Efficacy and safety of Huzhang Granule, a compound Chinese herbal medicine, for acute gouty arthritis: A double-blind, randomized controlled trial.

BACKGROUND: Acute gouty arthritis (AGA) is an inflammatory joint disease with a high prevalence. Typical medical interventions, including nonsteroidal anti-inflammatory drugs, colchicine and glucocorticoids, can have serious adverse reactions. Huzhang Granule (HZG), a compound Chinese herbal medicine, has been used to treat AGA for more than 30 years with satisfactory effects and no significant adverse reactions. However, the efficacy and safety of HZG in AGA patients remains unknown. OBJECTIVE: The present investigation was designed to examine the efficacy and safety profile of HZG in managing AGA patients. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: The current study was conducted as a noninferiority, randomized controlled clinical trial on 180 eligible enrolled participants. Participants were randomly assigned into the HZG and etoricoxib groups. Treatments were administered for 5 d, during which the HZG group received HZG and placebo etoricoxib, while the etoricoxib group received etoricoxib and placebo HZG in the same ratio (1:1). MAIN OUTCOME MEASURES: The primary outcome was pain experienced by the patient in the gout-afflicted joint from days 2 to 5 of the treatment window. The pain level was measured via a visual analogue scale, ranging from 0 mm to 100 mm. The secondary outcomes comprised joint tenderness and swelling, reduction of inflammatory biomarkers, and the patient's and investigator's global evaluations of therapeutic response. RESULTS: The mean reduction in pain was -51.22 mm (95% confidence interval [CI], [-53.42, -49.03] mm) for the HZG and -52.00 mm (95% CI, [-54.06, -49.94] mm) for the etoricoxib groups. The mean difference between the two groups was 0.78 mm (95% CI, [-2.25, 3.81] mm). All additional efficacy endpoints, covering decreased inflammation and pain relief, yielded compelling proof of noninferiority. Patients in the HZG group exhibited a comparatively lower rate of adverse events compared to those in the etoricoxib group (4.44% vs 13.33%; P ≤ 0.05). CONCLUSION: HZG and etoricoxib groups demonstrated similar levels of analgesic effectiveness. The safety and efficacy of HZG indicates that it can be used as a potential therapeutic option for treating AGA. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2000036970). Please cite this article as: Wang H, Chen ST, Ding XJ, Kuai L, Hua L, Li X, Wang YF, Zhang M, Li B, Wang RP, Zhou M. Efficacy and safety of Huzhang Granule, a compound Chinese herbal medicine, for acute gouty arthritis: A double-blind, randomized controlled trial. J Integr Med. 2024; 22(3): 270-278.

Remission of Dowager's hump by manipulative correction of spinal alignment: a case report.

Dowager's hump is described as excessive kyphotic curvature in the thoracic spine with a Cobb angle of more than 40 degrees. This case report presents a 61 years old female office clerk who experienced headaches and neck pain for 3 years that extended into her right shoulder and upper chest. She consulted her primary care physician two months before seeing the chiropractor when the neck pain worsened. A diagnosis of cervicalgia related to osteoarthritis was made based on cervical and thoracic X-ray findings. The patient received non-steroid anti-inflammatory drugs (celecoxib and etoricoxib) and stretching exercises at home. At the onset of chiropractic care, radiographs showed loss of cervical lordosis, narrowing at the C4-5, C5-C6, and C6-7 intervertebral disc space with marginal osteophytes. Based on these findings, a working diagnosis of cervicogenic headache was established. After treatment for 9 months, the patient showed improvement in symptoms and function from cervical curve radiographic change and dextro-convexity of the thoracic spine. Avoiding forward head flexion and maintaining correct posture in daily activities will be key mechanisms to prevent the reoccurrence of Dowager's hump. The improvement of symptoms following chiropractic therapy has been shown to correlate with radiographic markers of spinal realignment.

Cardiovascular Risks of Diclofenac Versus Other Older COX-2 Inhibitors (Meloxicam and Etodolac) and Newer COX-2 Inhibitors (Celecoxib and Etoricoxib): A Series of Nationwide Emulated Trials.

INTRODUCTION: Diclofenac has increased cardiovascular risks, but its risk profile compared with other COX-2 inhibitors remains unknown. AIMS: The aim of this study was to compare the cardiovascular risks of diclofenac versus other older and newer COX-2 inhibitors (coxibs). METHODS: Using Danish nationwide health registries (1999-2020), we conducted a series of emulated trials (n = 264). Eligible adults had no recent NSAID prescriptions, contraindications or conditions with low adherence. We included initiators of diclofenac (n = 1,600,202), meloxicam (n = 10,903), etodolac (n = 238,538), celecoxib (n = 77,591), and etoricoxib (n = 12,122). We computed the adjusted intention-to-treat incidence rate ratio (aIRR) with 95% confidence interval (CI) of major adverse cardiovascular events (MACE) within 30 days of initiation (5562 events). RESULTS: MACE was 20% increased among initiators of diclofenac compared with other older COX-2 inhibitors (aIRR 1.19, 95% CI 1.10-1.28), driven by cardiac death (aIRR 1.57, 95% CI 1.21-2.03). The effect appeared strongest for women (aIRR 1.28, 95% CI 1.15-1.43), individuals with high baseline cardiovascular risk (aIRR 1.32, 95% CI 1.05-1.66), and when comparing high-dose diclofenac with low doses of the other older COX-2 inhibitors (aIRR 1.31, 95% CI 1.13-1.52). The results reflected increased rates compared with both meloxicam (aIRR 1.46, 95% CI 0.94-2.26) and etodolac (aIRR 1.18, 95% CI 1.09-1.28). Diclofenac initiators had similar increased rates of MACE compared with coxibs (aIRR 0.96, 95% CI 0.85-1.08), consistent for celecoxib (aIRR 1.02, 95% CI 0.88-1.19) and etoricoxib (aIRR 0.85, 95% CI 0.66-1.10). CONCLUSIONS: The increased cardiovascular risks associated with diclofenac initiation were higher than for other older COX-2 inhibitors (meloxicam/etodolac) and comparable to coxibs (celecoxib/etoricoxib).

Facile synthesis of mesoporous alumina using hexadecyltrimethylammonium bromide (HTAB) as template: simplified sol-gel approach.

Herein the authors present the synthesis of surface functionalised mesoporous alumina (MeAl) for textural characterisation by a simplified sol-gel method obtained by using hexadecyltrimethylammonium bromide as a template. Etoricoxib (ETOX) was used as a model drug for the study. Alumina supported mesoporous material containing drug was characterised using instrumental technique namely Brunauer-Emmett-Teller surface area, Fourier transform-infrared, differential scanning calorimetry, transmission electron microscopy, X-ray diffraction, and field emission scanning electron microscopy. Diffusion study using a dialysis bag method used to check the release pattern of ETOX-loaded-MeAl. Results of characterisation study revealed the successful surface functionalisation of the drug on nanocomposite. The IC50 value obtained from cell viability study demonstrated the non-toxic behaviour of synthesised drug-loaded mesoporous alumina up to the tested concentration range. The present work has demonstrated that synthesised MeAl showed excellent stability with an expanded surface area suitable for carrier material for drug delivery system.

Noninvasive Interactive Neurostimulation Therapy for the Treatment of Low-Grade Lateral Ankle Sprain in the Professional Contact Sport Athlete Improves the Short-Term Recovery and Return to Sport: A Randomized Controlled Trial.

Ankle injuries are very common between professional athletes and recreational sports. Lateral stable ligaments injury can be treated conservatively. Noninvasive interactive neurostimulation (NIN) is a form of electric therapy that works by locating areas of lower skin impedance. The objective of this prospective, double-blinded, randomized controlled trial was to compare the results in terms of improvement of a foot functional score, lower level of reported pain, and return to sports in 2 groups of contact sport athlete affected by a grade I or II lateral ankle sprain. Patients were randomized using random blocks to the NIN program (group I) or a sham device (group II). The outcome measurements were the use of a self-reported Inability Walking Scale, patient-reported subjective assessment of the level of pain using a standard visual analogue scale, and daily intake of nonsteroidal antiinflammatory drugs (etoricoxib 60 mg). Patients were also reached by telephone at 2 and 4 months of follow-up to register their return to sport activity. Beyond baseline evaluation, follow-ups were done after 5 (1 week) and 10 sessions (2 weeks) of treatment, and then at 30 days after the end of therapy. Of the 70 athletes admitted to the study, 61 eligible patients were randomized using random blocks to group I (n = 32) and group II (n = 29). Group I patients showed better improvement in terms of functional impairment (Inability Walking Scale), reported pain (visual analogue scale), and daily intake of etoricoxib 60 mg. Athletes of group I registered a faster resuming of sport activities. This prospective, randomized trial showed NIN can improve short-term outcomes in athletes with acute grade I or II ankle sprain and that it can hasten resuming of sport activities.

Gastric and renal effects of COX-2 selective and non-selective NSAIDs in rats receiving low-dose aspirin therapy.

The consumption of low-dose aspirin (LDA) to prevent cardiovascular disease continues to increase worldwide. Consequently, the number of chronic LDA users seeking dental procedures that require complementary acute anti-inflammatory medication has also grown. Considering the lack of literature evaluating this interaction, we analyzed the gastric and renal effects caused by a selective COX-2 inhibitor (etoricoxib) and a non-selective COX-2 inhibitor (ibuprofen) nonsteroidal anti-inflammatory drug (NSAID) in rats receiving chronic LDA therapy. Male Wistar rats were divided into six experimental groups (carboxymethylcellulose (CMC) - vehicle; LDA; LDA + ibuprofen; ibuprofen; LDA + etoricoxib; and etoricoxib) and submitted to long-term LDA therapy with a subsequent NSAID administration for three days by gavage. After the experimental period, we analyzed gastric and renal tissues and quantified serum creatinine levels. The concomitant use of LDA with either NSAID induced the highest levels of gastric damage when compared to the CMC group (F = 20.26, p < 0.05). Treatment with either LDA or etoricoxib alone was not associated with gastric damage. No significant damage was observed on kidney morphology and function (F = 0.5418, p > 0.05). These results suggest that even the acute use of an NSAID (regardless of COX-2 selectivity) can induce gastric damage when combined with the long-term use of low-dose aspirin in an animal model. Additional studies, including clinical assessments, are thus needed to clarify this interaction, and clinicians should be careful of prescribing NSAIDs to patients using LDA.

Pharmacokinetic and pharmacodynamic herb-drug interaction of Andrographis paniculata (Nees) extract and andrographolide with etoricoxib after oral administration in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Andrographis paniculata Nees (Acanthacae) is commonly used medicinal plant in the traditional. Unani and Ayurvedic medicinal systems. It has broad range of pharmacological effects such as hepatoprotective, antioxidant, antivenom, antifertility, inhibition of replication of the HIV virus, antimalarial, antifungal, antibacterial, antidiabetic, suppression of various cancer cells and anti-inflammatory properties. Andrographolide (AN) is one of the active constituent of the A. paniculata Nees extract (APE). They have been found in many traditional herbal formulations in India and proven to be effective as anti-inflammatory drug AIM OF THE STUDY: To evaluate the pharmacokinetic and pharmacodynamic (anti-arthritic) herb-drug interactions of A. paniculata Nees extract (APE) and pure andrographolide (AN) with etoricoxib (ETO) after oral co-administration in wistar rats. MATERIALS AND METHODS: After oral co-administration of APE (200mg/Kg) and AN (60mg/kg) with ETO (10mg/kg) in rats, drug concentrations in plasma were determined using HPLC method. The main pharmacokinetic parameters of Cmax, tmax, t1/2, MRT, Vd, CL, and AUC were calculated by non-compartment model. Change in paw volume, mechanical nociceptive threshold, mechanical hyperalgesia, histopathology and hematological parameters were evaluated to study antiarthritic activity. RESULTS: Co-administration of ETO with APE and pure AN decreased systemic exposure level of each compound in vivo. The Cmax, AUC, t1/2 of ETO was decreased whereas Vd and CL of ETO was increased significantly after co-administration of ETO with pure AN and APE. In pharmacodynamic study, ETO alone and ETO+APE (10+200mg/kg) groups exhibited significant synergistic anti-arthritic activity as compared to groups ETO+AN, APE and AN alone. CONCLUSION: The results obtained from this study suggested that ETO, APE and pure AN existed pharmacokinetic herb-drug interactions in rat which is correlated with anti-arthritic study. Physicians and patients using A. paniculata should have the knowledge about its possible herb-drug interaction with ETO.

Gastric and renal effects of COX-2 selective and non-selective NSAIDs in rats receiving low-dose aspirin therapy

Abstract The consumption of low-dose aspirin (LDA) to prevent cardiovascular disease continues to increase worldwide. Consequently, the number of chronic LDA users seeking dental procedures that require complementary acute anti-inflammatory medication has also grown. Considering the lack of literature evaluating this interaction, we analyzed the gastric and renal effects caused by a selective COX-2 inhibitor (etoricoxib) and a non-selective COX-2 inhibitor (ibuprofen) nonsteroidal anti-inflammatory drug (NSAID) in rats receiving chronic LDA therapy. Male Wistar rats were divided into six experimental groups (carboxymethylcellulose (CMC) - vehicle; LDA; LDA + ibuprofen; ibuprofen; LDA + etoricoxib; and etoricoxib) and submitted to long-term LDA therapy with a subsequent NSAID administration for three days by gavage. After the experimental period, we analyzed gastric and renal tissues and quantified serum creatinine levels. The concomitant use of LDA with either NSAID induced the highest levels of gastric damage when compared to the CMC group (F = 20.26, p < 0.05). Treatment with either LDA or etoricoxib alone was not associated with gastric damage. No significant damage was observed on kidney morphology and function (F = 0.5418, p > 0.05). These results suggest that even the acute use of an NSAID (regardless of COX-2 selectivity) can induce gastric damage when combined with the long-term use of low-dose aspirin in an animal model. Additional studies, including clinical assessments, are thus needed to clarify this interaction, and clinicians should be careful of prescribing NSAIDs to patients using LDA.

Etoricoxib and the treatment of ankylosing spondylitis.

INTRODUCTION: Nonsteroidal anti-inflammatory drugs (NSAIDs) are first-line therapies in the management of patients with ankylosing spondylitis. This chronic inflammatory skeletal disorder, a subtype of spondyloarthritis, is characterized by inflammatory back pain and affects young adults causing important suffering and disability. Long-term use of conventional NSAIDs is associated with a risk of gastrointestinal complications. Etoricoxib is a specific cyclooxygenase 2 inhibitor with strong anti-inflammatory effects and a favorable pharmacokinetic profile for the management of inflammatory disorders. The drug has been associated with reduced severe gastrointestinal adverse events. However, the cardiovascular safety of cyclooxygenase 2 inhibitors has been debated. AREAS COVERED: This review discusses etoricoxib in the treatment of ankylosing spondylitis. Literature searches were performed in PubMed, Web of Science, and the Cochrane library based on the terms "etoricoxib" and "ankylosing spondylitis" or "spondyloarthritis" as well as "safety" and "side-effects." EXPERT OPINION: Etoricoxib is useful in the first-line management of ankylosing spondylitis patients. Its anti-inflammatory effects and relative protection against severe gastrointestinal side effects should be balanced with negative effects on the cardiovascular system and an overall subjective tolerance not better than that of conventional NSAIDs. Whether etoricoxib will also become a mainstay in the prevention of structural damage in ankylosing spondylitis is not yet clear.

Pharmacokinetics and cardiovascular effect of etoricoxib in the absence or presence of St. John's Wort in rats.

The effect of chronic administration of etoricoxib (EXB), in the absence or presence of St. John's Wort (SJW), on its pharmacokinetic parameters and blood pressure was investigated in rats.Rats were divided into 3 groups, each group received daily different oral treatment for 3 weeks. Rats' blood pressures were monitored initially, after 1 and 3 weeks of treatment, and after 1 week of discontinuing dosing of both drugs. EXB pharmacokinetic parameters in the absence or presence of SJW were calculated after 3 weeks.SJW was significantly affected EXB pharmacokinetic parameters. The steady state peak plasma concentration and terminal half-life were reduced by 32% and 91%, respectively, due to a > 3 fold increase in its apparent clearance which is a concentration and time dependent effect. EXB was significantly increased (P<0.001) Rats' blood pressure while, co-administration of EXB and SJW was not significantly affect (P>0.05) rats' blood pressure as compared to the control.Monitoring blood pressure of patients anticipated taking EXB for extended period should be advised. The co-administration of SJW with EXB should be avoided since SJW would greatly reduce EXB concentrations by inducing its metabolism.

Effect of isolated fractions of Harpagophytum procumbens D.C. (devil's claw) on COX-1, COX-2 activity and nitric oxide production on whole-blood assay.

The present study evaluates the effect of isolated fractions of Harpagophytum procumbens (devil's claw) on cyclooxygenase (COX-1 and COX-2) activities and NO production using a whole blood assay. The activity of COX-1 was quantified as platelet thromboxane B(2) production in blood clotting and COX-2 as prostaglandin E(2) production in LPS-stimulated whole blood. Total NO(2) (-)/NO(3) (-) concentration was determined by Griess reaction in LPS stimulated blood. Assays were performed by incubation of isolated fractions obtained by flash chromatography monitored with HPLC, TLC and identified by (1)HNMR, containing different amounts of harpagoside with blood from healthy donors. Indomethacin and etoricoxib were the positive controls of COX-1 and COX-2 Inhibition. Data shows that fraction containing the highest concentration of harpagoside inhibited indistinctively COX-1 and COX-2 (37.2 and 29.5% respectively) activity and greatly inhibited NO production (66%). In contrast the fraction including iridoid pool increased COX-2 and did not alter NO and COX-1 activities. The fraction containing cinnamic acid was able to reduce only NO production (67%). Our results demonstrated that the harpagoside fraction is the main responsible for the effect of devils claw on these enzyme activities. However, other components from devil's claw crude extract could antagonize or increase the synthesis of inflammatory mediators.

Inhibitory effect of selective cyclooxygenase-2 inhibitor lumiracoxib on human organic anion transporters hOAT1 and hOAT3.

Nonsteroidal anti-inflammatory drugs (NSAIDs) delay renal excretion of antifolate methotrexate by inhibiting human organic anion transporters hOAT1 (SLC22A6) and hOAT3 (SLC22A8). In this study, we performed uptake experiments using Xenopus laevis oocytes to assess the inhibitory effect of selective cyclooxygenase-2 inhibitors on hOAT1 and hOAT3. The uptake of methotrexate into oocytes was increased by the injection of hOAT1 and hOAT3 cRNA, and transport was strongly inhibited by lumiracoxib. The apparent 50% inhibitory concentrations of lumiracoxib were estimated to be 3.3 µM and 1.9 µM for uptake of p-aminohippurate by hOAT1 and of estrone sulfate by hOAT3, respectively. Eadie-Hofstee plot analysis showed that lumiracoxib inhibited hOAT1 and hOAT3 in a competitive manner. For other cyclooxygenase-2 inhibitors celecoxib, etoricoxib, rofecoxib and valdecoxib, slight to moderate inhibition of hOAT3 only was observed. These findings show that lumiracoxib has inhibitory potential toward hOAT1 and hOAT3, comparable to that of nonselective NSAIDs.

Effect of etoricoxib, a cyclooxygenase-2 selective inhibitor on aberrant crypt formation and apoptosis in 1,2 dimethyl hydrazine induced colon carcinogenesis in rat model.

Etoricoxib, a second generation selective cyclooxygenase-2 (COX-2) inhibitor had been studied for the chemopreventive response at its therapeutic anti-inflammatory dose in 1,2-dimethylhydrazine (DMH) induced colon carcinogenesis in rat model. Eight to ten weeks old male rats of Sprague-Dawley strain were divided into four groups. While group 1 served as control and received the vehicle of the drugs, group 2 and 3 were administered freshly prepared DMH in 1mM EDTA-saline (pH 7.0) (30 mg/kg body wt/week, subcutaneously). Group 3 was also given a daily treatment of etoricoxib (0.6 mg/kg body wt orally) while the group 4 received the same amount of etoricoxib only, prepared in 0.5% carboxymethyl cellulose. Animals were sacrificed at the end of 6 weeks, body weight recorded and the colons were subjected to macroscopic and histopathological studies. The maximum number of raised mucosal lesions called the multiple plaque lesions (MPL) were found in the DMH group which significantly reverted back in the DMH + etoricoxib group, while very few MPLs were recorded in the control and etoricoxib only group. Similarly, the number of aberrant crypt foci (ACF), the point of future carcinogenic growth, was recorded more in the DMH group and significantly less in the DMH + etoricoxib group. The histopathological analysis showed the presence of severe hyperplasia, occasional dysplasia and aggregates of lymphoid cells in the localized regions. Etoricoxib group showed near normal histological features with the crypt architecture and the surrounding stromal tissue remaining intact. To ascertain the molecular mechanism of such anti-carcinogenic features the colonocytes were isolated and studied in primary culture for the evidence of apoptosis by fluorescent staining and genotoxic changes by single cell gel electrophoresis assay (comet assay) which shows that the DMH treated animals produced much less apoptotic nuclei but more comet producing cell, while these features were reverted back with the etoricoxib treatment. The cytoplasmic expression of COX-2 protein was studied in paraffin sections of the colon by immunohistochemistry with COX-2 specific antibody which showed a very high presence of this inducible enzyme with the DMH group while in all other groups of animals it was not visible or weekly expressed. The anti-inflammatory effect of the drug, etoricoxib was also validated by a carrageenan-induced inflammation in rat model which showed an extremely high anti-inflammatory response within the dose range used in the present study. Also the growth profile of all the animals remained the same throughout the six week period of the investigation as there was no change in the body weight. It appears that apoptosis remains the dominant anti-proliferative end effect of this drug, mediated by an inhibition of the proinflammatory COX-2 isoform although further molecular probings are needed to arrive at a conclusive agreement in favor of the chemoprotective use of such drugs in colon cancers.

Cardiovascular and hematologic effects produced by chronic treatment with etoricoxib in normotensive rats.

PURPOSE: Evaluate the cardiovascular and hematological effects produced by chronic treatment with two dosis of etoricoxib in Wistar normotensive rats. METHODS: Thirty rats have been used and divided into one control group and two etoricoxib (10mg/kg and 30mg/kg) treatments groups for 60 days. The mean arterial pressure (MAP) was taken during the whole experimental period and at the end of this period, under anesthesia blood samples were taken, and further the withdrawn of the aorta, heart, brain, liver, and kidneys for the anatomopathologic study. RESULTS: The treatment with etoricoxib (30mg/Kg) produced a significant increase of the MAP from the 28th day of the experiment and from the platelets when compared to the control group and to the group treated with 10mg/Kg, besides producing a highly significant difference in hematocrit and in the red blood cells in relation to the control group. On the other hand the treatment with etoricoxib has not caused histopathological changes when compared to the control. CONCLUSION: These data show that the chronic treatment with etoricoxib leads to increase of the MAP, and to important hematological changes which seem to be associated to the hemoconcentration although not producing anatomopathological significant changes.

Determination of two COX-2 inhibitors in serum and synovial fluid of patients with inflammatory arthritis by ultra performance liquid chromatography-inductively coupled plasma mass spectroscopy and quadrupole time-of-flight mass spectrometry.

The determination of two sulphur-containing drugs, the COX-2 inhibitors celecoxib and etoricoxib, in the serum and synovial fluid of inflammatory arthritis patients, is described using a sensitive ultra performance liquid chromatography-inductively coupled plasma mass spectroscopy (UPLC/ICPMS) method. Confirmation of the identity of the analytes in the samples was also performed by electrospray quadruple time-of-flight mass spectrometry in positive electrospray ionisation mode. The two COX-2 inhibitors were extracted from serum and synovial fluid following dilution with acetate buffer (pH 5) and liquid-liquid extraction (LLE) into ethyl acetate. Extracted samples were then analysed using UPLC/ICPMS with sulphur-specific detection. The limit of detection by UPLC/ICPMS was 0.45 ng/ml of sulphur in both serum and synovial fluid. The UPLC/ICPMS method was applied to the analysis of samples from patients receiving either 200 mg/day of celecoxib (2x 100 mg), 90 mg/day etoricoxib or placebo. The range of concentrations detected in the samples for the two drugs was from 0.3 to 3.3 microg/ml.

Experimentally induced various inflammatory models and seizure: understanding the role of cytokine in rat.

BACKGROUND: The mechanism of epileptogenesis is not well established. There is higher incidence of seizures among patients with chronic inflammatory disease. Cytokines are rapidly induced in the brain after a variety of stimuli including inflammation. Aim of this study was to produce various inflammatory models and seizure to understand the role of TNFalpha in above mentioned models. MATERIALS AND METHODS: A total of 54 male rats were included in the study. Animals were divided into 3 groups of colitis, arthritis, and cotton wool granuloma. Each group had 3 subgroups of control, model and treatment. At the end of 3 days in colitis, 17 days in arthritis and 7 days in cotton wool granuloma groups a subconvulsive dose of PTZ (40 mg/kg i.p) was injected to note seizure onset and seizure score. Brain samples were subjected to DNA fragmentation testing. Presence of inflammation was confirmed by morphology and histology. Plasma and brain TNFalpha levels were measured. RESULTS: The models of colitis, arthritis and CWG were effectively produced as evidenced by morphology and histology scores (p<0.001). Seizure onset was reduced and grade was increased (p<0.001). Thalidomide reduced the morphological, histological (p<0.002), DNA fragmentation and seizure grade (p<0.001) while increased seizure onset (p<0.001) in the arthritis group. TNFalpha levels in both plasma and brain were reduced following thalidomide treatment (p<0.002) in arthritis group. There were no significant findings in colitis or cotton wool granuloma groups. CONCLUSION: Inflammation was associated with decreased threshold to PTZ induced seizure. Thalidomide is effective in reducing the extent of arthritis as well as reducing the seizure scoring and increasing seizure onset in the adjuvant arthritis group. Thalidomide was also effective in reducing TNFalpha levels thus contributing to its antiepileptic activity.

Anti-inflammatory and analgesic actions of etoricoxib (an NSAID) combined with misoprostol.

This study has evaluated the anti-inflammatory and analgesic responses of etoricoxib, a selective COX-2 non-steroidal anti-inflammatory drug combined with misoprostol in pre-clinical assays. Groups of animals (mice and rats) were subjected to rat's paw edema induced by carrageenan, and writhing and formalin tests in mice. Treatment with etoricoxib, misoprostol, and etoricoxib combined with misoprostol inhibited the inflammation process by 35 %, 30 %, and 61 %, respectively in the rat paw edema induced by carrageenan with the greatest effects being obtained in the group treated with etoricoxib combined to misoprostol. In the writhing test, etoricoxib inhibited the number of writhes by 33 %, and by 27 % when combined with misoprostol. In the first phase of the formalin test (nociceptive), treatment with the combination of etoricoxib and misoprostol inhibited significantly this process by 45 %, while in the second phase (inflammatory), etoricoxib inhibited this by 97 %, the etoricoxib + misoprostol inhibited this by 78 %, respectively. The responses observed have demonstrated that the combination of etoricoxib and misoprostol increased the anti-inflammatory response, but it did not show effect in the peripheral analgesic response.

Selective COX-2 inhibitors and risk of thromboembolic events - regulatory aspects.

In the 1990s, the pharmaceutical industry developed selective COX-2 inhibitors (coxibs) as alternatives to conventional nonsteroidal anti-inflammatory drugs (NSAIDs), with the expectation of similar analgetic and anti-inflammatory efficacy but a reduced risk of adverse gastrointestinal (GI) effects. Marketing authorisation (MA) was granted for rofecoxib and celecoxib as first representatives of this new pharmacological class at the end of the 1990s in the EU. In the following years MAs were granted for the 'second generation' coxibs etoricoxib, parecoxib/valdecoxib and lumiracoxib. However, data from large clinical 'outcome studies' as well as epidemiological data raised concerns about the cardiovascular (CV) safety of the coxibs. In consequence, two comprehensive review processes (referrals) were initiated by the European Medicines Agency (EMEA). As a result, in the EU the use of coxibs has been contraindicated in patients with established coronary heart disease, cerebrovascular disease and peripheral arterial disease and a number of warning statements concerning CV, GI and skin toxicity have been introduced in the coxib product informations. This article provides a description of the regulatory actions taken and discusses some specific aspects of the past and future regulatory assessment of coxibs.

Efficacy of etoricoxib 60 mg/day and diclofenac 150 mg/day in reduction of pain and disability in patients with chronic low back pain: results of a 4-week, multinational, randomized, double-blind study.

BACKGROUND AND METHODS: The efficacy and safety of etoricoxib 60 mg/day in patients with established chronic low back pain (CLBP) were compared with those of diclofenac 150 mg/day in a 4-week, multicentre, randomized, double-blind, parallel-group trial. Four hundred and forty-six adult patients with CLBP (Quebec Task Force on Spinal Disorders Class 1 or 2) and with worsening pain upon discontinuation of pre-study analgesic medication were enrolled in the study. The study primary efficacy endpoint was change from baseline in Low Back Pain Intensity Scale (LBP-IS) score over the 4-week treatment period. Secondary and other efficacy endpoints included: changes in Roland and Morris Disability Questionnaire (RMDQ), Patient Global Assessment of Response to Therapy (PGART) and Low Back Pain Bothersomeness Scale (LBP-BS) scores. Early efficacy was assessed using PGART and LBP-IS scores 4 h after the first dose on the mornings of Days 1, 2 and 3. The overall safety and tolerability of etoricoxib 60 mg/day during 4 weeks of treatment were also assessed. RESULTS: The least-squares mean time-weighted change from baseline LBP-IS score over 4 weeks was -32.94 mm (95% CI -36.25, -29.63) for etoricoxib, indicating substantial efficacy in relief of pain. The treatment difference for the primary outcome was 2.51 mm (95% CI -1.50, 6.51), fulfilling the prespecified equivalence criterion of 95% confidence interval wholly within +/- 10 mm. Etoricoxib improved all secondary and other efficacy outcomes. There were no statistically significant between-group differences in the proportion of patients with one or more clinical adverse events (AEs) (etoricoxib 35%, diclofenac 39%), or the proportion of patients who discontinued due to AEs (etoricoxib 7%, diclofenac 5%). CONCLUSIONS: The results of this study confirm that, for adult patients with CLBP, etoricoxib 60 mg once daily over 4 weeks is effective for relief of pain and improvement of physical function and comparable to high-dose diclofenac 150 mg daily.