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Biomedical subjects

K D Rainsford

Publications and source records attributed to K D Rainsford.

At least 19 recordsLinked to original sources
PubMed2006

Influenza ("Bird Flu"), inflammation and anti-inflammatory/analgesic drugs.

The spectre of an influenza pandemic is being widely mooted. Most of the strategies explored to date for controlling or treating the condition have centred on controlling the spread of the infection, the use of vaccines or anti-viral agents. There has been relatively little discussion about treating the lung and systemic inflammatory reactions that occur during influenza infection. In this review a range of therapeutic agents are proposed to treat the inflammatory reactions, principally in the lung as well as the systemic cytokine-mediated immuno-inflammatory reactions that may be a major cause of the morbidity and mortality associated with influenza infections. Among these are pentoxifylline, the statins, the macrolide antibiotics (e.g. azithromycin, clarithromycin, erythromycin), resveratrol (a component of wine and fruits with inhibitory effects on influenza virus replication) and nutraceuticals (including those that contain flavonoids, the marine oils eicosapentanoic and docosanoic acids or the green-lipped mussel extract, Liprinol which may by virtue of the inhibitory effects on the production or actions of pro-inflammatory cytokines, be useful for their anti-inflammatory actions. The efficacy, mode of actions and side effects of non-steroidal anti-inflammatory drugs (NSAIDs) are considered. There are a number of issues relating to their use in treating the inflammatory reactions in the respiratory tract. Among these are the development of gastro-intestinal ulcers and bleeding and hepato-renal reactions in patients that may because of severe systemic inflammation be prone to the development of these adverse reactions. There are also theoretical issues concerning the impact of COX-1 mediating reduction in prostaglandin and increased cytokine production that might have some negative consequences for respiratory inflammation.In conclusion, further consideration should be given to exploring the actions of these anti-inflammatory agents to control the respiratory inflammatory in influenza infections which can have serious consequences for the outcome of the infection.

Animals↗
PubMed2006

Paracetamol [acetaminophen]-induced gastrotoxicity: revealed by induced hyperacidity in combination with acute or chronic inflammation.

Paracetamol is regarded as a relatively safe drug in the gastro-duodenal region of humans but recent epidemiological investigations have suggested that at high doses there may be an increased risk of ulcers and bleeding. To investigate the possibility that inflammatory conditions and gastric acidity may play a role in potentiating development of gastric mucosal injury from paracetamol in rats (as noted previously with various non-steroidal anti-inflammatory drugs) we studied the gastric irritant effects of paracetamol and some phenolic and non-phenolic analgesics and antipyretics in rats with adjuvant or collagen II induced arthritis or zymosan-induced paw inflammation and given 1.0 ml hydrochloric acid (HCl) 0.1 M and/or an i. p. injection of the cholinomimetic, acetyl-beta-methyl choline chloride 5.0 mg/kg. Gastric lesions were determined 2 h after oral administration of 100 or 250 mg/kg paracetamol or at therapeutically effective doses of the phenolic or non-phenolic analgesics/antipyretics. The results showed that gastric mucosal injury occurred with all these agents when given to animals that received all treatments so indicating there is an adverse synergy of these three factors, namely: (i) intrinsic disease; (ii) hyperacidity; and (iii) vagal stimulation for rapidly promoting gastric damage, both in the fundic as well as the antral mucosa, for producing gastric damage by paracetamol, as well as the other agents. Removing one of these three predisposing factors effectively blunts/abolishes expression of this paracetamol-induced gastrotoxicity in rats. These three factors, without paracetamol, did not cause significant acute gastropathy.

Acetaminophen↗
PubMed2006

Current status of the therapeutic uses and actions of the preferential cyclo-oxygenase-2 NSAID, nimesulide.

This review summarizes the principal therapeutic responses to the preferential COX-2 NSAID, nimesulide, in treating musculo-skeletal joint symptoms and various acute and chronic pain conditions and the mode of action in relation to therapy in these states. In extensive studies in laboratory animal models and clinical trails in patients nimesulide has been found to have potent analgesic, anti-inflammatory and anti-pyretic activities. It is approved for use in over 50 countries worldwide (including those in the EU, South and Central America, China, India and some other South-East Asia) for the treatment of acute pain, the symptomatic treatment of painful osteoarthritis and primary dysmenorrhoea. Its mode of action in these states is related to the preferential inhibition of the production of cyclo-oxygenase-2 (COX-2) and other inflammatory mediators whose production is controlled by stimulation of cyclic-3 ,5'-adenosine monophosphate (cAMP); this means that nimesulide is a multi-factorial drug in controlling inflammation and pain. The adverse reaction profile of nimesulide is, in general, like that of other NSAIDs. It does, however, have relatively low occurrence of gastro-intestinal (GI) side effects which is related to its low propensity to inhibit the physiologically important COX-1 in the GI mucosa and important physicochemical properties (high pKa of 6.5 and lipophilicity) as well as inhibiting of mast cell derived histamine and acid secretion in the stomach. In contrast with the coxibs, nimesulide has not been found to have appreciable cardiovascular toxicity.

Animals↗
PubMed2006

Chronic effects of celecoxib, a cyclooxygenase-2 inhibitor, cause enhanced alcohol-induced liver steatosis in rats.

BACKGROUND: The pathogenetic role of prostaglandins in steatosis, the first stage of alcoholic liver injury, is not well understood, especially that involving the inflammatory reactions controlled by prostaglandins and pro-inflammatory cytokines in the liver. We, therefore, studied the chronic effects of the COX-2 inhibitor, celecoxib, given to ethanol-treated rats. METHODS: Rats were fed ethanol and a low dose of celecoxib (approximately 20 mg/kg daily) in a high-fat/low-carbohydrate liquid diet for six weeks. RESULTS: Ethanol treatment caused liver steatosis, moderate cellular infiltration and enhanced levels of plasma alanine transaminase (ALT) and tumour necrosis factor-alpha (TNF-alpha). Co-administration of celecoxib further increased the steatosis, relative liver weights and increased plasma ALT and TNF-alpha levels above those in ethanol-treated rats. Also, celecoxib counteracted the ethanol-induced increase in hepatic prostaglandin E(2) receptor EP4 mRNA expression. In contrast, celecoxib alone increased plasma ALT and TNF-alpha levels. CONCLUSIONS: These results suggest that prolonged low-dose celecoxib treatment with ethanol enhances alcohol-induced steatosis and liver inflammatory reactions above that from ethanol or celecoxib alone. It is suggested that reduction in PGE(2) by treatment with celecoxib removes the endogenous protective effect of this prostaglandin.

Alanine Transaminase↗
PubMed2006

Nimesulide -- a multifactorial approach to inflammation and pain: scientific and clinical consensus.

BACKGROUND: This paper summarises the outcome from a consensus meeting, held in Rome on 5 October 2005, that aimed to review the state of the art regarding the non-steroidal anti-inflammatory drug (NSAID) nimesulide, with reference to its chemical, pharmacokinetic, pharmacological and clinical characteristics. SCOPE: The meeting aimed to provide a continuous and up-to-date evaluation of the clinical and safety profile of nimesulide, and of its role in the treatment of inflammatory pain, in light of existing therapeutic alternatives, through a revision and critical discussion on the information available on the drug among authoritative experts in different fields of medical science. FINDINGS: The members of the Consensus Report Group on Nimesulide (CRGN) recognised that nimesulide is an NSAID which exerts its analgesic, anti-inflammatory and antipyretic activities thanks to unique chemical and pharmacokinetic characteristics, and to a multifactorial mechanism of action, which goes beyond its preferential inhibitory activity on the COX-2 enzyme. Nimesulide was found to be at least as effective, or superior, to placebo and other NSAIDs, with a particularly fast onset of analgesic action. The safety profile is in line with that expected from the class, with evidence of a better gastrointestinal safety profile. CONCLUSIONS: Based on the available evidence, the CRGN concluded that nimesulide remains an effective and safe therapeutic choice for the treatment of various painful inflammatory conditions, with a rapid onset of analgesic activity and an overall positive benefit/risk profile.

Analgesics, Non-Narcotic↗
PubMed2006

Arthritis and cannabinoids: HU-210 and Win-55,212-2 prevent IL-1alpha-induced matrix degradation in bovine articular chondrocytes in-vitro.

Cannabinoids have analgesic, immunomodulatory and anti-inflammatory properties and attenuate joint damage in animal models of arthritis. In this study the mechanisms of action of the synthetic cannabinoid agonists, HU-210 and Win-55,212-2, were studied to determine if they affected interleukin-1 alpha (IL-1alpha)-induced proteoglycan and collagen degradation in bovine nasal cartilage explant cultures and prostaglandin E2 (PGE2) production in primary cultures of bovine articular chondrocytes. The effects of the inactive enantiomer, Win-55,212-3, were compared with those of the active enantiomer, Win-55,212-2, to determine if the effects were cannabinoid (CB)-receptor mediated. The chondrocytes and explants were stimulated by IL-1alpha (100 U mL(-1) identical with 0.06 nM and 500 U mL(-1) identical with 0.3 nM, respectively). Proteoglycan breakdown was determined as sulfated glycosaminoglycan (sGAG) release using the dimethylmethylene blue assay. Collagen degradation was determined as hydroxyproline in the conditioned culture media and cartilage digests. PGE2 was determined by ELISA. Expression of cannabinoid receptors, CB1 and CB2; cyclooxygenase-1 and -2 (COX-1 and COX-2); inducible nitric oxide synthase (iNOS); as well as activation of nuclear factor-kappa B (NF-kappaB) in chondrocytes were studied using immunoblotting techniques and immunofluorescence. The results showed that HU-210 and Win-55,212-2 (5-15 microM) significantly inhibited IL-1-alpha stimulated proteoglycan (P < 0.001) and collagen degradation (P < 0.001). Win-55,212-2 (5-10 microM) also significantly inhibited PGE2 production (P < 0.01). At 5 microM, Win-55,212-2 inhibited the expression of iNOS and COX-2 and activation of NF-kappaB. Chondrocytes appeared to constitutively express cannabinoid receptors CB1 and CB2. It is concluded that biologically stable synthetic cannabinoids protect cartilage matrix from degradation induced by cytokines and this effect is possibly CB-receptor mediated and involves effects on prostaglandin and nitric oxide metabolism. Cannabinoids could also be producing these effects via inhibition of NF-kappaB activation.

Animals↗
PubMed2005

Effects of cannabinoids on nitric oxide production by chondrocytes and proteoglycan degradation in cartilage.

Cannabinoids have been reported to have anti-inflammatory effects and reduce joint damage in animal models of arthritis. This suggests a potential therapeutic role in arthritis of this group of compounds. Cannabinoids were studied to determine whether they have direct effects on chondrocyte metabolism resulting in cartilage protection. Synthetic cannabinoids, R-(+)-Win-55,212 (Win-2) and S-(-)-Win-55,212 (Win-3) and the endocannabinoid, anandamide, were investigated on unstimulated or IL-1-stimulated nitric oxide (NO) production in bovine articular chondrocytes as well as on cartilage proteoglycan breakdown in bovine nasal cartilage explants. Win-2 significantly inhibited (P < 0.05) NO production in chondrocytes at 1-10 microM concentrations. The combined CB(1) and CB(2) cannabinoid receptor antagonists, AM281 and AM630, respectively, at 100 microM did not block this effect, but instead they potentiated it. Anandamide and Win-2 (5-50 microM) also inhibited the release of sulphated glycosaminoglycans in bovine cartilage explants. The results suggest that some cannabinoids may prevent cartilage resorption, in part, by inhibiting cytokine-induced NO production by chondrocytes and also by inhibiting proteoglycan degradation.

Animals↗
PubMed2005

Introduction - The coxib controversies.

Much concern has arisen in the past year concerning the occurrence of serious cardiovascular adverse reactions from rofecoxib, celecoxib and some other members of the coxib group of NSAIDs. Factors underlying the sudden appearance of these events have been proposed to include the use of high doses of the drugs, undue reliance on their safety profile from controlled clinical trails and potent marketing leading to exposure of a large population who would inevitably present risks of cardiovascular adverse events. Suggestions are presented for future uses of the coxibs and approaches for their more cautious use and marketing. The use of the term "COX-2 inhibitor" to describe the coxibs is unhelpful and should be avoided since all NSAIDs have some degree of COX-2 inhibitory effect, though they may vary in their selectivity. Coxibs should be set aside in a group of their own within the broader category of the NSAIDs in view of both their cardiovascular risk and unique pharmacology.

Animals↗
PubMed2004

Cannabinoids in pain and inflammation.

Cannabinoids exhibit medicinal properties including analgesic, anti-inflammatory and immunosuppressive properties. This paper reviews some of the recent findings in the study of cannabinoids in pain and inflammation. Some of the effects of cannabinoids are receptor mediated and others are receptor independent. Endocannabinoids naturally reduce pain and are cerebroprotective. Natural and synthetic cannabinoids have the potential to reduce nociception, reverse the development of allodynia and hyperalgesia, reduce inflammation and inflammatory pain and protect from secondary tissue damage in traumatic head injury.

Animals↗
PubMed2003

Gastrointestinal mucosal injury following repeated daily oral administration of conventional formulations of indometacin and other non-steroidal anti-inflammatory drugs to pigs: a model for human gastrointestinal disease.

Non-steroidal anti-inflammatory drugs (NSAIDs) vary in their propensity to cause damage in different regions of the gastrointestinal (GI) tract in laboratory animals and humans. This may depend on the type of drug formulation as well as the intrinsic pharmacological properties of the drugs. The purpose of this study was to determine the effects of NSAIDs, with cyclooxygenase 1 and 2 inhibitory activity but with different potency as inhibitors of prostaglandin production, when given orally as tablet/capsule formulations of NSAIDs for 10 days to pigs, a species that has close resemblance in structure and function of the tract to that in humans. Three capsule or tablet formulations of NSAIDs were given orally to pigs for 10 days. GI bleeding was measured by determination of radioactive iron in the faeces from (59)Fe-pre-labelled red blood cells. The blood loss was compared with the pathological changes in the GI mucosa observed at autopsy, mucosal myeloperoxidase (MPO) activity as an index of leucocyte infiltration, and plasma and mucosal concentrations of the drugs at termination assayed by high-performance liquid chromatography. Mucosal damage and bleeding varied according to the type of NSAID. Gastroduodenal ulcers and lesions occurred with the cyclooxygenase inhibitors indometacin (indomethacin) (Indocid capsules 10 or 5 mg kg(-1) day(-1) b.i.d.), aspirin (USP tablets 150 mg kg(-1) day(-1) b.i.d) and naproxen (Apotex tablets 50 or 75 mg kg(-1) day(-1) b.i.d.), and there was an increase in the cumulative (i.e. 10-day) blood loss at higher doses of indometacin and naproxen, and with aspirin. There was no statistically significant increase in gastric or intestinal mucosal MPO activity in the non-damaged mucosa with these drugs and this was confirmed by histological observations in non-lesioned areas of the mucosa. Indometacin produced focal ulcers in the caecum but this was not observed with the other drugs. All the NSAIDs produced significant blood loss coincident with gastric ulceration but no increase in gastric or intestinal MPO activity. Plasma concentrations of the non-aspirin NSAIDs were within the range encountered therapeutically in humans. The mucosal concentrations of indometacin in the gastric and intestinal mucosa correlated with mucosal injury. These findings show that: (i) NSAIDs vary in their propensity to produce mucosal injury in different regions of the GI tract according to their pharmacological properties and formulation; (ii) mucosal injury from some NSAIDs may not directly relate to blood loss at low doses of NSAIDs and this may depend on inhibition of platelet aggregation; and (iii) the occurrence of caecal ulcers uniquely observed with indometacin treatment may be relevant to the development of intestinal pathology (e.g. diaphragm-like structures) seen occasionally in humans. These results suggest that the pig model employed in the present studies may be useful for investigations of GI damage from NSAID tablets/capsules, especially in regions that are generally inaccessible to routine endoscopic investigations in humans (e.g. the proximal regions of the large intestine).

Administration, Oral↗
PubMed2003

Discovery, mechanisms of action and safety of ibuprofen.

Ibuprofen was the product of a long research programme during the 1950s and 1960s to develop a 'super aspirin' for the treatment of rheumatoid arthritis which was as effective as current alternatives but safer. Selected for development in 1964 after several promising compounds had proved disappointing at the clinical stage, ibuprofen was found to have a short elimination half-life and exceptional gastrointestinal tolerability. Ibuprofen was introduced in the United Kingdom in 1966 and in the United States in 1974, and was the first non-steroidal anti-inflammatory drug (NSAID) licensed for over-the-counter use in the UK in 1983 and in the US the following year. Ibuprofen is a non-cyclo-oxygenase selective NSAID but recent evidence suggests additional anti-inflammatory properties are due to modulation of leucocyte activity, reduced cytokine production, inhibition of free radicals and signalling transduction. Ibuprofen may also exert a central analgesic action in the dorsal horn. Future roles for ibuprofen may include protection against certain cancers and Alzheimer's disease.

Animals↗
PubMed2001

Effects of nimesulide and its metabolites or manufacturing intermediates on the viability and growth of the human hepatoma HepG2 cell line.

Hepatitis and fulminant hepatic failure have, infrequently, been associated with nimesulide. To establish if nimesulide or its analogues have direct cytotoxic activity on liver cells, experiments were undertaken to investigate the effects of nimesulide and its principal metabolites and production intermediates on the viability and growth of the human hepatoma cell line, HepG2, in vitro. The parent drug, metabolites or production intermediates as well as formulations of nimesulide were incubated for 6-48 hr with HepG2 cells and the extent of toxicity determined using the mitochondrial selective redox dye 3-4,5-dimethylthazol-2-yl)-2,4-diphenyl tetrazolium bromide (MTT). The results showed that there was no appreciable cytotoxic activity exhibited by nimesulide and its principle metabolites or production intermediates on HepG2 cells.

Anti-Inflammatory Agents, Non-Steroidal↗