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Dapsone has been shown to possess anti-inflammatory activity in a variety of animal models. It possesses oral anti-oedema activity especially pronounced in novel models of acute inflammation, viz. anti-IgG and reversed passive Arthus oedemas. However, it is not very active in the guinea pig u.v. erythema model. It is effective in chronic models such as adjuvant arthritis and the cotton pellet granuloma although multiple administration may also produce cyanosis. Antipyretic and analgesic effects for dapsone have been demonstrated and are similar to those produced by phenylbutazone. It inhibits zymosan-induced beta-glucuronidase release from cultured macrophages and also the activity of this enzyme. Dapsone does not appear to be ulcerogenic in the rat.

A cell-mediated immune colitis in guinea-pigs was examined for its response to several drugs used in the management of colitis as an attempt to obtain an appropriate model for evaluating potentially new anticolitic drugs. The experimentally-induced colitis was readily reproducible and possessed several features in common with the clinical disease: diarrhoea, rectal bleeding and body weight loss, together with ulceration and haemorrhage of the distal colon. Sulphasalazine, prednisolone and disodium chromoglycate appeared not to influence the manifestations of the colitis nor the macroscopic features of the inflamed colon. Azathioprine (AZA) at 100 mg/kg but not at 30 mg/kg modified the colitis in some but not all animals. This model appears to be of little value for the screening of anti-colitic agents.

Total serum copper and ceruloplasmin oxidase activities have been measured over a 24-h period in rats and guinea-pigs treated with 100 mg/kg body weight of copper (II) aspirinate. In the rat, administration s.c. produced higher total serum copper levels than oral administration at all time intervals studied, whereas in the guinea-pig, oral administration produced the higher level after 1 h and s.c. administration the higher level after 5 h. In both species, the rate of elimination of the additional copper was faster following oral administration. Ceruloplasmin oxidase activity appeared to be inhibited in certain cases but rose in all cases except for orally treated rats after 24 h. The initial rise in serum copper was due mainly to copper present on albumin. The increased albumin copper was detected directly by electrophoresis of serum samples and subsequent determination of the copper level in the portions of the strip which contained proteins. After s.c. administration to the rat, the amount of ultrafilterable copper was raised by a detectable amount. 7 h after s.c. or oral administration of copper aspirinate, the thiol concentration of the serum was reduced in both rats and guinea-pigs. The relationship of these levels to the anti-inflammatory action of copper (II) aspirinate in rats and guinea-pigs is discussed.

A comparison of the anti-inflammatory (AI) activity of copper compounds in models of kaolin-induced paw oedema and u.v. erythema in the rat and guinea pig is described. The results demonstrated considerable species variation, the guinea pig being more sensitive to the AI and irritant effects of copper aspirinate and the other copper compounds. The route of administration of these compounds was also an important factor in interpreting AI activity obtained. Indeed, the counter-irritation effects of the copper compounds may be largely responsible for the AI activity obtained after subcutaneous administration. The comparison between copper aspirinate and aspirin, performed in order to determine whether a copper complex of an AI drug was more active than the parent AI compound, failed to produce a clear difference in activity although copper aspirinate was more effective than aspirin in certain cases. It is concluded that this study highlights the complexities of copper therapy against inflammatory processes and furthermore indicates the importance of species, the model of inflammation and route of drug administration in interpreting data obtained with copper containing compounds.

We investigated the therapeutic effect of two gold salts, gold sodium thiomalate (GST, i.m.) and auranofin (p.o.), D-penicillamine (p.o.) and benoxaprofen (p.o.) in rat collagen-induced arthritis using type II collagen from fetal bovine articular cartilage. GST, but not auranofin, reduced hind paw edema and bone pathology. However, auranofin reduced serum copper and zymosan-induced prostaglandin production from peritoneal macrophages. In contrast, GST increased both serum copper and macrophage prostaglandin production by zymosan. Benoxaprofen reduced both hind paw edema and pathology, whereas D-penicillamine was without effect. None of these treatments influenced the circulating level of antibody to type II collagen.

The effects of administering drugs 2 days after antigen sensitization in a combined model of delayed type hypersensitivity (DTH) and humoral immunity (HI) in the mouse are described and compared with a previous study in which drugs were administered prior to sensitization using the same model. Low doses of cyclophosphamide (CY) administered after antigen sensitization were found to enhance DTH to methylated bovine serum albumin (MBSA). In addition, high doses of this drug suppressed DTH for 3 days after challenge, and then enhanced the response for a further 5 days. The HI response to sheep red blood cells (SRBC) was simultaneously suppressed by a range of CY doses. A number of different drug types demonstrated a similar pattern of dose-dependent DTH effects. However, unlike the previous study DTH enhancement was not confined to the alkylating agents. Either DTH enhancement or suppression was also observed after treatment with a number of other drugs. HI was suppressed by several drugs, in particular by a number of alkylating agents and anti-metabolites. Selective effects on one or other limbs of the immune response were observed. The mode(s) of action of drugs active in the present study are uncertain but possible explanations are discussed in terms of the elimination and subsequent recovery of specific cell populations.

Wy-25,110, the p-OH metabolite of fentiazac was approximately 100 times less potent than fentiazac after oral administration in rat carrageenan edema and 100-130 times less potent as an inhibitor of prostaglandin synthesis by mouse peritoneal macrophages. In addition, Wy-25,110 was one twelfth as active as fentiazac against immunologic-induced inflammation on day 16 in rat adjuvant arthritis. Wy-25,110 was also much less potent than fentiazac when administered intravenously, suggesting that inadequate oral absorption does not account for its lack of potency. Thus it seems unlikely that the p-OH metabolite contributes greatly to the antiinflammatory properties of fentiazac.

An immune colitis based on a delayed-type hypersensitivity reaction was induced in dinitrochlorobenzene (DNCB)-sensitized guinea-pigs by intrarectal challenge with DNCB. A low challenge dose (0.25% DNCB) induced mild inflammatory changes in the distal colon and rectum characterized by goblet cell depletion. A higher challenge concentration (5% DNCB) resulted in severe colonic ulceration with crypt abscess formation. The inflammatory mediators, histamine, 5-hydroxytryptamine (5HT), glandular kallikrein and PGE2 were measured in freeze-dried colonic mucosae. Histamine content was three times control (p less than 0.01) in 0.25% DNCB induced colitis, although no significant change was observed in 5% DNCB challenged animals. Mucosal 5HT content was significantly reduced (p less than 0.01) after both challenges. Glandular kallikrein content did not differ from control, while PGE2 was significantly (p less than 0.05) increased at both challenge doses. The possible significance of these changes with respect to severity of inflammation and aetiology of colitis is discussed.

Antihistamine-resistant anaphylactic bronchospasm in guinea pigs is increased with increasing doses of antigen (ovalbumin, OA) challenge. This was observed in passively and actively sensitized animals, and by both i.v. and aerosol routes of antigen challenge. At a challenge concentration of 100 mg/kg OA, antihistamines were virtually inactive. Indeed, the resulting bronchospasm was inhibited by isoproterenol, theophylline and ketotifen but not any anticholinergics, anti-5HT, SRS-A antagonists, arachidonic acid lipoxygenase inhibitors or antiallergic drugs. However, in the presence of chlorpheniramine, the response was antagonized by SRS-A antagonists (FPL 55712 and isamoxole), but not the lipoxygenase inhibitors (BW 755C, ETYA, NDGA and phenidone). This suggests that the antihistamine-resistant bronchospasm produced in guinea pigs challenged with high antigen concentrations might be the result of SRS-A release. This is by no means certain since the currently available SRS-A antagonists possess other mechanisms of action; furthermore, the failure of lipoxygenase inhibitors to influence this response is not consistent with a role for SRS-A. Elucidation of the mechanism of the antihistamine-resistant bronchospasm awaits development of more specific SRS-A antagonists.

A model has been developed in the mouse in which methylated bovine serum albumin (MBSA) and sheep red blood cells have been used to produce delayed type hypersensitivity (DTH) and humoral immunity (HI), respectively. The time course between antigen sensitization and challenge was chosen such that cyclophosphamide (CY), administered prior to sensitization, produced DTH enhancement and also produced suppression of HI when administered at high doses. A number of other drugs have been examined in this model but only CY-like drugs, viz. alkylating agents, produced similar DTH enhancement. DTH was suppressed in a few cases. The HI response was enhanced or suppressed by a number of unrelated drugs. CY was the only alkylating agent to suppress the antibody titre. The mechanisms for these drug effects are uncertain. However, a number of drugs elicit effects on either DTH or HI which suggests there is selective removal of certain cell populations rather than non-specific cytotoxicity. Possible theories for the effects observed are discussed. These studies also suggest that CY possesses unique properties in this particular model.

Platelet activating factor (PAF-acether) is a potential mediator of asthma and inflammation. Recently, the suggestion was made that inhibition of PAF-acether by disodium cromoglycate (DSCG) might be partly responsible for the effectiveness of DSCG in asthma. We have extended these studies and examined the effects of antiallergic and bronchodilator drugs on PAF-acether induced bronchospasm after i.v. administration in guinea pigs and in vitro platelet aggregation in rabbits. Neither DSCG nor Wy-41,195, a potent orally effective antiallergic, altered either of the PAF-acether responses. Furthermore, aerosolized ipratropium, promethazine, ketotifen and FPL 55712 failed to affect the PAF-acether-induced bronchospasm. The same drugs were also ineffective against platelet aggregation induced by PAF-acether. In contrast, aerosolized thiazinamium chloride inhibited the bronchospasm and also inhibited PAF-acether-induced platelet aggregation. Thiazinamium chloride possessed weak antiaggregatory effects against ADP and was without effect against arachidonic acid-induced platelet aggregation. Both lipoxygenase and cyclooxygenase products of arachidonic acid metabolism appear to be involved in PAF-acether bronchospasm since i.v. administered lipoxygenase inhibitors (phenidone, BW755c and NDGA) and indomethacin independently inhibited this in vivo response. However, these drugs failed to alter platelet aggregation to PAF-acether. Thiazinamium chloride may be capable of directly antagonizing the PAF-acether-induced platelet aggregatory response and, in addition, inhibiting the synthesis and/or effects of bronchoconstrictor amines and endogenously generated arachidonic acid metabolites.

The numbers and subtypes of leukotriene (LT) receptors have only recently been investigated and more work is needed to evaluate the distribution of receptors on tissues and cells in both normal and pathological states. Classification of the heterogeneity of LT receptors may assist in the discovery of new antiallergy and antiinflammatory drugs much in the same way as the study of different adrenergic receptors has benefited cardiovascular drug discovery. The clinical evaluation of the currently available LT antagonists is awaited with interest; however, their therapeutic role in the treatment of asthma, a primary goal for the majority of these agents, will require painstaking clinical appraisal. They seem unlikely to supplant the currently used bronchodilators but may provide a valuable prophylactic adjunct that may suppress some of the inflammatory events that occur in obstructive lung disease. Whether the LT antagonists modify the hyperreactive state that prevails in asthma is also the subject of much speculation.

The antiinflammatory activity of the immunomodulatory agent Wy-18,251 (3-(p-chlorophenyl)thiazolo-[3,2-a]benzimidazole-2-acetic acid) was examined using a variety of antiinflammatory, analgesic and antipyretic animal models in comparison to aspirin, levamisole and indomethacin. The acute antiinflammatory and analgesic activity of Wy-18,251 (ED50 = 100-200 mg/kg, p.o.) was similar to aspirin, but in contrast to aspirin Wy-18,251 failed to demonstrate antipyretic activity. Wy-18,251 (10-100 mg/kg, p.o.) also inhibited chronic inflammatory responses in the adjuvant- and collagen-induced arthritis models. Wy-18,251 was a modest inhibitor of prostaglandin biosynthesis but did not inhibit either 5- or 15-lipoxygenase enzymes. Wy-18,251 (up to 480 mg/kg, p.o.) produced little gastrointestinal pathology in 16 h fasted rats. The combined immunomodulatory and antiinflammatory activity of Wy-18,251 suggests that this agent may have therapeutic promise in certain immunoinflammatory diseases including rheumatoid arthritis.

Inhibitors of arachidonic acid (AA) metabolism and other pharmacologic agents were evaluated against ear edema produced in mice by tetradecanoylphorbol acetate (TPA) or AA. Drugs were administered orally and topically either 30 min prior to AA or 30 min after TPA, except for steroids which were administered 2.5-3 hr prior to AA. Several cyclooxygenase (CO) inhibitors including indomethacin, aspirin, piroxicam and timegadine were without effect when administered orally against either irritant; the same drugs inhibited TPA edema when they were administered topically. Mixed CO/lipoxygenase (LO) inhibitors, phenidone and BW755C, were active orally against AA edema (ED50S of 84 and 65 mg/kg, respectively) and against TPA edema (ED50S of 235 and 88 mg/kg, respectively). Phenidone was more active topically against AA edema (ED50, 0.1 mg/ear) than BW755C (ED50, 2.8 mg/ear); however, BW755C was more active topically against TPA edema (ED50, 0.2 mg/ear) than phenidone (ED50, 0.6 mg/ear). Methylprednisolone was very effective in the AA (oral ED50, 17 mg/kg; topical ED50, greater than 1 mg/ear) and TPA models (oral ED50, 4.3 mg/kg; topical ED50, 0.03 mg/ear. MK-447 was topically and orally effective only in the TPA model. Not surprisingly, drugs were more effective topically than orally in both mouse ear edema assays. The models were somewhat selective for CO and CO/LO inhibitors; however, dapsone was orally effective in the ear models, and a number of mediator antagonists and CNS drugs, especially anti-psychotics, were topically active primarily against TPA edema. These models may be useful for the detection of in vivo activity of CO/LO or 5-LO inhibitors.

Wy-41,770 [(5H-dibenzo[a,d]cyclohepten-5-ylidene)acetic acid], a novel acrylic acid, was compared to indomethacin and aspirin in standard antiinflammatory, analgesic and antipyretic animal models. The acute antiinflammatory, analgesic and antipyretic activity of Wy-41,770 (oral ED50S 50-170 mg/kg) was similar to aspirin; however, it was considerably more potent orally in adjuvant arthritis in the rat (ED50, 16 mg/kg) and urate-induced synovitis in the dog (ED50, 4.5 mg/kg). Wy-41,770 was a weak inhibitor of prostaglandin biosynthesis and did not inhibit either 5- or 15-lipoxygenase. Furthermore, the cellular migration characteristic of carrageenan pleurisy was not affected by Wy-41,770. Unlike a majority of NSAIDs, it produced no gastric irritation in rats after either acute or chronic oral administration over the range 400-800 mg/kg. The major mechanism of action of Wy-41,770 has yet to be identified but does not seem to involve interference of arachidonic acid metabolism.

The effects of a number of steroids administered intra-articularly in a chronic model of fibrin-induced monoarticular arthritis in the rabbit have been investigated. Org 6216 hydrocortisone acetate, prednisolone tertiary butyl acetate and triamcinolone hexacetonide each suppressed the joint swelling produced 14 days after antigen challenge. These anti-inflammatory effects lasted for at least 7 days. Hydrocortisone semisuccinate was inactive in this model. In addition, the effects of the same compounds and several other anti-inflammatory steroids and indomethacin administered locally with adjuvant was assessed on the resultant paw oedema produced in the rat. The local anti-inflammatory activity, the duration of action and the systemic effects of these drugs varied considerably and only Org 6216, hydrocortisone acetate, prednisolone tertiary butyl acetate and indomethacin produced anti-inflammatory effects throughout the 4 days of the experiments and were devoid of significant adrenolytic and thymolytic activity.

Several gold salts were compared in kaolin-induced rat paw oedema, u.v. erythema in guinea pigs, delayed type hypersensitivity and humoral immunity in mice, and adjuvant-induced arthritis in the rat. In the latter the additional parameters of serum gold and copper levels and lysosomal enzyme activity were determined. In addition, the in vitro inhibition of several lysosomal enzymes derived from mouse macrophages was studied. The gold compounds examined were aurothiomalate, aurothioglucose, triethylphosphine gold chloride (SK & F 36914) and its glucopyranoside derivative (SK & F D-39162), triphenylphosphine gold chloride and sodium gold chloride dihydrate. SK & F 36914 and SK & F D-39162 has significant activity after oral dosage upon paw kaolin and u.v. erythema in rats and guinea pigs, respectively. Gastric swelling also occurred. In Wistar rats, adjuvant arthritis was little affected by the gold salts but in the Lewis rats there was suppression. In both strains there was less elevation in serum copper levels with treatment by SK & F 36914 and SK & F D-39162, but not by aurothiomalate. None of the compounds had any measurable effect on delayed hypersensitivity or humoral antibody levels in mice. The in vitro activities of cathepsin B1 and cathepsin D were inhibited by all the gold compounds. Reactivity of gold compounds with glutathione and cysteine in vitro was dependent on compound solubility and the nature of the gold ligand. Considerable differences exist between the profiles of activity for the different gold salts evaluated. These observations indicate that some gold salts do possess anti-inflammatory activity with a potency similar to that of indomethacin.

Utilizing an adjuvant arthritis model in rats, we examined humoral immunity to collagen and inflammation in animals with active disease and during drug therapy. Humoral immunity to types I or II collagen was not detected in the sera of rats with advanced adjuvant arthritis; this was in marked contrast to rats with type II collagen-induced arthritis which possessed serum antibodies to native and denatured type II collagen. Hind paw edema and bone pathology were monitored as parameters of inflammation. A new investigational drug, Wy-41,770, was most effective in reducing all of these aspects of inflammatory disease while indomethacin, methylprednisolone, and D-penicillamine caused a less significant diminution of only some of these parameters of inflammation. Antibodies to collagen were not detected in the sera of rats treated with the drugs under study. These data demonstrate that adjuvant arthritis can occur in rats in the absence of antibodies to types I or II collagen.

A comparative study of tissue gold levels produced in guinea-pigs after the oral administration of either triethylphosphine gold chloride or Myocrisin (sodium aurothiomalate) or after the injection of Myocrisin intramuscularly is reported. Gold concentrations were determined 5, 24 and 168 hours after administration in stomach, small intestine, large intestine, kidney, liver and spleen and 5 and 24 hours after administration in skin, adrenals, heart, lung and brain. In gastrointestinal tissues, tissue gold concentrations were highest with triethylphosphine gold chloride. The stomach gold level 5 hours after oral administration of triethylphosphine gold chloride is particularly high and, taken in conjunction with the other gastrointestinal gold levels measured, suggests that a stomach rather than an intestinal absorption mechanism may predominate. A more extensive time-course study on kidney and liver is reported and the possible relationship between tissue concentration and toxicity is discussed.

The development of novel anti-inflammatory drugs (AID) has been claimed to be dependent on the discovery of models of inflammation that differ from those currently used for drug screening, e.g. carrageenen paw oedema and u.v. erythema. We have thus evaluated the effect of a variety of drugs in a number of novel models of inflammation in the rat produced in the hind paw. We have utilized kaolin, zymosan, anti-rat IgG (anti-IgG) and the Reversed Passive Arthus (RPA) reaction to produce these oedema models. We found that the non-steroidal AID's, e.g. aspirin, flufenamic acid, indomethacin, naproxen, and phenylbutazone, were active in all four tests. Of the nine novel AID examined, levamisole and tetramisole demonstrated considerable activity in all four tests and dapsone was especially active in the anti-IgG and RPA tests. In contrast, the anti-rheumatic d-penicillamine was inactive in all four models. Each of the ten compounds tested which has been claimed to influence complement function, was active in the RPA but not in the kaolin model. These results are discussed in the context of the aetiology of each oedema and the suspected mode of action of the various drugs.