sulindac and Edema

Sulindac is chemopreventive and has utility in patients with familial adenomatous polyposis; however, side effects preclude its long-term use. NOSH-sulindac (AVT-18A) releases nitric oxide and hydrogen sulfide, was designed to be a safer alternative. Here we compare the gastrointestinal safety, anti-inflammatory, analgesic, anti-pyretic, anti-platelet, and anti-cancer properties of sulindac and NOSH-sulindac administered orally to rats at equimolar doses. Gastrointestinal safety: 6h post-administration, number/size of hemorrhagic lesions in stomachs were counted. Tissue samples were frozen for PGE2, SOD, and MDA determination. Anti-inflammatory: 1h after drug administration, the volume of carrageenan-induced rat paw edemas was measured for 5h. Anti-pyretic: fever was induced by LPS (ip) an hour before administration of the test drugs, core body temperature was measured hourly for 5h. Analgesic: time-dependent analgesic effects were evaluated by carrageenan-induced hyperalgesia. Antiplatelet: anti-aggregatory effects were studied on collagen-induced platelet aggregation of human platelet-rich plasma. Anti-cancer: We examined the effects of NOSH-sulindac on the growth properties of 12 human cancer cell lines of six different tissue origins. Both agents reduced PGE2 levels in stomach tissue; however, NOSH-sulindac did not cause any stomach ulcers, whereas sulindac caused significant bleeding. Lipid peroxidation induced by sulindac was higher than that from NOSH-sulindac. SOD activity was significantly lowered by sulindac but increased by NOSH-sulindac. Both agents showed similar anti-inflammatory, analgesic, anti-pyretic, and anti-platelet activities. Sulindac increased plasma TNFα whereas this rise was lower in the NOSH-sulindac-treated animals. NOSH-sulindac inhibited the growth of all cancer cell lines studied, with potencies of 1000- to 9000-fold greater than that of sulindac. NOSH-sulindac inhibited cell proliferation, induced apoptosis, and caused G2/M cell cycle block. These results demonstrate that NOSH-sulindac is gastrointestinal safe, and maintains the anti-inflammatory, analgesic, antipyretic, and antiplatelet properties of its parent compound sulinsac, with anti-growth activity against a wide variety of human cancer cells.

Topics: Administration, Oral; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Antipyretics; Cell Line, Tumor; Cell Survival; Dinoprostone; Edema; Fever; Hydrogen Sulfide; Hyperalgesia; Male; Malondialdehyde; Nitric Oxide; Nitric Oxide Donors; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Sulindac; Superoxide Dismutase

Tea has been shown to possess several health beneficial properties primarily due to its polyphenolic content. The major polyphenolic compounds in black tea leaves are theaflavins (TFs) formed by oxidative coupling of catechins in tea leaves during its processing. In this paper, we report the characterization of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear inflammatory model and the inhibitory effects of major black tea TFs derivatives on this inflammation. In addition, the effect on inflammatory biomarkers, such as proinflammatory cytokines and arachidonic acid metabolites, are reported as well. A single topical application of TPA to ears of CD-1 mice induced a time- and dose-dependent increase in edema as well as formation of proinflammatory cytokine proteins interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) in mouse ears. A single topical application of equimolar of black tea constituents (TF, theaflavin-3-gallate, theaflavin-3'-gallate, and theaflavin-3,3'-digallate) strongly inhibited TPA-induced edema of mouse ears. Application of TFs mixture to mouse ears 20 min prior to each TPA application once a day for 4 days inhibited TPA-induced persistent inflammation, as well as TPA-induced increase in IL-1beta and IL-6 protein levels. TFs also inhibited arachidonic acid (AA) metabolism via both cyclooxygenase (COX) and lipoxygenase pathways. This observation was substantiated by decreased amounts of AA metabolites prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) levels. Combined application of TF and sulindac, a nonsteroidal anti-inflammatory drug resulted a significant synergetic anti-inflammatory effect. Oral administration of TFs or the hot water extract of black tea leaves also significantly inhibited TPA-induced edema in mouse ears. In conclusion, proinflammatory cytokines, IL-1beta and IL-6, as well as the intermediated metabolites of AA, PGE2, and LTB4 are good biomarkers for inflammation. Black tea constituents, TF and its derivatives, had strongly anti-inflammatory activity in vivo which may be due to their ability to inhibit AA metabolism via lipoxygenase and COX pathways.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Biflavonoids; Catechin; Dinoprostone; Drug Synergism; Ear; Edema; Female; Gallic Acid; Inflammation; Interleukin-1; Interleukin-6; Leukotriene B4; Lipoxygenase; Mice; Prostaglandin-Endoperoxide Synthases; Sulindac; Tea; Tetradecanoylphorbol Acetate

A purified bacterial cell walls suspension from human dental plaque were biochemically prepared to serve as flogogenous agent in producing experimental inflammatory models in rats. In the vascular permeability inhibition assay (edemogenic test), the subcutaneous implantation of the flogogenous agent elicited an acute inflammatory reaction highly susceptible to the effects of the non-steroidal anti-inflammatory drugs (NSAIDs). The intradermal injection of the flogogenous agent in the dorsum of rats developed experimental granulomas also susceptible to the anti-inflammatory effects of the NSAIDs. Otherwise, the antimitotic effect of drugs was carried out in the model of cellular proliferation of duodenal mucosa of rats by incorporation of tritiated thymidine (3H TdR) in the DNA. These models of acute and chronic inflammation, and the antimitotic model permitted us to evaluate the anti-inflammatory and antimitotic effects of sulindac, ibuprofen, naproxen and glucametacin. In the antiexudative activity, evaluated by the edemogenic test, naproxen was the more effective drug followed by sulindac, ibuprofen and glucametacin (in a decreasing order of potency) to inhibit the exudative response induced by the bacterial cell walls suspension, in all experimental periods. In the chronic anti-inflammatory activity, evaluated by the granuloma inhibition assay, all drugs were capable to demonstrate effectiveness against the development of the experimental granulomas induced by an intradermal injection of the flogogenous agent. In the model of cellular proliferation, all tested drugs demonstrated antimitotic activity in all experimental periods (4, 6 and 8 days), also. Sulindac induced the higher antimitotic effect, in all experimental periods, followed by ibuprofen, naproxen and glucametacin in a decreasing order of efficacy. There was a positive correlation between the antiexudative, anti-proliferative, and antimitotic effects.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Capillary Permeability; Cell Division; Cell Wall; Child; Dental Plaque; DNA Replication; Duodenum; Edema; Exudates and Transudates; Granuloma; Growth Inhibitors; Humans; Ibuprofen; Indomethacin; Inflammation; Intestinal Mucosa; Naproxen; Rats; Sulindac

The synthesis of the new sulindac (3) analogue (Z)-5,6-methylenedioxy-2-methyl-1-(p-methylsulfinylbenzylidene)-3- indenyl acetic acid (1) from natural safrole (2), an abundant natural product occurring as the principal chemical constituent of Sassafraz oil, is described. The principal feature of this route is shortness, stereoselectivity, and high overall yield. The new analogue is produced in a yield of approximately 30% from the natural product. The results include the anti-inflammatory activity of 1 as well as that for its corresponding sulfide (12), a synthetic precursor of 1 that may be an important metabolic product of 1 by analogy to 3 itself. The anti-inflammatory profiles of these derivatives, measured in the carrageenan-induced rat paw edema test, indicated a 50% effective dose of 42 mg/kg for 1 and of 23 mg/kg for 12, confirming the structure-activity relationships of these agents. These results indicate that the new analogue 1 could represent a prodrug with a similar therapeutic profile to that of the pharmaceutical product 3.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Edema; Indenes; Rats; Safrole; Stereoisomerism; Structure-Activity Relationship; Sulindac

A 67 year old female patient from the capital with acute onset of a severe symmetrical synovitis affecting the flexor digitorum tendon sheaths, wrists and hand joints with pitting edema of the dorsum of both hands is described. She was seronegative for latex test and improved with low doses of prednisone. This syndrome described previously went into complete remission although stopping therapy.

Topics: Aged; Edema; Female; Hand; Humans; Prednisone; Sulindac; Synovitis; Tenosynovitis