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Acacia nilotica L., also known as babul, belonging to the Fabaceae family and the Acacia genus, is typically used for ornamental purposes and also as a medicinal plant found in tropical and subtropical areas. This plant is a rich source of bioactive compounds. The current study aimed to elucidate the hypoglycemic, anti‐inflammatory, and neuroprotective potential of A. nilotica's crude methanolic extract. The results of the in vitro antidiabetic assay revealed that methanolic extract of A. nilotica inhibited the enzyme α‐glucosidase (IC50: 33 μg mL−1) and α‐amylase (IC50: 17 μg mL−1) in a dose‐dependent manner. While in the anticholinesterase enzyme inhibitory assay, maximum inhibition was shown by the extract against acetylcholinesterase (AChE) (637.01 μg mL−1) and butyrylcholinesterase (BChE) (491.98 μg mL−1), with the highest percent inhibition of 67.54% and 71.50% at 1000 μg mL−1, respectively. This inhibitory potential was lower as compared to the standard drug Galantamine that exhibited 82.43 and 89.50% inhibition at the same concentration, respectively. Moreover, the methanolic extract of A. nilotica also significantly inhibited the activities of cyclooxygenase 2 (COX‐2) and 5‐lipoxygenase (5‐LOX) in a concentration‐dependent manner. The percent inhibitory activity of 5‐LOX and COX‐2 ranged from 42.47% to 71.53% and 43.48% to 75.22%, respectively. Furthermore, in silico, in vivo, and clinical investigations must be planned to validate the above‐stated bioactivities of A. nilotica. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?Arachidonic acid (AA) stimulates NO production in antral mucous cells without any increase in [Ca2+]i. Given that the intracellular AA concentration is too low to measure, the relationship between AA accumulation and NO production remains uncertain. Is AA accumulation a key step for NO production?What is the main finding and its importance?We demonstrated that AA accumulation is a key step for NO production. The amount of AA released could be measured using fluorescence‐HPLC. The intracellular AA concentration was maintained at < 1 μM. Nitric oxide is produced by AA accumulation in antral mucous cells, not as a direct effect of [Ca2+]i. In the present study, we demonstrate that NO production is stimulated by an accumulation of arachidonic acid (AA) mediated via peroxisome proliferation‐activated receptor α (PPARα) and that the NO produced enhances Ca2+‐regulated exocytosis in ACh‐stimulated antral mucous cells. The amount of AA released from the antral mucosa, measured by fluorescence high‐performance liquid chromatography (F‐HPLC), was increased by addition of ionomycin (10 μM) or ACh, suggesting that AA accumulation is stimulated by an increase in [Ca2+]i. The AA production was inhibited by an inhibitor of cytosolic phospholipase A2 (cPLA2‐inhα). GW6471 (a PPARα inhibitor) and cPLA2‐inhα inhibited NO synthesis stimulated by ACh. Moreover, indomethacin, an inhibitor of cyclooxygenase, stimulated AA accumulation and NO production. However, acetylsalicylic acid did not stimulate AA production and NO synthesis. An analogue of AA (AACOCF3) alone stimulated NO synthesis, which was inhibited by GW6471. In antral mucous cells, indomethacin enhanced Ca2+‐regulated exocytosis by increasing NO via PPARα, and the enhancement was abolished by GW6471 and cPLA2‐inhα. Thus, AA produced via PLA2 activation is the key step for NO synthesis in ACh‐stimulated antral mucous cells and plays important roles in maintaining antral mucous secretion, especially in Ca2+‐regulated exocytosis. [ABSTRACT FROM AUTHOR]

Aim: Non‐steroidal anti‐inflammatory drugs (NSAIDs) are commonly used to control postoperative pain; however, their postoperative use has been associated with anastomotic leakage after gastrointestinal surgery. This systematic review and meta‐analysis aimed to determine the correlation between the use of NSAIDs and anastomotic leakage. Methods: We conducted a comprehensive electronic literature search up to August 2018 to identify studies comparing anastomotic leakage in patients with and without postoperative NSAID use following gastrointestinal surgery. We then carried out a meta‐analysis using random‐effects models to calculate odds ratios (OR) with 95% confidence intervals (CI). Results: Twenty‐four studies were included in this meta‐analysis, including a total of 31 877 patients. Meta‐analysis showed a significant association between NSAID use and anastomotic leakage (OR 1.73; 95% CI = 1.31‐2.29, P <.0001). Subgroup analyses showed that non‐selective NSAIDs, but not selective cyclooxygenase‐2 inhibitors, were significantly associated with anastomotic leakage. However there was no significant subgroup difference between selective and non‐selective NSAIDs. Conclusion: Results of this meta‐analysis indicate that postoperative NSAID use is associated with anastomotic leakage following gastrointestinal surgeries. Caution is warranted when using NSAIDs for postoperative analgesic control in patients with gastrointestinal anastomoses. [ABSTRACT FROM AUTHOR]

The article titled "Electrospun Nanofibrous Composite Membranes for Long-Term Release of Celecoxib for Achilles Tendon Reconstruction Following Injury" discusses the development of a new implantable combination of nanofibers for Achilles tendon reconstruction. The nanofibers, called celecoxib-collagen-bupivacainepoly(lactic-co-glycolic acid) (CCBP), show improved therapeutic application and higher load-to-failure values compared to healthy tendons and nanofibers with doxycycline. The authors suggest that CCBP is a promising scaffold for repairing ruptured Achilles tendons and is superior to existing materials. [Extracted from the article]

Abstract: We recently reported that the nonselective cyclooxygenase (COX) inhibitor ketorolac attenuated sweating but not cutaneous vasodilation during moderate‐intensity exercise in the heat. However, the specific contributions of COX‐1 and COX‐2 to the sweating response remained to be determined. We tested the hypothesis that COX‐1 but not COX‐2 contributes to sweating with no role for either COX isoform in cutaneous vasodilation during moderate‐intensity exercise in the heat. In thirteen young males (22 ± 2 years), sweat rate and cutaneous vascular conductance were measured at three forearm skin sites that were continuously treated with (1) lactated Ringer's solution (Control), (2) 150 μmmol·L−1 celecoxib, a selective COX‐2 inhibitor, or (3) 10 mmol L−1 ketorolac, a nonselective COX inhibitor. Participants first rested in a non heat stress condition (≥85 min, 25°C) followed by a further 70‐min rest period in the heat (35°C). They then performed 50 min of moderate‐intensity cycling (~55% peak oxygen uptake) followed by a 30‐min recovery period. At the end of exercise, sweat rate was lower at the 150 μmol·L−1 celecoxib (1.51 ± 0.25 mg·min−1·cm−2) and 10 mmol·L−1 ketorolac (1.30 ± 0.30 mg·min−1·cm−2) treated skin sites relative to the Control site (1.89 ± 0.27 mg·min−1·cm−2) (both P ≤ 0.05). Additionally, sweat rate at the ketorolac site was attenuated relative to the celecoxib site (P ≤ 0.05). Neither celecoxib nor ketorolac influenced cutaneous vascular conductance throughout the experiment (both P > 0.05). We showed that both COX‐1 and COX‐2 contribute to sweating but not cutaneous vasodilation during moderate‐intensity exercise in the heat in young men. [ABSTRACT FROM AUTHOR]

Background and Purpose: Postoperative pain is one of the most common manifestations of acute pain and is an important problem faced by patients after surgery. Moreover, neuronal trauma or chemotherapeutic treatment often causes neuropathic pain, which induces disabling and distressing symptoms. At present, treatments of both painful conditions are inadequate. α-Spinasterol, which is well characterized as a transient receptor potential vanilloid 1 antagonist, has anti-inflammatory, antioxidant and antinociceptive effects. Therefore, we investigated its antinociceptive potential on postoperative and neuropathic pain, as well as its effect on COX-1 and COX-2 activities.Experimental Approach: Nociceptive responses in a postoperative pain model (surgical incision-induced) or different neuropathic pain models (trauma or chemotherapy-induced) were investigated in mice.Key Results: Oral administration of α-spinasterol reduced postoperative pain, when given as a pre- (0.5 h before incision) or post-treatment (0.5 h after incision), and reduced cell infiltration in the injured tissue. α-Spinasterol also reduced the mechanical allodynia induced by partial sciatic nerve ligation and the mechanical and cold allodynia induced by paclitaxel. Moreover, α-spinasterol inhibited COX-1 and COX-2 enzyme activities without altering the body temperature of animals. Importantly, α-spinasterol did not alter spontaneous or forced locomotor activity. Furthermore, it did not cause gastric damage or liver and kidney changes, nor did it alter cell viability in the cerebral cortex and spinal cord slices of mice.Conclusion and Implications: α-Spinasterol is an effective and safe COX inhibitor with antinociceptive effects in postoperative and neuropathic pain models. Therefore, it is an interesting prototype for the development of novel analgesic drugs. [ABSTRACT FROM AUTHOR]

Corneal diseases are an extensive cause of blindness worldwide and continue to persist as a challenging public health concern. Recently, various lipid-based therapies have been advocated for the modulation of corneal diseases; however, the number of studies is still very limited. Here we focus on developments and challenges on lipid-based therapies for dry eye disease, diabetic neuropathy, and Fuchs' endothelial corneal dystrophy. All three diseases are highly prevalent conditions and involve corneal stress and inflammation. Lipid-based therapeutics discussed includes cyclooxygenase inhibitors, essential fatty acids, and resolvin analogs. Lipids also show increasing promise as biomarkers of disease and are explored in this review. [ABSTRACT FROM AUTHOR]

Obesity is often characterized by chronic inflammation that may contribute to increased cardiovascular risk via sympathoexcitation and decreased vasodilator responsiveness. We hypothesized that obese individuals would have greater indices of inflammation compared with lean controls, and that cyclooxygenase inhibition using ibuprofen would reduce muscle sympathetic nerve activity ( MSNA) and increase forearm blood flow in these subjects. We measured MSNA, inflammatory biomarkers ( C-reactive protein [ CRP] and Interleukin-6 [ IL-6]), and forearm vasodilator responses to brachial artery acetylcholine and sodium nitroprusside in 13 men and women (7 lean; 6 obese) on two separate study days: control ( CON) and after 800 mg ibuprofen ( IBU). CRP (1.7 ± 0.4 vs. 0.6 ± 0.3 mg/L; P < 0.05) and IL-6 (4.1 ± 1.5 vs. 1.0 ± 0.1pg/mL; P < 0.05) were higher in the obese group during CON and tended to decrease with IBU (IL-6: P < 0.05; CRP: P = 0.14). MSNA was not different between groups during CON (26 ± 4 bursts/100 heart beats (lean) versus 26 ± 4 bursts/100 heart beats (obese); P = 0.50) or IBU (25 ± 4 bursts/100 heart beats (lean) versus 30 ± 5 bursts/100 heart beats (obese); P = 0.25), and was not altered by IBU. Forearm vasodilator responses were unaffected by IBU in both groups. In summary, an acute dose of ibuprofen did not alter sympathetic nerve activity or forearm blood flow responses in healthy obese individuals, suggesting that the cyclooxygenase pathway is not a major contributor to these variables in this group. [ABSTRACT FROM AUTHOR]

New Findings What is the central question of this study? We aimed to investigate the effects of the cyclo-oxygenase (COX) inhibitor indomethacin on resistance vessel function in young and older adults and to test the hypothesis that indomethacin will attenuate forearm vascular conductance during reactive hyperaemia., What is the main finding and its importance? Older adults demonstrated an attenuated vasodilator response to ischaemia after COX inhibition compared with their younger counterparts. This suggests that older adults do not compensate for the vascular changes induced by an acute dose of indomethacin. Long-term use of indomethacin may increase vascular resistance and reduce the response to acute haemodynamic stress in older adults. The risk for potential adverse cardiovascular consequences of COX inhibition should be considered., We have previously shown that non-selective cyclo-oxygenase inhibition, via indomethacin, unfavourably increased central blood pressure in older adults, with little effect in young adults. In addition, the vasoactive prostaglandins have been shown to contribute to both peripheral vasodilator responses and large artery function; however, there is little information available in older adults and conflicting reports in young adults on the extent to which resistance vessel function is influenced by indomethacin. Thus, we tested the hypothesis that cyclo-oxygenase inhibition using indomethacin would attenuate forearm vascular conductance during reactive hyperaemia in older adults compared with young adults. Forearm blood flow responses to 5 min of forearm ischaemia were measured in 26 healthy adults (13 young, 25 ± 5 years old; and 13 older, 65 ± 6 years old), using venous occlusion plethysmography before and after indomethacin. Baseline forearm blood flow and vascular conductance were not different between groups during either trial, and there were no age-related differences prior to cyclo-oxygenase inhibition. Peak forearm vascular conductance and blood flow were similar between groups before indomethacin, but lower in older adults after indomethacin compared with young adults (27 ± 4 versus 41 ± 4 ml (100 ml)−1 min−1 (100 mmHg)−1, P = 0.02; and 23 ± 3 versus 33 ± 3 ml (100 ml)−1 min−1, P = 0.02, respectively). These results, in conjunction with our previous findings in large arteries, suggest that ageing alters the effect of cyclo-oxygenase inhibition on vascular responses, and specifically, the resistance vessel responses underlying reactive hyperaemia. [ABSTRACT FROM AUTHOR]

Indomethacin is a cyclo-oxygenase inhibitor, and shows therapeutic potential for various eosinophilic skin diseases, particularly eosinophilic pustular folliculitis. One of the unique characteristics of indomethacin is that, unlike other non-steroidal anti-inflammatory drugs, it is a potent agonist of chemoattractant receptor-homologous molecule expressed on T helper type 2 cells ( CRTH2), a receptor for prostaglandin D2 ( PGD2). This study investigated the pharmacological actions of indomethacin on eosinophil migration to clarify the actual mechanisms underlying the therapeutic effects of indomethacin on eosinophilic pustular folliculitis. Eosinophils exhibited chemokinetic and chemotactic responses to both PGD2 and indomethacin through CRTH2 receptors. Pre-treatment of eosinophils with indomethacin greatly inhibited eosinophil migration to PGD2 and, to a much lesser extent, to eotaxin ( CCL11); these effects could be mediated by homologous and heterologous desensitization of eosinophil CRTH2 and CCR3, respectively, by agonistic effects of indomethacin on CRTH2. Indomethacin also cancelled a priming effect of Δ12- PGJ2, a plasma metabolite of PGD2, on eosinophil chemotaxis to eotaxin. Indomethacin down-modulated cell surface expression of both CRTH2 and CCR3. Hair follicle epithelium and epidermal keratinocytes around eosinophilic pustules together with the eccrine apparatus of palmoplantar lesions of eosinophilic pustular folliculitis were immunohistochemically positive for lipocalin-type PGD synthase. Indomethacin may exert therapeutic effects against eosinophilic skin diseases in which PGD2- CRTH2 signals play major roles by reducing eosinophil responses to PGD2. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE To evaluate the role of 2-arachidonoyl glycerol (2AG) in the regulation of nausea and vomiting using animal models of vomiting and of nausea-like behaviour (conditioned gaping). EXPERIMENTAL APPROACH Vomiting was assessed in shrews ( Suncus murinus), pretreated with JZL184, a selective monoacylglycerol lipase (MAGL) inhibitor which elevates endogenous 2AG levels, 1 h before administering the emetogenic compound, LiCl. Regulation of nausea-like behaviour in rats by exogenous 2AG or its metabolite arachidonic acid (AA) was assessed, using the conditioned gaping model. The role of cannabinoid CB1 receptors, CB2 receptors and cyclooxygenase (COX) inhibition in suppression of vomiting or nausea-like behaviour was assessed. KEY RESULTS JZL184 dose-dependently suppressed vomiting in shrews, an effect prevented by pretreatment with the CB1 receptor inverse agonist/antagonist, AM251. In shrew brain tissue, JZL184 inhibited MAGL activity in vivo. In rats, 2AG suppressed LiCl-induced conditioned gaping but this effect was not prevented by AM251 or the CB2 receptor antagonist, AM630. Instead, the COX inhibitor, indomethacin, prevented suppression of conditioned gaping by 2AG or AA. However, when rats were pretreated with a high dose of JZL184 (40 mg·kg−1), suppression of gaping by 2AG was partially reversed by AM251. Suppression of conditioned gaping was not due to interference with learning because the same dose of 2AG did not modify the strength of conditioned freezing to a shock-paired tone. CONCLUSIONS AND IMPLICATIONS Our results suggest that manipulations that elevate 2AG may have anti-emetic or anti-nausea potential. LINKED ARTICLES This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit . To view Part I of Cannabinoids in Biology and Medicine visit [ABSTRACT FROM AUTHOR]

Hyaluronan (HA) is a key molecule of the extracellular matrix that is thought to be critically involved in both atherosclerosis and restenosis. Recently, it has been demonstrated that the cyclooxygenase (COX) products, prostacyclin and prostaglandin E2, induce HA synthesis in vitro by transcriptional up-regulation of HA-synthase 2 (HAS2) and HAS1. The relative roles in atherosclerotic and restenotic artery disease of tissue specifically expressed COX-1 and COX-2 are still under debate. Thus, the present study aimed to investigate the effect of COX isoform inhibition on HA-accumulation and regulation of HAS isoform expression in two models of pathologic artery remodelling in vivo. Firstly, ApoE-deficient mice were treated with a prototypic isoform non-selective inhibitor, indomethacin or with a prototypic COX-2 selective inhibitor, rofecoxib, for 8 weeks. Aortic HAS mRNA expression and HA-accumulation in atherosclerotic aortic root lesions were analyzed. Secondly, neointimal hyperplasia was induced by carotid artery ligation in ApoE-deficient mice on a high fat diet and the effects of the COX inhibitors were determined after 4 weeks of treatment. Intimal HA-accumulation was markedly reduced in both models by indomethacin and rofecoxib. This coincided with a strong inhibition of HAS1 mRNA expression in both models and with decreased HAS2 mRNA in the aorta of ApoE-deficient mice. HAS3 was not affected. The repression of HA-accumulation by both COX-2 selective and non-selective COX inhibition implicates COX-2 in the regulation of HA synthesis via stimulation of HAS1 and HAS2 expression in vivo. Modulation of vascular HA-accumulation might play a role in chronic effects of COX inhibitors on the progression of atherosclerosis. [ABSTRACT FROM AUTHOR]

Background and Purpose: Non-steroidal anti-inflammatory drugs (NSAIDs) are analgesic and anti-inflammatory by virtue of inhibition of the cyclooxygenase (COX) reaction that initiates biosynthesis of prostaglandins. Findings in a pulmonary pharmacology project gave rise to the hypothesis that certain members of the NSAID class might also be antagonists of the thromboxane (TP) receptor.Experimental Approach: Functional responses due to activation of the TP receptor were studied in isolated airway and vascular smooth muscle preparations from guinea pigs and rats as well as in human platelets. Receptor binding and activation of the TP receptor was studied in HEK293 cells.Key Results: Diclofenac concentration-dependently and selectively inhibited the contraction responses to TP receptor agonists such as prostaglandin D2 and U-46619 in the tested smooth muscle preparations and the aggregation of human platelets. The competitive antagonism of the TP receptor was confirmed by binding studies and at the level of signal transduction. The selective COX-2 inhibitor lumiracoxib shared this activity profile, whereas a number of standard NSAIDs and other selective COX-2 inhibitors did not.Conclusions and Implications: Diclofenac and lumiracoxib, in addition to being COX unselective and highly COX-2 selective inhibitors, respectively, displayed a previously unknown pharmacological activity, namely TP receptor antagonism. Development of COX-2 selective inhibitors with dual activity as potent TP antagonists may lead to coxibs with improved cardiovascular safety, as the TP receptor mediates cardiovascular effects of thromboxane A2 and isoprostanes. [ABSTRACT FROM AUTHOR]

ABSTRACT C-reactive protein (CRP) plays a role in the pathogenesis of cardiovascular disease. It is a marker and predictor of cardiovascular disease. CRP possesses numerous cardiovascular effects (clotting, generation of oxygen radicals, increase in the expression of adhesion molecules and plasminogen activator inhibitor-1, plaque destabilization) that could result in cardiovascular disease. This review describes the effects of various cardiovascular drugs on the levels of CRP in health and disease. Cyclooxygenase inhibitors (aspirin, rofecoxib, celecoxib), platelet aggregation inhibitors (clopidogrel, abciximab), lipid lowering agents (statins, ezetimibe, fenofibrate, niacin, diets), β-adrenoreceptor antagonists and antioxidants (vitamin E), as well as angiotensin converting enzyme (ACE) inhibitors (ramipril, captopril, fosinopril), reduce serum levels of CRP; while enalapril and trandolapril have not been shown to have the same effect. Angiotensin receptor blockers (ARBs) (valsartan, irbesartan, olmesartan, telmisartan) markedly reduce serum levels of CRP. The findings with other ARBs (losartan and candesartan) were inconsistent. Antidiabetic agents (rosiglitazone and pioglitazone) reduce CRP levels, while insulin is ineffective. Calcium channel antagonists have variable effects on CRP levels. Hydrochlorothiazide and oral estrogen do not affect CRP. The CRP-lowering effect of statins is more pronounced than their lipid lowering effect and is not dependent on their hypolipemic activity. The effect of atorvastatin on CRP seems to be dose-dependent. CRP-lowering effect of statins is likely to contribute to the favorable outcome of statin therapy. The data suggest that lipid lowering agents, ACE inhibitors, ARBs, antidiabetic agents, antiinflammatory and antiplatelet agents, vitamin E, and β-adrenoreceptor antagonists lower serum or plasma levels of CRP, while vitamin C, oral estrogen and hydrochlorothiazide do not affect CRP levels. [ABSTRACT FROM AUTHOR]

ABSTRACT Eighteen million Americans have type 2 Diabetes Mellitus (DM) while another 40 million have impaired glucose tolerance. Atherosclerotic heart disease is the leading cause of death in patients with diabetes mellitus. In addition to the increased risk for Cardio Vascular Disease (CVD), patients with diabetes have a worse prognosis than nondiabetics when they suffer an ischemic event. Insulin resistance is increasingly recognized as a chronic, low-level, inflammatory state. Hyperinsulinemia has been proposed as the forerunner of hypertension, low high-density lipoprotein cholesterolemia, hypertriglyceridemia, abdominal obesity, and altered glucose tolerance, linking all these abnormalities to the development of coronary vascular disease. Atherosclerosis and insulin resistance share similar pathophysiological mechanisms, due to the actions of proinflammatory cytokines. The dynamic inflammatory milieu found in diabetes explains the susceptibility of diabetics to CVD and the potential mechanism by which aspirin may prevent CVD in diabetics. Aspirin decreases the risk for CVD in diabetic patients by a variety of established and novel mechanisms. Therapeutic strategies that lesson the CVD risk in diabetic patients, including the use of aspirin for primary and secondary prevention, are potentially very important. This review article addresses the antiatherosclerotic effects of aspirin, the potential anti-diabetic effects of aspirin, and the clinical trial evidence for CVD prevention by aspirin in diabetics. We also present recommendations for the use of aspirin in the diabetic population and the current guidelines put forth by the American Heart Association and by the American Diabetes Association. [ABSTRACT FROM AUTHOR]

1. The effects of racemic (rac) ibuprofen and its S(+)- and R(-)-enantiomers on functions of human polymorphonuclear cells (PMN) and platelets were studied in vitro. 2. Rac-ibuprofen inhibited PMN functions (O2- generation, beta-glucuronidase release, LTB4 formation). Similar IC50 values (40-100 microM) were obtained for the S(+)- and R(-)-enantiomers. 3. All forms of ibuprofen inhibited cyclooxygenase-related platelet functions (aggregation, thromboxane formation). The S(+)-enantiomer was about twice as active as the racemate while the R(-)-enantiomer was at least 10-fold less active. This demonstrates that the S(+) is the only cyclooxygenase inhibitory component of the racemate. 4. The concentrations of rac-ibuprofen in PMN and platelets were similar to those in the incubation medium and represented equal concentrations of the enantiomers. This indicates that neither interconversion nor tissue accumulation of the compounds occurred. 5. These data indicate that antineutrophil effects of ibuprofen on human PMN are independent of cyclooxygenase inhibition. Therefore, R(-)-ibuprofen may be superior to the S(+)-isomer for the treatment of PMN-dependent inflammatory diseases. However, effective free drug concentrations may not be obtained in vivo.

1. Four healthy male subjects received racemic ibuprofen (200, 400, 800 and 1200 mg), orally, on four occasions, 2 weeks apart, according to a four-way Latin-square design, in order to investigate the influence of increasing dose of ibuprofen on the magnitude and duration of its antiplatelet effect as well as on the relationship between such effect and drug concentration. 2. The antiplatelet effect of ibuprofen was assessed by measuring the inhibition of platelet thromboxane B2 (TXB2) generation during the controlled clotting of whole blood. The plasma unbound concentration of S(+)-ibuprofen, the enantiomer shown in an in vitro study to be responsible for the inhibitory effect of platelet TXB2 generation, was measured using an enantioselective method. 3. The maximum percentage inhibition of TXB2 generation increased significantly with dose from a mean +/- s.d. of 93.4 +/- 1.2% after the 200 mg dose to 98.8 +/- 0.3% after the 1200 mg dose, and there was an increase with dose in the duration of inhibition of TXB2 generation. The effect of ibuprofen on platelet TXB2 generation was transient and mirrored the time-course of unbound S(+)-ibuprofen in plasma; on all but one of the 16 occasions, serum TXB2 concentrations returned to at least within 10% of the pretreatment concentrations within 24 h of ibuprofen administration. 4. For each subject, the relationship between the percentage inhibition of TXB2 generation and the unbound concentration of S(+)-ibuprofen in plasma was modelled according to a sigmoidal Emax equation. The mean plasma unbound concentration of S(+)-ibuprofen required to inhibit platelet TXB2 generation by 50% (EC50) was 9.8 +/- 1.0 micrograms l-1.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied the effect of tenidap sodium, a new antiinflammatory/antirheumatic drug (120 mg/day for 7 days), on eicosanoid production and neutrophil degranulation in patients with rheumatoid arthritis. Endogenous prostaglandin E2 levels and ex vivo production of leukotriene B4 (LTB4) were measured in synovial fluid samples obtained at baseline and 1 week later. We measured peripheral blood polymorphonuclear cell (PMN) degranulation following surface-bound IgG stimulation, a possible 5-lipoxygenase product-mediated event, by determining lactoferrin and elastase release into the culture fluid. We found decreased levels of endogenous prostaglandin E2 as measured by radioimmunoassay, and decreased ex vivo production of LTB4 by PMN as measured by high performance liquid chromatography, in synovial fluid samples from patients who took tenidap. Release of the granule proteins lactoferrin and elastase was decreased in PMN obtained from patients receiving tenidap, as well as in the PMN incubated in vitro with tenidap. Improvement in clinical measures paralleled the biochemical changes. The unique 5-lipoxygenase inhibitory property of tenidap, as measured by LTB4 production and degranulation, suggests that it may have clinical activity which differentiates it from nonsteroidal antiinflammatory drugs.

1. The kinetics of weal formation and disappearance following intradermal injection of histamine, compound 48/80 and antigen were measured in indomethacin and inert geltreated human forearm skin. 2. Rates of formation went in descending order for histamine, 48/80 and antigen; rate constants of disappearance for equal sized weals were the same for histamine and 48/80 but were much less for antigen. The corresponding half-lives were 77, 73 and 160 min for histamine, 48/80 and antigen weal disappearance respectively. 3. Cyclo-oxygenase inhibition by topical indomethacin had no effect either on the immediate weal and flare responses or on the rates of formation and disappearance of the weals. 4. These findings together with previous studies using H1-receptor antagonists indicate that 48/80 acts by histamine release but that antigen releases both histamine and an additional material or materials which are not related to cyclo-oxygenase activity. 5. Exacerbation of chronic idiopathic urticaria by cyclo-oxygenase inhibitors is therefore likely to be part of the urticarial disease process.

We studied the effects of gold sodium thiomalate (GST) and a new antirheumatic drug, tenidap sodium ([Z]-5-chloro-2,3-dihydro-3-[hydroxy-2-thienylmethylene]-2-oxo-1H- indole-1-carboxamide, sodium salt), previously known as CP-66,248-2, in a model system of macrophage differentiation using a myelomonocytic cell line. HL-60 cells can be stimulated by vitamin D3 to differentiate along a monocytic pathway. Monocytic HL-60 cells express CD14 (Leu-M3), a macrophage surface marker, and develop the capacity to produce the second complement component (C2) in response to stimulation with cytokines such as gamma-interferon. The effects of GST and tenidap sodium were compared with the effects of dexamethasone and a variety of nonsteroidal antiinflammatory drugs in this model system. We found that GST inhibited the capacity of HL-60 cells to produce C2 but did not inhibit the expression of CD14. Tenidap sodium inhibited C2 production as well as CD14 expression, and it partially reversed the decrease in 3H-thymidine incorporation by HL-60 cells, which accompanies monocytic differentiation. At concentrations that inhibited C2 production by HL-60 cells, tenidap sodium did not inhibit C2 production by monocytes. Neither dexamethasone nor the other nonsteroidal antiinflammatory drugs tested possessed these activities. Thus, both GST and tenidap inhibit markers of monocytic differentiation in HL-60 cells, and this activity may relate to their antirheumatic activities.

1 The ubiquitous actions of the cyclo-oxygenase inhibitors are described. 2 These include the inhibitory effect on prostaglandin synthesis and the direct effect of aspirin on lymphocytes and their ability to produce lymphokines. 3 Aspirin reduces some types of platelet aggregation possibly involving inhibition of the precursors of thromboxane A2 and prostacyclin. 4 The therapeutic implications in relation to transient ischaemic attacks, coronary artery disease and reno-allograft rejection are discussed. 5 The beneficial and adverse effects on the gastro-intestinal tract are described. 6 The effects of aspirin-like drugs on the genito-urinary tract are described with particular reference to their adverse effects on labour and their therapeutic effect on dysmenorrhoea.

In eight normotensive male volunteers indomethacin decreased both the peak urine flow rate and total sodium excreted within 1 h of an intravenous dose of frusemide. Resting effective renal plasma flow and glomerular filtration rate were unchanged by indomethacin, but the increase in both parameters after frusemide was inhibited. The early increase in plasma renin activity after frusemide was inhibited by indomethacin. Indomethacin decreased urinary excretion of PGE by 80% and the increase after frusemide was abolished. The urinary excretion of a metabolite of systemic PGI2 was unaltered in the 40-60 min period following frusemide. The early haemodynamic effects of frusemide are likely to be prostaglandin mediated, but there was no evidence of any change in systemic PGI2 synthesis after frusemide.

1 3-hydroxy-5-trifluoromethyl-N-[2-(2-thienyl)-2-phenyl-ethenyl]-benzo(B) thiophene-2-carboxamide (L-652,343) is a 5-lipoxygenase and cyclo-oxygenase inhibitor in vitro. 2 In psoriasis increased concentrations of arachidonic acid transformation products are found in the lesional skin which may be important in the pathogenesis of the disease. We have measured the effect of orally administered L-652,343 on the concentration of LTB4 and prostaglandins in the lesional skin. 3 Eight patients with stable chronic plaque psoriasis received 500 and 250 mg of L-652,343, 12 h apart. A chamber technique was used to collect skin exudate samples from abraded plaques before and at 4, 24 and 48 h after the first dose. Exudates were analysed for LTB4 by a neutrophil chemokinesis assay and for PGE2 and PGD2 by RIA. 4 PGE2 and PGD2 levels were significantly reduced at 4 and 24 h after the first dose of L-652,343 but LTB4 levels were not affected indicating inhibition of the cyclo-oxygenase pathway but not of the 5-lipoxygenase pathway. This shows the importance of confirming that the action of 5-lipoxygenase inhibiting drugs in vitro occurs in vivo.

N-Acetyl chitohexaose (NACOS-6) was able to display chemotactic response of human neutrophils in vitro. In order to analyze the mechanism, a series of chemotaxis studies by means of neutrophils treated with inhibitors of phospholipase A2, cyclooxygenase, or lipoxygenase to NACOS-6 was conducted. The treatment of neutrophils with inhibitors of phospholipase A2 or cyclooxygenase resulted in decrease of number of migrated cells. However, the lipoxygenase inhibitors did not exhibit the same effect. On the other hand, the treatment of neutrophils with inhibitors of phospholipase A2 or lipoxygenase resulted in decrease of chemotactic response to Formyl-Met-Leu-Phe (FMLP), although the cyclooxygenase inhibitors did not inhibit chemotaxis of neutrophils. Neutrophils added to exogenous prostaglandin E2 (PGE2) caused an enhanced chemotactic response to NACOS-6. These results indicate that the mechanism of chemotactic response to NACOS-6 was different from that of FMLP, and that the response was enhanced by PGE2 released from the neutrophils with stimulation of NACOS-6.

An animal model, antigen-induced arthritis in the rabbit, was used to investigate the synthesis of arachidonic acid oxidation products (eicosanoids) by tissues of the knee joints during the initiation and early phase of this developing chronic destructive lesion. High concentrations of immunoreactive prostaglandin E2 and immunoreactive leukotriene B4 were found to be present in the synovial fluid in the early lesion. These levels rapidly declined, as did the ability of the infiltrating cells of the arthritic joint fluids to synthesize leukotriene B4. Articular cartilage and synovial lining were maintained for 24 hours in nonproliferative organ culture, and the synthesis of eicosanoids was measured by assay of the culture fluids. The synovial lining was the major source of eicosanoids. Synthesis of prostaglandin E2, prostacyclin, thromboxane A2, and leukotriene B4 by the arthritic synovial lining was low during the first few days, but reached maximal values between day 5 and day 15 of disease duration. Maximal eicosanoid production occurred around the time that damage to articular cartilage and bone has been reported to occur, though it is not certain that these two events are linked. It was demonstrated that, in chronic lesions, the arthritic synovial lining was still producing elevated levels of eicosanoids compared with levels in the control tissue.

Nonenzymatic, trypsin sensitive cytokines derived from lectin stimulated normal human mononuclear cells have been shown to induce release of proteoglycan and collagen degrading proteinase activity from chondrocytes in cartilage organ and isolated suspension culture systems. Active chondrocyte protein and RNA synthesis were required to induce activity. Cytokines responsible were of both monocyte and T cell origin. Direct monokine catabolic induction and monokine/lectin-triggered lymphokine inducing activity could be demonstrated. Cyclooxygenase inhibitors and direct or indirect modulation of mononuclear cell or chondrocyte cAMP levels had no effect on factor synthesis or activity. Hydrocortisone abrogated the effect. Cytokines responsible were heat labile, unaffected by reduction/alkylation or neuraminidase exposure, and stable over a pH range of 3-10.

Previous studies from our laboratory have demonstrated that the aggregation response of platelets inhibited by agents blocking cyclooxygenase activity could be restored to a normal state of sensitivity by prior stimulation of alpha-adrenergic receptors. Since cyclooxygenase activity and thromboxane synthesis are not absolutely required for irreversible platelet aggregation, it is important to define precisely what role this pathway serves in platelet physiology. The present study has evaluated the influence of agents that selectively block arachidonic acid conversion at different steps of synthesis. Inhibition of peroxidase, cyclooxygenase, lipoxygenase, and thromboxane synthetase blocked the second wave response of platelets to several agonists, but did not cause dissociation of aggregates preformed by prior exposure to arachidonate (AA) or adenosine diphosphate. Phospholipase (A2/C) inhibitors, similar to prostaglandin inhibitors, blocked the second wave response of platelets to the action of agonists and, in addition, caused dissociation of aggregates induced by aggregating agents. Results of our study demonstrate that when single agonists are tested at threshold concentrations, products of arachidonate metabolism may play a role in the activation process. However, continued generation of these metabolites does not appear to be essential for the maintenance of irreversible aggregation. When a combination of agents or high concentration of physiological agonists are used, both activation and irreversible aggregation can be secured independent of prostaglandin synthesis or the release reaction.

1. We have compared the effects of diflunisal on prostaglandin (PG) synthetase from human platelets and sheep seminal vesicles (SSV) by measuring malonaldehyde, PG products, and rabbit aorta contraction. 2. Aspirin inhibits PG synthetase by covalently acetylating the enzyme. Inhibition is dependent on time and aspirin concentration. Aspirin is 37-fold more potent in inhibiting enzyme in human platelets compared with enzyme from SSV. 3. Diflunisal inhibits PG synthetase from intact human platelets and SSV equally (50% inhibition at 3-5 micronM). The drug does not covalently modify the enzyme, and inhibition is not time dependent. Diflunisal probably acts at a site similar to aspirin since the drug will inhibit acetylation of the enzyme by aspirin. 4. The results suggest that diflunisal is relatively less inhibitory to platelet function than is aspirin.

We studied the effect of 3 weeks' treatment with 4 x 200 mg of sulphinpyrazone daily (six healthy volunteers) on proaggregatory thromboxane A2 (TxA2) and antiaggregatory prostacyclin (PGI2). Platelet TxA2 production was evaluated by measuring its stable metabolite, immunoreactive thromboxane B2, from serum, and vessel wall PGI2 production by measuring its stable metabolite, immunoreactive 6-keto-prostaglandin F1 alpha in plasma. The TxA2 production (initially 209.0 +/- 27.1 ng/ml, mean +/- s.e. mean) decreased to about 30% from the second day of the treatment onwards, and it recovered in three days after the discontinuation of the treatment. PGI2 (initially 33.6 +/- 3.6 pg/ml) did not change. The shift of the balance between TxA2 and PGI2 to the dominance of antiaggregatory PGI2 during sulphinpyrazone treatment may be involved with the efficacy of the drug in the secondary prevention of myocardial infarction.