DM-NASH, and its effect may be achieved by inhibiting the expression of Rho/ROCK pathway.

Preemptive use of etodolac on tooth sensitivity after in-office bleaching: a randomized clinical trial

Abstract Purpose: This study determined the effectiveness of the preemptive administration of etodolac on risk and intensity of tooth sensitivity and the bleaching effect caused by in-office bleaching using 35% hydrogen peroxide. Material and methods: Fifty patients were selected for this tripleblind, randomized, crossover, and placebo-controlled clinical trial. Etodolac (400 mg) or placebo was administrated in a single-dose 1 hour prior to the bleaching procedure. The whitening treatment with 35% hydrogen peroxide was carried out in two sessions with a 7-day interval. Tooth sensitivity was assessed before, during, and 24 hours after the procedure using the analog visual scale and the verbal rating scale. Color alteration was assessed by a bleach guide scale, 7 days after each session. Relative risk of sensitivity was calculated and adjusted by session, while overall risk was compared by the McNemar's test. Data on the sensitivity level of both scales and color shade were subjected to Friedman, Wilcoxon, and Mann-Whitney tests, respectively (α=0.05). Results: The preemptive administration of etodolac did not affect the risk of tooth sensitivity and the level of sensitivity reported, regardless of the time of evaluation and scale used. The sequence of treatment allocation did not affect bleaching effectiveness, while the second session resulted in additional color modification. The preemptive administration of etodolac in a single dose 1 hour prior to in-office tooth bleaching did not alter tooth color, and the risk and intensity of tooth sensitivity reported by patients. Conclusion: A single-dose preemptive administration of 400 mg of etodolac did not affect either risk of tooth sensitivity or level of sensitivity reported by patients, during or after the in-office tooth bleaching procedure.

Cyclooxygenase-2 Inhibitor Reduces Hepatic Stiffness in Pediatric Chronic Liver Disease Patients Following Kasai Portoenterostomy

PURPOSE: The purpose of this study was to define the role of cyclooxygenase-2 inhibitors (COX-2i) in reducing hepatic fibrosis in pediatric patients with chronic liver disease. MATERIALS AND METHODS: From September 2009 to September 2010, patients over 2 years old who visited our outpatient clinic for follow-up to manage their chronic liver disease after Kasai portoenterostomy for biliary atresia, were included in this study. Volunteers were assigned to the study or control groups, according to their preference. A COX-2i was given to only the study group after obtaining consent. The degree of hepatic fibrosis (liver stiffness score, LSS) was prospectively measured using FibroScan, and liver function was examined using serum analysis before and after treatment. After 1 year, changes in LSSs and liver function were compared between the two groups. RESULTS: Twenty-five patients (18 females and 7 males) were enrolled in the study group. The control group included 44 patients (26 females and 18 males). After 1 year, the least square mean values for the LSSs were significantly decreased by 3.91±0.98 kPa (p=0.004) only in the study group. Serum total bilirubin did not decrease significantly in either group. CONCLUSION: COX-2i treatment improved the LSS in patients with chronic liver disease after Kasai portoenterostomy for biliary atresia.

Effects of Combination Therapy with Celecoxib and Doxycycline on Neointimal Hyperplasia and Inflammatory Biomarkers in Coronary Artery Disease Patients Treated with Bare Metal Stents

PURPOSE: Cyclooxygenase (COX)-2 and matrix metalloproteinase (MMP)-9 play a key role in the pathogenesis of in-stent restenosis. We investigated the effect of a short-term therapy of celecoxib, a COX-2 inhibitor, with or without doxycycline, an MMP inhibitor, after coronary stenting on inflammatory biomarkers and neointimal hyperplasia. MATERIALS AND METHODS: A total of 75 patients (86 lesions) treated with bare metal stents were randomized into three groups: 1) combination therapy (200 mg celecoxib and 20 mg doxycycline, both twice daily), 2) celecoxib (200 mg twice daily) only, and 3) non-therapy control. Celecoxib and doxycycline were administered for 3 weeks after coronary stenting. The primary endpoint was neointimal volume obstruction by intravascular ultrasound (IVUS) at 6 months. The secondary endpoints included clinical outcomes, angiographic data, and changes in blood levels of inflammatory biomarkers. RESULTS: Follow-up IVUS revealed no significant difference in the neointimal volume obstruction among the three treatment groups. There was no difference in cardiac deaths, myocardial infarctions, target lesion revascularization or stent thrombosis among the groups. Blood levels of high-sensitivity C-reactive protein, soluble CD40 ligand, and MMP-9 varied widely 48 hours and 3 weeks after coronary stenting, however, they did not show any significant difference among the groups. CONCLUSION: Our study failed to demonstrate any beneficial effects of the short-term therapy with celecoxib and doxycycline or with celecoxib alone in the suppression of inflammatory biomarkers or in the inhibition of neointimal hyperplasia. Large scale randomized trials are necessary to define the role of anti-inflammatory therapy in the inhibition of neointimal hyperplasia.

High-throughput screening assays for cyclooxygenase-2 and 5-lipoxygenase, the targets for inflammatory disorders.

High-throughput screening (HTS) involves testing of compound libraries against validated drug targets using quantitative bioassays to identify ‘hit’ molecules that modulate the activity of target, which forms the starting point of a drug discovery effort. Eicosanoids formed via cyclooxygenase (COX) and lipoxygenase (LOX) pathways are major players in various inflammatory disorders. As the conventional non-steroidal anti-inflammatory drugs (NSAIDs) that inhibit both the constitutive (COX-1) and the inducible (COX-2) isoforms have gastric and renal side effects and the recently developed COX-2 selective anti-inflammatory drugs (COXIBs) have cardiac side effects, efforts are being made to develop more potent and safer anti-inflammatory drugs. Current assay methods for these enzymes, such as oxygraphic, radioisotopic, spectrophotometric etc. are not compatible for screening of large number of compounds as in drug discovery programs. In the present study, HTS-compatible assays for COX-1, COX-2 and 5-LOX were developed for screening of compound libraries with the view to identify potential anti-inflammatory drug candidates. A spectrophotometric assay involving co-oxidation of tetramethyl-p-phenylene diamine (TMPD) during the reduction of prostaglandin G2 (PGG2) to PGH2 was adopted and standardized for screening of compounds against COX-1 and COX-2. Similarly, the HTS-compatible FOX (ferrous oxidation-xylenol orange) based spectrophotometric assay involving the formation of Fe3+/xylenol orange complex showing absorption in the visible range was developed for screening of compounds against 5-LOX.

Increased Expression of Cyclooxygenase-2 is Associated with the Progression to Cirrhosis

BACKGROUND/AIMS: To investigate the degree of cyclooxygenase-2 (COX-2) protein expression in chronic hepatitis and cirrhosis. METHODS: COX-2 protein expression was evaluated in 43 cases of chronic hepatitis and 24 cases of cirrhosis using immunohistochemical techniques. The COX-2 immunohistochemical staining score was assessed using the scoring systems of Pazirandeh et al and Qiu et al. and each scoring system was based on a sum of the parameters of staining intensity and distribution. RESULTS: The mean COX-2 expression scores in chronic hepatitis and cirrhosis were 2.5 +/- 1.3 vs. 3.3 +/- 1.1 (p = 0.008), and 3.2 +/- 2.0 vs. 4.5 +/- 1.7 (p = 0.006), respectively, based on the Pazirandeh et al. and Qiu et al. scoring systems. The percentage samples of high COX-2 expression score (4 to 5) in chronic hepatitis and cirrhosis were 16.3% vs. 45.8% (p = 0.022), and 23.3% vs. 50% (p = 0.021), respectively, based on the two scoring systems. The mean COX-2 expression scores based on the severity of hepatic fibrosis scored using Ishak's modified staging system (fibrosis score 0 to 3 vs. 4 to 6) were 2.4 +/- 1.3 vs. 3.2 +/- 1.1 (p = 0.009), and 3.1 +/- 2.0 vs. 4.3 +/- 1.8 (p = 0.009), respectively, based on the two scoring systems. CONCLUSIONS: COX-2 expression was significantly higher in liver cirrhosis group than in chronic hepatitis. COX-2 expression scores according to Ishak's staging was significantly higher in the advanced fibrosis group. COX-2 may play a role in the progression of hepatic fibrosis.

Guidelines of Prevention and Treatment for NSAID-related Peptic Ulcers / 대한소화기학회지

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used medications in Korea. Gastrointestinal toxicity, including peptic ulcer, is a common adverse effect of NSAIDs. Risk factors for NSAID-related peptic ulcer include a previous history of peptic ulcer, advanced age, high dose, concomitant use of corticosteroids, anticoagulants, other NSAIDs including low-dose aspirin. Preventive measure(s), such as COX-2 inhibitor, proton pump inhibitor or misoprostrol, should be done for patients requiring NSAID therapy who have high-risk factor(s) for peptic ulcer. Low dose aspirin also increases the risk of peptic ulcer, so preventive measure(s) should be done for high-risk patients. The eradication of Helicobacter pylori is recommended for high-risk NSAID-users. Treatment strategies for peptic ulcers in NSAID users are mostly the same for peptic ulcers in NSAID non-users.

Espondilite anquilosante e anestesia / Ankylosing spondylitis and anesthesia

JUSTIFICATIVA E OBJETIVOS: A espondilite anquilosante (EA) é uma doença inflamatória crônica das articulações, incluída no grupo das espondiloartropatias soronegativas. A característica principal dessa doença é a fusão óssea da coluna vertebral que leva à perda permanente da flexibilidade do dorso e do pescoço. Outras grandes articulações e tecidos conectivos poderão estar afetados pelo processo inflamatório. A EA acomete principalmente homens entre 20 e 40 anos; é rara após os 50 anos. As mulheres correspondem somente à minoria de pacientes. Há pouca informação sobre a EA na literatura anestésica. O objetivo deste artigo foi revisar aspectos da EA de interesse para o anestesiologista, permitindo um adequado manuseio perioperatório. CONTEUDO: Estão definidas as características da espondilite anquilosante quanto à clínica e a conduta anestésica. CONCLUSÕES: Os pacientes com doenças crônicas da coluna vertebral apresentam desafios específicos para o anestesiologista. O manuseio da via aérea e o acesso ao neuroeixo poderão ser difíceis. Preferência tem sido dada à anestesia geral, mesmo com via aérea difícil reconhecida, evitando-se a anestesia no neuroeixo. O grau de envolvimento da coluna cervical determinará o quanto poderá ser difícil a intubação traqueal. Cuidado especial deve ser tomado para evitar a manipulação excessiva da coluna cervical, que poderia levar ao trauma da medula espinhal.

BACKGROUND AND OBJECTIVES: Ankylosing spondylitis (AS) is a chronic inflammatory disease of the joints, included in the group of seronegative spondyloarthropathies. Its main characteristic is the fusion of the bones in the spine, which causes loss of flexibility of the back and neck. Other large articulations and connective tissues can be affected by the inflammatory process. It affects mainly men between the ages of 20 and 40; it is rare after the age of 50. Women represent a minority of patients. There is little information about AS in the anesthetic literature. The objective of this article was to review the characteristics of AS pertaining anesthesiology for an adequate perioperative handling. CONTENTS: The clinical characteristics of ankylosing spondylitis pertaining to the anesthetic conduct are reviewed. CONCLUSIONS: Patients with chronic diseases of the spine represent specific challenges to the anesthesiologist. Handling of the airways and the access to the neuroaxis can be difficult. Most anesthesiologists prefer to use general anesthesia, avoiding the neuroaxis, in those patients, despite the presence of difficult airways. The degree of spine involvement will determine how difficult the tracheal intubation might be. Special care should be taken to avoid excessive manipulation of the neck, which could cause trauma to the spinal cord.

JUSTIFICATIVA Y OBJETIVOS: La espondilitis anquilosante (EA) es una enfermedad inflamatoria crónica de las articulaciones, incluida en el grupo de las espondiloartropatías soronegativas. La característica principal de esa enfermedad es la fusión ósea de la columna vertebral que conlleva a la pérdida permanente de la flexibilidad del dorso y del cuello. Otras grandes articulaciones y tejidos conectivos podrán estar afectados por el proceso inflamatorio. La EA acomete principalmente a hombres entre los 20 y 40 años; es rara después de los 50 años. Las mujeres corresponden solamente a la minoría de pacientes. Existe poca información sobre la EA en la literatura anestésica. El objetivo de este artículo fue revisar aspectos de la EA de interés para el anestesiólogo, permitiendo un adecuado manoseo perioperatorio. CONTENIDO: Están definidas las características de la espondilitis anquilosante en cuanto a la clínica y la conducta anestésica. CONCLUSIONES: Los pacientes con enfermedades crónicas de la columna vertebral presentan desafíos específicos para el anestesiólogo. El manoseo de la vía aérea y el acceso al neuro-eje podrán ser difíciles. La preferencia ha sido dada a la anestesia general, incluso con la vía aérea de difícil acceso, evitando la anestesia en el neuro-eje. El grado de involucración de la columna cervical determinará cuanto podrá ser difícil la intubación traqueal. Un cuidado especial debe tenerse para evitar la manipulación excesiva de la columna cervical, lo que podría conllevar al trauma de la médula espinal.