Non-selective Cyclooxygenase Inhibitor Research Articles

Comparative analysis of the effect of diclofenac sodium and etoricoxib on energy metabolism in rat liver in the acute general cooling model

When the ambient temperature decreases, physiological mechanisms that prevent heat loss are activated. However, under cold stress hypothermia develops, which significantly disrupts the functioning of the body and can be transformed into life-threatening. Preventive use of nonsteroidal anti-inflammatory drugs, especially diclofenac sodium and etoricoxib, has been found to reduce the severity of cold trauma. Given that their frigoprotective effect can accompany the impact on the synthesis of eicosanoids when exposed to low temperatures, it is advisable to study mechanisms for preventing hypothermia independent of cyclooxygenase, particularly the influence on energy metabolism. The aim of the study was to figure out the effect of diclofenac sodium and etoricoxib on the indicators of energy metabolism in the liver of rats after acute general cooling. Experiments were carried out on 28 sexually mature male rats, which were given diclofenac sodium (7 mg/kg), etoricoxib (5 mg/kg), or solvent 30 minutes before cold trauma intragastrically (in the intact control and pathology control groups). Acute hypothermia was caused by exposure of animals for 2 hours at a temperature of -18°C. Rectal temperature was measured before and after acute general cooling. The content of lactate, pyruvate and adenosine triphosphate in the liver was measured and the lactate/pyruvate ratio was calculated. Diclofenac sodium, unlike etoricoxib, was found to significantly reduce the severity of hypothermia. Both nonsteroidal anti-inflammatory drugs prevent energy metabolism disorders caused by exposure to cold, namely, reducing the concentration of lactic acid and the ratio of lactate/pyruvate, increasing the content of pyruvate and adenosine triphosphate in the liver of animals. Etoricoxib normalizes the content of energy metabolism intermediates to their levels in intact animals. Diclofenac sodium has a similar effect, the expression of which is inferior to the selective cyclooxygenase-2 inhibitor. Therefore, when administered prophylactically before acute general cooling, diclofenac sodium effectively prevents hypothermia in rats, surpassing etoricoxib. Etoricoxib completely prevents a decrease in the content of pyruvate and adenosine triphosphate, as well as the accumulation of lactic acid in the liver. Diclofenac sodium is inferior to etoricoxib in its effect on energy metabolism, which indicates other mechanisms of frigoprotective action of a non-selective cyclooxygenase inhibitor. The frigoprotective and energotropic properties of nonsteroidal anti-inflammatory drugs dissociate.

Diuretic and Natriuretic Effects of Hesperidin, a Flavanone Glycoside, in Female and Male Hypertensive Rats

Hesperidin (HSP) is a major flavanone glycoside in citrus fruits, including sweet oranges and lemons. It demonstrates numerous pharmacological activities, such as antihypertensive effects and cardiac and kidney tissue protection. However, its effect on modulating renal function has yet to be properly explored. Female and male Wistar spontaneously hypertensive rats (SHR) were used to test the effect of HSP on renal function. The rats were divided into different groups, treated orally, and placed in metabolic cages for urine collection for 8 h. HSP, at doses of 0.3-3 mg/kg, led to an increase in urine volume in both female and male SHR. This effect was associated with increased Na+ elimination (3 mg/kg) without causing any change in K+ excretion or pH and conductivity values. When given HSP in combination with hydrochlorothiazide (HCTZ) or amiloride (AMLR), urine volume and Na+ elimination were significantly increased compared to the group that received only HSP. In relation to K+ excretion, the depleting effect of HCTZ and the sparing of AMLR prevailed in both groups. Pre-treatment with a non-selective cholinergic receptor antagonist, atropine, partially prevented HSP-induced diuresis and natriuresis in male SHR, but this effect was not demonstrated with the non-selective inhibitor of the enzyme cyclooxygenase, indomethacin. This study shows the diuretic action of HSP in hypertensive rats, an activity probably associated with the cholinergic pathway. Although various biological actions have already been defined for HSP, this pioneering research reveals its potential as a diuretic medicine.

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low birth weight infants.

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low birth weight infants.

Endocrine and behavioral effects in male rats after birth with their pregnant mother taking ibuprofen

Ibuprofen, a non-selective inhibitor of cyclooxygenase, is one of the most used non-steroidal anti- inflammatory drugs (NSAID) and pain relievers. Its effect on developing fetal neuroendocrine system when taken by a pregnant mother does not well established. The aim of this study was to evaluate the long-term consequences of the administration of ibuprofen to pregnant rats with regard to hormonal profile and sexual differentiation of the brain in male offspring. Pregnant rats were given ibuprofen per os in a dose of 30 mg/kg bw twice a day during days 15-21 of gestation. On the 2 and 10 postnatal days (PND), anogenital distance (AGD) was measured in male pups. In adulthood, sexual behavior, hormone levels, and hypothalamic-pituitary-adrenal axis (HPAA) response to acute immobilization stress were studied. Prenatal ibuprofen increased AGD on PND 2 and caused incomplete masculinization of copulative behavior in adult offspring. Significant increases in the latent periods of the first mount, the first intromission, and a decrease in the number of intromissions were observed. Basal blood plasma levels of testosterone, estradiol, and corticosterone, as well as HPAA response to immobilization stress, did not change. Orchidectomized and primed with estradiol and progesterone males did not exhibit lordosis response to the presence of a sexually experienced male. Conclusion: Administration of ibuprofen to female Wistar rats during the last week of gestation disrupts partially neuroendocrine programming of male-type copulative behavior in male offspring with no changes in female-type sexual behavior and HPAA function. It is hypothesized that incomplete masculinization of the developing fetal brain with ibuprofen is due to two co-operative mechanisms: inhibition of synthesis of testosterone in the fetal gonads and prostaglandin E2 in the preoptic area of the hypothalamus.

Novel thiadiazol derivatives; design, synthesis, biological activity, molecular docking and molecular dynamics

Currently, selective COX-2 inhibitors are used as a novel alternative approach in the course of pain management due to their reduced adverse that generally occur after COX-1 inhibition by non-selective COX inhibitors. In this work, 16 new thiadiazole derivatives (3a-3p) were designed, synthesized and biologically evaluated for their COX-1 and COX-2 inhibitory potential using the in vitro fluorometric method. The biological evaluation showed that compounds 3c and 3d displayed significant activity against COX-2 with IC50 values of 0.350±0.015 µM and 0.134±0.004 µM, respectively, making the compound 3d similar in its activity to the reference drug celecoxib (IC50=0.132±0.005 µM). Further docking simulation also revealed that the most active derivative (3d) interacted with the enzyme active site in a similar manner to celecoxib. The binding modes of the compound on COX-2 were fully elucidated by molecular dynamics studies.

Anoxia/reoxygenation enhances spontaneous contractile activity via TRPA1 channel and COX2 activation in isolated rat whole bladder.

Bladder ischemia/reperfusion is an important etiologic factor for overactive bladder disease. The occurrence of this disease is closely associated with enhanced spontaneous contractile activity of the bladder. However, the relationship between bladder ischemia/reperfusion and altered spontaneous bladder contractions (SBC) remains poorly studied. Therefore, the present study investigated whether ischemia/reperfusion affects SBC ex vivo. SBC was measured using isolated whole bladder preparations from rats. The preparations were exposed to anoxia (95% N2 ) for 0.5-6 h, followed by reoxygenation (95% O2 ) in Krebs medium. Anoxia followed by reoxygenation significantly enhanced the amplitude of SBC without affecting its frequency in an anoxic duration-dependent manner. The 5 h anoxia/reoxygenation-induced enhancement of SBC amplitude was completely suppressed by an antioxidant combination of L(+)-ascorbate/D, L-α-tocopherol, or N-acetyl cysteine. Additionally, the enhanced SBC amplitude was inhibited in a concentration-dependent manner by the nonselective TRP antagonist ruthenium red, or selective TRPA1 antagonists HC-030031 or AP-18. A similar inhibitory effect was obtained after repeated treatment with the TRPA1 agonist allyl isothiocyanate, as it induced acute desensitization of TRPA1 channels. Further, the enhanced SBC amplitude was significantly diminished by the nonselective cyclooxygenase (COX) inhibitor indomethacin or selective COX2 inhibitor NS-398, but not by the selective COX1 inhibitor SC-560 and 5-lipoxygenase inhibitor MK-886. The study findings reveal that the spontaneous contractile activity of the bladder is significantly enhanced in response to anoxia/reoxygenation, and that oxidative stress and activation of TRPA1 and COX2 (the resulting production of prostaglandins) are involved in the enhanced SBC activity.

Cross-species comparisons reveal resistance of human skeletal stem cells to inhibition by non-steroidal anti-inflammatory drugs.

Fracture healing is highly dependent on an early inflammatory response in which prostaglandin production by cyclo-oxygenases (COX) plays a crucial role. Current patient analgesia regimens favor opioids over Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) since the latter have been implicated in delayed fracture healing. While animal studies broadly support a deleterious role of NSAID treatment to bone-regenerative processes, data for human fracture healing remains contradictory. In this study, we prospectively isolated mouse and human skeletal stem cells (SSCs) from fractures and compared the effect of various NSAIDs on their function. We found that osteochondrogenic differentiation of COX2-expressing mouse SSCs was impaired by NSAID treatment. In contrast, human SSCs (hSSC) downregulated COX2 expression during differentiation and showed impaired osteogenic capacity if COX2 was lentivirally overexpressed. Accordingly, short- and long-term treatment of hSSCs with non-selective and selective COX2 inhibitors did not affect colony forming ability, chondrogenic, and osteogenic differentiation potential in vitro. When hSSCs were transplanted ectopically into NSG mice treated with Indomethacin, graft mineralization was unaltered compared to vehicle injected mice. Thus, our results might contribute to understanding species-specific differences in NSAID sensitivity during fracture healing and support emerging clinical data which conflicts with other earlier observations that NSAID administration for post-operative analgesia for treatment of bone fractures are unsafe for patients.

INHIBITION OF SELECTIVE AND NON-SELECTIVE SICLOOXYIGENASE ON ANSIOLITIC EFFECTS INDUCED DIAZEPAM IN MICE

Stress is the source of many sociological, medical, and economic problems. Moreover, stresses are known as the etiology of several diseases. Prostaglandins and all four receptors affect the brain, even thought to affect behavior. Hence, the inactivation of cyclooxygenase (COX) causes a decrease in levels of prostaglandins that contribute to stress development, thus decreasing the anxiolytic effect of diazepam. This study aims to see the effect of selective and non-selective COX inhibitors decreasing the Anxiolytic effect of diazepam using the EPM (Elevated Plus Maze) method in male white mice; animals were grouped to use Tragakan 2%, Diazepam 0.065 mg/kg BB and Tragakan 2% after an hour, Diazepam 0.065 mg/kg BB and then an hour later gives Ketoprofen 0.65 mg/kg BB for non-selective COX Inhibitor effect group, Diazepam 0.065 mg/kg BW, and then an hour later gives Celecoxib 0.65 mg/kg BB for group use of selective Cox-2 Inhibitor, test parameter in this study is the duration in open arm. Results showing decreased duration on open arm group has given diazepam combination ketoprofen or celecoxib are different P value <0.05 than diazepam only. Decline duration was highest shown by animals given celecoxib, so that could be stated gift selective COX-2 inhibitors bring down the effect of anxiolytic diazepam bigger.

Quantitative and Qualitative Estimation of Marketed Naproxen Tablets Available in Bangladesh

Naproxen is a non-steroidal anti-inflammatory drug (NSAID) working as a non-selective cyclooxygenase (COX) inhibitor to treat inflammation, pain, fever, and various disease conditions. The current study was conducted to determine and compare several in vitro quality parameters, often commercially available 500 mg naproxen brands available in Bangladesh. According to the existing protocols, different physical parameters such as uniformity of weight, hardness, friability, disintegration time and dissolution were determined. A validated UV-visible spectrophotometric approach was used to assess the content uniformity of drug material in the collected brands. All the brands taken for this study complied with the official specifications of physical parameters. These brands contained active ingredients ranging from 91.37% up to 101.18%. On the other hand, two brands (C4 and C8) of naproxen tablets failed to meet the specification of United States Pharmacopoeia (USP), 90-110% of the labeled claim for the 500 mg naproxen tablet. These sub-standard brands possessed only 88.16% and 86.67% naproxen sodium. In conclusion, the current study indicated that eight out of the ten brands complied with quality parameters and can be used correspondingly. Bangladesh Pharmaceutical Journal 25(2): 175-179, 2022 (July)

Comparative analysis of the use of non-steroidal anti-inflammatory drugs in Montenegro, Finland and Croatia in the period 2010-2019.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used drugs. However, numerous studies have shown that non-selective cyclooxygenase (COX) inhibitors can also significantly increase the risk of cardiovascular side effects. Diclofenac has the highest risk, while naproxen has the lowest risk of developing these complications. The aim of the study was to analyze the structure and amount of NSAIDs consumed in Montenegro, Finland and Croatia in the last 10 years. In our study, we used 90% drug use (DU90) and ATC/DDD methodology. Drug consumption is shown in DDD/1000 inhabitants/day, and drug prices per DDD in Euros (€). Pearson's correlation test was used to examine the correlation between the number of drugs consumed and their price. Diclofenac consumption is 3 to 4 times higher in Montenegro compared to Croatia, and 9 to 10 times higher than in Finland. The average price of diclofenac in Montenegro was around € 0.07 per DDD, in Finland around € 0.26 per DDD and in Croatia € 0.19 per DDD. In Montenegro, the Pearson correlation test did not show a statistically significant association between high diclofenac consumption and its DDD price but showed a positive strong correlation between DDD price growth and naproxen consumption growth. The situation in Montenegro regarding the consumption of diclofenac is unfavorable and it is necessary to change the attitude and awareness of doctors and patients about the use of diclofenac. It is also necessary to replace diclofenac with naproxen, which is a slightly more expensive but safer drug.

Rosa damascena Miller essential oil relaxes rat thoracic aorta through the NO-cGMP-dependent pathway

AimThis study aimed to investigate the effects of Rosa damascena Mill. essential oil on the vascular activity of rat thoracic aorta and its underlying mechanisms. MethodsExperiments were performed using the isolated tissue bath model and Wistar rats. 0.1, 1, 10, and 100 µg/mL concentrations of rose oil were administered in all groups. To determine the vasoactive effects of rose oil, submaximal contractions were conducted by applying 10−5 M PE and 45 mM KCl separately in both endothelium-intact and -denuded segments. Time-matched distilled water groups were formed for control. To evaluate the role of endothelium-derived vasodilative factors, endothelium-intact segments were incubated with nitric oxide synthase inhibitor L-NAME, soluble guanylate cyclase inhibitor ODQ, and a non-selective cyclooxygenase inhibitor INDO. The statistical significance level was considered as p < 0.05. Results1, 10, and 100 µg/mL rose oil doses led to vasorelaxation in thoracic aortas precontracted with 10−5 M PE (p: 0.029, p: 0.000, p: 0.000, respectively). In precontracted thoracic aortas with 45 mM KCl, the significant effect of rose oil persisted, albeit slightly diminished. When the endothelium was removed, the relaxant effect of rose oil was partially reduced, but still significant (p: 0.035, p: 0.028, p: 0.000, respectively). Preincubations with L-NAME and ODQ significantly attenuated rose oil-induced relaxation of endothelium-intact aortas precontracted with 10−5 M PE. In contrast, preincubation INDO did not modulate rose oil-induced relaxation. ConclusionIn conclusion, it was shown for the first time that rose oil can significantly mediate vasorelaxation in both PE and KCl precontracted rat thoracic aortas. Rose oil induced vasodilation with or without endothelium in a concentration-dependent manner. It was also shown that rose oil-induced vasorelaxant effects were reduced by L-NAME or ODQ pretreatment, but not modulated by INDO. These results demonstrated that rose oil-induced endothelium-dependent vasodilation is mediated by the NO-cGMP-dependent pathway.

Non-steroidal anti-inflammatory drugs (NSAIDs), pain and aging: Adjusting prescription to patient features.

A narrative review of papers published from January 2011 to December 2021, after a literature search in selected databases using the terms "pharmacokinetics", "ibuprofen", "diclofenac", "acemetacin", "naproxen", "etodolac" and "etoricoxib" was performed. From 828 articles identified, only eight met the inclusion criteria. Selective COX-2 inhibitors are associated with higher cardiovascular risk, while non-selective COX inhibitors are associated with higher gastrointestinal risk. NSAIDs with lower renal excretion with phase 2 metabolism are less likely to induce adverse effects and drug-drug interactions. Patients with frequent NSAID use needs, such as elderly patients and patients with cardiovascular disease or impaired renal function, will benefit from lower renal excretion (e.g. acemethacin, diclofenac, and etodolac) (level of evidence 3). Polymedicated patients, elderly patients, and patients with chronic alcohol abuse will be at a lower risk for adverse effects with NSAIDs that undergo phase 2 liver biotransformation, namely, acemethacin and diclofenac (level of evidence 3). Young patients, patients dealing with acute pain, or with active and/or chronic symptomatic gastritis, selective COX-2 inhibitors (celecoxib or etoricoxib) may be a better option (level of evidence 2). Knowing the individual characteristics of the patients, combined with knowledge on basic pharmacology, offers greater safety and better adherence to therapy. PERSPECTIVE: Although there are several NSAIDs options to treat pain, physicians usually take special care to its prescription regarding cardiovascular and gastrointestinal side effects, despite the age of the patient. In this paper, based on the best evidence, the authors present a review of the safest NSAIDs to use in the elderly.

PERMISSIVE ROLE OF ANGIOTENSIN II IN MANTENANCE OF ENDOTHELIUM-DEPENDENT VASODILATION IN CEREBRAL MICROCIRCULATION

Objective: A number of data suggest, rather controversial, permissive role of angiotensin II (ANGII) in maintaining vasodilator responses in microcirculation, via its interaction with AT1 receptors (AT1R). This study aimed to determine the role of ANGII and AT1R in the mechanisms of flow-induced dilation (FID) in middle cerebral arteries (MCA) and incidence of oxidative stress at the functional, cellular and molecular level in the cerebral vasculature and in the serum of Sprague-Dawley (SD) rats fed high salt diet (HS). Design and method: Eleven-week old, male SD rats were randomly assigned to control group (CTRL, 0.4% NaCl in rat chow); Losartan group (rats on a standard diet given the AT1R blocker losartan (1 mg/mL) in drinking water); HS group (7 days 4% NaCl in rat chow) or HS+ANGII group (7 days HS with 3 days ANGII administration via osmotic minipumps (100 ng/kg/min on days 4–7)). FID of MCA was determined in absence/presence of the NOS inhibitor L-NAME, the non-selective cyclooxygenases inhibitor indomethacin, and the superoxide dismutase mimetic TEMPOL. Gene and protein expression of antioxidative enzymes and enzymes involved in FID mechanisms were determined by RT-qPCR and western blot. Vascular NO and superoxide/ROS levels were assessed by direct fluorescence. Serum systemic oxidative stress parameters was measured by spectrophotometry. All experimental procedures conformed to the EU Directive 2010/63/EU. Results: HS or AT1R blockade impaired FID and increased oxidative stress. Supplementation of ANGII restored the mechanisms of FID in MCA of rats fed HS diet to the ones present in CTRL rats without affecting arterial blood pressure by decreasing systemic oxidative stress and decreasing superoxide/ROS levels and increased NO bioavailability in the vascular wall of HS treated rats. The AT1R blockade resulted in significantly attenuated endothelium-dependent dilation, changed mechanisms of FID, increased vascular and systemic oxidative stress and decreased expression/ activity of antioxidative enzymes. Conclusions: ANGII is crucial in the preservation of vascular oxidative stress-antioxidant system balance and via AT1R, in maintenance of physiological vasodilation mechanisms of MCA. Suppression of ANGII is a key link between HS intake and development of endothelial dysfunction, and impaired regulation of cerebral blood flow.

A new series of thiosemicarbazone-based anti-inflammatory agents exerting their action through cyclooxygenase inhibition.

In an endeavor to identify potent anti-inflammatory agents, new thiosemicarbazones (TSCs) incorporated into a diaryl ether framework (2a-2l) were prepared and screened for their in vitro inhibitory effects on cyclooxygenases (COXs). 4-[4-(Piperidin-1-ylsulfonyl)phenyl]-1-[4-(4-cyanophenoxy)benzylidene]thiosemicarbazide (2c) was the most potent and selective COX-1 inhibitor in this series, with an IC50 value of 1.89 ± 0.04 µM. On the other hand, 4-[4-(piperidin-1-ylsulfonyl)phenyl]-1-[4-(4-nitrophenoxy)benzylidene]thiosemicarbazide (2b) was identified as a nonselective COX inhibitor (COX-1 IC50 = 13.44 ± 0.65 µM, COX-2 IC50 = 12.60 ± 0.78 µM). Based on molecular docking studies, the diaryl ether and the TSC groups serve as crucial moieties for interactions with pivotal amino acid residues in the active sites of COXs. According to MTT test, compounds 2b and 2c showed low cytotoxic activity toward NIH/3T3 cells. Their in vivo anti-inflammatory and antioxidant potencies were also assessed using the lipopolysaccharide-induced sepsis model. Compounds 2b and 2c diminished high-sensitivity C-reactive protein, myeloperoxidase, nitric oxide, and malondialdehyde levels. Both compounds also caused a significant decrease in aspartate aminotransferase levels as well as alanine aminotransferase levels. In silico pharmacokinetic studies suggest that compounds 2b and 2c possess favorable drug-likeness and oral bioavailability. It can be concluded that these compounds may act as orally bioavailable anti-inflammatory and antioxidant agents.

Clinical Pharmacology of Paracetamol in Infants and Children

Paracetamol (acetaminophen) has analgesic and antipyretic effects similar to those of aspirin but has only weak anti-inflammatory effects. It is a nonselective cyclooxygenase inhibitor which acts at the peroxidase site of the enzyme and is thus distinct among the nonsteroidal anti-inflammatory drugs. The major metabolites of paracetamol are paracetamol glucuronide and paracetamol sulphate and the minor metabolites are mercapturic acid cysteine conjugates and N-acetyl-p-benzoquinone imine. The last is a highly reactive intermediate and it reacts with sulfhydryl groups in glutathione and is harmless. Paracetamol may be administered orally, rectally, or intravenously. In infants, the oral dosing of paracetamol consist in a loading dose of 20 mg/kg following by subsequent doses of 10 to 15 mg/kg, and in children, the dose varies with the child age and body-weigh. Paracetamol has been found efficacy and safe in infants and children but it may induce adverse-effects. The elimination half-life of paracetamol is 11.0 and 4.38 hours in more immature preterm infants and in less immature preterm infants, respectively, and it is 3.45 hours in children. Propranolol interacts with drugs. The prophylaxis, treatment, and trials with paracetamol have been investigated in infants and children. Paracetamol may induce toxicity and it crosses the human placenta and migrates into the breast milk in significant amounts. The aim of this study in the review of paracetamol dosing, efficacy and safety, adverse-effects, metabolism, pharmacokinetics, drug interaction, prophylaxis, treatment, trials, toxicity in infants and children, and paracetamol transfer across the human placenta and migration into the breast milk.

Safety and Efficacy of Postoperative Nonsteroidal Anti-inflammatory Drugs in Sports Medicine.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for multimodal pain control after surgery. These medications work by selective or nonselective inhibition of cyclooxygenase, which has downstream effects on thromboxanes, prostaglandins, and prostacyclins. Clinical studies have shown beneficial effects for alleviating pain and reducing opioid consumption after surgery. Within hip arthroscopy, there is evidence that postoperative NSAIDs can also reduce the risk of symptomatic heterotopic bone formation. However, preclinical and animal studies have raised concern over the effect of NSAIDs on bone and soft-tissue healing. In addition, selective and nonselective cyclooxygenase 2 inhibitors may have different safety profiles regarding postoperative soft-tissue healing. The purpose of this review was to outline the mechanisms of action, efficacy, and effect on soft-tissue healing of postoperative NSAIDs and to provide evidence-based recommendations for appropriate use.

The influence of non-steroidal anti-inflammatory drugs with different mechanisms of action on the course of stress reaction, the functional state of kidneys, liver, and heart on the model of acute general cooling

Inhibitors of the arachidonic acid cascade have significant potential as the agents for the prevention of severe cold injuries. The results of the previous studies have demonstrated the pronounced frigoprotective properties of certain non-steroidal anti-inflammatory drugs, primarily diclofenac sodium, etoricoxib, darbufelone mesylate, under the conditions of acute general cooling.&#x0D; The aim of the study: to investigate the effect of non-steroidal anti-inflammatory drugs with various mechanisms of action on the course of the stress reaction, the functional state of the kidneys, liver, and heart using the model of acute general cooling.&#x0D; Materials and Methods: The experiment was carried out using 35 outbreed male rats weighing 256±5 g. The studied drugs were administered intragastrically 30 minutes before cold injury modelling: diclofenac sodium at a dose of 7 mg/kg, etoricoxib at a dose of 5 mg/kg, darbufelone mesylate at a dose of 20 mg/kg. Acute general cooling was induced by exposure at –18 °C for 2 hours. The efficacy of the studied drugs was evaluated by the values as follows: the body temperature (measured rectally), the course of a stress reaction according to the criteria of “the stress triad”, the functional state of the kidney and liver according to the changes in the blood serum biochemical parameters, the functional state of the heart according to the electrocardiogram.&#x0D; Results: It was found that etoricoxib and darbufelone mesylate, and especially diclofenac sodium, demonstrate frigoprotective properties, reducing the severity of hypothermia, have stress-protective activity and a beneficial effect on the functional state of the kidneys. All investigated non-steroidal anti-inflammatory drugs prevent a decrease in myocardial contractility (by the effect on the systolic index) and lengthening of the QT interval caused by acute cold injury. Diclofenac sodium, unlike etoricoxib and darbufelone mesylate, does not enhance the effect of acute general cooling on intraventricular conduction. Under acute exposure to cold, no significant changes in the functional state of the liver were observed, including the groups receiving the nonsteroidal anti-inflammatory medicines.&#x0D; Conclusions: The prophylactic administration of the arachidonic acid cascade inhibitors, especially the non-selective COX-2 inhibitor diclofenac sodium, reduces the severity of the stress response, contributes to the maintenance of the renal and cardiac function. There are no significant changes in the functional state of the liver under conditions of the experiment

Neural circuits mediating circulating interleukin-1β-evoked fever in the absence of prostaglandin E2 production

Infectious diseases and inflammatory conditions recruit the immune system to mount an appropriate acute response that includes the production of cytokines. Cytokines evoke neurally-mediated responses to fight pathogens, such as the recruitment of thermoeffectors, thereby increasing body temperature and leading to fever. Studies suggest that the cytokine interleukin-1β (IL-1β) depends upon cyclooxygenase (COX)-mediated prostaglandin E2 production for the induction of neural mechanisms to elicit fever. However, COX inhibitors do not eliminate IL-1β-induced fever, thus suggesting that COX-dependent and COX-independent mechanisms are recruited for increasing body temperature after peripheral administration of IL-1β. In the present study, we aimed to build a foundation for the neural circuit(s) controlling COX-independent, inflammatory fever by determining the involvement of brain areas that are critical for controlling the sympathetic outflow to brown adipose tissue (BAT) and the cutaneous vasculature. In anesthetized rats, pretreatment with indomethacin, a non-selective COX inhibitor, did not prevent BAT thermogenesis or cutaneous vasoconstriction (CVC) induced by intravenous IL-1β (2 µg/kg). BAT and cutaneous vasculature sympathetic premotor neurons in the rostral raphe pallidus area (rRPa) are required for IL-1β-evoked BAT thermogenesis and CVC, with or without pretreatment with indomethacin. Additionally, activation of glutamate receptors in the dorsomedial hypothalamus (DMH) is required for COX-independent, IL-1β-induced BAT thermogenesis. Therefore, our data suggests that COX-independent mechanisms elicit activation of neurons within the DMH and rRPa, which is sufficient to trigger and mount inflammatory fever. These data provide a foundation for elucidating the brain circuits responsible for COX-independent, IL-1β-elicited fevers.

Effects of cyclooxygenase and soluble epoxide hydrolase inhibitors on apoptosis of cultured primary equine chondrocytes

BackgroundApoptosis is an important mechanism underlying chondrocyte loss in osteoarthritis that could be affected by modulation of lipid signaling via inhibition of cyclooxygenases (COX) and soluble epoxide hydrolase (sEH). ObjectiveTo determine the impact of inhibiting COX and sEH alone or in combination on apoptosis of equine chondrocytes. MethodsCultured primary equine chondrocytes were subjected to serum deprivation or incubation with 1 μg/ml tunicamycin for 24 h to induce apoptosis via caspase activation and endoplasmic reticulum (ER) stress, respectively. Cells were treated with the non-selective COX inhibitor phenylbutazone, the COX-2 selective inhibitor firocoxib and the sEH inhibitor t-TUCB alone or in combination. The inhibitors were used at half-maximal (IC50), 80% of maximal (IC80) and 10-fold the 80% inhibitory concentration (10xIC80) for the equine enzymes. Apoptosis was quantified via ELISA technique. Data were analyzed with unpaired two-tailed t-test or one-way ANOVA followed by Bonferroni's post-hoc while correcting for multiple comparisons via statistical hypothesis testing. P < 0.05 was considered significant. ResultsIn the caspase model, 10xIC80t-TUCB significantly decreased whereas 10xIC80 phenylbutazone significantly enhanced apoptosis. Apoptosis enhancement by phenylbutazone was significantly attenuated by concurrent 10xIC80t-TUCB. The remaining treatments and concentrations had no effect on apoptosis development. In the ER stress model, IC50 and IC80 phenylbutazone and firocoxib significantly enhanced apoptosis, which was fully prevented by concurrent 10xIC80t-TUCB. Main limitationsIn vitro findings that will need to be verified in vivo. ConclusionsChondrocyte apoptosis caused by ER stress can be enhanced by COX inhibition but prevented by concurrent inhibition of sEH.

Near-Infrared Fluorescent Heptamethine Cyanine Dyes for COX-2 Targeted Photodynamic Cancer Therapy.

We designed and synthesized two heptamethine cyanine-based theranostic probes that aimed to target COX-2 in cancer cells. One is I-IR799-CXB, in which I-IR799 is conjugated to the COX-2-specific inhibitor, celecoxib, and another is I-IR799-IMC, where the non-selective COX inhibitor, indomethacin, was used. I-IR799 is a heptamethine cyanine derivative that can be activated by near-infrared light for photodynamic therapy (PDT) purposes. I-IR799-CXB and I-IR799-IMC were tested for their cancer-targeting capacity and photodynamic efficiency toward hepatocellular carcinoma (HepG2) cells relative to normal liver cells, alpha mouse liver 12 (AML12) cells. Interestingly, after conjugation, I-IR799-IMC exhibited better tumour targetability and PDT efficiency than I-IR799-CXB.