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Analgesic Action (analgesic + action)
Selected AbstractsEffect of the oral absorption of benzenesulfonanilide-type cyclooxygenase-1 inhibitors on analgesic action and gastric ulcer formationJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 12 2008Xiaoxia Zheng Abstract A benzensulfonanilide-type cyclooxygenase-1 (COX-1)-selective inhibitor, ZXX2-77: 4-amino-4,-chloro- N -methylbenzenesulfonanilide (4a), has been reported as a novel analgesic that does not cause gastric damage. This compound has a weak analgesic effect but has potent in vitro COX-1 inhibitory activity. Since the reason for the weak analgesic effect in vivo was thought to be the low rate of oral absorption, the blood concentration of ZXX2-77 (4a) was measured in rats. It was found that the Cmax value (1.2 µM) of ZXX2-77 (4a) at a dose of 30 mg/kg did not reach the COX-1 IC50 value (3.2 µM). On the other hand, ZXX2-79 (4b) (SO2NH derivative of ZXX2-77 (4a); 4-amino-4,-chlorobenzenesulfonanilide), which shows less potent COX inhibitory activities (COX-1 IC50,=,12 µM, COX-2 IC50,=,150 µM) than those of ZXX2-77 (4a) in vitro, was found to be more absorbable (Cmax,=,16 µM at a dose of 30 mg/kg in rats) than ZXX2-77 (4a). Furthermore, ZXX2-79 (4b) not only showed a potent analgesic effect in a formalin test but also caused little gastric damage. These findings indicate that demethylated sulfonamide compounds are more easily absorbed than are N -methylated sulfonamide compounds and suggest that COX-1-selective inhibitors will be useful as analgesics that do not cause gastric damage. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci [source] Cellular Actions Of Opioids And Other Analgesics: Implications For Synergism In Pain ReliefCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 7 2000MacDonald J Christie SUMMARY 1. ,-Opioid receptor agonists mediate their central analgesic effects by actions on neurons within brain regions such as the mid-brain periaqueductal grey (PAG). Within the PAG, ,-opioid receptor-mediated analgesia results from inhibition of GABAergic influences on output projection neurons. We have established that ,-opioid receptor activation in the PAG causes a presynaptic inhibition of GABA release that is mediated by activation of a voltage-dependent K+ channel via 12-lipoxygenase (LOX) metabolites of arachidonic acid. 2. At a cellular level, ,-opioid agonists have also been shown to open inwardly rectifying K+ channels, close voltage-gated Ca2+ channels and presynaptically inhibit glutamatergic synaptic transmission in the PAG. 3. The ,-opioid receptor-mediated presynaptic inhibition of GABAergic transmission was abolished by phospholipase A2 inhibitors and non-specific LOX and specific 12-LOX inhibitors. Cyclo-oxygenase (COX) and specific 5-LOX inhibitors did not reduce the inhibitory effects of ,-opioid agonists. 4. The opioid actions on GABAergic transmission were mimicked by arachidonic acid and 12-LOX metabolites, but not 5-LOX metabolites. The efficacy of ,-opioids was enhanced synergistically by treatment of PAG neurons with inhibitors of the other major enzymes responsible for arachidonic acid metabolism, COX and 5-LOX. 5. These results explain a previously described analgesic action of COX inhibitors in the central nervous system that was both independent of prostanoid release and inhibited by opioid receptor antagonists and they also explain the synergistic interaction of opioids with COX inhibitors. These findings also suggest new avenues for the development of centrally active analgesic agents involving combinations of lowered doses of opioids and specific 5-LOX inhibitors. [source] Importance of pharmaceutical composition and evidence from clinical trials and pharmacological studies in determining effectiveness of chondroitin sulphate and other glycosaminoglycans: a critiqueJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 10 2009Professor K.D. Rainsford Abstract Objectives Chondroitin sulphate (CS) has attracted much interest over the past two decades or so as a biological agent for use in the relief of pain and joint symptoms in osteoarthritis. Earlier clinical investigations produced variable, if encouraging results. This variability was partly due to limitations on the study designs and the lack of availability of standardized CS. Recently, high quality and fully standardized CS (Condrosulf) has become available and its effects have been studied in large-scale osteoarthritis trials, which are discussed here. Key findings There is now evidence for symptom - and structure-modifying (radio-logically-observed) effects. These studies show that CS (a) has slow onset of response and that relief of pain may not be like that of the direct analgesic actions of non-steroidal anti-inflammatory drugs (NSAIDs), (b) there are indications of reduced need for intake of analgesics (e.g. NSAIDs) in patients taking CS, and (c) quality of life and cost-benefits may be associated with use of CS. Safety evaluations show that the incidence of adverse reactions is low. Pharmacokinetic studies indicate that although oral absorption is relatively fast CS has moderate oral bioavailability (15,24%) and that depolymerised and degraded CS that is evident after absorption, together with CS itself, may take some time to accumulate in target joints. The pharmacodynamic actions of CS indicate that it has anti-inflammatory effects that include multiple actions involving reduction of catabolic reactions and enhanced anabolic (proteoglycan) synthetic reactions in cartilage and may block osteoclast activation in bone. Further studies are required to (a) establish the effects of depolymerised and degraded CS on degradation of cartilage and bone in vitro, and (b) MRI and other investigations of the effects in osteoarthritis of long-term CS treatment. Summary The findings from this review show there may be potential value of CS in reducing the dependence on intake of NSAIDs and analgesics in patients with osteoarthritis, while at the same time having favourable safety. [source] Collagen-induced arthritis as a model of hyperalgesia: Functional and cellular analysis of the analgesic actions of tumor necrosis factor blockadeARTHRITIS & RHEUMATISM, Issue 12 2007Julia J. Inglis Objective There is a disparity in the animal models used to study pain in rheumatoid arthritis (RA), which tends to be acute in nature, and models used to assess the pathogenesis of RA. The latter models, like human RA, are lymphocyte-driven and polyarthritic. We assessed pain behavior and mechanisms in collagen-induced arthritis (CIA), the model of preclinical arthritis used most commonly in the field of immunology. We then validated the model using anti,tumor necrosis factor (anti-TNF) therapy, which has analgesic effects in models of inflammation as well as in human RA. Methods CIA was induced in DBA/1 mice by immunization with type II collagen at the base of the tail. Swelling and mechanical and thermal hyperalgesia were assessed before and for 28 days after the onset of arthritis. Spontaneous behavior was assessed using an automated activity monitor. Glial activity was assessed by glial fibrillary acidic protein expression, and nerve damage was evaluated by activating transcription factor 3 expression. The actions of anti-TNF therapy on nociception were then evaluated. Results Arthritis resulted in a decrease in the threshold for thermal and mechanical stimuli, beginning on the day of onset. Decreased spontaneous activity was also observed. A significant increase in the number of hyperplasic spinal cord astrocytes was observed beginning 10 days after the onset of arthritis. Anti-TNF therapy was profoundly analgesic, with an efficacy similar to that of cyclooxygenase 2 inhibition, and reduced astrocyte activity in CIA. Conclusion This study shows that the CIA model is suitable for testing not only antiinflammatory but also analgesic drugs for potential use in RA, and highlights the importance of using appropriate disease models to assess relevant pain pathways. [source] | ||||||||||