Contact hypersensitivity to haptens of the European standard series and corticosteroid series in the population of adolescents and adults with atopic dermatitis.

BACKGROUND: Until recently, it was thought that in patients with atopic dermatitis (AD), contact hypersensitivity phenomenon occurs less frequently than in the general population because of the impaired cellular immune response. OBJECTIVE: The aim of this study was to evaluate the incidence of contact dermatitis in the population of patients with AD. METHODS: A total of 39 patients with clinical diagnosis of AD during remission were patch tested with 28 European Baseline Series allergens and 8 corticosteroids allergens in different concentrations and media. Twenty-nine (74.3%) patients were female and 10 (25.6%) patients were male. Thirty-three (84.6%) patients were older than 18 years. The mean duration of AD was 20 years. RESULTS: Nineteen (48%) patients had an allergic reaction to at least 1 European Standard Series allergen, and 5 (12.8%) patients had an allergic reaction to at least 1 corticosteroid. The most common allergens giving positive results were nickel sulfate (28.2%), potassium dichromate (20.5%), cobalt chloride (12.8%), and phenylenediamine, budesonide, betamethasone, clobetasol, and dexamethasone (7.7% each). CONCLUSIONS: This study shows that allergic contact hypersensitivity is common among patients with AD and affects up to 40% of cases. Contact allergy to corticosteroids becomes a serious problem in the treatment of chronic inflammatory dermatoses such as AD.

Efficacy of levamisole for the treatment of slow spreading vitiligo.

Levamisole can be used as an immunomodifier for an effective treatment of vitiligo. A clinical trial was done to assess the efficacy of levamisole in patients of vitiligo. The study was conducted in the department of Dermatology and Venereology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh from January 2010 to July 2011. A total number of sixty patients were assigned purposively. Among them thirty patients were belonged to Group A, treated with levamisole alone and another thirty patients belonged to Group B, treated with levamisole 160 mg weekly with topical 0.1% fluocinolone acetonide acetate on the lesions once a day for a duration of 6 months. Patients were followed up every 2 weeks interval and were continued up to 6 weeks. Out of all patients from group A, the mean sizes of the lesions were 8.17cm before treatment but 5.90cm, 4.32cm, and 3.57cm at 1st visit, 2nd visit and 3rd visit respectively after treatment. In Group B, the mean sizes of the lesions were 7.50cm before treatment but 4.92cm, 3.00cm, and 4.75cm at 1st visit, 2nd visit and 3rd visit respectively after treatment. Among the respondents of Group A & B, 25(83.3%) and 27(90%) were cured respectively. This study observed that Levamisol with topical 0.1% fluocinolone was more responsive in percentage but the difference was not statistically significant.

Clinical development of new treatments for diabetic macular oedema.

The benchmark treatment for diabetic macular oedema, the major cause of visual impairment in patients with diabetes mellitus, has traditionally been laser photocoagulation; however, as laser treatment does not always improve vision or even prevent further loss in many cases, several new pharmacotherapies that are injected into the vitreous for diabetic macular oedema have been successfully trialled over the past decade. Others are currently being evaluated. The two major classes of these drugs are steroids and vascular endothelial growth factor antagonists. In this article we briefly review the major clinical studies recently conducted in this field.

Evaluation of four drugs for inhibition of paracentesis-induced blood-aqueous humor barrier breakdown in cats.

OBJECTIVE: To compare inhibitory effects of topically applied 1% prednisolone acetate suspension, 0.03% flurbiprofen solution, 0.1% dexamethasone suspension, and 0.1% diclofenac solution on paracentesis-induced blood-aqueous barrier breakdown in cats. ANIMALS: 9 healthy cats. PROCEDURES: Paracentesis of the anterior chamber was performed in both eyes of each cat. One eye of each cat was treated with a topically administered anti-inflammatory medication (1% prednisolone [n = 7 cats], 0.03% flurbiprofen [7], 0.1% dexamethasone [9], or 0.1% diclofenac [8]) immediately following paracentesis and at 6, 10, and 24 hours after paracentesis. The contralateral untreated eye served as the control eye. Each cat had a 6-day washout period between experimental drugs. Breakdown of the blood-aqueous barrier was quantified by use of laser flaremetry. RESULTS: Topical administration of 1% prednisolone significantly reduced aqueous humor flare at 4, 8, and 26 hours after paracentesis. Topical administration of 0.1% diclofenac significantly reduced aqueous humor flare at 8 and 26 hours after paracentesis. Topical administration of 0.1% dexamethasone and 0.03% flurbiprofen did not significantly decrease flare at any time point. There were significant differences in intraocular pressures between NSAID-treated eyes and untreated contralateral eyes. CONCLUSIONS AND CLINICAL RELEVANCE: Topical administration of 1% prednisolone and 0.1% diclofenac significantly reduced intraocular inflammation in cats with paracentesis-induced uveitis. Topical administration of 1% prednisolone or 0.1% diclofenac may be appropriate choices when treating cats with anterior uveitis. Topical administration of diclofenac and flurbiprofen should be used with caution in cats with a history of ocular hypertension.

Outcomes of birdshot chorioretinopathy treated with an intravitreal sustained-release fluocinolone acetonide-containing device.

PURPOSE: To evaluate outcomes in birdshot chorioretinopathy following intravitreal implantation of a fluocinolone acetonide-containing drug delivery device. DESIGN: Retrospective, multicenter, interventional case study. METHODS: University- and community-based tertiary care. Twenty-two HLA-A29+ birdshot patients (36 eyes) were implanted with a sustained-release corticosteroid device and followed for up to 3 years. Main outcome measures were Snellen acuity, intraocular inflammation, adjunctive therapy, cataract, ocular hypertension, or glaucoma. Paired Wilcoxon statistics were used to analyze visual acuities; paired McNemar statistics were used to analyze presence or absence of other outcomes. RESULTS: Nineteen of 22 patients (32 eyes) completed 12 months of follow-up with improvement in median visual acuity (P=.015). Prior to implantation, 18 of 22 patients (82%) received immunosuppressive therapy versus 1 of 19 (5%) by 12 months (P<.001). Eyes with zero vitreous haze increased from 7 of 27 scored eyes (26%) at baseline to 30 of 30 eyes (100%) by 12 months (P<.001). Cystoid macular edema decreased from 13 of 36 eyes (36%) at baseline to 2 of 32 eyes (6%) at 12 months (P=.006). Five of 24 phakic eyes at baseline exited the study before surgery; all other eyes received cataract surgery. One hundred percent of study eyes had ocular hypertension, required intraocular pressure-lowering therapy, or had glaucoma surgery by 12 months. CONCLUSIONS: Implantation of a fluocinolone acetonide-containing intraocular device in birdshot chorioretinopathy can improve vision, control inflammation, and eliminate systemic therapy. There is a high incidence of cataract progression and intraocular hypertension or glaucoma.

Herpetic necrotizing retinitis following flucinolone acetonide intravitreal implant.

PURPOSE: To report a case of herpes simplex virus-induced herpetic necrotizing retinitis after placement of a flucinolone acetonide (Retisert) intravitreal implant. DESIGN: Interventional case report. METHODS: Retrospective chart review. RESULTS: A 22-year-old male with idiopathic unilateral panuveitis since 2002 that was intolerant of systemic immunosuppressive therapy received a flucinolone acetonide implant 6 years later. Intraocular inflammation was completely quiescent until 1 year following the implant, when he developed retinitis. To the authors' knowledge, this is the first reported case of polymerase chain reaction-proven herpetic necrotizing retinitis following implantation of a Retisert device. CONCLUSIONS: Although rare, herpetic necrotizing retinitis can occur in the setting of local ocular immunosuppression with the Retisert intravitreal implant. This potential infection should be considered in the face of recurrent uveitis following Retisert implantation.

[Acquired amegakaryocytic thrombocytopenia after thymectomy in a case of pure red cell aplasia associated with thymoma].

The association of thymoma with pure red cell aplasia has been well documented, but amegakaryocytic thrombocytopenia is not a recognized paraneoplastic syndrome complicating thymoma. We report a case of thymoma-complicated pure red cell aplasia and amegakaryocytic thrombocytopenia in a 73-yr-old woman. Pure red cell aplasia was diagnosed seven months after the detection of thymoma. One year after the diagnosis of pure red cell aplasia and seven months after thymectomy, bone marrow aspiration and biopsy showed an absence of megakaryocytes, marked erythroid hypoplasia with normal myeloid series. A diagnosis of amegakaryocytic thrombocytopenia and pure red cell aplasia was made. Oral steroid maintenance therapy resulted in recovery of platelet count. She has still transfusion-dependent anemia but platelet and neutrophil counts had been maintained in normal range for more than five months, until the last follow-up. We think that autoreactive T cells may induce a clinical autoimmune response even after eradication of thymoma, and aplastic anemia as a late complication following thymectomy was described in previous cases. This patient also has to be under a close observation because of the possibility to evolve into aplastic anemia.

Efficacy of steroid therapy on adult patients with severe pneumonia.

Optimal management of steroid therapy for severe pneumonia is an urgent issue. One hundred forty-eight elderly patients enrolled in our study were treated for severe pneumonia in a university hospital in Tokyo from 1998 through 2002. Steroid drugs were given to 82 patients (55.4%), whereas 66 (44.6%) received no steroids. Based on this main division, retrospective analyses were performed with regard to patient characteristics, antimicrobial agents, use or nonuse of mechanical ventilators, and prognoses. Significant difference was not seen in age, sex, underlying disease, isolated pathogens, and artificial respirator between the steroid and nonsteroid groups. Partial pressure of oxygen in arterial blood/fraction of inspired oxygen (Pao(2)/Fio(2)) ratio was significantly lower in the steroid (227.2 +/- 96.9) compared with the nonsteroid group (271.6 +/- 86.4) (P < 0.01). Prognoses were evaluated 21 days after treatment initiation. Significant differences appeared: First, the average cure rate of patients who took steroids within 3 days after starting treatment was 62.7%, whereas the rate was 12.9% (P < 0.001) in those who did not take steroids earlier than the 4th day. The cure rate of the nonsteroid group was 39.3% (P < 0.001). Second, the total dose of steroids (methylprednisolone) given within 7 days was less in cured cases (774 +/- 749 mg) than in noncured cases (1,190 +/- 768 mg) (P < 0.05). In conclusion, steroids should be administered in the early stage after onset of pneumonia, and large doses of steroids becomes a compounding factor in the prognosis of pneumonia.

Photo-conversion of two epimers (20R and 20S) of pregna-5,7-diene-3beta, 17alpha, 20-triol and their bioactivity in melanoma cells.

Pregna-5,7-dienes and their hydroxylated derivatives can be formed in vivo when there is a deficiency in 7-dehydrocholesterol (7-DHC) Delta-reductase function, e.g., Smith-Lemli-Opitz syndrome (SLOS). Ultraviolet B (UVB) radiation induces photoconversion of 7-DHC to vitamin D3, lumisterol3 and tachysterol3. Two epimers (20R and 20S) of pregna-5,7-diene-3beta,17alpha,20-triol (4R and 4S, respectively) were synthesized and their UVB photo-conversion products identified as corresponding 9,10-secosteroids with vitamin D-like and tachysterol-like structures, and 5,7-dienes with inverted configuration at C-9 and C-10 (lumisterol-like). The number and character of the products and the dynamics of the process were dependent on the UVB dose. At high UVB doses, the formation of multiple oxidized derivatives of the primary products, and the formation of 5,7,9(11)-triene, were observed. The production of vitamin D-like, tachysterol-like and lumisterol-like derivatives was also observed in human skin treated with 4R and 4S, and subjected to UV irradiation, as shown by RP-HPLC. Newly synthesized compounds inhibited melanoma growth in dose dependent manner, and some of them showed equal or higher potency than 1,25(OH)2D3. In summary, we have characterized for the first time the products of UV induced conversion of pregna-5,7-diene-3beta,17alpha,20-triols and documented that the newly synthesized compounds have antiproliferative properties against melanoma cells.

Corticosteroids reduce postoperative morbidity after third molar surgery: a systematic review and meta-analysis.

PURPOSE: The purpose of this study was to apply meta-analytical methods to measure the effect of corticosteroids (CS) on edema, trismus, and pain at early and late postoperative periods after third molar (M3) removal. MATERIALS AND METHODS: A systematic search of the literature was carried out to identify eligible articles. The primary predictor variable was perioperative CS exposure (yes or no). The 3 outcome variables were edema, trismus, and pain assessed during the early (1-3 days) and late (>3 days) postoperative time periods. Standardized mean differences (SMD) for edema and weighted mean differences (WMD) for trismus and pain were pooled across studies. Differences between the 2 treatment groups were assessed using random effects models and metaregressions for both early and late postoperative assessments. RESULTS: Twelve trials met the inclusion criteria. Subjects receiving CS had significantly less edema during both early (SMD, 1.4; 95% confidence interval [CI], 0.6, 2.2; P < .001) and late (SMD, 1.1; 95% CI, 0.1, 2.0; P = .03) time periods after surgery and less trismus than controls during the early and late postoperative periods (early WMD, 4.1 mm; 95% CI, 2.8 mm, 5.5 mm; P < .001; late WMD, 2.7 mm; 95% CI, 0.8 mm, 4.6 mm; P = .005). Average pain levels were not significantly different between the 2 groups (early WMD, 0.4 visual analog scale [VAS]; 95% CI, -0.04 VAS, 0.9 VAS; P = .07; late WMD, 0.5 VAS; 95% CI, -0.6 VAS, 1.5 VAS; P = .4). CONCLUSIONS: The findings of this study suggest that perioperative administration of corticosteroids produces a mild to moderate reduction in edema and improvement in range of motion after M3 removal.

In vitro anti-inflammatory activities of new steroidal antedrugs: [16alpha,17alpha-d] Isoxazoline and [16alpha,17alpha-d]-3'-hydroxy-iminoformyl isoxazoline derivatives of prednisolone and 9alpha-fluoroprednisolone.

A series of new anti-inflammatory steroidal antedrugs with C-16,17-isoxazoline ring system were synthesized and their pharmacological activities were evaluated. We reported earlier that these compounds are promising antedrugs based on the results of 5-day rat croton oil ear edema assay. In the present study, most of these compounds showed high binding affinities to the glucocorticoid receptor of liver cytosol. 21-acetyloxy-9alpha-fluoro-11beta-hydroxy-3,20-dioxo-1,4-pregnadieno [16alpha,17alpha-d] isoxazoline (FP-ISO-21AC) and 11beta,21-dihydroxy-9alpha-fluoro-3,20-dioxo-1,4-pregnadieno [16alpha,17alpha-d] isoxazoline (FP-ISO-21OH) were found 5.0-, 5.3-fold more potent than prednisolone, respectively. Inhibitory effects of the antedrugs on the nitric oxide (NO) production were assessed using LPS-stimulated RAW 264.7 murine macrophage cells. All these steroidal antedrugs exhibited concentration-dependent inhibition of NO production, but their relative potencies were lower than prednisolone. In vitro metabolism study in rat plasma showed that FP-ISO-21AC and 21-acetyloxy-9alpha-fluoro-11beta-hydroxy-3,20-dioxo-1,4-pregnadieno [16alpha,17alpha-d]-3'-hydroxyiminoformyl isoxazoline (FP-OXIM-21AC) were hydrolyzed rapidly, with the half-lives of 2.1 and 4.2 min, respectively. The half-lives of FP-ISO-21OH and 11beta,21-dihydroxy-9alpha-fluoro-3,20-dioxo-1,4-pregnadieno [16alpha,17alpha-d]-3'-hydroxyiminoformyl isoxazoline (FP-OXIM-21OH) were 92.2 and 110.2 min, respectively.

Synthesis and pharmacological evaluations of new steroidal anti-inflammatory antedrugs: 9alpha-Fluoro-11beta,17alpha,21-trihydroxy-3,20-dioxo-pregna-1,4-diene-16alpha-carboxylate (FP16CM) and its derivatives.

In continuing efforts to develop potent anti-inflammatory steroids without systemic adverse effects, methyl 9alpha-fluoro-11beta,17alpha,21-trihydroxy-3,20-dioxo-pregna-1,4-diene-16alpha-carboxylate (FP16CM) and its 16-alkoxycarbonyl derivatives (FP16CE, FP16CP and FP16CB) were synthesized based on the antedrug concept. The steroids were evaluated for their pharmacological activities and adverse systemic effects. All steroidal antedrugs showed both binding affinity to the glucocorticoid receptor in liver cytosol and inhibitory effect on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophage cell. These compounds also inhibited croton-oil-induced ear edema and showed no systemic effects such as thymus atrophy and suppression of corticosterone level after 5-day treatment. Among those compounds tested, FP16CM showed the highest activities in receptor binding, NO inhibition and ear edema, these activities were comparable to those of prednisolone. Hydrolysis study in plasma showed that FP16CB was hydrolyzed rapidly, with the half-live (T1/2) of 3.2 min and the half-lives of other compounds were between 16.9 and 29.4 min. These results support the antedrug concept, of which the decrease in systemic adverse effects is attributed to fast hydrolysis to inactive metabolite in the systemic circulation.

Metabolism of steroidal anti-inflammatory antedrugs in vitro: methyl 3,20-dioxo-11beta,17alpha,21-trihydroxy-1,4-pregnadiene-16alpha-carboxylate; its 9alpha-fluorinated, and their 21-O-acyl derivatives.

The in vitro hydrolysis rates of steroidal anti-inflammatory antedrugs, methyl 3,20-dioxo-11beta,17alpha,21-trihydroxy-1,4-pregnadiene-16alpha-carboxylate (P16CM), its 9alpha-fluorinated analogue (FP16CM), and their 21-O-acyl derivatives (P16CM-acetyl, FP16CM-acetyl, FP16CM-propionyl, FP16CM-valeryl, and FP16CM-pivalyl) were investigated in rat plasma. These steroids were synthesized based on the antedrug concept. P16CM and FP16CM were hydrolyzed to inactive steroid-16-carboxylate, with half-lives of 90.0 and 99.4 min, respectively. The metabolite was positively identified by NMR and elemental analysis. To determine the relative hydrolysis rate of the C21-O-acyl versus the C16-methoxycarbonyl group, P16CM- and FP16CM-21-O-acyl derivatives were also studied. The hydrolysis rates of all 21-O-acyl groups were much faster than that of the 16-methoxycarbonyl group. The half-lives of P16CM-acetyl, FP16CM-acetyl, FP16CM-valeryl, and FP16CM-propionyl were 6.3, 16.8, 23.2, and 18.4 min, respectively. On the other hand, FP16CM-pivalyl showed relatively slow hydrolysis rate (T(1/2): 59.7 min). These results clearly indicate that 21-O-acyl group is metabolized first to active compound, P16CM or FP16CM, followed by the hydrolysis of 16-methoxycarbonyl to corresponding inactive steroid-16-carboxylates as the major metabolites. Collectively, the results of the present study support the previous reports where decrease in adverse systemic effects without losing local anti-inflammatory activity was attributed to the hydrolysis of the active agents to inactive acidic metabolites in the systemic circulation. This study thus shows that the incorporation of a 16-methoxycarbonyl coupled with a 21-O-acyl moiety may be a fundamentally sound synthetic strategy in the development of locally active anti-inflammatory steroids having reduced systemic adverse activities.

The diagnosis of lichen-planus-like contact dermatitis to chlorpheniramine maleate.

In spite of the common use of the diagnostic category of lichen-planus-like contact dermatitis, we were unable to find established criteria for such a condition. An atypical distribution of otherwise typical lichen planus lesions is usually considered as a feature of a lichenoid eruption. When facing unusual or unexpected clinical features, it is always advisable to consider an adverse reaction to a medical intervention as a potential option. We report a lichen-planus-like eruption occurring after contact with a topical agent containing chlorpheniramine maleate. To our knowledge, this is the first reported case of lichen-planus-like contact dermatitis associated with chlorpheniramine maleate.

Effect of chirality at C-20 of methyl 11beta,17alpha,20-trihydroxy-3-oxo-1,4-pregnadien-21-oate derivatives on antiinflammatory activity.

In an effort to determine the C-20 chirality effect on the antiinflammatory activity of 17beta-glycolate esters, methyl 11beta,17alpha,20-trihydroxy-3-oxo-1,4-pregnadien-21-oate and its 9alpha-fluoro analog, their acetonide and their carbonate derivatives were synthesized and evaluated. The agents were tested for their binding potency to the macrophage glucocorticoid receptor, and their effect on LPS-induced nitric oxide generation in RAW 264.7 cells. The acetonide derivatives showed the highest binding affinity while the triols and carbonates bound rather poorly to the receptors. With the exception of the triols, the alpha-isomer in each pair of the agents exhibited higher binding affinity to the receptor than its corresponding beta-isomer, clearly indicating that C-20 chirality has a significant effect on antiinflammatory activity. In addition, the alpha-isomers of the acetonides showed substantially higher binding affinity than the parent compound, prednisolone. In contrast to the high binding activity exhibited by some of the acetonides, all of the agents showed weak inhibitory effect on NO generation. Metabolic inactivation during assessment of NO inhibition may play a role in the divergence noted between receptor affinity and the measured biologic activity resulting from the binding.

New steroidal antiinflammatory antedrugs: Methyl 3,20-dioxo-9 alpha-fluoro-11 beta,17 alpha,21-trihydroxy-1,4-pregnadiene-16 alpha-carboxylate and its 21-O-acyl derivatives.

In a continuing effort to increase local to systemic activity ratios of potent steroidal antiinflammatory antedrugs, a series of 21-O-acyl derivatives of methyl 3,20-dioxo-9 alpha-fluoro-11 beta,17 alpha,21-trihydroxy-1,4-pregnadiene-16 alpha-carboxylate, FP16CM, were synthesized. These derivatives were evaluated for antiinflammatory activity and their adverse effects in an acute and semi-chronic croton oil-induced ear edema bioassay. Following a single topical application in the croton oil-induced ear edema bioassay, treatment with all the compounds resulted in dose-dependent inhibition of edema. From these dose-response profiles, the following ID(50) values (nmol/ear resulting in a 50% reduction of edema) were calculated: prednisolone (Pred); 454, FP16CM; 255, 21-acetate (FP16CM-acetyl); 402, 21-propionate (FP16CM-propionyl); 474, 21-valerate (FP16CM-valeryl); 446 and 21-pivalate (FP16CM-pivalyl); 219 nmol. In a 5-day semi-chronic study at the equipotent doses, the novel steroidal antedrugs did not significantly alter body weight gain, thymus weights or plasma corticosterone levels unlike the parent compound Pred. The compounds were assessed for high-affinity glucocorticoid receptor binding and glucocorticoid-mediated inhibition of nitric oxide (NO) generation in an in vitro RAW 264.7 macrophage cell culture system. Binding affinities for cytosolic glucocorticoid receptors were Pred; 85, FP16CM-acetyl; 86, FP16CM-propionyl; 169, FP16CM-valeryl; 149, FP16CM-pivalyl; 126 nM, respectively. Concomitant potencies for inhibition of NO generation by macrophages stimulated with lipopolysaccharide were Pred; 159, FP16CM-acetyl; 377, FP16CM-propionyl; 405, FP16CM-valeryl; 344, FP16CM-pivalyl; 311 nM, respectively. Collectively, results of these investigations suggest that esterification of 21-OH with various anhydrides did not improve receptor binding, inhibition of NO generation and ear edema inhibition, however, serum corticosterone level and local over systemic activities (L/S) were markedly improved.

[Studies on the production of 16 beta-methyl-11 alpha,17 alpha,21-trihydroxy-1,4-pregnadiene-3,20-dione from 16 beta-methyl-17 alpha,21-dihydroxy-1,4-pregnadiene-3,20-dione-21-acetate by Absidia].

An Absidia sp. 28 strain was shown to have higher activity of 11 alpha-hydroxylation using 16 beta-methyl-17 alpha,21-dihydroxy-1,4-pregnadiene-3,20-dione as a substrate. It was found that 21-acetylization of substrate could increase 11 alpha-hydroxylation rate conspicuously. The yield of the 11 alpha-hydroxylation by this strain was 73% in the conversion of 0.5% concentration of 21-acetated substrate under optimum conditions.

New steroidal anti-inflammatory antedrugs: methyl 3,20-dioxo-9 alpha-fluoro-11 beta,17 alpha,21-trihydroxy-1,4-pregnadiene-16 alpha-carboxylate and methyl 21-acetyloxy-3,20-dioxo-11 beta, 17 alpha-dihydroxy-9 alpha-fluoro-1,4-pregnadiene-16 alpha-carboxylate.

Focused efforts have been made to increase local-to-systemic activity ratios of potent anti-inflammatory steroids for local and/or topical applications. The approach taken in the present investigation is based upon the concept of "antedrug," defined as a locally active compound that exerts its action at the application site but rapidly undergoes a predictable biotransformation to an inactive metabolite that is readily excreted upon entry into the systemic circulation. In continuing efforts to synthesize potent, anti-inflammatory steroids without systemic glucocorticoid activities, 9 alpha-fluoro-methyl 11 beta, 17 alpha, 21-trihydroxy-3,20-dioxo-pregna-1,4-diene-16 alpha-carboxylate (FP16CM) and its 21-acetate derivative (FP16CMAc) have been synthesized and screened. Novel antedrugs were evaluated for antiinflammatory activity in the acute croton oil-induced ear edema bioassay, adverse systemic effects in the 5-day croton oil model, receptor binding, and concomitant L-tyrosine-2-oxoglutarate aminotransferase (EC 2.6.1.5) (TAT) enzyme induction in HTC cells in culture. Following a single topical application in the croton oil-induced ear edema bioassay, treatment with all compounds resulted in dose-dependent inhibition of edema. From these dose-response profiles, the following ID50 values (nmol resulting in a 50% reduction of edema) were calculated: 817, 540, 266, and 67 for hydrocortisone (HC), prednisolone (P), FP16CM, and FP16CMAc, respectively. Calculated relative potencies, setting HC = 1.0, were P, 1.5; FP16CM, 3.1, and FP16CMAc, 12.2. Results of the 5-day rat croton oil ear edema bioassay indicated that, in contrast to the parent compound P, the novel steroidal antedrugs did not significantly alter body weight gain, thymus weights, or plasma corticosterone levels. Relative binding potencies for cytosolic HTC glucocorticoid receptors were 1.0, 20.1, 5.4, and 2.5 for HC, P, FP16CM, and FP16CMAc, respectively. As predicted by the antedrug concept, FP16CM and FP16CMAc were very weak agonists for induction of TAT in HTC cells. Collectively, results of these investigations suggest that modification of P, which included addition of the 9-fluoro and 16-methoxycarbonyl group alone or in conjunction with a 21-acetoxy moiety, increase topical anti-inflammatory activity without significant adverse systemic effects. These new antedrugs may be useful as anti-inflammatory steroids for local applications.