Inhibition Of Prostaglandin Synthesis Research Articles

Nonsteroidal Anti-Inflammatory Drug Prescriptions Are Associated With Increased Stress Fracture Diagnosis in the US Army Population.

ABSTRACTStress fractures are common in military personnel and endurance athletes, and nonsteroidal anti‐inflammatory drug (NSAID) use is widespread in these populations. NSAIDs inhibit prostaglandin synthesis, which blunts the anabolic response of bone to physical activity and could therefore increase risk of stress fracture. The objective of this study was to determine whether prescribed NSAIDs were associated with stress fracture diagnoses among US Army soldiers. We also aimed to establish whether acetaminophen, an analgesic alternative to NSAIDs, was associated with stress fracture risk. A nested case‐control study was conducted using data from the Total Army Injury and Health Outcomes Database from 2002 to 2011 (n = 1,260,168). We identified soldiers with a diagnosis of stress fracture (n = 24,146) and selected 4 controls per case matched on length of military service (n = 96,584). We identified NSAID and acetaminophen prescriptions 180 to 30 days before injury (or match date). We also identified soldiers who participated in basic combat training (BCT), a 10‐week period of heightened physical activity at the onset of Army service. Among these individuals, we identified 9088 cases and 36,878 matched controls. Conditional logistic regression was used to calculate incident rate ratios (RR) for stress fracture with adjustment for sex. NSAID prescription was associated with a 2.9‐fold increase (RR = 2.9, 95% confidence interval [CI] 2.8–2.9) and acetaminophen prescription with a 2.1‐fold increase (RR = 2.1, 95% CI 2.0–2.2) in stress fracture risk within the total Army population. The risk was more than 5‐fold greater in soldiers prescribed NSAIDs (RR = 5.3, 95% CI 4.9–5.7) and more than 4‐fold greater in soldiers prescribed acetaminophen (RR = 4.4, 95% CI 3.9–4.9) during BCT. Our results reveal an association between NSAID and acetaminophen prescriptions and stress fracture risk, particularly during periods of heightened physical activity. Prospective observational studies and randomized controlled trials are needed to support these findings before clinical recommendations can be made. © 2018 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).

The efficacy of oleuropein against non-steroidal anti-inflammatory drug induced toxicity in rat kidney.

Indomethacin is generally used in clinical therapeutics as a non-steroidal anti-inflammatory drug. However, its use has been limited due to the gastrointestinal and renal toxic effects of this drug. These toxic effects were associated with not only the inhibition of prostaglandin synthesis but also drug-elevated oxidative stress. To ameliorate these toxicities, natural antioxidants can be used as an alternative and/or combination therapies. Therefore, the current study was conducted to assess the renoprotective effects of oleuropein against indomethacin-induced renal damages. Male Sprague-Dawley rats were pretreated with oleuropein (75, 150, and 300 mg/kg), and then treated with indomethacin (25 mg/kg). To evaluate kidney function, serum blood urea nitrogen, uric acid, and creatinine were measured. In addition, prostaglandin E2 , tumor necrosis factor-alpha, endothelial nitric oxide synthase, caspase-3, oxidant/antioxidant status, and 8-Oxo-2'-deoxyguanosine levels were determined for the antioxidative and anti-inflammatory effects of oleuropein. Tissue sections were also histopathologically assessed. The biochemical and histopathological analysis proved the toxic effects of indomethacin on kidney. However, the pretreatment with oleuropein (300 mg/kg) protects kidney from indomethacin-induced damages. Our study proved that prior administration of oleuropein has renoprotective activity against indomethacin-associated toxicities.

Predictors, Treatment and Prevention of Preterm Labour: A Review

Preterm labour (PTL) is one of the leading causes of neonatal morbidity and mortality throughout the world. It is also a major public health problem for its long-term disabilities like cerebral palsy and visual disturbance. Preterm labour is a multifactorial problem and its overall global incidence is 11.1 per 100 live births with a significant regional variation. About 45-50% of preterm deliveries are spontaneous, 30% are associated with preterm prelabour rupture of membranes (PPROM) and another 15-25% is induced for maternal and/or foetal risk. Previous history of PTL is an important risk factor; risk is 14.3% after one preterm birth and 28% after two preterm births. Other important risk factors are multiple pregnancy, polyhydramnios, bicornuate uterus, cervical incompetence & bacterial vaginosis. Prediction of PTL is very difficult but identification of risk factors, assessment of cervical length by ultrasonography and detection of foetal fibronectin in cervical secretions are of great help. Advanced cervical dilatation (>3 cm) or PPROM associated with sufficient and frequent uterine contractions confirm the diagnosis of preterm labour. Prevention of PTL has been tried with prophylactic cervical cerclage, antibiotics and progesterone. PTL is treated with various tocolytic agents and glucucorticoids and antibiotics for local or systemic infection. Betamimetics, calcium channel blockers (nifedipine), prostaglandin synthesis inhibitors and magnesium sulfate are the commonly used tocolytics. Nifedipine has significantly fewer maternal adverse effects than betamimetics and magnesium sulphate. Antenatal corticosteroid treatment has been found to lower neonatal mortality, the risk of neonatal respiratory distress syndrome, intraventricular hemorrhage and necrotizing enterocolitis. The ultimate goal of prevention and management of preterm labour is to improve neonatal outcome and to reduce morbidity and mortality.Journal of Science Foundation, July 2017;15(2):57-63

Abstract 1937: Inhibition of a novel cancer target, PDE10, suppresses Wnt/β-catenin signaling and colon tumorigenesis: Benefits from combining with ornithine decarboxylase inhibitors

Abstract Sulindac has been shown in clinical trials to reduce the number and size of precancerous colon adenomas, but is not recommended for the long-term management of polyposis syndromes because of potentially fatal toxicities resulting from cyclooxygenase (COX) inhibition and the suppression of prostaglandin synthesis. Here we characterize the activity of a non-COX inhibitory sulindac derivative, MCI-030, that inhibits a novel cancer target, phosphodiesterase 10A (PDE10), recently reported to be overexpressed in colon tumors and essential for tumor cell growth (Oncogene 34:1499-509, 2015). PDE10 is an attractive cancer target because of limited expression and no known function in normal peripheral tissues. MCI-030 potently and selectively inhibits the growth of multiple colon tumor cell lines expressing PDE10 with IC50 values of 0.3 μM, but does not affect the growth of normal colonocytes (NCM460) that do not express PDE10. Sulindac inhibits colon tumor cell growth with IC50 values approximately 200 fold higher and modest tumor cell selectivity. MCI-030 is PDE10 selective, but sulindac inhibits multiple PDE isozymes (PDE2, 3, 5, and 10). MCI-030 treatment of colon tumor cells increased intracellular cGMP levels and activated protein kinase G at concentrations that inhibit recombinant PDE10 and tumor cell growth. Inhibition of PDE10 by MCI-030 or siRNA increased the phosphorylation and degradation of β-catenin and inhibited Wnt-induced nuclear translocation to suppress TCF-mediated transcription of cyclin D and survivin, leading to cell cycle arrest and apoptosis. With attractive pharmacokinetics and ability to achieve high concentrations in colon mucosa following oral administration, MCI-030 was tested in the APC+/min-FCCC mouse model of colon tumorigenesis. At 7-8 weeks of age, mice endoscopically determined to be adenoma-free were assigned to receive either control or MCI-030 supplemented diet (1500ppm) for 14 weeks. MCI-030 reduced the multiplicity of colonic adenomas by 50% (control: 3.95 ± 0.81 vs. MCI-030: 1.95 ± 0.58, P < 0.05) and incidence by 36.7%. MCI-030 also reduced the multiplicity of polypoid adenomas (36%), microadenomas (69%), and flat adenomas (100%, P < 0.05). These data indicate that MCI-030 strongly inhibits tumorigenesis in a predictive preclinical mouse model of colorectal cancer without discernable toxicity and could be effective together with colonoscopy in humans to reduce polyp formation and prevent malignant progression. In addition, in vitro colony formation and transformation assays using human colon tumor cells showed benefits of combining MCI-030 with the ornithine decarboxylase inhibitor, DFMO, supporting testing of this novel combination in the APC+/min-FCCC mouse model as a strategy to further improve efficacy. Funding from NCI R01CA131378, R01CA148817, R01CA197147, and R01CA155638. Citation Format: Gary A. Piazza, Ashleigh Neese, Kevin Lee, Adam Keeton, Yulia Maxuitenko, Veronica Ramirez Alcantara, Kristy Berry, Jacob Valiyaveettil, Antonio Ward, Luciana Madeira da Silva, Jennifer Scalici, Bing Zhu, Tyler Mattox, Xi Chen, Margie Clapper, Harry Cooper, Wen-Chi Chang. Inhibition of a novel cancer target, PDE10, suppresses Wnt/β-catenin signaling and colon tumorigenesis: Benefits from combining with ornithine decarboxylase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1937.

Current evidence for central analgesic effects of NSAIDs: an overview of the literature.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for a variety of painful conditions. Their peripheral anti-inflammatory effect due to inhibition of prostaglandin synthesis is well documented. In the late 1980's, animal data suggested for the first time that NSAIDs might have central effects as well. Since that time, central inflammatory and nociceptive pathways that are potential targets of NSAIDs have been extensively studied in both animal and human models. This review provides an overview of the relevant literature implicated in the central effects of NSAIDs. The role of different enzymes and mediators, as well as the central effects of NSAIDs are discussed. Literature search was performed by PubMed NCBI. A large body of evidence supports the central effects of NSAIDs in animal models of inflammatory pain conditions. Relevant mechanisms that underlie this central action involve spinal upregulation of the enzyme cyclooxygenase, increased spinal prostaglandin E2 production, modulation of inhibitory fast synaptic currents in lamina I and II of the dorsal horn, and glycine-dependent modulation of pain. Results from animal models are not yet sufficiently supported by human studies. This does not necessarily imply that the central effects of NSAIDs are irrelevant to human pain, but rather that methodological and regulatory barriers are the limiting step to translating findings from animal studies to human research protocols.

Illicium verum Extract Exhibited Anti-inflammatory Action in Rodents

Background: Illicium verum Hook. f. (Star anise) has been traditionally used for the treatment of abdominal colic, vomiting, pain, nervousness, insomnia and rheumatism. Objective: The present study was conducted to investigate the anti-inflammatory properties of Illicium verum extracts. Methods: Different extracts of I. verum (IV-Ext-1, IV-Ext-3 and IV-Ext-4) were screened for their anti-inflammatory potential using carrageenan-induced paw edema in mice. The mechanism of action was explored using paw edema tests (carrageenan, histamine, serotonin and prostaglandins) in rats and anti-oxidant activity (DPPH assay). Reverse phase HPLC was used for chemical characterization of extracts. Results: The IV-Ext-3 was found to be the most potent anti-inflammatory agent (38% inhibition) using carrageenan-induced paw edema. The anti-inflammatory effect was observed during both the initial (IC50: 260 mg/kg) and late phases (IC50: 200 mg/kg). Similar IC50 of 200 mg/kg was observed in both phases of histamine-induced paw edema. However, the extract failed to cause 50% inhibition in serotonin-induced edema (IC25: 400 mg/kg) and was also ineffective against Prostaglandin- E2 induced edema. Furthermore, the IV-Ext-3 appeared to be an effective antioxidant (IC50: 12 µg/ml). The HPLC chromatogram of IV-Ext-3 showed the presence of anti-inflammatory constituents such as shikimic acid (1.6%) and anethole (0.25%), 3, 4-dihydroxybenzoic acid (0.003%) and p-hydroxy methyl benzoate (0.117%) along with some polar hydroxyl derivatives of benzoic acids. Conclusion: Among all the extracts of I. verum, IV-Ext-3 was found to be the most effective antiinflammatory agent which can be attributed to multiple anti-inflammatory constituents, antihistamine and antioxidant potentials. Keywords: Star anise, anti-histamine, prostaglandins synthesis inhibitor, antioxidant, anti-inflammatory, edema.

Long-term outcome in inherited nephrogenic diabetes insipidus.

BackgroundInherited nephrogenic diabetes insipidus (NDI) is a rare disorder characterized by impaired urinary concentrating ability. Little clinical data on long-term outcome exists.MethodThis was a single-centre retrospective medical record review of patients with a diagnosis of NDI followed between 1985 and 2017. We collected available data on growth, weight, school performance, complications and comorbidities.ResultsWe identified 36 patients with available data and a clinical diagnosis of NDI, which was genetically confirmed in 33 of them. Patients presented at a median age of 0.6 years and median length of follow-up was 9.5 years. Chief symptoms at presentation were faltering growth, vomiting/feeding concerns, polyuria/polydipsia, febrile illness and hypernatraemic dehydration. Median weight standard deviation scores (SDS) improved from −2.1 at presentation to 0.2 at last follow-up. In contrast, height SDS remained essentially unchanged at −1.1 at presentation and −0.9 at last follow-up. Most patients were treated with prostaglandin synthesis inhibitors and thiazides, yet weaned off during school age without an obvious change in urine output. Median estimated glomerular filtration rate at last follow-up was 81 mL/min/1.73 m2. Urological complications were noted in 15 patients, constipation in 11 and learning difficulties in 5. Median age at resolution of nocturnal enuresis was 11 years. Estimated median daily fluid intake at median age of 13 years was 3800 mL/m2.ConclusionThe overall prognosis in inherited NDI is favourable with regular treatment. As expected, most complications were related to polyuria. There is an apparent loss of efficacy of medications during school age. Our data inform the prognosis and management of patients with NDI.

Comparison of the Effects of Local Injection and Oral Intake of Diclofenac and Atorvastatin in Alveolar Bone Density Assessed with CT in Experimental Periodontitis in Rat

Objectives The first cause of tooth loss in developed countries is periodontitis. Chronic periodontitis is the most common form of periodontitis and it is characterized by loss of periodontal attachment, destruction of alveolar bone and eventual loss of teeth. Atorvastatin is a statin drug used for the treatment of high cholesterol. Statins can stop the inflammatory process by inhibiting the cholesterol pathway. Diclofenac is an NSAID with anti-inflammatory, anti-pyretic and analgesic effects. Its primary mechanism is through the inhibition of prostaglandins synthesis by the inhibition of the cyclooxygenase enzyme (COX). The purpose of this study is to compare the effects of local injected and oral intake of Diclofenac and atorvastatin on alveolar bone density measured in HUs with the use of a CT scan in a periodontitis-induced model in rats.Methods Thirty rats were randomly divided into 6 groups of 5 rats each. Ligatures were placed around the left second maxillary molar to induce periodontitis for 10 days. Administration of 12.5 mg/kg of oral atorvastatin (group 1), 0.25 mg/kg of injectable atorvastatin (group 2), 7.5mg/kg of oral Diclofenac (group 3), 6.25mg/kg of injectable Diclofenac (group 4), the oral solvent without medicine as oral control (groups 5), and the injectable solvent without medicine as injectable control (group 6). In each group, the right side of maxilla was considered as control group (without ligature and drug interaction). At day eleven, the rats were sacrificed and the maxillary bone was separated from the soft tissue and fixed in 4% formalin. The prepared samples were then radiologically evaluated to determine the bone density with CT in fixed exposure conditions.Results There was a statistically significant difference between the alveolar bone density of the oral atorvastatin group and the oral Diclofenac (P = 0.006). There was no statistical significant difference in alveolar bone density between the injectable atorvastatin and the injectable Diclofenac groups (P=0.228).Conclusion Both atorvastatin and Diclofenac have shown better results when assessing bone density in a periodontitis rat model as compared to controls. Additionally, Diclofenac has been shown to be more effective at both oral and injectable administrations as compared with atorvastatin in the prevention of loss of bone density in a rat model with periodontitis.

VIP is involved in peripheral CRF-induced stimulation of propulsive colonic motor function and diarrhea in male rats.

We investigated whether vasoactive intestinal peptide (VIP) and/or prostaglandins contribute to peripheral corticotropin-releasing factor (CRF)-induced CRF1 receptor-mediated stimulation of colonic motor function and diarrhea in rats. The VIP antagonist, [4Cl-D-Phe6, Leu17]VIP injected intraperitoneally completely prevented CRF (10 µg/kg ip)-induced fecal output and diarrhea occurring within the first hour after injection, whereas pretreatment with the prostaglandins synthesis inhibitor, indomethacin, had no effect. In submucosal plexus neurons, CRF induced significant c-Fos expression most prominently in the terminal ileum compared with duodenum and jejunum, whereas no c-Fos was observed in the proximal colon. c-Fos expression in ileal submucosa was colocalized in 93.4% of VIP-positive neurons and 31.1% of non-VIP-labeled neurons. CRF1 receptor immunoreactivity was found on the VIP neurons. In myenteric neurons, CRF induced only a few c-Fos-positive neurons in the ileum and a robust expression in the proximal colon (17.5 ± 2.4 vs. 0.4 ± 0.3 cells/ganglion in vehicle). The VIP antagonist prevented intraperitoneal CRF-induced c-Fos induction in the ileal submucosal plexus and proximal colon myenteric plexus. At 60 min after injection, CRF decreased VIP levels in the terminal ileum compared with saline (0.8 ± 0.3 vs. 2.5 ± 0.7 ng/g), whereas VIP mRNA level detected by qPCR was not changed. These data indicate that intraperitoneal CRF activates intestinal submucosal VIP neurons most prominently in the ileum and myenteric neurons in the colon. It also implicates VIP signaling as part of underlying mechanisms driving the acute colonic secretomotor response to a peripheral injection of CRF, whereas prostaglandins do not play a role. NEW & NOTEWORTHY Corticotropin-releasing factor (CRF) in the gut plays a physiological role in the stimulation of lower gut secretomotor function induced by stress. We showed that vasoactive intestinal peptide (VIP)-immunoreactive neurons in the ileal submucosal plexus expressed CRF1 receptor and were prominently activated by CRF, unlike colonic submucosal neurons. VIP antagonist abrogated CRF-induced ileal submucosal and colonic myenteric activation along with functional responses (defecation and diarrhea). These data point to VIP signaling in ileum and colon as downstream effectors of CRF.

Chapter 54 - Antipyretic therapy: clinical pharmacology

Fever depends on a complex physiologic response to infectious agents and other conditions. To alleviate fever, many medicinal agents have been developed over a century of trying to improve upon aspirin, which was determined to work by inhibiting prostaglandin synthesis. We present the process of fever induction through prostaglandin synthesis and discuss the development of pharmaceuticals that target enzymes and receptors involved in prostaglandin-mediated signal transduction, including prostaglandin H2 synthase (also known as cyclooxygenase), phospholipase A2, microsomal prostaglandin E2 synthase-1, EP receptors, and transient potential cation channel subfamily V member 1. Clinical use of established antipyretics will be discussed as well as medicinal agents under clinical trials and future research.

The Determination and Clinical Significance of Prostaglandin E2 in Blood and Urine of Patients with Renal Colic.

This study explores the role of prostaglandin E2 (PGE2) in the etiology of urolithiasis in acute renal colic by analyzing the PGE2 levels in blood and urine throughout the clinical course of renal colic. From June 2015 to November 2017, a total of 60 patients with acute renal colic were enrolled in the study. Blood and urine samples were taken before and after administration of drug to inhibit prostaglandin synthesis; further blood and urine samples were obtained from the patients 2 weeks after their recovery. The concentration of PGE2 in blood and urine samples was determined by using a Human Prostaglandin E2 ELISA Kit. The mean concentration of PGE2 was 420 ± 50.3 ng/L in blood and 600 ± 70.1 ng/L in urine when the patients had renal colic. After drug therapy, these concentrations fell to 300 ± 40.4 ng/L in blood and 500 ± 54.5 ng/L in urine. After 2 weeks the PGE2 concentration was 220 ± 47.5 ng/L and 300 ± 50.2 ng/L in blood and urine, respectively. Compared with PGE2 levels after medication, these concentrations were significantly higher during acute renal colic (p < 0.05). The synthesis and release of PGE2 increase at the onset of renal colic, suggesting that PGE2 plays an important role in acute renal colic. Administration of a prostaglandin synthesis inhibitor is a reliable way to treat renal colic.

Neopioidni analgetici u savremenom lečenju bola

Pain is a symptom of most diseases that can significantly impair the patient's quality of life. In many diseases it is impossible to eliminate the cause of pain therefore the real goal of treatment is the removal of pain as a symptom, by application of analgesics. Contemporary pharmacotherapy employs conventional (opioid and non-opioid analgesics - NSAIDs and paracetamol) and adjuvant analgesics (antiepileptics, antidepressants and others). Analgesic effect of non-opioid analgesics is mainly the consequence of prostaglandin synthesis inhibition. They are effective for pain of mild/moderate intensity. In acute pain there is no difference in efficiency between NSAIDs and paracetamol, so the choice of the drug is individual. In chronic pain, when inflammation is present, NSAIDs are more effective than paracetamol. Long-term use of high doses of NSAIDs is often accompanied by side effects. In order to reduce their frequency, a careful assessment of risk for each patient should be made, a drug with a low risk of certain side effects should be chosen, the dose and duration of treatment should be limited and the possibility of topical application should be considered. The need for long-term use of NSAIDs should be reviewed periodically.

Intracameral Use of Nepafenac: Safety and Efficacy Study

ABSTRACTPurpose: To test the intracameral safety of nepafenac and its efficacy in inhibiting prostaglandin synthesis during phacoemulsification surgery.Methods: The safety evaluation was conducted in normal eyes of rabbits, 0.1ml of 0.3% and 1% nepafenac was injected intracamerally. Extensive studies to detect adverse response ranged from a gross examination of eyes under slit lamp biomicroscope, fluorescein dye test, Schirmer tear test, test for corneal sensitivity, intraocular pressure measurement (IOP), specular microscopy, electroretinography(ERG), and histopathological examination of intraocular tissues. Efficacy of nepafenac was studied by intracameral injection of 0.1%, 0.3% nepafenac, nepafenac 0.3%+1% lignocaine, and 1% lignocaine alone, before phacoemulsification surgery and intraoperative mydriasis along with PGE2(ProstaglandinE2) secretion were recorded.Results: Single 0.1ml of 0.3% or 1% nepafenac did not significantly (p > 0.05) alter physiological parameters and histology of cornea, iris, and retina. Nepafenac 0.3% effectively inhibited PGE2 secretion. No significant (p > 0.05) prevention of miosis was recorded with 0.1% or 0.3% nepafenac. However, a combination of 0.3% nepafenac + 1% lignocaine and 1% lignocaine alone significantly (p < 0.05) arrested miosis during the intraoperative period.Conclusion: An intracameral concentration of up to 1% nepafenac does not adversely affect the rabbit eye. Nepafenac fails to prevent miosis but inhibits prostaglandin release during phacoemulsification surgery.

Two common mild analgesics have no effect on general endocrine mediated endpoints in zebrafish (Danio rerio)

Mild analgesics such as acetylsalicylic acid (ASA) and acetaminophen (APAP) exert their pain-relieving effect in humans by inhibition of prostaglandin synthesis. Prostaglandins play key roles in developmental and reproductive processes in vertebrates, and in recent years, it has been suggested that weak analgesics might also act as endocrine disrupters. In a set of experiments we investigated if ASA and APAP affect well-established endocrine endpoints in zebrafish (Danio rerio), which is a commonly used model organism in the investigation of endocrine disrupting chemicals. Zebrafish were exposed to APAP (0.22, 2.3, and 30mgL−1) or ASA (0.2, 0.5, 1.7, and 8.2mgL−1) from hatch to sexual maturity in a test design resembling the OECD Fish Sexual Development Test. No effects on sex ratio and vitellogenin levels were observed. Adult zebrafish were exposed to high concentrations (mgL−1) of ASA or APAP for eight or 14days. ASA reduced the levels of prostaglandin E2, but had no effect on the concentration of 11-ketotestosterone and vitellogenin.Overall, ASA decrease prostaglandin E2 concentrations, but well-established endpoints for endocrine disruption in zebrafish are generally not affected by aquatic exposure neither during development nor adulthood. According to the WHO/IPCS definition of an endocrine disrupter, the present results do not define APAP and ASA as endocrine disrupters.

Role of Cyclooxygenase Inhibitors in Diminution of Dissimilar Stress-induced Depressive Behavior and Memory Impairment in Rats

Memory functions can be considerably affected by various life events and stress has shown to be a chief regulator. Different stress patterns have distinct effects on the overall functioning of the brain. Stress provokes inflammation not only in the periphery but also in the brain. Neuroinflammation causes alterations in neuronal structure and function, which eventually progress to the development of neurodegenerative diseases. Inflammatory reactions are modulated through communication between the nervous, endocrine and immune systems. An excessive release of stress hormones and changes in the neurotransmission system may cause cognitive impairments. The present study investigated dissimilar stress-related memory deficits and their diminution by non-steroidal anti-inflammatory drugs (NSAIDs). Treatment with cyclooxygenase inhibitors, which inhibit prostaglandin synthesis, has enhanced memory functions in a number of neuroinflammatory states. In this study, rats were exposed to a series of dissimilar stressors and behavioral parameters for depression and memory functions were examined. Corticosterone, serotonin (5-HT) and dopamine (DA) levels were also estimated. Results from the forced swim test, elevated plus maze test and Morris water maze test showed significant effects of NSAIDs. A significant decrease in plasma corticosterone and increased DA and 5-HT levels were observed in NSAID-treated dissimilar-stressed rats. This study demonstrates the therapeutic potential of NSAIDs for dissimilar stress-induced depressive behaviors and impaired memory functions and related hormonal and neurochemical changes in the rat brain.

A dose response study of the effect of prostaglandin E2 on thermal nociceptive sensitivity

Inhibition of prostaglandin (PG) biosynthesis has been used to relieve pain for thousands of years. Today non-steroidal anti-inflammatory drugs (which largely inhibit PG synthesis) are widely used to treat pain. Four main types of PGs (PGD2, PGE2, PGF2 and PGI2) are synthesized from arachidonic acid during inflammation and have been demonstrated to impact nociception. PGE2 has been the most studied and utilized for its pain producing properties and has been demonstrated to increase hypersensitivity in rodent nociceptive behavioral models when applied centrally and/or peripherally. Surprisingly, there are no published reports that use withdrawal from radiant light beam (Hargreaves apparatus) to examine the dose response effect of peripherally applied PGE2 on thermal nociceptive hypersensitivity. To address this gap in the literature, we performed a dose response study examining the effect of PGE2 on thermal hypersensitivity (assessed using a Hargreaves apparatus) where rats were injected with 0.003–30μg of PGE2, intradermally into the hindpaw. Thermal hypersensitivity was assessed by measuring withdraw latency from a radiant light beam (Hargreaves test) and our primary objective was to determine the dose of PGE2 causing the most pronounced increase in thermal hypersensitivity (i.e. lowest withdraw latency). A secondary objective was to determine the minimum dose of PGE2 required to cause statistically significant decreases in thermal withdrawal latency as compared to rats injected with vehicle. We found that rats injected with the 30μg dose of PGE2 exhibited the most pronounced thermal nociceptive hypersensitivity though secondary analysis showed that rats injected with PGE2 doses of 0.03–30μg had lower withdrawal latencies as compared to rats injected with vehicle. This work fills an evidence gap and provides context to guide dose selection in future rodent pain behavior studies.

Elixir for the aging mind: An empirical review of the neuroprotective effect of meditation in elderly

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the synthesis of prostaglandins, which comprise an important compensatory mechanism for maintaining renal blood flow, glomerular filtration, and water and electrolyte homeostasis in the setting of a number of pathophysiologic states including CKD. CKD patients are, therefore, at risk for adverse renal side-effects of NSAIDs, including acutely worsened renal function, hyperkalemia, hyponatremia, sodium retention, and exacerbation of hypertension. Although these effects are generally reversible upon discontinuation of the drugs, CKD patients must be monitored closely while taking NSAIDs.Evidence suggests that heavy cumulative NSAID consumption is capable of causing chronic kidney injury with manifestations similar to those seen in classic analgesic nephropathy, including chronic interstitial nephritis and papillary necrosis. The pathogenesis of this disorder is probably renal medullary ischemia resulting from diversion of blood flow to the cortex that occurs with suppression of prostaglandin synthesis. CKD due to NSAIDs is probably rare.Extra caution is indicated when (1) committing patients to high-dose, long-term NSAID therapy, or (2) recommending NSAID therapy of any duration to patients with CKD or other risk factors for adverse renal side-effects including advanced age, use of diuretics, congestive heart failure, cirrhosis, and hypertension.

Effect of paracetamol on semen quality.

Several published studies, both direct and indirect, have connected paracetamol, also named acetaminophen, a commonly used over-the-counter analgesic and antipyretic medication, with semen quality and male infertility, although as yet this connection is unclear. This review addresses the effect of paracetamol on semen quality and hence on male factor infertility. We searched the MEDLINE database from January 1980 through January 2017 for English-language articles using the key words "paracetamol" and "acetaminophen" versus "sperm." References from articles were used only if relevant. In summary, paracetamol, when used at high doses, appears to change semen quality, particularly sperm morphology, and hence its fertilising ability. Such effect of paracetamol on semen quality may occur by suppressing testosterone synthesis, inducing oxidative stress, provoking apoptosis of spermatocytes, reducing nitric oxide production and inhibiting prostaglandin synthesis. Further research, particularly clinical research, will be very important to confirm these effects.

Investigation of anti-arthritic potential of Acacia torta (roxb.) craib

Background: Acacia torta (Roxb.) Craib, traditionally used in respiratory, circulatory, digestive, musculo-skeletal, skin diseases etc., Numerous plants of this genus have been used in folk medicine to treat stomach pain, cough, diarrhoea, piles, sore-throat; as astringent, antipyretic, antimicrobial, antimalarial, antiviral, anti-oxidant and as anti-hypertensive. Hence, the present study was aimed to investigate the anti‐arthritic potential of Acacia Torta (Roxb.) Craib, since, systematic study of this plant has not been carried out.Methods: Ethanol and water were used to prepare stem extract by soxhlet extraction method. The extract is evaluated by using Freund’s complete adjuvant induced arthritis in albino wistar rats at the dose of 100mg/kg/p.o. and 400mg/kg/p.o. and indomethacin at 10mg/kg were used for the study.Results: The hydro alcoholic extract of the stem Acacia torta (Roxb.) Craib in crude form contains phytoconstituents like saponins, tannins, steroids, and triterpenes. The reference standard, Indomethacin at the dose of 10 mg/kg showed significant inhibition of paw edema by 71.61% (P &lt;0.001), as compared to the vehicle control. Treatment with the hydro alcoholic extract of stem Acacia Torta at doses of 100 and 400 mg/kg caused significant inhibition of paw edema by 59.26% (P &lt;0.001) and 69.14% (P &lt;0.001) respectively, was observed on 21st day, as compared to the vehicle control.Conclusions: The data obtained from the present study indicated that several factors may contribute to the anti-inflammatory and anti-arthritic activity of hydro alcohol extract of the stem Acacia torta (Roxb.) Craib. adjuvant induced arthritis showed inhibition of prostaglandin synthesis might be the major mechanism by which the hydro alcoholic extract of the stem Acacia torta (Roxb.) Craib exerts anti-inflammatory and arthritic activity.

Sympatholytic effect of intravascular ATP is independent of nitric oxide, prostaglandins, Na+ /K+ -ATPase and KIR channels in humans.

Intravascular ATP attenuates sympathetic vasoconstriction (sympatholysis) similar to what is observed in contracting skeletal muscle of humans, and may be an important contributor to exercise hyperaemia. Similar to exercise, ATP-mediated vasodilatation occurs via activation of inwardly rectifying potassium channels (KIR ), and synthesis of nitric oxide (NO) and prostaglandins (PG). However, recent evidence suggests that these dilatatory pathways are not obligatory for sympatholysis during exercise; therefore, we tested the hypothesis that the ability of ATP to blunt α1 -adrenergic vasoconstriction in resting skeletal muscle would be independent of KIR , NO, PGs and Na+ /K+ -ATPase activity. Blockade of KIR channels alone or in combination with NO, PGs and Na+ /K+ -ATPase significantly reduced the vasodilatatory response to ATP, although intravascular ATP maintained the ability to attenuate α1 -adrenergic vasoconstriction. This study highlights similarities in the vascular response to ATP and exercise, and further supports a potential role of intravascular ATP in blood flow regulation during exercise in humans. Exercise and intravascular ATP elicit vasodilatation that is dependent on activation of inwardly rectifying potassium (KIR ) channels, with a modest reliance on nitric oxide (NO) and prostaglandin (PG) synthesis. Both exercise and intravascular ATP attenuate sympathetic α-adrenergic vasoconstriction (sympatholysis). However, KIR channels, NO, PGs and Na+ /K+ -ATPase activity are not obligatory to observe sympatholysis during exercise. To further determine similarities between exercise and intravascular ATP, we tested the hypothesis that inhibition of KIR channels, NO and PG synthesis, and Na+ /K+ -ATPase would not alter the ability of ATP to blunt α1 -adrenergic vasoconstriction. In healthy subjects, we measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (FVC) to intra-arterial infusion of phenylephrine (PE; α1 -agonist) during ATP or control vasodilatator infusion, before and after KIR channel inhibition alone (barium chloride; n=7; Protocol 1); NO (l-NMMA) and PG (ketorolac) inhibition alone, or combined NO, PGs, Na+ /K+ -ATPase (ouabain) and KIR channel inhibition (n=6; Protocol 2). ATP attenuated PE-mediated vasoconstriction relative to adenosine (ADO) and sodium nitroprusside (SNP) (PE-mediated ΔFVC: ATP: -16±2; ADO: -38±6; SNP: -59±6%; P<0.05 vs. ADO and SNP). Blockade of KIR channels alone or combined with NO, PGs and Na+ /K+ -ATPase, attenuated ATP-mediated vasodilatation (∼35 and ∼60% respectively; P<0.05 vs. control). However, ATP maintained the ability to blunt PE-mediated vasoconstriction (PE-mediated ΔFVC: KIR blockade alone: -6±5%; combined blockade:-4±14%; P>0.05 vs. control). These findings demonstrate that intravascular ATP modulates α1 -adrenergic vasoconstriction via pathways independent of KIR channels, NO, PGs and Na+ /K+ -ATPase in humans, consistent with a role for endothelium-derived hyperpolarization in functional sympatholysis.