Dual inhibitory effects of azapropazone on both neutrophil migration and function: relation to cardiovascular protection

Mousa, Shaker A.; Brown, Rowine Hayes; Mackin, William M.; Turlapaty, Prasad; Smith, Ronald D.; Timmermans, Pieter B.M.W.M.

doi:10.1007/978-94-009-0713-3_9

Cited by 2 publications

(2 citation statements)

References 17 publications

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“…It is also possible that there may be species differences in response to leucocyte-related injury. It is known, for example, that the NSAID effects on leucocyte accumulation and superoxide production in pig leucocytes resemble those in humans (Mousa et al 1989). These effects may be different to those in rats and rabbits, which were employed in those studies where NSAID-related leucocyte changes during mucosal injury was previously observed (Wallace et al 1990).…”

Section: Discussionmentioning

confidence: 99%

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

Rainsford

Stetsko

Sirko

et al. 2003

Journal of Pharmacy and Pharmacology

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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 endos...

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Section: Discussionmentioning

confidence: 99%

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

Rainsford

Stetsko

Sirko

et al. 2003

Journal of Pharmacy and Pharmacology

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“…In the swine model, hemodynamic parameters are not significantly different between the control and the AZP groups. The data generated from this model, in which myocardial tissue leveis of xanthine oxidase are low, suggest that the role of AZP as a xanthine oxidase inhibitor may be secondary to its primary effect on PMN functions (23,30).…”

Section: In Vivo Actions In Animal Modelsmentioning

confidence: 98%

Pharmacology of Azapropazone: Potential Utility in the Treatment of Ischemia/Reperfusion Injury

Mousa¹,

Rainsford

Timmermans³

1992

Cardiovascular Drug Reviews

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This article reviews the pharmacology of azapropazone and provides a likely link between its anti-inflammatory and myocardial cytoprotective efficacy in myocardial ischemidreperfusion injury.Azapropazone (AZP) is a chemically unique substituted benzotriazine nonsteroidal anti-inflammatory drug (NSAID). AZP was one of the early representatives of the class of NSAIDs to be introduced after phenylbutazone (PBZ) and indomethacin. Twenty years of clinical experience have been gained with AZP, which was developed and successfully introduced into a number of European countries for the treatment of a wide range of rheumatic conditions (47). Currently, AZP is under evaluation as a potential protective agent in different disease states involving neutrophil infiltration (1 3,25,29,32).This drug differs chemically from PBZ; a detailed comparison (structural, spectroscopic, and chemical) of AZP with PBZ reveals major differences (6,48). Although AZP undergoes enol formation (unlike PBZ), it is less acidic because of the differences in the restriction in rotation of AZP compared with the phenyl groups of PBZ. The dimethylamino substituent is present only in AZP and this markedly enhances its aqueous solubility by interaction of the nitrogen of this group with the hydroxyl moiety at low pH (such as in the stomach). There are also major differences in pharmacokinetics, metabolism, and pharmacodynamic actions of AZP compared to PBZ (48) (see reviews of Ref. 39). These considerations suggest that AZP should be classified separately from PBZ. It is important to note that the OH and = 0 groups in the formal structure of AZP depicted in Fig. 1 are interchangeable.

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Dual inhibitory effects of azapropazone on both neutrophil migration and function: relation to cardiovascular protection

Cited by 2 publications

References 17 publications

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

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

Pharmacology of Azapropazone: Potential Utility in the Treatment of Ischemia/Reperfusion Injury

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