Croton Oil-induced Ear Edema Research Articles

Effects of prostaglandin antagonist phloretin derivatives on mouse ear edema induced with different skin irritants

Edema was induced in one ear of male mice of the CFLP strain with solutions of different skin irritants (croton oil 10 μL/35 μg, dithranol 10 μL/30 μg, capsaicin 10 μL/40 μg or arachidonic acid to 10 μL/2 mg per ear). Edema, determined by the edema-disk gravimetric technique, was inhibited in a dose-dependent manner by the intraperitoneally administered prostaglandin antagonists polyphloretin phosphate (PPP) or di-4-phloretin phosphate (DPP). With croton oil-induced mouse ear edema, DPP 10 mg/kg caused a 38% inhibition, PPP 25 mglkg a 33% inhibition. With dithranol-induced edema DPP 0.5 mglkg caused a 57% inhibition, while PPP 25 mglkg was needed to exert a similar effect. Doses of DPP and PPP needed to cause a >40% inhibition of edema were 10 mglkg and 25 mglkg, respectively, for capsaicin, and 25 mg/kg and 100 mglkg for arachidonic acid. The inhibition of the ear edema by the phloretin derivatives was: dithranol > croton oil > capsaicin > arachidonic acid. This probably reflects the different contributions of prostaglandins to the inflammation.

Time-dependent cytokine production in the croton oil-induced mouse ear oedema and inhibition by prednisolone.

Time-dependent cytokine production in the croton oil-induced mouse ear oedema and inhibition by prednisolone.

Steroidal anti-inflammatory antedrugs: Synthesis and pharmacological evaluation of 16α-alkoxycarbonyl-17-deoxyprednisolone derivatives

In a continuing effort to minimize the systemic adverse effects of potent anti-inflammatory steroids, a series of 16α-alkoxycarbonyl-17-deoxyprednisolone derivatives: methyl ( 8a), ethyl ( 8b), isopropyl ( 8c), and benzyl ( 8d) 11β,21-dihydroxy-3,20-dioxo-1,4-pregnadiene-16α-carboxylate, was synthesized and evaluated for their topical and local anti-inflammatory activities. In the acute croton oil-induced ear edema dose-response bioassay, the topical anti-inflammatory potencies of these esters relative to prednisolone, 1, were: 8a: 1.0, 8b: 1.3, 8c: 4.0, 8d: 4.7 and 1: 1.0. The putative metabolite, 11β,21-dihydroxy-3,20-dioxo-1,4-pregnadiene-16α-carboxylic acid, 7, was inactive in this test. A seven day cotton pellet granuloma bioassay was employed to study the local and systemic anti-inflammatory activities of these steroids. The local anti-inflammatory potencies of these esters relative to prednisolone, 1, were 1.3, 1.5, 2.3, 2.5, and 1.0 for 8a, 8b, 8c, 8d, and 1, respectively. In this semi-chronic study, only prednisolone exhibited significant untoward side effects, such as reduction in thymus weights, normal body weight gain, and normal plasma corticosterone levels. The increase in the topical and local potencies of these steroid esters was consistent with the increase in their 1-octanol/buffer partition coefficient. The ratio of local to systemic anti-inflammatory activity of 8c and 8d was four times that of prednisolone. The effects of increasing the size of the alkoxy group of these new steroids on both topical and local anti-inflammatory activity and their concomitant decrease in untoward systemic effects were unequivocally demonstrated. The reduction of the adverse systemic effects is attributed to the presence of the metabolically labile 16-carboxy ester moiety which is metabolized into the inactive steroid acid upon entry into the systemic circulation (antedrug concept).

New steroidal antiinflammatory antedrugs: steroidal [16 alpha,17 alpha-d]-3'-carbethoxyisoxazolines.

Novel steroidal antiinflammatory antedrugs, 11 beta,20-dihydroxy-3,20-dioxo-3'-(ethoxycarbonyl)-isoxazolino[16,17 - d]pregna-1,4-diene (2a) and 9-fluoro-11 beta,20-dihydroxy-3,20-dioxo-3'-ethoxy- carbonylisoxazolino[16,17-d]pregna-1,4-diene (2b) were prepared in 97% yield via 1,3-dipolar cycloaddition of carbethoxyformonitrile (CEFNO) to 11 beta,21-dihydroxy-3,20-dioxopregna-1,4,-16-triene (1a) and 11 beta,21-dihydroxy-3,20-dioxo-9-fluoropregna-1,4,16-triene (1b), respectively, which were prepared via five steps from prednisolone and 9-fluoroprednisolone, respectively. The treatment of steroids 2a and 2b with acetic anhydride in pyridine led to the corresponding 21-acetates 3a and 3b, respectively, in 95% yield. Dose-response profiles of the croton oil-induced ear edema bioassay in rats were used to calculate the following ID50 values (nmol/ear resulting in a 50% reduction of edema): prednisolone (P), 540 nmol; 2b, 135 nmol; and 3b, 101 nmol. Inhibition of edema did not exceed 50% following application of either 2a or 3a. Relative potency calculations indicated that 2b was 4-fold and 3b 5.3-fold more potent than the parent compound P when applied topically. No significant adverse systemic effects were seen following treatments with 3b. These results suggest that C-9-fluorination, side-chain hydroxy group esterification, and [16 alpha,17 alpha-d]-3'-carbethoxyisoxazoline additions to the conventional steroid P improve topical antiinflammatory activity without concomitant increases in adverse systemic activity.

Effects of Alkaloids Extracted from the Stem Bark of Hunteria zeylanica on Acute Inflammation in Experimental Animals.

The effects of crude alkaloids extracted from the stem bark of Hunteria zeylanica GARD. (H. zeylanica) on acute inflammatory responses such as carrageenin-induced paw edema in rats and croton oil- and arachidonic acid-induced ear edema in mice were investigated. Oral administration of H. zeylanica alkaloid extract (200-400 mg/kg) significantly suppressed the paw swelling induced by carrageenin. In the croton oil-induced ear edema, topically applied H. zeylanica alkaloid extract, at doses of 200 and 400 mg/ml, also significantly reduced ear edema. Moreover, the extract (50-200 mg/kg, p.o.) reduced in a dose-dependent manner the ear swelling induced by topically applied arachidonic acid (2 mg/ear). These results suggest that the inhibitory effects of H. zeylanica alkaloid extract on acute edema formation are partly due to inhibition of 5-lipoxygenase and cyclooxygenase activity.

Antiinflammatory effects of Tremulacin, a Salicin-related substance isolated from Populus tomentosa Carr. leaves

Tremulacin was shown to inhibit carrageenan-induced paw edema in rats and croton oil-induced ear edema in mice. It was also found to inhibit peritoneal leucocyte migration in rats and acetic acid-induced writhing responses in mice. Experiments with isolated longitudinal muscle strips of sensitized guinea pig ileum showed that tremulacin decreased the biosynthesis of Slow Reaction Substance of Anaphylaxis. Tremulacin exerted inhibitory effects on leukotriene B4 biosynthesis in intrapleural leucocytes. These results suggest that the mechanism of antiinflammatory actions of tremulacin is relevant to inhibition of 5-lipoxygenase activity. This is quite different from non-steroid antiinflammatory drugs, such as aspirin, which inhibits prostaglandin synthesis and being a cyclooxygenase inhibitor.

Novel Fluorinated Antiinflammatory Steroid with Reduced Side Effects: Methyl 9α-Fluoroprednisolone-16-carboxylate

In an effort to test the hypothesis that 9α-fluorination of a steroidal antedrug would enhance receptor binding affinity and local antiinflammatory activity, without concomitantly increasing adverse systemic effects, a fluorinated analog,10, of methyl 11β,21-dihydroxy-3,20-dioxo-1,4-pregnadiene-16α-carboxylate (DP16CM,1) was synthesized and evaluated. In the acute rat croton oil-induced ear edema bioassay,10was found to be twice as potent as1. This increase in topical potency was consistent with enhanced binding affinity of10, relative to1. The IC50values for displacement of [3H] dexamethasone from glucocorticoid receptors of rat hepatoma tissue culture cells were 0.16, 1.2, and 0.03 μM for10, 1, and prednisolone, respectively. Following multiple topical ID50applications of prednisolone,1, and its new fluorinated analog,10, in the rat subacute croton oil-induced ear edema bioassay, only prednisolone exhibited significant untoward effects, such as reduction in relative thymus and adrenal weights, plasma corticosterone levels, and normal body weight gain. Thus, while fluorination of1enhanced its topical potency, there was not a concomitant increase in untoward systemic effects. This lack of adverse systemic effects is ostensibly due to the presence of the metabolically labile 16-carboxylate ester moiety.

Synthesis of 6-(Methoxycarbonyl)prednisolone and Its Derivatives as New Antiinflammatory Steroidal Antedrugs

The synthesis and pharmacological evaluation of 6-(meth- oxycarbonyl)prednisolone (11) (a 3:1 mixture of 6a-isomer 11a and 60-isomer 11b), its 21-ol acetates 13a (6a-isomer) and 13b (60- isomer), and 17,21-diol acetonide 14 (a 6:1 mixture of 6a-isomer 14a and 60-isomer 14b) as local antiinflammatory steroidal antedrugs are described. The lead compound 11 was prepared via 12 steps from hydrocortisone (1). In the croton oil-induced ear edema assay, the topical antiinflammatory activity of 13a was higher than that of its eplmer13b. Except for 13a, the compounds (11,13b, and 14) showed less activity than prednisolone. The systemic activities were assessed after 5 days of consecutive administration of these compounds at equiactive doses. Neither 11 nor 14 depressed plasma corticosteroid levels or significantly altered adrenal weights. Thymic involution was absent for 14,15 % for 11, and 47 % for prednisolone at the equiactive doses. Both 13a and 13b showed significant reduction of adverse systemic effects assessed as the increase of body weight and the decreases of adrenal and thymus weights. The putative metabolite, carboxylic acid 12, showed 26 times less topical antiinflammatory activity than prednisolone. These results suggest that introduction of a labile methoxycarbonyl group at the C-6 position of prednisolone results in retention of antiinflammatory activity while reducing systemic effects noted following topical application of the parent compound prednisolone.

Synthesis, characterization, and antiinflammatory activity of Naproxen complexes with rare earth (III)

RE(III) complexes of Naproxen(HNap) have been synthesized and characterized by elemental analyses, conductance measurements, solubilities, thermal analysis, infrared, proton magnetic resonance, and electronic spectral data. The elemental analyses reveal the presence of 1:3 (metal:ligand) stoichiometry and the IR spectra suggest the carboxylate group of HNap functions, as a bridging ligand to coordinate to RE(III) ions. The electronic spectra recorded in solid exhibit only slight shifts in visible regions, on which β, δ and b 1 2 of covalent parameters have been calculated. Formalin-induced rat paw edema and croton oil-induced rat ear edema inflammatory models were chosen to examine the antiinflammatory activity of Nd(III) complex, which ascertained enhanced antiinflammatory activity relative to the ligand.

Dermatopharmacologic investigations of halobetasol propionate in comparison with clobetasol 17-propionate

Both halobetasol propionate and clobetasol 17-propionate exerted very marked antiinflammatory, antiproliferative, and vasoconstrictive effects during evaluation in a range of dermatopharmacologic models. Halobetasol propionate was distinctly more potent than clobetasol 17-propionate in the ultraviolet-induced dermatitis inhibition assay in guinea pigs and in the rat model of oxazolone-induced late inflammatory reaction. Halobetasol propionate was slightly more potent than clobetasol 17-propionate in inhibiting croton oil-induced ear edema in rats and mice and in the mouse model of oxazolone-induced early inflammatory reaction. In the cotton-pellet granuloma assay in rats and the epidermal hyperplasia inhibition assay in guinea pigs, halobetasol propionate was distinctly superior to clobetasol 17-propionate. There was a trend in favor of halobetasol propionate in the cutaneous vasoconstriction assay performed in volunteers with ethanol solutions of halobetasol propionate and clobetasol 17-propionate. In a further vasoconstriction assay, performed with a 0.05% concentration of both halobetasol propionate and clobetasol 17-propionate in cream and ointment formulations, halobetasol propionate ointment yielded the highest blanching score. In a hypothalamic-pituitary-adrenal axis study in volunteers, effects of 0.05% halobetasol propionate ointment and 0.05% clobetasol 17-propionate ointment on serum cortisol levels were similar. The overall efficacy trends demonstrated in these dermatopharmacologic studies are in agreement with predictions made from corticosteroid structure and activity relationships and the results of two clinical trials comparing halobetasol propionate and clobetasol 17-propionate ointments in the treatment of plaque psoriasis.

Synthesis and pharmacological evaluation of conjugates of prednisolone and non-steroidal anti-inflammatory agents

Esters of prednisolone with ibuprofen and indomethacin were prepared by coupling the 21-hydroxy moiety of the glucocorticoid to the carboxylic group of the non-steroidal anti-inflammatory agents. The local and systemic anti-inflammatory activities of the conjugates were evaluated using the cotton pellet granuloma bioassay and their topical activity evaluated by the croton oil-induced ear edema assay, in male Sprague-Dawley rats. The results indicate that these conjugates possess greater local and topical anti-inflammatory activity than prednisolone. In the subacute ear edema bioassay, the conjugates displayed no discernible untoward systemic effects, unlike prednisolone and prednisolone acetate, which elicited significant adverse systemic effects, at equipotent doses. These findings suggest that the chemical coupling of prednisolone and non-steroidal anti-inflammatory agents produced compounds with enhanced anti-inflammatory potencies and reduced systemic toxicities, particularly when administered topically.

How specific is the arachidonic acid-induced mouse ear oedema for lipoxygenase (LO)- and cyclooxygenase (CO)-inhibitors?

Arachidonic acid (AA) applied topically to the ears of mice produces an acute transient inflammatory reaction with immediate erythema and oedema formation (maximum at 1 h) and elevated tissue concentrations of prostaglandins (PGs) and leukotrienes (LTs) [1]. From inhibitor studies it has been concluded that this model may be especially suitable for the detection of LO-inhibitors in vivo [2]. We have tested different pharmacological classes of compounds to re-evaluate the specificity of this model. The same compounds were also tested in the croton oil-induced ear oedema model in mice and rats.

Topical anti-inflammatory activity of esters of steroid 21-OIC acids

Prednisolone derivatives, methyl 20 α- and 20 β-dihydroprednisolonate and methyl 17,20 α- and 17,20 β-acetonidodihydroprednisolonate have been evaluated for their topical anti-inflammatory activity in the croton oil induced ear edema test. The order of anti-inflammatory potency was prednisolone > methyl 17,20 α-acetonidodihydroprednisolonate > methyl 17,20 β-acetonidodihydroprednisolonate > methyl 20 β-dihydroprednisolonate > methyl 20 α-dihydroprednisolonate. This order was paralleled by the compounds' octanol-aqueous partition coefficients. Furthermore, after two consecutive days topical administration of an equipotent anti-inflammatory dose, only prednisolone significantly decreased plasma corticosterone levels and relative thymus weight, while the new steroid derivatives had no effect on these parameters, indicating their lack of systemic side effects.

Salbutamol as a topical anti-inflammatory drug.

SummaryUsing croton oil-induced rat ear edema, hydrocortisone and salbutamol show anti-inflammatory activity when applied topically. Both drugs act to some extent even when applied after the inflam...