thromboxane-b2 and Pain

Our objective was to evaluate the efficacy, the gastroduodenal safety, and the effects on arachidonic acid products of meloxicam, a new acidic enolic non-steroidal anti-inflammatory drug which preferentially inhibits cyclo-oxygenase-2 over cyclo-oxygenase-1, versus piroxicam in patients with osteoarthritis of the knee. Meloxicam 7.5 mg or piroxicam 20 mg daily was administered for 4 weeks in this double-blind parallel-groups randomised study. The efficacy for pain relief of the two tested medications was assessed by means of visual analogue scale and other clinical parameters. Pre- and post-treatment endoscopies were performed, and the findings were scored and recorded. The gastric fluid was aspirated at each time and prostaglandin E2, thromboxane B2 and leukotriene B4 were determined by ELISA. There was no significant difference between the groups regarding the primary efficacy. Changes in endoscopic findings by means of Lanza score showed statistically significant differences between the two treatment groups in favour of meloxicam at all sites--gastric, duodenal and total. Within-group comparisons showed a statistically significant difference (worsening) in gastric and total score with piroxicam, but no significant difference with meloxicam. The frequency of clinically relevant cases (total score >2) also showed a statistically significant worsening in the piroxicam group. The better GI tolerability of meloxicam was also suggested by fewer adverse GI events and no withdrawals due to adverse events compared with piroxicam. The pre-/post-study gastric juice concentration of PGE2, TXB2, and LTB4 in the meloxicam group was 135.2 +/- 85.8/71.2 +/- 32.2, 116.3 +/- 81.7/99.4 +/- 107.5 and 388 +/- 321/223 +/- 98 pg/ml respectively. The pre-/post-study gastric juice concentration of PGE2, TXB2 and LTB4 in the piroxicam group was 105.7 +/- 43.1/68.2 +/- 34.9, 94.0 +/- 50.9/105.9 +/- 121.1 and 625 +/- 1574/828 +/- 1464 pg/ml, respectively. Both meloxicam and piroxicam significantly inhibited gastric PGE2 levels after 4 weeks' treatment; however, there was no difference between these two groups. Neither of these medications had an effect on TXB2. Only meloxicam inhibited LTB4 concentration significantly, and the between-groups difference was significant. Meloxicam 7.5 mg once daily had better gastrointestinal tolerability and an efficacy comparable to that of piroxicam 20 mg over 4 weeks in patients with osteoarthritis of the knee.

Topics: Adult; Aged; Arachidonic Acid; Cyclooxygenase Inhibitors; Digestive System; Dinoprostone; Double-Blind Method; Endoscopy, Digestive System; Female; Gastric Juice; Humans; Leukotriene B4; Male; Meloxicam; Middle Aged; Osteoarthritis, Knee; Pain; Pain Measurement; Piroxicam; Safety; Thiazines; Thiazoles; Thromboxane B2

Our aim was to determine the amounts of eicosanoids in blood and synovial tissue of patients with knee arthrosis and to examine the effects of 2 doses of tepoxalin (50 mg twice, 200 mg twice), administered p.o. for 3.5 days. Concentrations of leukotriene B4 (LTB4, LTC4, and thromboxane B2 (TXB2) were measured in blood before and after oral administration of tepoxalin and release of prostaglandin E2 (PGE2), 6-keto-PGF1alpha, and LTC4 was measured in incubation media of synovial tissue, taken at surgery from patients treated with tepoxalin. Radioimmunoassay (RIA) was used to determine the levels of the eicosanoids. LT and TXB2 release was reduced by tepoxalin in both doses used. Under these conditions, PGE2, 6-keto-PGF1alpha, and LTC4 release from synovial tissue was detectable only after stimulation with calcium ionophore A23187. Washed synovial tissue, in which tepoxalin concentrations should be reduced, released higher amounts of all eicosanoids measured than directly incubated synovial tissue did. Pain after tepoxalin administration was significantly reduced. Relevant drug concentrations were detected in plasma and synovial fluid. Tepoxalin was well tolerated and had no marked adverse effects. At 400 mg, tepoxalin is a dual inhibitor of cyclooxygenase (CO) and 5-lipoxygenase (5-LO) in blood and synovial tissue.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Aged; Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Arthroplasty, Replacement, Knee; Dinoprostone; Double-Blind Method; Drug Administration Schedule; Female; Humans; Knee Joint; Leukotriene Antagonists; Leukotriene B4; Leukotriene C4; Male; Middle Aged; Pain; Pain Measurement; Premedication; Pyrazoles; Radioimmunoassay; Synovial Membrane; Thromboxane B2

Prostaglandin E2 (PGE2), one of the terminal products in the cyclooxygenase pathway, plays an important role in various inflammatory responses. To determine whether selective inhibition of PGE2 may relieve these inflammatory symptoms, we synthesized a selective PGE2 synthesis inhibitor, compound A [1-(6-fluoro-5,7-dimethyl-1,3-benzothiazol-2-yl)-N-[(1S,2R)-2-(hydroxymethyl)cyclohexyl]piperidine-4-carboxamide], then investigated the effects on pyrexia, arthritis and inflammatory pain in guinea pigs. In LPS-stimulated guinea pig macrophages, compound A selectively inhibited inducible PGE2 biosynthesis in a dose-dependent manner whereas enhanced the formation of thromboxane B2 (TXB2). Compound A suppressed yeast-evoked PGE2 production selectively and enhanced the production of TXB2 and 6-keto PGF1αin vivo. In addition, compound A relieved yeast-induced pyrexia and also suppressed paw swelling in an adjuvant-induced arthritis model. The effect on gastrointestinal (GI) ulcer formation was also evaluated and compound A showed a lower GI adverse effect than indomethacin. However, compound A failed to relieve yeast-induced thermal hyperalgesia. These results suggest that selective inhibition of PGE2 synthesis may have anti-pyretic and anti-inflammatory properties without GI side effect, but lack the analgesic efficacy.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Benzothiazoles; Depression, Chemical; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fever; Guinea Pigs; Imidazoles; Indomethacin; Inflammation; Macrophages; Pain; Peptic Ulcer; Phenanthrenes; Piperidines; Stimulation, Chemical; Thromboxane B2

In order to determine the effective dose, the effects of orally administered ketoprofen were evaluated in pigs following intravenous challenge with Escherichia coli endotoxin. One hour after the challenge, five groups of pigs were treated with either tap water or ketoprofen (0.5 mg/kg, 1 mg/kg, 2 mg/kg or 4 mg/kg). The body temperature was measured and a total clinical score was calculated after assessing the general behaviour, respiratory rate and locomotion of the pigs. Thromboxane B(2) and ketoprofen concentrations were analysed from blood samples. Ketoprofen treatment significantly reduced the rectal temperature and total clinical scores, and lowered blood thromboxane B(2) concentrations when compared with the control group. Ketoprofen plasma concentrations were lower than previously reported in healthy pigs after similar doses. The appropriate dose of orally administered ketoprofen in pigs in this model is 2 mg/kg, as the higher dose of 4 mg/kg failed to provide an additional benefit.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Dose-Response Relationship, Drug; Endotoxins; Female; Ketoprofen; Male; Pain; Pain Measurement; Random Allocation; Swine; Swine Diseases; Thromboxane B2

Freund's complete adjuvant (FCA) is an animal model of inflammatory pain commonly used in the screening of COX-inhibitors. However, there is little understanding of how behavioural measures of the anti-inflammatory effect in the FCA model correlate to differences in mechanism of action and whether such endpoints equally reflect drug activity in humans. In the current investigation we evaluate the time course of the analgesic effect for different endpoints after treatment with drugs with varying degrees of selectivity for COX-1 and COX-2. We also assess prostaglandin (PGE(2)) and thromboxane (TXB(2)) inhibition to establish the correlation between behavioural measures and the degree of selectivity for COX-1 and COX-2.. Sprague-Dawley rats were treated with FCA by intra-plantar injection. On post-inoculation day (PID) 7, rats received a single oral dose of naproxen, diclofenac, ketorolac or rofecoxib. Drug treatment continued until PID 21. A control group received placebo only. Behavioural endpoints for inflammatory pain and blood samples for biomarkers were obtained at various time points before and after dosing to characterise the time course of drug effect and disease progression.. COX-inhibitors showed no effect on the dynamic plantar test. In contrast, full analgesia was observed after drug administration for weight bearing capacity (WBC) and paw pressure (PP), with varying duration of the effect for each of the endpoints. No tolerance to drug effect was observed up to 14 days of chronic treatment. Rofecoxib showed an increase in baseline pain threshold values after chronic treatment, which may be related to its pharmacokinetic characteristics.. Changes in paw pressure threshold seem to best reflect the anti-hyperalgesic properties of COX-inhibitors with enough sensitivity to enable estimation of the dose-exposure-response curve.

Topics: Animals; Behavior, Animal; Biomarkers; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dinoprostone; Disease Models, Animal; Drug Evaluation, Preclinical; Endpoint Determination; Freund's Adjuvant; Inflammation; Inflammation Mediators; Male; Membrane Proteins; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Sensitivity and Specificity; Thromboxane B2; Time Factors

One hind quarter of 27 healthy lactating cows was infused with 100 microg Escherichia coli endotoxin. Two hours later, nine of the cows were given physiological saline by intramuscular injection, nine were given 4 mg/kg ketoprofen orally, and nine were given 3 mg/kg ketoprofen by intramuscular injection. Ketoprofen administered either orally or parenterally significantly reduced the effect of the endotoxin on rectal temperature, ruminal contractions and respiratory rate. The size of the udder, the signs of pain and the concentrations of thromboxane B2, especially in plasma, were also reduced, and the appearance of their milk was almost normal. The response of cows to the oral treatment was as rapid as it was to intramuscular treatment.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Temperature; Cattle; Endotoxins; Female; Injections, Intramuscular; Ketoprofen; Lactation; Mastitis, Bovine; Milk; Pain; Pain Measurement; Thromboxane B2

To study the therapeutic effects of the series of Muskone (the Muskone includes Slender Dutchmanspipe Root, Tumuxiang, and not Slender Dutchmanspipe Root) on experimental myocardial infarct and pain in rats.. Coronary artery ligation was applied for the model of myocardial infarct. Therapeutic effects were evaluated by measuring parameters of histomorphometry, blood plasm of ET, 6- keto-PGF1alpha and TXB2. Intraperitoneal injection acetic was applied for the model of ache, the frequency and eclipse period of writhing were evaluated its effect of resisting pain.. The Muskone including Radix Aristolociae, the Muskone including Radix Inulae and the Muskone without Radix Aucklandiae all can decrease the area of myocardial infarction in rats, the level of TXB2, ET, and the frequency of writhing significantly. Also it can increase the level 6-keto-PGF1alpha, the ratio of 6-keto-PGF1alpha and TXB2. Single Radix Aristolociae or Radix Inulae only relieved pain.. The Muskone including Radix Aristolociae, the Muskone including Radix Inulae and the Muskone without Radix Aucklandiae all have significant therapeutic effect on both myocardial infarction and pain, while single Radix Aristolociae or Radix Inulae only can relieve pain.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aristolochia; Cycloparaffins; Drug Combinations; Drugs, Chinese Herbal; Endothelins; Female; Inula; Male; Mice; Mice, Inbred ICR; Myocardial Infarction; Pain; Plants, Medicinal; Rats; Rats, Wistar; Thromboxane B2

The synthetic chalcone derivative 1-(2,4-dichlorophenyl)-3-(3-(6,7-dimethoxy-2-chloroquinolinyl))-2-propen-1-one (ClDQ) was evaluated for its anti-inflammatory, analgesic and immunomodulatory efficacy in-vitro and in-vivo. ClDQ concentration-dependently inhibited the production of nitric oxide (NO) (IC50 4.3 microM) and prostaglandin E(2) (PGE(2)) (IC50 1.8 microM) in RAW 264.7 macrophages stimulated with lipopolysaccharide. Human mononuclear cell proliferation was significantly inhibited by 10 microM ClDQ. Oral administration of ClDQ (10-30 mg kg(-1)) in the 24-h zymosan-stimulated mouse air-pouch model produced a dose-dependent reduction of cell migration as well as NO and PGE(2) levels in exudates. ClDQ (20 mg kg(-1), p.o.) inhibited ear swelling and leucocyte infiltration in the delayed-type hypersensitivity response to 2,4-dinitrofluorobenzene in mice. In the rat adjuvant-arthritis model, this compound reduced joint inflammation as well as PGE(2) and cytokine levels. In addition, ClDQ displayed analgesic effects in the phenylbenzoquinone-induced abdominal constriction model in mice and in the late phase of the nociceptive response to formalin. Our findings indicated the potential interest of ClDQ in the modulation of some immune and inflammatory conditions.

Topics: Abdominal Injuries; Administration, Oral; Animals; Arthritis, Experimental; Blood Platelets; Cell Line; Cyclooxygenase 1; Cyclooxygenase 2; Dinitrofluorobenzene; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Hypersensitivity; Female; Formaldehyde; Group II Phospholipases A2; Group IV Phospholipases A2; Humans; Inflammation; Lipopolysaccharides; Lymphocyte Activation; Macrophages; Mice; Microsomes; Nitrites; Pain; Pain Measurement; Phospholipases A; Pyridazines; Rats; Rats, Inbred Lew; Thromboxane B2; Zymosan

1. Bradykinin-induced vascular pain in conscious rats, hyperalgesia in the rat hind paw, rat hind paw edema induced by compound 48/80 and carrageenin and dye exudation induced by intraperitoneal injection of 0.7% acetic acid in mice were all inhibited by sodium nonivamide acetate (SNA). 2. Collagen and arachidonic acid-induced rabbit platelet aggregations were inhibited by SNA and capsaicin. In human platelet microsomes, prostaglandin E2 formation in arachidonic acid metabolite was not inhibited by SNA but was inhibited by capsaicin and indomethacin; thromboxane B2 formation and its synthetase activity were inhibited by SNA and capsaicin. 3. In the extracellular recording, SNA could not decrease the action potential amplitude of the vagus nerve. 4. The motor activity of mice induced by caffeine (1.0 mg/kg) was inhibited by SNA and capsaicin.

Topics: Animals; Bradykinin; Capsaicin; Dermatologic Agents; Dinoprostone; Humans; Mice; Pain; Platelet Aggregation; Platelet Aggregation Inhibitors; Rabbits; Rats; Rats, Wistar; Tail; Thromboxane B2; Thromboxane-A Synthase

The analgesic effects of the non-steroidal anti-inflammatory drugs (NSAIDs) flunixin and dipyrone were assessed in healthy sheep with no pre-existing inflammation, and in sheep with a chronic inflammatory lesion, using a mechanical noxious stimulus. Saline and dexamethasone were given as controls. Blood taken from healthy sheep after NSAID administration was assayed for thromboxane B2 (TxB2) to compare the ability of these drugs to inhibit cyclo-oxygenase. Both flunixin and dipyrone produced a small but statistically significant rise in pain thresholds (18% and 21% of maximum possible effect respectively) in the healthy sheep which peaked at 30 min and had returned to pre-drug values by 2-3 h. In the lame sheep a similar effect occurred but the response was smaller, much more variable and tended to be prolonged. Saline and dexamethasone had no effect on thresholds over 6 h in either group of sheep. The rise in thresholds was prevented by pre-treatment with naloxone (an opioid antagonist) or atipamezole (an alpha 2-adrenergic antagonist) in the healthy sheep. Naloxone and atipamezole had no effect on thresholds when given alone to healthy sheep. Both NSAIDs inhibited the production of TxB2 to a similar extent. These results indicate that central mechanisms may be involved in NSAID analgesia.

Topics: Adrenergic alpha-Antagonists; Analgesia; Animals; Anti-Inflammatory Agents, Non-Steroidal; Clonixin; Dipyrone; Double-Blind Method; Drug Interactions; Female; Foot Rot; Imidazoles; Injections, Intravenous; Lameness, Animal; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Random Allocation; Sheep; Sheep Diseases; Thromboxane B2

Prostaglandin levels in plasma and peritoneal fluid were determined in 10 sterilized women with pelvic pain without pathological findings. Another 15 healthy women were regarded as controls. The 6-keto-PGF1 alpha levels in peritoneal fluid collected from patients with pelvic pain were significantly higher than that from the controls (p less than 0.05). The results indicated that prostaglandins might play an important role in pelvic pain following sterilization.. Prostaglandin (PG) levels in plasma and peritoneal fluid were determined in 10 sterilized women with pelvic pain without pathological findings. Another 15 women who were healthy were regarded as controls. The 6-keto-PGF(1alpha) levels in peritoneal fluid collected from patients with pelvic pain were significantly higher than that from controls (p 0.05. The results indicated that PGs might play an important role in pelvic pain following sterilization.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Dinoprost; Female; Humans; Pain; Pelvis; Peritoneal Cavity; Prostaglandins; Prostaglandins E; Radioimmunoassay; Reference Values; Sterilization, Tubal; Thromboxane B2

Thromboxane A2 exerts powerful effects on vascular smooth muscle tone and platelet aggregability. Previous studies have demonstrated increases in transcardiac thromboxane B2 (a stable thromboxane A2 metabolite) in patients with unstable angina and recent chest pain. To determine whether these increases in transcardiac thromboxane B2 are unique to the unstable anginal syndrome or are merely a consequence of ongoing myocardial ischemia, simultaneous ascending aortic and coronary sinus blood samples were obtained for quantitation of thromboxane B2 in 52 patients with a history of chest pain. Provocation was performed with (1) rapid cardiac pacing in 23 patients, (2) cold pressor stress in 19 patients, and (3) sustained isometric exertion in 10 patients. Of the 52 patients, only 5 had a substantial (greater than 3-fold) increase in coronary sinus thromboxane B2 in response to provocation: 1 had unstable angina and chest pain during the previous 48 hours and 4 had a myocardial infarction within the previous 6 weeks. Similarly, only 7 had a greater than 3-fold increase in the coronary sinus/aortic thromboxane B2 ratio in response to provocation: 1 had unstable angina and recent chest pain, 5 had a recent myocardial infarction, and 1 had both of these. There were no other clinical features unique to these patients. The remaining patients with similar diagnoses did not develop a marked increase in coronary sinus thromboxane B2 or the coronary sinus/aortic thromboxane B2 ratio with provocation. None of the 35 patients with stable ischemic heart disease or nonischemic chest pain syndromes had a substantial increase in coronary sinus thromboxane B2 or the coronary sinus/aortic thromboxane B2 ratio (p less than 0.001 for both coronary sinus thromboxane B2 and the coronary sinus/aortic thromboxane B2 ratio in comparison with the 17 patients with recent unstable angina or myocardial infarction). Thus, generous amounts of thromboxane B2 are released into the coronary circulation after provocation in some patients with unstable angina or recent myocardial infarction but not in those with stable ischemic heart disease or nonischemic chest pain syndromes.

Topics: Adult; Aged; Angina Pectoris; Aorta; Cardiac Pacing, Artificial; Cold Temperature; Coronary Disease; Coronary Vessels; Electrocardiography; Female; Humans; Isometric Contraction; Male; Middle Aged; Pain; Thromboxane B2; Thromboxanes