Showing papers in "Inflammation Research in 1986"

The Croton oil ear test revisited

Abstract: Introduction Among the few tests available to detect the activity of topical antiinflammatory drugs, the Croton oil (CO) ear test is one of the most commonly used [1 3]. In this test the inflammatory response (IR) is usually quantified by measuring the increase in ear plug weight (EPW) at a single time-interval after CO application, when the IR is maximal. In this paper this experimental model of inflammation has been reevaluated in terms of time-course, contribution of granulocyte infiltration (GI) to the IR and response to both steroidal and non steroidal antiinflammatory drugs.

Pharmacology of an extract of salai guggal ex-Boswellia serrata, a new non-steroidal anti-inflammatory agent.

Abstract: Pharmacological evaluation of alcoholic extract of salai guggal (AESG) has been carried out in experimental animals. AESG displayed marked anti-inflammatory activity in carrageenan induced oedema in rats and mice and dextran oedema in rats. It was equally effective in adrenalectomised rats. In formaldehyde and adjuvant arthritis, AESG produced prominent anti-arthritic activity but no significant effect was observed in cotton pellet-induced granuloma test. It inhibited inflammation induced increase in serum transaminase levels and leucocyte counts but lacked any analgesic or anti-pyretic effects. The gestation period or parturition time in pregnant rats or onset time of castor oil-induced diarrhoea was unaffected by AESG and no significant effect was seen on cardiovascular, respiratory and central nervous system functions. No ulcerogenic effects were found in the rat stomach. The oral and intraperitoneal LD50 was greater than 2 g/Kg in mice and rats.

Enhanced formation of sulfidopeptide-leukotrienes in ulcerative colitis and Crohn's disease: inhibition by sulfasalazine and 5-aminosalicylic acid.

Abstract: Release of sulfidopeptide (SP)-leukotrienes (LT)in vitro from normal human colonic mucosa and from mucosal tissue obtained from patients with Crohn's disease (CD) and ulcerative colitis (UC) was investigated. It was found that inflamed mucosal tissue released significantly more SP-LT than normal colonic mucosa both under control conditions and after addition of calcium ionophore A23187. These results indicate the presence of endogenous stimuli as well as an increased responsiveness to an exogenous stimulus of LT formation in the inflamed mucosa. Sulfasalazine (SASP), a drug used in inflammatory bowel diseases, and its active metabolite 5-aminosalicylic acid (5-ASA) were found to inhibit colonic mucosal SP-LT formation, while only 5-ASA inhibited simultaneously synthesis of another arachidonic acid-derived inflammatory mediator, prostaglandin (PG) E2. The results suggest that SP-LT might be important mediators of inflammation in CD and UC.

Leukotrienes in inflammation.

Abstract: In conclusion the leukotrienes appear to fulfill the major criteria as mediators of inflammation. They have been shown to be present at a variety of inflammatory sites and to be generated by cells involved in inflammatory sequelae following an inflammatory stimulus. Their effects on the microvasculature and inflammatory cells are consistent with a pro-inflammatory role and the effects of LTB4 in particular on a range of immune responses may indicate a role in the more chronic phases of inflammatory disease. It remains to be conclusively proven that specific inhibition of LT generation or antagonism of LT action will lead to a reduction in inflammatory symptomology in human disease however the data so far provides some hope that drugs with such properties may find a place in the medicinal armamentarium in the relatively near future.

Studies of eicosanoid production in the air pouch model of synovial inflammation.

Abstract: The time course of the inflammatory reaction in the rat air pouch model of synovial inflammation has been investigated at different stages of development of the lining structure using immune (pertussis vaccine) and non-immune (carrageenan) irritants. Exudate volumes and leucocyte numbers were greater with carrageenan than with pertussis vaccine but with both irritants much greater reactions were obtained when the irritant was injected at a time when the air pouch architecture most closely resembled synovium (i.e. 6 days). The time course of fluid accumulation following carrageenan in 6 day pouches was not interrupted when exudate was aspirated from the pouch six days after carrageenan injection. In the 6 day old air pouch PGE2 and 6-oxo-PGF1α concentration peaked at 6 hours and 24 hours respectively. With carrageenan and pertussis vaccine stimulation, LTB4 concentrations were maximal at 3–6 hours with both irritants and low concentrations were still present at 13 days. The presence of a lining structure was found to influence concentrations of PGE2 in the air pouch. Pre-treatment with colchicine or 5-fluorouracil to reduce cell accumulation was not found to effect the modified PGE2 response. Our findings suggest that the presence of a synovial like lining structure may induce changes in composition in respect to cellular content and in putative mediator concentrations. We conclude that it is important in elucidating the mechanisms involved in arthritic inflammation to study injury in a cavity linedby macrophages and fibroblasts.

Oxygen free radicals interact with indomethacin to cause gastrointestinal injury.

Abstract: In the present study it was shown that, unlikely MK447, a known oxygen free radical compound, PGE2 is much less effective against indomethacin-induced G.I. ulcers than against ethanol damage. It seems likely that factors other than PG deficiency (such as oxygen free radicals), could be involved in the pathogenesis of NSAID-induced G.I. damage. Some compounds that can capture free radicals (aminopyrine, thiourea and its derivative, MK 447) or that inhibit the lipoxygenase pathway (MK 447, salicylazosulfapyridine, BW 755, benoxaprofen) are able to abolish indomethacin-induced G.I. damage. After irradiation with hydroxyl free radicals, indomethacin reacts with them to cause marked G.I. injury, even at a submaximal dose, one poorly ulcerogenic by itself. The above findings suggest that oxygen free radicals are one of the causal factors in the formation of NSAID-induced G.I. side effects. Some of the data in this paper were presented at Fermo, August 31, 1984 (Advanced course on 'oxygen and sulfur radicals in chemistry and medicine') and at the 9th Iuphar International Congress of Pharmacology in London, July 30, 1984.

In vivo inhibition of plasma protein leakage and Salmonella enteritidis-induced mortality in the rat by a specific paf-acether antagonist: BN 52021.

Abstract: The effects of BN 52021, a new specific paf-acether receptor antagonist and the total Ginkgo Biloba extract (GBE 761) from which this product was isolated, were studied in the rat on paf-acether-induced permeability and cell number changes and on endotoxin-induced lethality. Their activities were compared to those of cyclooxygenase, 5-lipoxygenase and phospholipase A2 inhibitors. BN 52021 given s.c. or orally exerted a dose-related inhibition of paf-acether deleterious effects as well as of endotoxin lethality whereas the other drugs tested were poorly effective. These results strongly suggest paf-acether involvement in endotoxic and septic shock.

Role of T lymphocytes in murine collagen induced arthritis.

Abstract: Collagen type II induced arthritis (CIA) was first described by David Trentham and Andrew Kang in 1977 after screening different components purified from joint tissue for arthritogenic capacity in rats [1]. Intradermal injections of fractions enriched for cartilagenous collagen (mainly type II) led to the development of a severe polyarthritis about 2 weeks after immunization. CIA has subsequently been induced in a wide variety of laboratory animals, such as mice [2] and primates [3]. The mouse model for CIA has proved to be a very rewarding model for studies of autoimmune reactions that cause arthritis. Such studies have indicated that both T-cell mediated immunity and humoral immunity are involved in the pathogenesis of CIA. The model should offer possibilities both to investigate how different immune reactions may synergize in causing arthritis, and to find ways to interfere therapeutically in a multifaceted but also well defined experimental animalarthritis model. The present view mainly concentrates on studies that illuminate the role of T lymphocytes in murine CIA. With this aim we first discuss some general features of the model, secondly we describe some of our own studies on long term cultured arthritogenic collagen II reactive T helper cells, and thirdly we describe

Anti-inflammatory activity of Commiphora molmol.

Abstract: The petroleum ether extract of the oleo-gum resin of Commiphora molmol, at a dose of 500 mg/kg body weight, produced significant inhibition of carrageenan induced inflammation and cotton pellet granuloma. The extract also showed significant antipyretic activity in mice. Further studies on the fractionation of phytoconstituents and their mechanism of action are in progress.

Potential therapeutic efficacy of inhibitors of human phospholipase A2 in septic shock.

Abstract: Soluble phospholipase A2 has been implicated in the pathogenesis of local and systemic inflammatory reactions. Elevated levels of circulating phospholipase A2 (PLA2) correlate with the severity of circulatory collapse and pulmonary dysfunction in gram-negative septic shock. Characterization of septic shock serum PLA2 revealed a calcium-dependent enzyme with absolute 2-acyl specificity with a pH optimum of 7.5. We tested a number of therapeutic agents for their ability to inhibit PLA2 from human septic shock serum. Chloroquine, chlorpromazine, dexamethasone base, dexamethasone sodium phosphate, indomethacin, lidocaine, oleic acid, palmitic acid, promethazine, trans-retinoic acid, rutin and dl-α-tocopherol were all studied over the range of 10−2 to 10−7 M. All agents, with the sole exception of dexamethasone base, inhibited PLA2 activity at concentrations greater than 10−3M. PLA2 inhibition by dexamethasone sodium phosphate was factitious, due to the formation of calcium-phosphate complexes. Of the 11 agents studied, chlorpromazine was the most effective, with an IC50 of 7.5×10−5 M, a membrane concentration achievable within its therapeutic range. Inhibition was non-competitive, with an apparent Ki of 5 nM. Since serum PLA2 levels correlate with mortality in both experimental endotoxemia and clinical gram-negative septic shock, and chlorpromazine was previously shown to improve survival in these conditions, we postulate that its therapeutic efficacy resides at least in part in its PLA2-inhibitory activity.

Blood platelets in human essential hypertension.

Abstract: Blood platelets of patients with essential hypertension display signs of both increased sensitivityin vitro to aggregating stimuli believed to contribute to thrombosis and of activationin vivo possibly expressing the release of vasoactive products. The mean features of the modified platelet profile in hypertension include an increased α2-adrenergic receptor density, an enhanced rate of adhesion/aggregation in particular in response to ADP and arachidonic acid, a greater sensitivity for thrombin and adrenaline to stimulate increases in cytoplasmatic-free Ca2+, increased resting levels of cytoplasmatic-free Ca2+, a reduced content of serotonin often combined with a defective uptake mechanism, a facilitated efflux rate of noradrenaline, an exaggerated release reactionin vivo as indicated by the increased plasma levels of Betathromboglobulin and a shortened platelet life span. These changes occur to various extents in some, but not all, hypertensive patients and are not always strictly related to the degree of blood pressure increase. On the contrary, platelet cyclooxygenase and thromboxane synthetase activity are in the normal range.

Disease modifying activity of HWA 486 on the development of SLE in MRL/1-mice

Abstract: The novel isoxazol derivative HWA 486 has been shown to prevent the onset of adjuvant disease in Lewis rats [1]. In those studies, the diminished arthritic response was correlated with an improved response of lymphocytes to Tand B-cell mitogens. Further studies on healthy mice indicated that this substance selectively influences the T-cell dependent B-cell formation of antibodies, yet does not have any effects on polyclonal activation of T-cells or T-cell independent B-cells [2]. Due to the immunopharmacological profile of this agent, we felt that HWA 486 could be effective against an autoimmune disease which is characterized by massive production ofautoantibodies. The studies presented here describe the activity of this substance on the disease development of autoimmune MRL Mpf lpr/lpr (MRL/1) mice. This strain, which spontaneously develops a disease very similar to human systemic lupus erythematosus (SLE), forms antibodies against certain types of self-antigens, the most prevalent of which are those to double-stranded DNA (dsDNA). Unlike other murine strains that develop SLE, rheumatoid factor (RF) together with the development of necrotic polyarthritis can be detected in these mice. Further symptoms include hypergammaglobulinaemia, and glomerulonephritis.

Anti-inflammatory activity of some Saudi Arabian medicinal plants.

Abstract: Five plants which have been used for the treatment of rheumatism, arthritis and gout in the traditional medicine of Saudi Arabia, were evaluated for their anti-inflammatory properties. Of these the ethanolic extract of Capparis decidua and the aqueous extract of Capparis spinosa were found to possess significant anti-inflammatory activity against carrageenan induced oedema in rats. These two plants were also tested for their antipyretic and analgesic activity. C. decidua was found to possess significant antipyretic effect. Both of them are devoid of analgesic activity.

Physiological concentrations of zinc inhibit the release of histamine from human basophils and lung mast cells

Abstract: We have previously shown that physiological concentrations of zinc (congruent to 7 X 10(-6) M) inhibit the release of histamine from human basophil leukocytes (Marone et al., J. Pharmacol. Exp. Ther. 217: 292, 1981). In these experiments we compared the effect of zinc chloride on the release of chemical mediators from human basophils and mast cells isolated from human lung. Preincubation (5 min, 37 degrees C) of human basophils and lung mast cells with zinc chloride (10(-6)-3 X 10(-5) M) caused dose-related inhibition of histamine and peptide leukotriene C4 (LTC4) release induced by anti-IgE. Increase Ca2+ concentrations (0.3 to 6 mM) in the extracellular medium completely reversed the inhibitory effect of zinc on anti-IgE-mediated histamine secretion. Zinc chloride was a competitive antagonist of the action of Ca2+ in histamine secretion induced by anti-IgE with a dissociation constant (Kd) of about 10(-5) M in both the basophil and mast cell systems. Thus physiological concentrations of zinc inhibit the release of histamine from human basophils and lung mast cells, presumably by blocking Ca2+ uptake induced by anti-IgE activation.

Studies on type II collagen induced arthritis in mice.

Abstract: A consistent and reproducible polyarthritis was induced in mice by immunizing them with type II collagen in Complete Freunds adjuvant (CFA) and Bacillus Calmette-Guerin (BCG) vaccine. Several inbred strains of mice were investigated for the ability to develop collagen induced arthritis (CIA). DBA/1 mice (H-2q) produced the highest incidence and the most severe arthritis of all the strains examined. Viable BCG vaccine was essential for the induction of a reproducible disease in this strain. The effects of some anti-inflammatory and anti-rheumatic compounds were examined on the developing and established lesions of CIA. These effects were determined by assessing the paw inflammation using a subjective scoring system and measuring foot weight. Furthermore, levels of serum amyloid P component (SAP) were also determined. Benoxaprofen, cyclophosphamide, indomethacin and prednisolone inhibited the paw inflammation in the developing disease whilst the anti-rheumatic compounds auranofin and D-penicillamine exacerbated the paw inflammation. Cyclophosphamide and prednisolone inhibited the established lesions but only prednisolone prevented the development of further lesions in the established disease. The SAP levels in the prednisolone treated group were also reduced. Auranofin treatment exacerbated the inflammation of both the established and the developing lesions in the same animal. D-penicillamine was inactive in the established disease.

Antagonism of histamine and leukotrienes by azelastine in isolated guinea pig ileum.

Abstract: The effects of azelastine on histamine- and leukotriene C4 and D4 (LTC4, LTD4)-induced contractile responses in isolated guinea pig ileum were investigated. Following a 2-min contact with the ileum, azelastine produced competitive antagonism of histamine (pA2 = 8.24). Following a 15-min contact, azelastine at 2.5 X 10(-9) M exerted competitive antagonism, but at higher concentrations (10, 40 and 160 X 10(-9) M) it not only shifted histamine concentration-effect curves to the right but also suppressed its maximum. Thus, azelastine exerts a dual (competitive/noncompetitive) antagonism of histamine depending upon the concentration and duration of contact. Azelastine and FPL 55712 (a known LT receptor antagonist) produced concentration-dependent antagonism of LTC4 and LTD4. Azelastine and compound FPL 55712 also exerted concentration-dependent reversal (relaxation) of pre-existing LTC4-induced contractions. In conclusion, the potent H1-histamine and leukotriene receptor blocking activities of azelastine may contribute to its antiasthmatic/antiallergic activities.

FMLP-activated neutrophils evoke histamine release from mast cells.

Abstract: Human neutrophils, having been activated by the chemotactic peptide N-formylmethionyl-leucyl-phenylalanine (FMLP), evoke histamine release from rat serosal mast cells. The release is dependent on FMLP concentration and it can be inhibited by disodium cromoglycate and by a flavonoid, silymarin, which displays free radical scavenging properties. Silymarin inhibition of neutrophil-mediated histamine release is dose-dependent. These results further stress the concept of a neutrophil-mast cell interaction, which may be involved in inflammatory processes.

Pharmacological studies of antigen-induced arthritis in BALB/c mice. I. Characterization of the arthritis and the effects of steroidal and non-steroidal anti-inflammatory agents.

Abstract: Chronic monoarticular allergic arthritis was induced in BALB/c mice using methylated BSA as antigen and Freund's complete adjuvant, together with Bordetella pertussis as a secondary adjuvant. The optimum conditions for induction of chronic persistent arthritis and the histological characteristics of the arthritic lesion are described. Both the synovitis and erosive progression of the arthritis could be suppressed by daily treatment with prednisolone (1–10 mg/kg) or dexamethasone (0.5–2.5 mg/kg) for 4 weeks commencing 2 weeks after the induction of arthritis. In contrast, daily treatment with the non-steroidal anti-inflammatory agents ibuprofen (50–100 mg/kg), flurbiprofen (1–9 mg/kg) or indomethacin (0.1–3 mg/kg) had no significant effect on either the synovitis or erosions as judged histologically. Synovial fluid differential leukocyte counts were altered by treatment with ibuprofen and indomethacin but not by flurbiprofen or the corticosteroids. The suppressive effect of the corticosteroids was not due to either suppression of antibody synthesis or alteration of the number of leukocytes in the peripheral circulation.

Inhibition of antigen-induced lung anaphylaxis in the guinea-pig by BN 52021 a new specific paf-acether receptor antagonist isolated from Ginkgo biloba.

Abstract: Paf-acether appears to be a potent mediator released in response to allergen exposure in sensitized animals and it could contribute to clinical manifestations of allergic asthma. In order to ascertain this assumption the inhibition of antigen-induced lung anaphylaxis in guinea-pig by BN 52021, a new highly specific paf-acether antagonist, was studied. Ovalbumin injected into passively sensitized guinea-pig induced a large bronchoconstriction which was accompanied by thrombocytopenia and leukopenia. Treatment of animals with BN 52021 i.v., five minutes before challenge, strongly (at the doses of 1 and 2 mg/kg) or totally (at 0.1 mg/kg) inhibited the bronchoconstriction and partially reduced the thrombocytopenia and leukopenia the thrombocytopenia occurring after challenge. These results confirm that paf-acether and platelets might play a key role in asthma. BN 52021 and other paf-acether antagonist could provide a new group of potent prophylactic anti-asthma drugs.

A comparison of air pouch, sponge and pleurisy models of acute carrageenan inflammation in the rat.

Abstract: A comparative assessment of the time course of changes in three models of acute carrageenan-induced inflammation, the six-day air pouch, polyester sponge and pleurisy models, was obtained by measuring exudate volume, leucocyte numbers, PGE2 concentrations and lactate dehydrogenase activity at 2, 6 and 24 h. The greatest increases in exudate volume, leucocyte numbers and PGE2 concentration and the smallest rise in protein occurred in the air pouch model. Increases in lactate dehydrogenase were greatest in the sponge and least in the pleural exudate, indicating that the least cell damage occurred in the pleurisy model. PGE2 was not detectable in most pleural exudate samples. The actions of two steroids, betamethasone and dexamethasome, at two dose levels, 80 and 160 μg/kg, were assessed in each model. Overall, the six-day air pouch was found to be most satisfactory and most sensitive for assessing the actions of the steroids. The sponge model was either less sensitive or gave inconsistent responses, for the variables measured, than the cavity models of inflammation. Since the six-day air pouch has previously been shown to resemble synovium, our findings indicate that it is likely to be superior to the other two models as a model of joint inflammation.

Evidence for a role of the plasma kallikrein-kinin system in acute inflammation: reduced exudation during carrageenin- and kaolin-pleurisies in kininogen-deficient rats.

Abstract: Experimental pleurisy was induced by intrapleural injection of carrageenin or kaolin in three strains of rat: Brown Norway-Katholiek (B/N-Ka), Brown Norway-Kitasato (B/N-Ki) and Sprague-Dawley (SD). B/N-Ka rats (kininogen-deficient) showed significantly less pleural fluid accumulation and exudation rate than SD rats or than B/N-Ki rats (normal). The result indicates the involvement of the plasma kallikrein-kinin system in these pleurisies and a role of high-molecular-weight kininogen is suggested.

Rat jejunal mucosal response to histamine and anti-histamines in vitro. Comparison with antigen-induced changes during intestinal anaphylaxis.

Abstract: We previously showed that rats sensitized to egg albumin (EA) respond toin vivo intraluminal antigen-challenge with decreased net absorption of water and electrolytes and depletion of mucosal histamine. However, administration of anti-histamines did not prevent the transport abnormalities. The presentin vitro studies examined the effect of histamine to alter net ion transport and the ability of diphenhydramine (DPH) and cimetidine (CIM) to block the responses to both histamine and antigen. Control rat jejunum was mounted in Ussing chambers and histamine was added to the serosal side either in the absence or presence of DPH or CIM. In control tissues histamine caused a transient increase in short-circuit current (Isc) in a dose-dependent manner between 10−5 and 10−4 M which was blocked by 10−5 M DPH but was unaffected by CIM in concentrations up to 10−4 M. There was no response to EA. Jejunum from sensitized rats exposed to EA demonstrated a biphasic Isc response: a rapid transient rise followed by a somewhat less elevated but sustained component. In tissues pre-treated with DPH the initial peak Isc response was significantly reduced. In the presence of the neurotoxin, tetrodotoxin, the initial peak was unaffected but the sustained component was reduced. Our results indicate that H1-receptors mediated the effects of histamine in rat jejunal mucosa but that during intestinal anaphylaxis histamine is responsible for only a portion of the antigen-induced transport abnormalities. Our data also suggest that IgE-mediated reactions in the intestine may involve an interaction between mast cell mediators and enteric nerves.

Functional differences between human cutaneous mast cells and basophils: a comparison of morphine-induced histamine release

Abstract: Intravenous administration of morphine sulfate often produces urticarial and hypotensive reactions associated with elevations in plasma histamine. The source of this histamine and mechanisms controlling its release are poorly understood. Previous studies of morphine-induced histamine release compared human leukocytes to rat peritoneal mast cells. The effects of morphine on human cutaneous mast cells has not been examined. We studiedin vitro histamine release from human basophils and human skin preparations containing cutaneous mast cells to evaluate their relative, contribution to the pharmacologic effects of morphine. Human skin mast cell preparations showed dosedependent histamine release over a morphine concentration range of 1.5×10−5 to 4.5×10−3 M, with peak release occurring at 5×10−4 M, with peak release occurring at 5×10−4 M. Clinically, morphine sulfate is usually injected as a 1.5×10−2 M solution. Histamine release was calcium dependent and equivalent to that obtained with 3 and 10 mM strontium. Morphologic examination revealed degranulation and exocytosis occurring in morphine-stimulated tissue but not in specimens exposed to buffer alone. Lactate dehydrogenase levels did not increase following morphine incubation, thus supporting a noncytolytic mechanism of histamine release. Basophils, in contrast, showed no significant histamine release from exposure to morphine up to 10−2 M. Concanavalin A, as a positive control in these same preparations, produced a mean histamine release of 21.0%. Our studies indicate distinct functional differences between human skin mast cell and human blood basophil responses to morphine sulfate. We conclude that the cutaneous and systemic reactions to morphine sulfate probably result from the release of histamine from mast cells rather than from basophils.

In the croton oil ear test the effects of non steroidal antiinflammatory drugs (NSAIDs) are dependent on the dose of the irritant

Abstract: The Croton oil (CO) ear test represents an inflammatory model widely used to assess the topical antiinflammatory activity of both steroidal and non steroidal drugs. A number of studies indicate that steroids are quite effective inhibitors of this inflammatory reaction (IR). On the contrary, the effects of non steroidal antiinflammatory drugs (NSAIDs) are controversial. In fact, it has been reported that NSAIDs do not affect at all or, in some cases inhibit, more or less markedly, this IR. Since CO is a strong irritant, we hypothesized that the variability of the effects displayed by these drugs might be related to the dose of the irritant used to induce the IR. Consistent with this hypothesis are the data of the literature, which clearly show that only a slight or no effect of NSAIDs is observed when high doses of the irritant are used to induce the IR (500 to 2500~g/ear) [1-3], while definite inhibitory effects are observed when low doses of the irritant (25 and 35 ~g/ear) [4, 5] are employed. In this paper we have compared the effects of NSAIDs on the mouse ear dermatitis induced by a low and a high dose of CO. The results show that the IR induced by the high CO dose is poorly or not at all affected by NSAIDs, while the IR induced by the low CO dose is strongly inhibited by these drugs. The lower effect of NSAIDs on the IR in-

Pharmacology of the novel H2 antagonist famotidine : in vitro studies

Abstract: The novel antiulcer drug famotidine was found to be a potent and selective inhibitor of histamine H2 receptors. Its activity on different parameters involving H2 receptors was higher than that of other compounds of the family: pA2 values were 8.33, 7.86 and 7.83 in the guinea pig atria, guinea pig papillary muscle and isolated rat gastric secretion, respectively. Apart from quantitative differences, famotidine differed from the other compounds, since it caused a competitive antagonism only at low concentrations and an unsurmountable antagonism at higher concentrations. The duration of the inhibitory action on the "in vitro" gastric secretion resembled that of cimetidine and ranitidine. Famotidine was highly effective (approximately 10 times as potent as ranitidine) also on the rat uterus (unsurmountable antagonism) and on the guinea pig gallbladder (pA2 value = 7.71). Famotidine was apparently devoid of non-specific effects concerning the gastrointestinal motility even at very high concentrations (10(-4) M). In this respect, famotidine appeared to be more selective than cimetidine and ranitidine at the H2 receptor level. The high potency, the peculiarity of the antagonism and the lack of side-effects on a number of isolated preparations, indicate this H2 antagonist as a very peculiar member of the group.

Vasoregulin, a glucocorticoid-inducible vascular permeability inhibitory protein.

Abstract: A vascular permeability inhibitory protein ‘Vasoregulin’ was induced by dexamethasone and other glucocorticoids in Namalva cells. Precipitates produced by trichloroacetic acid from cultured supernatant (crude released vasoregulin) suppressed serotonin-induced paw edema of mice (ID30=750 μg/mouse) when dosed 30 min. before serotonin. Carrageenan paw edema of rats was also suppressed (ID30 =9 mg/rat, s.c. and i.p., not by oral dosing) when the compound was injected at the same time as carrageenan and the edema determined after 3 hrs. The possible effect of glucocorticoid itself being contained in the vasoregulin preparation was excluded. The presence of Cu, Zn-superoxide dismutase (SOD), spermidine and spermine also gave good yields of vasoregulin in culture; SOD protected the inactivation of vasoregulin from superoxide radicalin vitro. Vasoregulin partially purified by Sephadex G-75 columns had no malonaldehyde-formation inhibitory capacity. Thus, vasoregulin is a glucocorticoid-inducible anti-inflammatory protein which differs from lipocortin.

Selective inhibition of leukotriene B4 formation by Ebselen: a novel approach to antiinflammatory therapy.

Abstract: Leukotriene B4 (LTB4) is a dihydroxy metabolite of arachidonic acid, released by stimulated leukocytes, and a potent stimulator of neutrophil responses. In addition, LTB4, in the presence of a vasodilator prostaglandin, produces pronounced plasma exudation in vivo. Consequently, LTB, is considered to be a putative mediator of inflammation. It is generated by a hydrolase from LTA 4 which in turn is synthesised from arachidonic acid by 5-1ipoxygenase and LTA,-synthethase. Other products, including LTC,, are formed enzymatically from LTA,. We now report ebselen (PZ 51), a synthetic organoselenium, antiinfiammatory [1] compound, selectively inhibits the formation of LTB, in human and porcine leukocytes, redirecting LTA4-breakdown towards an LTB4 6-trans isomer. Ebselen has previously been shown to exhibit glutathione (GSH) peroxidase-like activity in vitro and to inhibit the production of reactive oxygen species and PGE2 by macrophages [2-4]. In the present report we demonstrate that ebselen specifically inhibits the formation of LTB4 at lower concentrations than those at which it influences the production of 5-HPETE and LTA4.

Isolation and characterization of lipocortin (lipomodulin)

Abstract: Lipocortin is a phospholipase inhibitory protein whose synthesis is induced in various cells by glucocorticoids. At least three species with molecular weights of 40,000, 30,000, and 15,000 are presently known. This protein mimics the anti-inflammatory action of glucocorticoids in vitro as well as in vivo. The synthesis of the protein appears to be associated with the MHC genes.