Synthesis and evaluation of new indole-based chalcones as potential antiinflammatory agents.

In the present work, new indole-based chalcone derivatives were obtained via the reaction of 5-substituted-1H-indole-3-carboxaldehydes/1-methylindole-3-carboxaldehyde with appropriate acetophenones. The synthesized compounds were investigated for their in vitro COX-1 and COX-2 inhibitory activity. The most effective COX inhibitors were also evaluated for their in vivo antiinflammatory and antioxidant activities in LPS induced sepsis model. Furthermore, the CCK-8 assay was carried out to determine cytotoxic effects of all compounds against NIH/3T3 mouse embryonic fibroblast cells. 3-(5-Bromo-1H-indol-3-yl)-1-(4-cyanophenyl)prop-2-en-1-one (6) can be considered as a non-selective COX inhibitor (COX-1 IC50 = 8.1 ± 0.2 µg/mL, COX-2 IC50 = 9.5 ± 0.8 µg/mL), whereas 3-(5-methoxy-1H-indol-3-yl)-1-(4-(methylsulfonyl)phenyl)prop-2-en-1-one (1) inhibited only COX-1 (IC50 = 8.6 ± 0.1 µg/mL). According to in vivo studies, these compounds also displayed antiinflammatory and antioxidant activities.

Bronchial hyperresponsiveness in seasonal allergic rhinitis patients is associated with increased IL-18 during natural pollen exposure.

BACKGROUND: The mechanism of bronchial hyperresponsiveness (BHR) is not certain in seasonal allergic rhinitis (SAR) patients. OBJECTIVE: We aimed to investigate the effects of natural pollen exposure on IL-18 and its relationship with BHR. METHODS: Thirty-two SAR patients with grass pollen sensitivity, 14 nonallergic rhinitis (NAR) patients and 17 normal-controls were included. Sixteen SAR patients had BHR during pollen season and off-season. Serum IL-18 levels were measured in SAR patients during pollen season between May-August and off-season between November-February. IL-18 levels were measured in NAR patients and normal controls once. RESULTS: During pollen season, SAR patients with BHR had significantly increased levels of IL-18 than those without BHR (279.2 ± 161.1 versus 145.3 ± 101.0 pg/ml, p=0.012). Serum IL-18 levels were not different between SAR patients with and without BHR during off-season (233.8 ± 139.7 versus 183.2 ± 162.9 pg/ml, p=0.16). Serum IL-18 levels in SAR patients during pollen season (212.3 ± 148.8 pg/ml) and off-season (208.5 ± 151.5 pg/ml) were not different than those NAR patients (224.8 ± 180.1 pg/ml, p=0.98 and p=1.0, respectively) and normal controls (174.8 ± 76.0 pg/ml, p=0.60 and p=0.76, respectively). CONCLUSION: The results suggested us that BHR in SAR patients is associated with increased IL-18 during natural pollen exposure.

The treatment of osteoporosis in patients with rheumatoid arthritis receiving glucocorticoids: a comparison of alendronate and intranasal salmon calcitonin.

OBJECTIVE: The purpose of this study was to assess the effects of alendronate and intranasal salmon calcitonin (sCT) treatments on bone mineral density and bone turnover in postmenopausal osteoporotic women with rheumatoid arthritis (RA) receiving low-dose glucocorticoids. METHODS: Fifty osteoporotic postmenopausal women with RA, who had been treated with low-dose corticosteroids for at least 6 months, were randomized to receive alendronate 10 mg/day or sCT 200 IU/day for a period of 24 months. All patients received calcium supplementation 1,000 mg and vitamin D 400 IU daily. Bone mineral density (BMD) of the lumbar spine, femoral neck, and trochanter was measured annually using dual-energy X-ray absorptiometry. Bone metabolism measurements included urinary deoxypyridinoline (DPD), serum bone alkaline phosphatase (BAP), and serum osteocalcin (OC). RESULTS: Over 2 years, the lumbar spine (4.34%, P < 0.001), femoral neck (2.52%, P < 0.05), and trochanteric (1.29%, P < 0.05) BMD in the alendronate group increased significantly. The sCT treatment increased lumbar spine BMD (1.75%, P < 0.05), whereas a significant bone loss occurred at the femoral neck at month 24 (-3.76%, P < 0.01). A nonsignificant decrease in the trochanteric region was observed in the sCT group (-0.81%). The difference between the groups with respect to the femoral neck and trochanteric BMD was statistically significant ( P < 0.001 and P < 0.05, respectively). The decreases in urinary DPD (-21.87%, P < 0.001), serum BAP (-10.60%, P < 0.01), and OC (-19.59%, P < 0.05) values were statistically significant in the alendronate group, whereas nonsignificant decreases were observed in the sCT group (-5.77%, -1.96%, and -4.31%, respectively). A significant difference was found in the DPD and BAP levels between the two treatment groups in favor of the alendronate group at all time points ( P = 0.001 and P < 0.05, respectively). CONCLUSION: The results of this study demonstrated that alendronate treatment produced significantly greater increases in the femoral neck BMD and greater decreases in bone turnover than intranasal sCT in RA patients receiving low dose glucocorticoids.

Effects of the anti-ICAM-1 monoclonal antibody, allopurinol, and methylene blue on intestinal reperfusion injury.

PURPOSE: The aim of this study was to evaluate the effect of allopurinol, methylene blue, and a monoclonal antibody to the adhesion molecule ICAM-1 in intestinal ischemia and reperfusion injury. METHODS: The rats were divided into 5 groups. CG (n = 8) was untreated controls, SISG (n = 11) received sterile isotonic saline solution, ICAMG (n = 12) received a monoclonal antibody to rat ICAM-1, ALLOG (n = 12) received allopurinol, and MBG (n = 14) received methylene blue. Intestinal ischemia was performed for 60 minutes followed by 60 minutes of reperfusion. The agents were injected 10 minutes before the reperfusion to animals. After 60 minutes of reperfusion, the plasma samples for myeloperoxidase (MPO) activity, tumor necrosis factor alpha (TNF-alpha) and uric acid levels, and the intestinal biopsies of ileum and jejunum for histopathologic examination were taken. RESULTS: The mucosal damage was attenuated, and TNF-alpha level significantly decreased in ALLOG and ICAMG compared with SISG. The MPO activity was the lowest in ICAMG, and uric acid level was significantly decreased in ALLOG compared with the other groups. Methylene blue decreased TNF-alpha response to reperfusion injury but significantly increased the grade of the mucosal damage and the MPO activity. CONCLUSIONS: This study shows that prereperfusion application of allopurinol and monoclonal antibody to the adhesion molecule ICAM-1 may attenuate the damage caused by intestinal ischemia and reperfusion, but the different time-points for application, the effects observed in the different ischemia and reperfusion durations, and the long-term results also should be investigated in the same experimental model before the final conclusion. Methylene blue was not effective to prevent or attenuate the intestinal tissue injury, but because this was the first study examining the effect of methylene blue on intestinal reperfusion injury, further studies with the different doses, ischemic duration, and application times will be needed.

Bone remodelling markers and serum cytokines in patients with hyperthyroidism.

OBJECTIVE: This study was designed in order to evaluate bone turnover with bone formation and resorption markers in hyperthyroidism and its possible relationship with serum cytokines interleukin 6 (IL-6) and tumour necrosis-alpha (TNF-alpha), levels of thyroid hormones and thyroid autoantibodies. DESIGN AND PATIENTS: Twenty-six hyperthyroid patients including nine with Graves' disease, 14 with toxic multi-nodular disease and three toxic adenoma were studied. Twenty normal subjects served as the control group. MEASUREMENTS: Serum calcium, phosphorus, total and bone-specific alkaline phosphatase, procollagen type 1-C peptide (PICP), osteocalcin, IL-6 and TNF-alpha measurements were performed and deoxypyridinoline (free DPD), calcium, phosphorus and creatinine levels were measured in fasting morning urine specimens of all hyperthyroid patients and all controls. Also, serum total and free T3 and T4 and TSH were analysed and thyroid antiperoxidase and antithyroglobulin antibodies were determined in sera of hyperthyroid patients. Patients with hyperthyroidism received propylthiouracil treatment until the achievement of euthyroidism and then serum cytokine levels were remeasured. RESULTS: Mean serum values of osteocalcin, total and bone-specific alkaline phosphatase were all significantly higher in hyperthyroid patients than in normal controls. PICP levels were not significantly different between these two groups. Urinary deoxypyridinoline levels were markedly elevated in hyperthyroid patients compared to the control group. There was a significant positive correlation between urinary free DPD levels and serum free T3, free T4 and T4 levels. Serum free T4 levels also correlated with urinary calcium levels. Serum IL-6 values were significantly higher in hyperthyroid patients compared to control group. TNF-alpha levels were slightly lower in patients with hyperthyroidism. No significant correlation was found between bone remodelling markers and serum cytokines. Serum Il-6 levels were correlated positively with age. After the treatment period both IL-6 and TNF-alpha returned to levels comparable with euthyroid controls. CONCLUSION: Bone turnover is increased in favour of resorption and the rate of resorption is associated with the levels of thyroid hormones in hyperthyroidism. The increase in the levels of serum IL-6 in hyperthyroidism is not related directly with bone resorption seen in hyperthyroidism.