K. D. Rainsford

Gastric ulcerogenicity of non-steroidal anti-inflammatory drugs in mice with mucosa sensitized by cholinomimetic treatment

A novel technique is described for the assay of acute gastric irritancy of non‐steroidal anti‐inflammatory drugs (NSAIDs) in mice in which (a) the gastric mucosa is sensitized to the irritant actions of the drugs by coadministration of bethanechol chloride to increase acid and pepsin production, and (b) the area and number of haemorrhagic lesions in the glandular mucosa is measured quantitatively by visual image analysis. The technique has been used to assess the acute gastric irritancy of 20 NSAIDs in mice. In relation to published values for their acute and chronic anti‐inflammatory activities, drugs with low relative gastric irritancy (e.g. carprofen, chloroquine, diclofenac, fenbufen, tenoxicam, tilomisole) were differentiated from the drugs of higher relative irritancy.

Effects of antimalarial drugs on interleukin 1-induced cartilage proteoglycan degradation in-vitro

Previous studies having shown that chloroquine and hydroxychloroquine could reduce interleukin 1 (IL‐1)‐induced cartilage degradation in‐vitro, the effects of a range of antimalarial drugs on the cartilage proteoglycan degrading actions of porcine leucocyte (pI 4.8) α‐interleukin 1 (syn. catabolin) have been examined using the standard bovine nasal cartilage culture system. The anti‐IL‐1 effects in this system were specific to several aminoquinoline and aminoacridine analogues having a side chain with a tertiary amino group similar to that of chloroquine. Aminoquinoline compounds devoid of this side chain and the tertiary amino, as well as pyrimidines or biguanides with antimalarial activity were without effect. Mefloquine, the most potent of the compounds active against porcine α‐IL‐1, was only equipotent with chloroquine and its hydroxyanalogue against human recombinant α‐IL‐1. This suggests that there may be subtle differences in the receptors for these drugs and interleukins in bovine cartilage. The results provide further evidence for the specificity and utility of antimalarial drugs in the treatment of chronic inflammatory conditions, especially in relation to actions on IL‐1.

NSAIDs: take with food or after fasting?

Objective  Published and regulatory advice is to take NSAIDs with fluids and/or food irrespective whether NSAIDs are taken over the counter or long‐term. The basis for this recommendation is not clear and we sought to establish the reasons for it through a search of published literature and personal files.

Mucosal Lesions Induced in the Rat Intestinal Tract by the Anti-Inflammatory Drug, Wy-41,770, a Weak Inhibitor of Prostaglandin Synthesis, Contrasted with Those from the Potent Prostaglandin Inhibitor, Indomethacin

The intestinal ulcerogenic activity of the weak prostaglandin synthesis inhibitor drug Wy-41,770 [5H-dibenzo(a,d)-cyclohepten-5-ylidine] was contrasted with the potent synthesis inhibitor, indomethacin, in rats to establish the relationship of inhibition of prostaglandin synthesis to the intestinal damage. Wy-41,770 induced superficial erosions only in the cecum 26 hr after a single oral dose of 250 or 500 mg/kg of the drug, progressing to ulcers after 5 days dosing with ultrastructural evidence of bacteria in the mucosa. Indomethacin (5 or 10 mg/kg po) induced mucosal erosions in the ileum, initially at 26 hr progressing to ulcers after 5 days. Fewer bacteria were seen in the ileal mucosa of indomethacin-treated rats. Both drugs reduced prostaglandin E in those regions of the intestine coincident with the known accumulation of these drugs at sites of mucosal injury. Site-specific intestinal damage from these 2 drugs is associated with inhibition of the synthesis of mucosal-protective prostanoids, followed by pronounced bacterial invasion through the damaged mucosae with consequent appearance of local immuno-inflammatory reactions.

Gastrointestinal damage from nonsteroidal anti-inflammatory drugs.

The mechanisms underlying the development of gastrointestinal (GI) damage by the NSAIDs differ considerably from drug to drug. Aside from environmental or intersubject influence (e.g., concurrent disease, physical or sociopsychologic stress, dietary and genetic status), the intrinsic pharmacokinetic and physico-chemical differences in these drugs account for variations in their rate of absorption or uptake from the circulation into the GI mucosa. Differences in the preference for absorption in the different regions of the GI tract account for the propensity of these drugs to cause injury in those regions wherein they accumulate. Bacterial flora and food antigens may be particularly important in promoting injury in the lower intestinal tract, whereas in the sterile environment of the normal stomach these may have less significance (except in achlorhydric states). The multiple cellular actions of NSAIDs are reviewed and the consequences of inhibiting prostaglandin cyclo-oxygenase considered. Under some conditions, the excess production of vasoconstrictor leukotrienes/HETES relative to effects of cyclo-oxygenase inhibition is postulated to have particularly important consequences in the pathogenesis of mucosal injury by NSAIDs. These consequences are separate from the concept of prostaglandin deficiency previously suggested by others.

Synthesis and anti-inflammatory effects of some bis(2-benzimidazolyl)thioethers and their copper(II) chelates, orally administered to rats

Abstract A series of bis(2-benzimidazolyl)thioethers and their copper(II) chelates has been prepared and tested. All the ligands and copper(II) complexes synthesized were orally assayed in the rat for anti-inflammatory activity in both acute (carrageenan edema) and chronic (adjuvant arthritis) models of inflammation. Some compounds were also examined for gastric-irritancy potential. Among tested molecules, the copper complex with the unsubstituted lead structure (NSN) showed the best pharmacological activities, which seem to be dependent upon the presence and bioavailability of some intact complex in the gastrointestinal tract after oral administration. The compound did not exhibit any capacity to elicit significant lesion development of the gastric mucosa of stress-sensitized rats. Structure—activity relationships of the copper complexes are discussed.

Relations between gastric irritancy/ulcerogenicity and anti-oedemic activity of non-steroidal anti-inflammatory drugs.

Recently, Dearden & Nicholson (1984) reported a study of the relation between gastric irritancy and anti‐inflammatory activity for some 25 non‐steroidal anti‐inflammatory (NSAI) drugs in which they made statements concerning work by Rainsford that require clarification because there appears to be some misinterpretation—viz:

Distribution of azapropazone and its principal 8-hydroxy-metabolite in plasma, urine and gastrointestinal mucosa determined by HPLC

Methods are described for the HPLC determination of azapropazone and its 8‐hydroxyl metabolite in plasma, urine and gastrointestinal mucosae after purification of samples on reverse‐phase mini columns. Plasma levels of the drug in gouty patients receiving 900–2400 mg daily were relatively constant after 5 days, though overall the values were higher than after a single dose. Gastric absorption of azapropazone in rats is relatively rapid suggesting that the low gastric irritancy is probably due to its weak inhibitory effects on prostaglandin and mucus synthesis rather than slow gastric absorption.