Analgesic Anti-inflammatory Agents Research Articles

Analogs of 6-Bromohypaphorine with Increased Agonist Potency for α7 Nicotinic Receptor as Anti-Inflammatory Analgesic Agents.

Hypaphorines, tryptophan derivatives, have anti-inflammatory activity, but their mechanism of action was largely unknown. Marine alkaloid L-6-bromohypaphorine with EC50 of 80 μM acts as an agonist of α7 nicotinic acetylcholine receptor (nAChR) involved in anti-inflammatory regulation. We designed the 6-substituted hypaphorine analogs with increased potency using virtual screening of their binding to the α7 nAChR molecular model. Fourteen designed analogs were synthesized and tested in vitro by calcium fluorescence assay on the α7 nAChR expressed in neuro 2a cells, methoxy ester of D-6-iodohypaphorine (6ID) showing the highest potency (EC50 610 nM), being almost inactive toward α9α10 nAChR. The macrophages cytometry revealed an anti-inflammatory activity, decreasing the expression of TLR4 and increasing CD86, similarly to the action of PNU282987, a selective α7 nAChR agonist. 6ID administration in doses 0.1 and 0.5 mg/kg decreased carrageenan-induced allodynia and hyperalgesia in rodents, in accord with its anti-inflammatory action. Methoxy ester of D-6-nitrohypaphorine demonstrated anti-oedemic and analgesic effects in arthritis rat model at i.p. doses 0.05-0.26 mg/kg. Tested compounds showed excellent tolerability with no acute in vivo toxicity in dosages up to 100 mg/kg i.p. Thus, combining molecular modelling and natural product-inspired drug design improved the desired activity of the chosen nAChR ligand.

A Systematic Review and Meta-Analysis of Randomized Control Trials to Check Role of Non-Steroidal Anti-inflammatory Drugs as Protective Factor in Alzheimer Disease Subjects

Background: Alzheimer’s disease is the major neurodegenerative disease, affecting more than two third cases of dementia in the world. NSAIDs are widely used anti-inflammatory analgesic agents representing 7.7% of worldwide prescriptions of which 90% are in patients over 65 years old. Based on mixed findings observed by different RCTs, a systematic review and meta-analysis were conducted to develop a better understanding of the protective role of Non-steroidal anti-inflammatory drugs (NSAIDs) in AD. Methods: Database search was Pubmed, WebScience, and Embase. RCTs investigating the effect of NSAIDs on AD or test scores assessing cognitive function in people without AD at baseline were included. Three indicators were MMSE Score, ADAS-cog score, and CDR-sob. 10 studies were included in the present Meta-analysis. Results: For the ADAS-cog score, the pooled effect size was -0.31 with 95% CI -0.06 to 0.02, which was statistically significant (p = 0.03). MMSE score difference, the pooled effect size was -0.06 with 95% CI -0.22 to 0.10, which was statistically insignificant (p-value = 0.47). For the MMSE average score, the pooled effect size was -0.002 with 95% CI -0.03 to 0.07, which was statistically insignificant (p-value = 0.87). For the CDR-sob score difference, the pooled effect size calculated using the random effect model was -0.06 with 95% CI -0.39 to 0.05 which was statistically insignificant (p = 0.14). For CDR-sob average score, the pooled effect size calculated using the random effect model was 0.21 with 95% CI -0.09 to 0.51, which was statistically insignificant (p-value = 0.17). Conclusion: Present Meta-analysis shows that NSAIDs in general are not effective in the treatment of AD. They also have no protective effect against the development of AD on their sustained use.

Pharmacological evaluation of analgesic, anti-inflammatory and anti-pyretic activities of amaranthus spinosus stem.

The herbal medicines have stood the test of time for their safety, efficacy, lesser side effects, cultured and traditional acceptability. Natural plant-based product are promising for the drug discovery and they still continue to play a significant role in future drug development programs. Practitioners of herbal medicine generally use unpurified plant extracts containing several different constituents. The extracts of the plant (Stem) was evaluated for the different pharmacological activities. The need for safer and effective analgesic (Acetic Acid Induced Writhing Test, Eddy’s Hot Plate, Tail Flick Test) anti-inflammatory (Rat hind paw edema test) and antipyretic agents and the lack of enough scientific data to support the claims made in ancient literature prompted the present study. Key words: Analgesic, Anti-pyretic and Anti-inflammatory, Plant Amaranthus spinosus

Acute treatment with dexketoprofen reduces penicillin induced epileptiform activity in wistar albino rats (dexketoprofen in penicillin induced seizure model)

AimDexketoprofen trometamol is one of the most commonly used anti-inflammatory analgesic agents for pain control. This study aims to investigate the effect of dexketoprofen on penicillin-induced epileptiform activity in rats. MethodIn this study, 28 male Wistar rats weighing 220–240 g were used. Tripolar electrodes were implanted under urethane anesthesia. Epileptiform activity was induced by micro-injection of 500 units (IU) penicillin into the rats’ left somatomotor cortex. Dexketoprofen (5, 25, and 50 mg/kg) was administrated intraperitoneally after 30 min of penicillin injection. Epileptiform activity was evaluated by electrocorticography (ECoG). ResultsThe low dose of dexketoprofen administration (5 mg/kg) reduced the mean spike frequency of epileptiform activity 60 min after its injection. However, 25 and 50 mg/kg dexketoprofen significantly reduced the mean spike frequency 30 min after the dexketoprofen injection compared to the control group (p < 0.05). The amplitudes of epileptiform discharges in all groups were unaffected (p > 0.05). ConclusionThis study revealed that dexketoprofen had a significant anti-seizure effect when applied at 5 mg/kg, 25 mg/kg, and 50 mg/kg (especially at 25 and 50 mg/kg), in the penicillin-induced seizure model. The obtained data revealed that dexketoprofen might play an essential role against epileptic seizures.

Application of Dimethyl Sulfoxide as a Therapeutic Agent and Drug Vehicle for Eye Diseases.

Dimethyl sulfoxide (DMSO) is an amphipathic molecule widely used as a solvent for water-insoluble substances, cryopreserving, and cell-biological therapies. It has known properties as an inducer of cellular differentiation, a free radical scavenger, and a radioprotectant. In addition, DMSO is used for its various therapeutic and pharmaceutical properties, such as anti-inflammatory, local and systemic analgesic, antibacterial, antifungal, antiviral, and membrane penetration enhancement agents. DMSO treatment can be given orally, intravenously, or topically for a wide range of indications. The administration of DMSO exhibits favorable outcomes in human eye diseases with low to none observed ocular or systemic ocular toxicity. Nevertheless, DMSO is an essential and nonpatentable potential therapeutic agent that remains underexplored and ignored by pharmaceutical developers and ophthalmologists. This current review takes data from experimental and clinical studies that have been published to substantiate the potential therapeutic efficacy of DMSO and stimulate the research of its application in clinical ophthalmology. Given that DMSO is inexpensive, safe, and easily formulated into therapeutic medicinal products and conventional ophthalmological drugs, this compound should be further explored and studied in the treatment of a variety of acute and chronic ocular disorders.

Design, Synthesis and Pharmacological Evaluation of Gastro- Protective Anti-inflammatory Analgesic Agents based on Dual Oxidative Stress / Cyclooxygenase Inhibition.

Non-steroidal anti-inflammatory drugs (NSAIDs) derived local generation of reactive oxygen species (ROS) plays a crucial role in the formation of gastric ulceration. Therefore, anti-inflammatory analgesics with potent antioxidant activity could be a potential therapeutic strategy for the treatment of pain and inflammatory disorders without gastrointestinal (GI) side effects. In an effort to develop gastroprotective analgesic and anti-inflammatory agents, a series of 2-methylamino-substituted-1H-benzo[d] imidazol-1-yl) (phenyl) methanone derivatives were synthesized and evaluated in vitro for cyclooxygenase (COX) inhibition as well as anti-oxidant potential by the FRAP assay. The compounds with significant in vitro COX-1/COX-2 inhibitory activity and antioxidant activity were further screened in vivo for their anti-inflammatory and analgesic activities. Moreover, the ulcerogenic potential of test compounds was also studied. To gain insight into the plausible mode of interaction of compounds within the active sites of COX-1 and COX-2, molecular docking simulations were performed. Among the various synthesized molecules, most of the compounds showed good cyclooxygenase inhibitory activity and efficient antioxidant activity in FRAP assay. After preliminary and indicative in vitro assays, three compounds exhibited most significant antiinflammatory and analgesic activity with better gastric tolerability during their in vivo evaluation. Ligand interaction studies indicated highest dock score -43.05 of 1,2- disubstituted benzimidazole derivatives in comparison to the reference ligand -30.70. Overall studies provided us (2-((4-methoxyphenylamino) methyl) -1h-benzo [d] imidazol- 1-yl) (phenyl) methanone as a lead with potent gastro-protective anti-inflammatory and analgesic activities that can be used for future research. From the above results, it can be concluded that designing of multifunctional molecules with COX-1/COX-2 inhibitory and anti-oxidant activities could hold a great promise for further development of GI-safer NSAIDs.

Spontaneous healing of an isolated posterior inferior cerebellar artery dissection without stroke: a case report

BackgroundIsolated posterior inferior cerebellar artery dissections can cause subarachnoid hemorrhages or infarctions. Surgical and endovascular treatments for hemorrhagic stroke cases and medical treatments using antithrombotic agents for ischemic stroke cases have been performed, but there are very few reports on nonstroke isolated posterior inferior cerebellar artery dissections, and the treatment strategy for nonstroke cases has not been established.Case presentationA 48-year-old healthy male felt a severe, throbbing headache on the right side and came to our clinic on the fourth day following onset. MRI examinations revealed a right posterior inferior cerebellar artery dissection and showed no infarctions or hemorrhages. He was observed carefully with continuous monitoring of blood pressure, hydrated sufficiently, and given analgesic anti-inflammatory agents. Two weeks later, the dissected vessel’s diameter grew to the maximum size, though the patient’s headache rapidly improved around that day. Surgical or endovascular treatments for prevention of subarachnoid hemorrhage were recommended, but careful conservative therapy was continued in accordance with the patient’s wishes. Gradually, the dissection finding improved. Four months later, MRI examinations showed his right posterior inferior cerebellar artery was almost normal in size and shape.ConclusionsThis is the first detailed report on a nonstroke isolated posterior inferior cerebellar artery dissection that spontaneously occurred and healed, observed by serial high-resolution MRI examinations.

Design, facile synthesis, and evaluation of novel spiro- and pyrazolo[1,5-c]quinazolines as cholinesterase inhibitors: Molecular docking and MM/GBSA studies

Given the wide spectrum of biological uses of pyrazolo[1,5-c]quinazoline and spiro-quinazoline derivatives as anticancer, anti-inflammatory analgesic agents, and their therapeutic applications in neurodegenerative disorders, it is compulsory to find easy, efficient, and simple methods to obtain and chemically diversify these families of compounds, thereby improving their biological applications. In this paper, we report the design and eco-friendly two-step synthesis of novel, fused spiro-pyrazolo[1,5-c]quinazoline derivatives as cholinesterase inhibitors. In addition, we studied their protein-ligand interactions via molecular docking and MM/GBSA calculations for a further rational design of more potent inhibitors. In first step, 2-(1H-pyrazol-5-yl)anilines were obtained through microwave (MW) assisted solvent-free/catalyst-free conditions and the second step involved the synthesis of the spiro-pyrazolo[1,5-c]quinazolines by a cyclocondensation reaction between 2-(1H-pyrazol-5-yl)anilines and cyclic ketones, or acetophenones, using stirring at room temperature. The compounds were obtained in high purity, good yields (50–97%), and at varying reaction times. The spiro-compounds were evaluated as acetylcholinesterase and butyrylcholinesterase inhibitors (AChEIs/BuChEIs) respectively, and the most potent compound exhibited a moderate AChE inhibitory activity (5f: IC50 = 84 μM). Molecular docking studies indicated that the binding mode of the compound 5f share common characteristics with the galantamine/donepezil-AChE complexes. Moreover, free binding energy (ΔG) calculations showed a good agreement with the experimental biological activity values. Our theoretical results indicated that halogen bond interactions could be involved with differential potency of these compounds and provide a new starting point to design novel pyrazolo[1,5-c]quinazolines as new anti-Alzheimer agents.

Choosing and using non-steroidal anti-inflammatory drugs in haemophilia.

The management of pain and inflammation in haemophilic arthropathy is challenging due to the lack of anti-inflammatory analgesic agents perfectly suitable for this population. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the management of arthritis due to their analgesic and anti-inflammatory effects. Their use in persons with haemophilia (PWH), however, is limited due to increased risk of bleeding mainly from the upper gastrointestinal (UGI) tract. Cyclooxygenase-2 (COX-2) selective NSAIDs which have comparable analgesic effect to traditional NSAIDs (tNSAIDs) but with less UGI bleeding have been considered to be a suitable option for treatment of haemophilic arthropathy. COX-2 inhibitors, however, have an increased in the risk of cardiovascular (CV) disease. Although the atherosclerotic burden in PWH is similar to that in the general population, the risk of CV-related deaths is lower. PWH have a higher risk of GI bleeding and lower risk of thrombotic disease compared to general population. Therefore, when PWH require anti-inflammatory/analgesic agents, it seems reasonable to use lowest dose of COX-2 inhibitors for the shortest period together with a proton pump inhibitor. Helicobacter pylori infection should be tested for and eradicated prior to starting NSAID treatment in PWH. Furthermore, regular blood pressure and renal function test monitoring is required during COX-2 inhibitor treatment.

Benzimidazole derivatives: search for GI-friendly anti-inflammatory analgesic agents

Non-steroidal anti-inflammatory drugs (NSAIDs) have been successfully used for the alleviation of pain and inflammation in the past and continue to be used daily by millions of patients worldwide. However, gastrointestinal (GI) toxicity associated with NSAIDs is an important medical and socioeconomic problem. Local generation of various reactive oxygen species plays a significant role in the formation of gastric ulceration associated with NSAIDs therapy. Co-medication of antioxidants along with NSAIDs has been found to be beneficial in the prevention of GI injury. This paper describes the synthesis and biological evaluation of N-1-(phenylsulfonyl)-2-methylamino-substituted-1H-benzimidazole derivatives as anti-inflammatory analgesic agents with lower GI toxicity. Studies in vitro and in vivo demonstrated that the antioxidant activity of the test compounds decreased GI toxicity.

Marked varus deformity due to insufficiency fracture of the proximal tibia treated by open-wedge high tibial osteotomy: a case report

Insufficiency fractures occur most commonly in the pelvic girdle and the sacrum, followed by the tibia and the femoral neck. Because insufficiency fractures are often treated conservatively with rest, immobilization with cast or braces, antiinflammatory analgesic agents, and reduced activity, surgery is rarely indicated, except in patients with marked deformity, those in whom bone union is not achieved, and those with malunion. For this reason, few studies have reported surgery for insufficiency fracture of the proximal tibia [1–3]. In our case, marked varus deformity occurred in a short period, markedly interfering with gait and indicating a need for surgery. To our knowledge, no previous case report has discussed corrective open-wedge osteotomy as the primary surgery in patients with insufficiency fracture of the proximal tibia.

Antinociceptive and anti-inflammatory activities of extract and two isolated flavonoids of Carthamus tinctorius L

Ethnopharmacological relevanceSafflower (Carthamus tinctorius L.) has been long used both in the traditional system and folk medicine as an analgesic anti-inflammatory agent in China. The aim of the study was to evaluate the antinociceptive and anti-inflammatory activities of hydroalcoholic extract (HE) and two isolated kaempferol glycosides of Carthamus tinctorius L. to provide experimental evidence for its traditional use. Materials and methodsAntinociceptive effects of HE, kaempferol 3-O-rutinoside (K-3-R) and kaempferol 3-O-glucoside (K-3-G) were assessed in mice using the acetic acid-induced writhing test, formalin test and cinnamaldehyde test. The anti-inflammatory effects of HE, K-3-R and K-3-G were determined in two animal models: carrageenan-induced paw edema and xylene-induced ear edema. ResultsThe HPLC analysis showed the presence of K-3-R and K-3-G in Carthamus tinctorius L. HE (500 and 1000mg/kg) as well as K-3-R and K-3-G (150, 300 and 600mg/kg) produced significant inhibition on nociception induced by acetic acid and formalin. Oral treatment of HE, K-3-R and K-3-G at all doses significantly reduced both the nociceptive response and cinnamaldehyde-induced paw edema, effect that was superior to aspirin. In anti-inflammatory tests, HE and K-3-G significantly inhibited the paw edema during the both phases of carrageenan-induced inflammation while K-3-G suppressed the late phase inflammation only. HE (400 and 800mg/kg) and K-3-G (200, 400, 800mg/kg) produced significant dose-dependent inhibition of xylene-induced ear edema development. K-3-R only suppressed ear edema formation at a high dose (800mg/kg). ConclusionsThese results demonstrate that Carthamus tinctorius L. extract possess remarkable antinociceptive and anti-inflammatory activities which may be due to K-3-R and K-3-G at least in part, supporting the folkloric usage of the plant to treat various inflammatory and pain diseases.

PP257—Chlorogenic acid as potential anti-inflammatory analgesic agent

Nonsteroidal anti-inflammatory drugs represent 1 of the most widely prescribed drugs used for treatment of pain and inflammation. The prescription of current existing anti-inflammatory drugs is hampered by their adverse effects over time. In the recent years, there is an upsurge in the areas related to newer developments in the prevention of disease especially the role of free radicals and antioxidants. Phenolic compounds are receiving increased attention as epidemiologic studies have highlighted the association between the consumption of polyphenolic–rich food and beverages and the prevention of various human diseases.

Design, synthesis and molecular docking of some new 1,2,4-triazolobenzimidazol-3-yl acetohydrazide derivatives with anti-inflammatory-analgesic activities

The present work describes the synthesis and evaluation of some new acetohydrazones, 1,3,4-oxadiazoles and 1,2,4-triazoles of 1,2,4-triazolo[1,5-a]benzimidazole as anti-inflamm atory-analgesic agents. Structure elucidation of these compounds was confirmed by IR, (1)H NMR, and mass spectrometry along with elemental microanalyses. Most compounds exhibited significant anti-inflammatory activity in comparison to indomethacin. Further, some compounds were tested for their analgesic effects where two compounds showed results comparable to indomethacin at 4h interval. The most active anti-inflammatory and analgesic compounds (4c and 11a) were examined on gastric mucosa and didn't show any gastric ulcerogenic effect compared with the reference indomethacin. Moreover, LD50 of compounds (4c and 11a) were determined in mice; they were found non toxic up to 240 and 300mg/kg (i.p.). Also, docking simulation of some compounds into COX active sites was studied.

Synthesis and in-silico molecular docking simulation of 3-chloro-4-substituted-1-(2-(1H-benzimidazol-2-yl)phenyl))-azetidin-2-ones as novel analgesic anti-inflammatory agent

In the present investigation synthesis of some novel 1-(2-(1H-benzimidazol-2-yl)phenyl)-3-chloro-4-(Un/substitutedphenyl)azetidin-2-one (3a–3h) is reported. All these compounds were characterized by IR, Mass, 1H NMR and elemental analysis. The newly synthesized compounds were screened for analgesic and anti-inflammatory activities on acetic acid induced writhing in mice and carrageenan induced paw edema in rats. Compound 3g was found to have potent analgesic (46% at 20mg/kg b.w) and anti-inflammatory (66.5% at 20mg/kg b.w) activities as compared to standard drug nimesulide (20mg/kg b.w). To check binding modes and binding affinity of synthesized compounds were docked into the active sites of enzyme COX-II. Compounds 3a, 3e and 3h were found to have good affinity for COX-II. A good correlation is found between in silico docking analysis and in biological screening.

Design and synthesis of certain mesoionic sydnonyl styrylketones as potential nonsteroidal antiinflammatory agents

In an attempt to develop effective and safer analgesic anti-inflammatory agents, nine compounds belonging to 4-[1-oxo-3-(substituted aryl)-2-propenyl]-3-(4-methoxyphenyl) sydnones, containing the structural features of mesoionic sydnone and styrylketone, have been designed and synthesized by condensing 4-acetyl-3-(4-methoxyphenyl) sydnone with various substituted aryl aldehydes and characterized by spectral studies. They have been tested for analgesic activity by acetic acid induced writhing in mice and for anti-inflammatory activity by carrageenan induced rat paw edema at 100 mg/kg body weight p.o. The compounds containing furyl and chloro substituents showed highly significant analgesic effect, while those with dimethylamino, chloro and nitro substituents exhibited highly significant anti-inflammatory effect at the end of 3 h. The compounds that showed good analgesic and anti-inflammatory activities were evaluated for ulcerogenicity in rats to assess their gastric side effects at 100 mg/kg body weight p.o. They were found to be less ulcerogenic than the standard drug.

Thermoanalytical study of some anti-inflammatory analgesic agents

Thermogravimetry (TG), differential thermal analysis (DTA), differential scanning calorimetry (DSC) as well as X-ray diffraction powder (DRX) patterns and Fourier transformed infrared spectroscopy (FTIR) were used to study ketoprofen, ibuprofen, and naproxen. The chemical or physical properties of the studied compounds were established and when possible by X-ray powder diffractometry and/or infrared spectroscopy were used. In this investigation, quantum chemical approach was used to determine the molecular structures using Becke three-parameter hybrid method and the Lee–Yang–Par (LYP) correlation functional. The performed molecular calculations in this work were done using the Gaussian 03 routine. Theoretical calculations help in interpretations of FTIR spectra supplying structural and physicochemical parameters.

A method of assessing anti-inflammatory analgesic agents in extraction of mandibular impacted wisdom tooth

A method of assessing anti-inflammatory analgesic agents in extraction of mandibular impacted wisdom tooth

Changes in pain tolerance thresholds with administration of an analgesic anti-inflammatory agent and anti-anxiety agent

Changes in pain tolerance thresholds with administration of an analgesic anti-inflammatory agent and anti-anxiety agent

Preparation and Evaluation of Solid Dispersions of Aceclofenac

Aceclofenac is a potent anti-inflammatory analgesic agent indicated for acute and chronic treatment of rheumatoid arthritis, ostio arthritis, and onkylosing spondylytis. Aceclofenac is poorly water soluble and may show dissolution limited absorption. Solid dispersions (SDs) of Aceclofenac in PEG-6000, PVP were prepared by solvent evaporation method. The solid dispersion was characterized for physical appearance, solubility and IR. FTIR study reveled that drug was stable in SDs. Solubility of Aceclofenac from SDs increased in distilled water. The drug content was found to be high and uniformly distributed in the all formulation. Dissolution of drug increased from all the solid dispersion. Dissolution of Aceclofenac increased with increase in the proportion of carriers (1:1, 1:5, and 1:9). Of both the carriers used, dissolution of the drug was more in PEG 6000 based SDs. It is concluded that dissolution of the Aceclofenac could be improved by solid dispersion and PEG 6000 based solid dispersions were more effective in the enhancing the dissolution.