Inhibition Of Prostaglandin Synthesis Research Articles

Contracting human skeletal muscle maintains the ability to blunt α1‐adrenergic vasoconstriction during KIR channel and Na+/K+‐ATPase inhibition

During exercise there is a balance between vasoactive factors that facilitate increases in blood flow and oxygen delivery to the active tissue and the sympathetic nervous system, which acts to limit muscle blood flow for the purpose of blood pressure regulation. Functional sympatholysis describes the ability of contracting skeletal muscle to blunt the stimulus for vasoconstriction, yet the underlying signalling of this response in humans is not well understood. We tested the hypothesis that activation of inwardly rectifying potassium channels and the sodium-potassium ATPase pump, two potential vasodilator pathways within blood vessels, contributes to the ability to blunt α1 -adrenergic vasoconstriction. Our results show preserved blunting of α1 -adrenergic vasconstriction despite blockade of these vasoactive factors. Understanding this complex phenomenon is important as it is impaired in a variety of clinical populations. Sympathetic vasoconstriction in contracting skeletal muscle is blunted relative to that which occurs in resting tissue; however, the mechanisms underlying this 'functional sympatholysis' remain unclear in humans. We tested the hypothesis that α1 -adrenergic vasoconstriction is augmented during exercise following inhibition of inwardly rectifying potassium (KIR ) channels and Na(+) /K(+) -ATPase (BaCl2 +ouabain). In young healthy humans, we measured forearm blood flow (Doppler ultrasound) and calculated forearm vascular conductance (FVC) at rest, during steady-state stimulus conditions (pre-phenylephrine), and after 2min of phenylephrine (PE; an α1 -adrenoceptor agonist) infusion via brachial artery catheter in response to two different stimuli: moderate (15% maximal voluntary contraction) rhythmic handgrip exercise or adenosine infusion. In Protocol1 (n=11 subjects) a total of six trials were performed in three conditions: control (saline), combined enzymatic inhibition of nitric oxide (NO) and prostaglandin (PG) synthesis (l-NMMA+ketorolac) and combined inhibition of NO, PGs, KIR channels and Na(+) /K(+) -ATPase (l-NMMA+ketorolac+BaCl2 +ouabain). In Protocol2 (n=6) a total of four trials were performed in two conditions: control (saline), and combined KIR channel and Na(+) /K(+) -ATPase inhibition. All trials occurred after local β-adrenoceptor blockade (propranolol). PE-mediated vasoconstriction was calculated (%ΔFVC) in each condition. Contrary to our hypothesis, despite attenuated exercise hyperaemia of ∼30%, inhibition of KIR channels and Na(+) /K(+) -ATPase, combined with inhibition of NO and PGs (Protocol1) or alone (Protocol2) did not enhance α1 -mediated vasoconstriction during exercise (Protocol1: -27±3%; P=0.2vs. control, P=0.4vs. l-NMMA+ketorolac; Protocol2: -21±7%; P=0.9vs. control). Thus, contracting human skeletal muscle maintains the ability to blunt α1 -adrenergic vasoconstriction during combined KIR channel and Na(+) /K(+) -ATPase inhibition.

G145(P) Indomethacin vs ibuprofen to treat patent ductus arteriosus (pda) in neonates

Aims To compare gastrointestinal pathology, mortality and surgical ligation of PDA in infants treated for PDA with Ibuprofen and Indomethacin. Background PDA affects 60% of infants NSAIDs are effective pharmacological agents used to treat PDA. They inhibit prostaglandin synthesis via non-selective inhibition COX-1 and COX-2. COX-1 inhibition reduces cerebral, mesenteric and renal blood flow and alters platelet function. Ibuprofen has less COX1 inhibition, therefore may have reduced side effect profile. In our unit PDA treatment changed in 2010 from Indomethacin to Ibuprofen because of unavailability of Indomethacin. Methods Demographics and outcomes from babies Results Conclusion There was a significant reduction in early NEC during the Ibuprofen epoch compared to Indomethacin epoch. These results are similar to the reduction of NEC with Ibuprofen compared to Indomethacin (RR 0.68 (95% CI 0.47 to 0.99)) reported in a recent meta-analysis (Cochrane Database Syst Rev. 2013 Apr 30; 4:CD003481). As with all cohort studies there are confounding factors including demographics factors and potential alterations in clinical practice including feeding practices between the two epochs.

Changes of nitric oxide system and lipid peroxidation parameters in the digestive system of rats under conditions of acute stress, and use of nonsteroidal anti-inflammatory drugs

Abstract The use of nonsteroidal anti-inflammatory drugs (NSAIDs) in combination with being physiologically stressed often occurs in in the course of different pathologies. This situation may result in the alteration of digestive system functioning. The effect of stress brings about changes in the activity of nitric oxide synthase (NOS), arginase, cyclooxygenase (COX) and lipid peroxidation, whereas the use of NSAIDs interrupts the multiple functions of the cell via the inhibition of prostaglandins (PGs) synthesis. Taking into account that NOS and COX-systems are connected in their regulation, the aim of the study was to determine the role played by NOS and lipid peroxidation under conditions of the combined action of NSAIDs and stress. In our study, male rats were used. The NSAIDs (naproxen - a non-selective COX inhibitor, celecoxib - a selective COX-2 blocker, and the compound 2A5DHT (which is the active substance of dual COX, and the lipoxygenase (LOX) inhibitor, darbufelone) were all administered at a dose 10 mg/kg, prior to water restraint stress (WRS). WRS brought about an increase of inducible NOS (iNOS) activity in the intestinal mucosal and muscular membranes, as well as in the pancreas. Because of this, constitutive NOS izoform (cNOS) and arginase activities decreased. Moreover, the MDA concentration increased, indicating the development of oxidative stress. In our work, pretreatment with naproxen, as in the WRS model, engendered a decrease in iNOS activity. What is more, administration of Celecoxib did not change iNOS activity, as compared to WRS alone, and it showed a tendency to reduce lipid peroxidation. In addition, 2A5DHT prior WRS brought about a decrease of iNOS activity, with the subsequent rise of cNOS activity. Of note, MDA concentration decreased in all studied organs, indicating the reduction of lipid peroxidation under the action of the darbufelone active substance.

CJ-023,423 (Grapiprant) a Potential Novel Active Compound with Antihyperalgetic Properties for Veterinary Patients

Companion animals are now living longer and so are more commonly manifesting age- and pain-related disease. Nonsteroidal anti- inflammatory drugs are the most used drug in osteoarthritis and inflammatory pain of various aetiologies. Despite their safety profiles have been amended from the COX-non selective to the COX-2 selective inhibitor class, some adverse effects are still of concern especially in long term treatments. One prostaglandin (PG) downstream from the cyclooxygenase enzyme, PGE2, has been recognized as a pivotal mediator of pain and inflammation. The actions of PGE2 are produced by its interaction with four G-protein coupled receptors (EP1, EP2, EP3 and EP4). The EP4 receptor mediates PGE2-elicited sensitization of sensory neurons and studies have demonstrated that EP4 is a major receptor in mediating pain associated with both rheumatoid and osteoarthritis and in inflammation. CJ-023,423 (grapiprant) is a competitive antagonist of human and rat prostanoid EP4 receptors, under development for the control of pain and inflammation associated with osteoarthritisfor use in humans and dogs. A recent study has shown the good safety profile of this active ingredient in dogs. Despite this molecule is still far to be marketed because it pharmacokinetic/pharmacodynamics profile is need to be fully elucidated yet, it might be an interesting active ingredient for the veterinary medicine. activities. Two isoforms of COX, COX-1 and COX-2, have been identified. COX-1 is constitutively expressed throughout the body and it is thought to play an essential role in normal gastrointestinal and renal function, whereas COX-2 is induced in the presence of inflammation. NSAIDs inhibit both isoforms and inhibition of COX-1 is thought to cause the adverse gastrointestinal effects such as gastric erosion, ulceration and haemorrhage, whereas inhibition of COX-2 is associated with the therapeutic effects of NSAIDs. Thus, inhibition of PG synthesis by NSAIDs has demonstrated clear efficacy in the reduction of pain and inflammation and also has been shown to have putative effects beyond pain, including gastrointestinal and renal effects. These effects have been shown to be more severe in several animal species rather than in human beings (Khan and McLean, 2012). Selective COX-2 inhibitors were designed to prevent those adverse effects mediated by

Hypoxia-induced relaxation of porcine retinal arterioles in vitro depends on inducible NO synthase and EP4 receptor stimulation in the perivascular retina.

Hypoxia-induced relaxation of porcine retinal arterioles has been shown to be reduced during inhibition of prostaglandin synthesis and nitric oxide synthase (NOS). The purpose of this study was to identity the specific prostaglandin receptor(s) and source(s) of NO mediating this effect. Porcine retinal arterioles with preserved perivascular retinal tissue were mounted in a myograph and were exposed to hypoxia in the presence of one of the following: the general NO synthase inhibitor L-NAME, the selective iNOS inhibitor 1400W, the selective nNOS inhibitor 7-nitroindazole, the general cyclooxygenase (COX) inhibitor ibuprofen or an antagonist to the FP- (AL 8810), DP- (BWA868C), EP1 - (SC-19220), EP2 - (PF-044189) or EP4 receptors (GW627368X). The experiments were repeated after removal of the perivascular retinal tissue. Hypoxia induced relaxation of retinal arterioles with preserved perivascular retinal tissue. This relaxation was significantly reduced in the presence of L-NAME, 1400W, ibuprofen and the EP4 receptor antagonist GW627368X. The simultaneous addition of L-NAME or 1400W in combination with ibuprofen, but not GW627368X, reduced hypoxia-induced vasorelaxation additively as compared to the effect of the compounds individually. Hypoxia-induced vasorelaxation of porcine retinal arterioles is mediated by inducible NOS and stimulation of EP4 receptors acting through separate pathways, but mechanisms unrelated to the studied prostaglandin receptors and NOS products are also involved.

NSAIDs: learning new tricks from old drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) comprise a heterogeneous group of pharmacological agents used for the symptomatic treatment of fever, pain, and inflammation. Although the main mechanism of action of NSAIDs consists of inhibiting prostaglandin synthesis by blocking the enzyme cyclooxygenase (COX), clinical, and experimental data strongly indicate the existence of additional mechanisms. Some of the COX-independent effects are related to the ability of NSAIDs to penetrate biological membranes and disrupt important molecular interactions necessary for a wide array of cellular functions, including cell adhesion. These effects, in particular those that interfere with L-selectin function in neutrophils during the inflammatory response, may contribute to the anti-inflammatory properties that NSAIDs exert in vivo. Recent contributions in this field have shown that the anti-L-selectin effect of NSAIDs is related to the NADPH-oxidase-dependent generation of superoxide anion at the plasma membrane. These findings might represent a novel approach for developing new and effective anti-inflammatory compounds with a better safety profile than the currently available NSAIDs.

Different mechanisms of apolipoprotein E isoform-dependent modulation of prostaglandin E2 production and triggering receptor expressed on myeloid cells 2 (TREM2) expression after innate immune activation of microglia.

Several lines of evidence support immune response in brain as a mechanism of injury in Alzheimer disease (AD). Moreover, immune activation is heightened in apolipoprotein E (APOE) ε4 carriers; inhibitors of prostaglandin (PG) synthesis show a partially protective effect on AD risk from APOE ε4; and genetic variants in triggering receptor expressed on myeloid cells 2 (TREM2) are a rare but potent risk for AD. We tested the hypothesis that APOE ε4 inheritance modulates both the PGE2 pathway and TREM2 expression using primary murine microglia from targeted replacement (TR) APOE3/3 and APOE4/4 mice. Microglial cyclooxygenase-2, microsomal PGE synthase, and PGE2 expression were increased 2- to 25-fold in both genotypes by TLR activators; however, this induction was significantly (P < 0.01) greater in TR APOE4/4 microglia with TLR3 and TLR4 activators. Microglial TREM2 expression was reduced approximately 85% by all TLR activators; this reduction was approximately one-third greater in microglia from TR APOE4/4 mice. Importantly, both receptor-associated protein and a nuclear factor κ-light-chain-enhancer inhibitor blocked TR APOE4/4-dependent effects on the PGE2 pathway but not on TREM2 expression. These data demonstrate complementary, but mechanistically distinct, regulation of pro- and anti-inflammatory mediators in TR APOE4/4 murine microglia that yields a more proinflammatory state than with TR APOE3/3.

Antiinflammatory Activity of Hot Water Infusion of Nyctanthes arbo-tristis Flowers.

In Sri Lankan ethnomedicate it is claimed the flowers of Nyctanthes arbo-tristis is effective in the treatment of inflammatory conditions but this has not been scientifically validated. This experiment was carried to investigate the antinflammatory potential of hot water infusion of Nyctanthes arbo-tristis flowers. Oral antiinflammatory activity of hot water infusion of Nyctanthes arbo-tristis flowers (concentrations: 3.75, 7.5, 12.5 and 18.75 mg/kg) was assessed in rats using both acute (carrageenan-induced paw oedema assay) and chronic (formaldehyde induced-paw oedema and cotton pellet-granuloma tests) inflammatory models. In an attempt to investigate its mode of action, antihistamine activity (by wheal test), inhibition of prostaglandin synthesis (by enteropooling test), inhibition of Tumor necrosis factorα secretion (using human mononuclear cells), and suppression of vascular permeability (acetic acid-induced vascular permeability test) and cytotoxicity (Evans blue test) were assessed. In the carrageenan-induced paw oedema test, hot water infusion simultaneously suppressed both initial and late stages of inflammation in an inversely dose related manner. Hot water infusion also inhibited paw oedema in formalin and cotton pellet granuloma tests. In addition, this infusion exhibited marked anti histamine activity, prostaglandin synthesis inhibition and suppression of vascular permeability. These findings scientifically support the traditional use of Nyctanthes arbo-tristis flowers in treatment of inflammatory conditions.

How Nsaids Affect Lipid Monolayer and Bilayer Properties

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis by blocking cyclooxygenase and influence gramicidin channel lifetimes in planar lipid bilayers. In the past we studied how the NSAIDs salicylic acid, acetylsalicylic acid, acetaminophen, ibuprofen and diclofenac influenced the pressure-area curve in the aqueous subphase on dipalmitoyl-PC pressure-area curves at modestly supratheraputic dosages (1 mM concentrations in the subphase). We observed consistent changes that imply these NSAIDs interact strongly with the lipid head groups of monolayers. Here we report subsequent findings using umbrella sampling molecular dynamics. Each titratable NSAID was simulated, both protonated and unprotonated, with DPPC bilayers. The neutral NSAIDs have free energy wells as deep as −10 kcal/mol in the headgroup region, whereas charged molecules were uniformly repulsed from the bilayer. These findings call for further experiments on the pH dependency of drug-bilayer interactions and suggest that neutral NSAIDs, including protonated aspirin in the low pH chyme of the stomach, interact with cell membranes and could cause adverse side effects.

Evaluation of peripheral and central analgesic activity of ethanolic extract of Clerodendrum infortunatum Linn. in experimental animals

Background: Clerodendrum infortunatum Linn. (Verbenaceae) is an important and widely used medicinal plant. Though variously used in Ayurveda, Unani, and Homeopathy system of medicine in the case of ailments such as diarrhoea, skin disorders, venereal and scrofulous complaints, wounds, post-natal complications, as anti-helminthic, and external applications on tumors, the plant needs thorough investigation for its specific medicinal activity. This study evaluates both the central and peripheral analgesic effect of the ethanolic extract of the leaves of C. infortunatum Linn. (EECI) in the experimental animals. Methods: Acute toxicity test was done following the Organization of Economic Co-operation and Development guidelines. EECI (100 mg/kg, 200 mg/kg, and 400 mg/kg body weight [b.w.] p.o) was evaluated for central analgesic activity by the tail flick method and peripheral analgesic activity by the acetic acid (0.7%) induced writhing test, respectively. Using aspirin (300 mg/kg b.w. and 100 mg/kg b.w.) as the standard drug. Results: EECI significantly decreased the number of writhing in writhing test at all the doses (p&lt;0.01) and increased the reaction time in tail-flick method (p&lt;0.01) at all the doses. EECI in the dosage of 400 mg/kg b.w. produced effects which was comparable with that of the standard drug aspirin (p&lt;0.001) in writhing test (p&lt;0.001) and tail flick method (p&lt;0.001). Conclusion: The study showed significant central and peripheral analgesic activity of EECI which may be attributed to the inhibition of prostaglandin synthesis, phospholipase A2, and tumor necrosis factor alpha. C. infortunatum Linn. as a commercial source of analgesic drug should be subjected to further research.

A comparative evaluation of per rectal diclofenac sodium and paracetamol for postoperative analgesia in case of hydrocephalus

Background: Hydrocephalus is one of the most painful conditions, especially in pediatric population. Analgesia after neurosurgery requires good communication and close cooperation between members of the perioperative team. Diclofenac is a nonsteroidal anti-inflammatory drug with pronounced antirheumatic, anti-inflammatory, analgesic, and antipyretic properties. Diclofenac inhibits prostaglandin synthesis, which contributes to inflammation, pain, and fever. Paracetamol produces analgesia and antipyresis by a mechanism similar to that of salicylate, which involves inhibition of prostaglandin synthesis. Objectives: To compare the analgesic efficacy of rectally administered diclofenac sodium and paracetamol postoperatively in patients with hydrocephalus for postoperative pain relief. Also, to compare side effects of both the drugs. Materials and Methods: Fifty patients aged 1-8 years scheduled for ventriculoperitoneal shunt under general anesthesia were selected for the study. All the patients were divided into two groups, Group D and Group P. At the end of surgery, 15 min before extubation, patients of Group D were rectally administered with inj. diclofenac 1 mg/kg whereas those of Group P with inj. paracetamol 15 mg/kg. Pain was assessed using Wong–Baker Faces Pain Rating Scale (WBFPS). When the score was 4 or more, then inj. paracetamol 15 mg/kg was administered intravenously as rescue analgesia. Patients were also observed for duration and analgesia. We have also compared hemodynamic parameters and complications in both the groups postoperatively. Results: Heart rate and SpO2 were stable in after the operation. Pain score on WBFPS was statistically nonsignificant between both the groups. Duration of analgesia was significantly longer in Group D than in Group P. Incidence of side effects and complications were also comparable in both the groups. Conclusion: We conclude that both paracetamol and diclofenac are very well tolerated by rectal route with prolonged duration of analgesia with diclofenac for postoperative pain relief in pediatric patients with hydrocephalus.

Angiogenesis in the primate ovulatory follicle is stimulated by luteinizing hormone via prostaglandin E2.

Rapid angiogenesis occurs as the ovulatory follicle is transformed into the corpus luteum. To determine if luteinizing hormone (LH)-stimulated prostaglandin E2 (PGE2) regulates angiogenesis in the ovulatory follicle, cynomolgus macaques received gonadotropins to stimulate multiple follicular development and chorionic gonadotropin (hCG) substituted for the LH surge to initiate ovulatory events. Before hCG, vascular endothelial cells were present in the perifollicular stroma but not amongst granulosa cells. Endothelial cells entered the granulosa cell layer 24-36 h after hCG, concomitant with the rise in follicular PGE2 and prior to ovulation, which occurs about 40 h after hCG. Intrafollicular administration of the PG synthesis inhibitor indomethacin was coupled with PGE2 replacement to demonstrate that indomethacin blocked and PGE2 restored follicular angiogenesis in a single, naturally developed monkey follicle in vivo. Intrafollicular administration of indomethacin plus an agonist selective for a single PGE2 receptor showed that PTGER1 and PTGER2 agonists most effectively stimulated angiogenesis within the granulosa cell layer. Endothelial cell tracing and three-dimensional reconstruction indicated that these capillary networks form via branching angiogenesis. To further explore how PGE2 mediates follicular angiogenesis, monkey ovarian microvascular endothelial cells (mOMECs) were isolated from ovulatory follicles. The mOMECs expressed all four PGE2 receptors in vitro. PGE2 and all PTGER agonists increased mOMEC migration. PTGER1 and PTGER2 agonists promoted sprout formation while the PTGER3 agonist inhibited sprouting in vitro. While PTGER1 and PTGER2 likely promote the formation of new capillaries, each PGE2 receptor may mediate aspects of PGE2's actions and, therefore, LH's ability to regulate angiogenesis in the primate ovulatory follicle.

CXADR-like membrane protein (CLMP) in the rat ovary: stimulation by human chorionic gonadotrophin during the periovulatory period.

CXADR-like membrane protein (CLMP) is a novel cell-cell adhesion molecule. The present study investigated the spatiotemporal expression pattern of CLMP and its regulation in the rat ovary during the periovulatory period. Real-time polymerase chain reaction analysis revealed that Clmp mRNA was rapidly stimulated in intact ovaries by 4h after human chorionic gonadotrophin (hCG) treatment. In situ hybridisation analysis demonstrated that Clmp mRNA expression was stimulated in theca cells at 4h after hCG and remained elevated until 12h. Clmp mRNA was also upregulated in granulosa cells and was present in forming corpora lutea. Our data indicate that the protein kinase A but not the protein kinase C pathway regulates the expression of Clmp mRNA in granulosa cells. Phosphatidylinositol 3 kinase and p38 kinase are also involved in regulating Clmp mRNA expression. The stimulation of Clmp mRNA by hCG requires new protein synthesis. Furthermore, inhibition of epidermal growth factor receptor activation significantly inhibited Clmp mRNA expression, whereas inhibition of prostaglandin synthesis or progesterone action had no effect. The stimulation of CLMP in the rat ovary may be important in cell adhesion events during ovulation and luteal formation such as maintaining the structure and communication of ovarian follicular and luteal cells.

6-Substituted 9-fluoroquino[3,2-b]benzo[1,4]thiazines display strong antiproliferative and antitumor properties.

6-Substituted 9-fluoroquino[3,2-b]benzo[1,4]thiazines - a new type of tetracyclic azaphenothiazines-were obtained from of 6H-9-fluoroquinobenzothiazine by the introduction of appropriate substituents to the thiazine nitrogen atom (alkyl, aminoalkyl, amidoalkyl, sulfonamidoalkyl and nitrogen half-mustard groups). The compounds displayed differential cytotoxic as well as antiproliferative actions against human peripheral blood mononuclear cells (PBMC) stimulated with phytohemagglutinin A (PHA). In addition, they suppressed lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-α) production by whole blood human cell cultures. Two compounds (4 and 15, with the propargyl and methanesulfonamidopropyl groups) were selected for further experiments because of lack of cytotoxicity and strong antiproliferative actions. Compound 4 showed strong suppressive actions on growth of L1210, SW948, A-431 and CX-1 tumor cell lines which were close to those of cisplatin, the reference drug (e.g. GI50 of 2.28 μg/mL vs. 1.86 μg/mL for L1210 cells). Further, the compound appeared to be equally effective as cyclosporine A (CsA) in the inhibition of human two-way mixed lymphocyte reaction (MLR). The compound did not significantly inhibit interleukin 2 (IL-2)-induced growth of CTLL-2 cell line. In addition, inhibition of prostaglandin (PG) synthesis by indomethacin or block of PG receptors did not interfere with the inhibitory effect of the compound on PHA-induced cell proliferation. Therefore, it is likely that the compound acts by inhibiting cell cycle as proposed for other phenothiazines. Further studies are required for the elucidation of the mechanism of action and therapeutic utility of these compounds in more advanced in vivo models.

Diameter Changes of Retinal Arterioles During Acute Hypoxia In Vivo are Modified by the Inhibition of Nitric Oxide and Prostaglandin Synthesis

ABSTRACTPurpose: Inhibition of cyclooxygenase (COX) and nitric oxide synthesis (NOS) has previously been shown to modify hypoxia-induced relaxation of retinal arterioles in vitro. The purpose of the present study was to investigate whether these findings can be reproduced in vivo.Methods: Twenty healthy persons aged 20–55 years were examined. Using the dynamic vessels analyzer (DVA), the resting diameter and diameter changes during isometric exercise and flicker stimulation were studied before and during breathing of a hypoxic gas mixture. The examinations were carried out before and during intravenous infusion of the NOS-inhibitor l-NMMA, and were repeated on a second study day after topical administration of the COX-inhibitor diclofenac.Results: The resting diameter of retinal arterioles increased significantly during hypoxia and decreased significantly during l-NMMA infusion (p < 0.0001) which compensated for changes in the blood pressure. During hypoxia and l-NMMA infusion together contraction of retinal arterioles could not compensate for the increased blood pressure as assessed by a gain factor significantly lower than one (p = 0.002).The arteriolar contraction induced by isometric exercise was significantly reduced by diclofenac and flicker-induced dilatation of retinal arterioles was increased during l-NMMA infusion (p < 0.0001).Conclusion: Diameter changes of retinal vessels during acute hypoxia in vivo are modified by inhibiting NO and prostaglandin synthesis. The evidence points to possible new targets of intervention on the diameter regulation of retinal arterioles in diseases where retinal hypoxia is part of the disease pathogenesis.

Progesterone receptor expression declines in the guinea pig uterus during functional progesterone withdrawal and in response to prostaglandins.

Progesterone withdrawal is essential for parturition, but the mechanism of this pivotal hormonal change is unclear in women and other mammals that give birth without a pre-labor drop in maternal progesterone levels. One possibility suggested by uterine tissue analyses and cell culture models is that progesterone receptor levels change at term decreasing the progesterone responsiveness of the myometrium, which causes progesterone withdrawal at the functional level and results in estrogen dominance enhancing uterine contractility. In this investigation we have explored whether receptor mediated functional progesterone withdrawal occurs during late pregnancy and labor in vivo. We have also determined whether prostaglandins that induce labor cause functional progesterone withdrawal by altering myometrial progesterone receptor expression. Pregnant guinea pigs were used, since this animal loses progesterone responsiveness at term and gives birth in the presence of high maternal progesterone level similarly to primates. We found that progesterone receptor mRNA and protein A and B expression decreased in the guinea pig uterus during the last third of gestation and in labor. Prostaglandin administration reduced while prostaglandin synthesis inhibitor treatment increased progesterone receptor A protein abundance. Estrogen receptor-1 protein levels remained unchanged during late gestation, in labor and after prostaglandin or prostaglandin synthesis inhibitor administration. Steroid receptor levels were higher in the non-pregnant than in the pregnant uterine horns. We conclude that the decreasing expression of both progesterone receptors A and B is a physiological mechanism of functional progesterone withdrawal in the guinea pig during late pregnancy and in labor. Further, prostaglandins administered exogenously or produced endogenously stimulate labor in part by suppressing uterine progesterone receptor A expression, which may cause functional progesterone withdrawal, promote estrogen dominance and foster myometrial contractions.

Fractals and self-organized criticality in anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) act through inhibiting prostaglandin synthesis, a catalytic activity possessed by two distinct cyclooxygenase (COX-1 and COX-2) isozymes encoded by separate genes. The discovery of COX-2 launched a new era in NSAID pharmacology, resulting in the synthesis, marketing, and widespread use of COX-2 selective inhibitors. Extensive structural studies of the biology of prostaglandin synthesis and inhibition have explained some of the differences between COX-1 and COX-2 functionality, but others are still unexplained. Notably these include molecular differences that cause COX-1 inhibitors to produce a slight decrease, and COX-2 inhibitors to induce a significant increase, in heart attacks and strokes. These differences were unexpected because of the 60% overall COX-1 and COX-2 sequence similarity and the 1–2 conservation of catalytic sites. Hydropathic analysis shows important bicyclic differences between COX-1 and COX-2 on a large scale outside the catalytic pocket. These differences involve much stronger amphiphilic interactions in COX-2 than in COX-1, and may explain the selective antiplatelet effectiveness of COX-2. Success of the non-Euclidean structural analysis is the result of using the new Brazilian hydropathicity scale based on self-organized criticality (SOC) of universal protein modules.

Enhancement in Cortical Arousal by Caffeine Salicylate in Experimental Animal Models

Objective: It is aimed to evaluate contribution of two molecules of Caffeine salicylate, a combinatorial product, in the CNS stimulant, anti-inflammatory and an analgesic property in experimental animal models. Material and Methods: Caffeine salicylate is synthecised by one step reaction from caffeine and salicylic acid. Actophotometer and open field test were used for the CNS stimulant activity whereas formalin induced rat paw edema and tail immersion test were used to evaluate anti-inflammatory and analgesic properties in experimental animals. Results: The locomotor activity was increased from 37.1% for caffeine to 49.24% for caffeine salicylate. In open field test; number of crossing and rearing were increased from 42.34 % to 54.89% and 17.26% to 27.87% respectively. The % inhibition on rat paw edema 16.40% and 18.75% with caffeine salicylate as against diclofinac 51.0% and 62.5% at 60 and 120 min. respectively. The tail withdrawal time was prolonged by 25% with caffeine salicylate as against 78.88 % with pentazocine in wistar rats. The results of all experimental animal models were statistically significant. Conclusion: The enhancement in the cortical arousal by caffeine salicylate over caffeine may be due to contribution of antioxidant property of salicylate besides adenosine antagonism and mobilization of intracellular calcium induced dopamine release by caffeine portion of caffeine salicylate. The mild analgesic and anti-inflammatory activities of caffeine salicylate may be due to inhibition of prostaglandin synthesis and an antioxidant properties of salicylate portion of caffeine salicylate.

Evaluation of the reproductive toxicity of naproxen sodium and meloxicam in male rats.

Nonsteroidal anti-inflammatory drugs that are cyclooxygenase (COX) enzyme inhibitors have generally been used in short-term pain management and also to treat inflammation chronically. It is known that COX enzyme and prostaglandins play important roles in the regulation of reproductive functions in females. However, there are relatively few studies for the male reproductive system, and the results of these studies are contradictory. In this study, sperm count and motility, COX-1, COX-2, prostaglandin E1 (PGE1), prostaglandin E2 (PGE2), and prostaglandin F2α (PGF2α) levels in testis tissue, plasma follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone levels, and histopathological examination of testis tissue were evaluated after naproxen sodium and meloxicam administration in male rats. Also, testis superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and glutathione (GSH) levels were measured to investigate the oxidation status. According to our results, sperm count and motility were significantly decreased in treatment groups. Plasma hormone levels did not show any statistical differences between the groups. COX-1, PGE2, and PGF2α levels were significantly decreased, while the decreases in COX-2 and PGE1 levels did not show any significance statistically. Testis SOD, catalase, GPx, and GSH levels were decreased significantly. According to the results of histopathological examination, damage in seminiferous tubules, where spermatogenesis developed, was observed. In conclusion, naproxen sodium and meloxicam decreased the sperm count and motility and also induced the damage of seminiferous tubules as a direct effect without affecting plasma hormone levels in our study. The mechanism of the reproductive toxicity induced by these agents may be based on the inhibition of prostaglandin synthesis and the induction of oxidative stress can be emphasized as a secondary factor.

Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: evidence from human and murine studies

We evaluated the clinical effectiveness of variable courses of paracetamol on patent ductus arteriosus (PDA) closure and examined its effect on the in vitro term and preterm murine ductus arteriosus (DA). Neonates received one of the following three paracetamol regimens: short course of oral paracetamol (SCOP), long course of oral paracetamol (LCOP), and intravenous paracetamol (IVP) for 2-6 d. Pressure myography was used to examine changes in vasomotor tone of the preterm and term mouse DA in response to paracetamol or indomethacin. Their effect on prostaglandin synthesis by DA explants was measured by mass spectroscopy. Twenty-one preterm infants were included. No changes in PDA hemodynamics were seen in SCOP infants (n = 5). The PDA became less significant and eventually closed in six LCOP infants (n = 7). PDA closure was achieved in eight IVP infants (n = 9). On pressure myograph, paracetamol induced a concentration-dependent constriction of the term mouse DA, up to 30% of baseline (P < 0.01), but required >1 µmol/l. Indomethacin induced greater DA constriction and suppression of prostaglandin synthesis (P < 0.05). The clinical efficacy of paracetamol on PDA closure may depend on the duration of treatment and the mode of administration. Paracetamol is less potent than indomethacin for constriction of the mouse DA in vitro.