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Purpose: Difluprednate (DFP) is an approved corticosteroid, available as an ophthalmic emulsion (Durezol ® ), used to treat pain and inflammation of the eye following ocular surgeries. This study utilized hydroxypropyl-β-cyclodextrin (HPBCD)-based DFP ophthalmic solution for improved ocular delivery. Methods: The DFP-HPBCD complex formation was studied in the liquid and solid states. Phase solubility, molecular docking studies, differential scanning calorimetry, and Fourier transform infrared spectroscopy suggested inclusion complexation of DFP and HPBCD. Results: DFP-HPBCD-based eye drops (solution) provided 16 and 26 times higher transcorneal permeation when compared to the suspension (no HPBCD, control) and Durezol, respectively ( P  < 0.001). In addition, ocular drug distribution studies conducted in continuously perfused whole porcine eyes showed DFP permeated into all of the ocular tissues in significantly higher amounts than Durezol. Conclusions: The solution-based eye drops in this study is iso-osmotic, safe, and more permeable in porcine eyes compared to Durezol.

Three patients using a postoperative combination of topical ketorolac (Acular) and neomycin/polymyxin B sulfate/dexamethasone (Maxitrol) were diagnosed with atypical keratopathy soon after routine cataract surgery. An immediate retrospective analysis of hospital patients who had used this topical drug combination in the previous year identified 10 other patients who also had significant corneal pathology after uneventful cataract surgery. Five of the 13 affected patients had corneal melting and 1 patient had corneal perforation and endophthalmitis. At the last recorded follow-up appointment, 8 of the 13 patients had a visual acuity of 6/36 or worse. Corneal melting is a rare complication of topical nonsteroidal anti-inflammatory drugs (NSAIDs). We propose that the combined use of topical NSAIDs and other agents, such as neomycin and benzalkonium, that further compromise the corneal epithelium, should be used with vigilance and increased awareness of potential keratopathy and permanent visual morbidity.

PurposeTo evaluate safety and efficacy of difluprednate 0.05% ophthalmic emulsion for treatment of postoperative inflammation after cataract surgery in pediatric patients.MethodsThis was a phase 3B, multicentre, randomized, double-masked, active-controlled study of patients aged 0-3 years who underwent uncomplicated cataract surgery in one eye, with/without intraocular lens implantation. Patients were randomized to receive difluprednate 0.05% four times daily or prednisolone acetate 1% for 14 days post surgery, followed by tapering for 14 days. Safety included evaluation of adverse events. Primary efficacy was the proportion of patients with an anterior cell grade of 0 (no cells) at day 14; secondary efficacy was a global inflammation score.ResultsForty patients were randomized to each treatment group. Adverse drug reactions included corneal oedema (difluprednate 0.5%, n=1; prednisolone acetate 1%, n=0) and increased intraocular pressure or ocular hypertension (n=2/group). Mean intraocular pressure values during treatment were 2-3 mm Hg higher with difluprednate 0.05% compared with prednisolone acetate 1%; mean values were similar between groups by the first week after treatment cessation. At 2 weeks post surgery, the incidence of complete clearing of anterior chamber cells was similar between groups (difluprednate 0.05%, n=30 (78.9%); prednisolone acetate 1%, n=31 (77.5%). Compared with prednisolone acetate 1%, approximately twice as many difluprednate 0.05%-treated patients had a global inflammation assessment score indicating no inflammation on day 1 (n=12 (30.8%) vs n=7 (17.5%) and day 8 (n=18 (48.7%) vs n=10 (25.0%).ConclusionsDifluprednate 0.05% four times daily showed safety and efficacy profiles similar to prednisolone acetate 1% four times daily in children 0-3 years undergoing cataract surgery., Competing Interests: KM and KG are employees and own stocks/shares of Alcon Laboratories, Inc. The other authors declare no conflict of interest.

To evaluate the efficacy and safety of treatment of diabetic macular edema (persistent type) with difluprednate ophthalmic emulsion 0.05 % (off label use). 20 patients with persistent diabetic macular edema were enrolled. In all subjects, more than 4 months had passed since prior treatment. All patients were treated with difluprednate ophthalmic emulsion 0.05 % three times daily for 3 months. At the end of 3 months the visual acuity had increased by two lines to a mean value of 0.61 ± 0.18 on logMAR from a baseline value of 0.885 ± 0.20 and the central retinal thickness had decreased from 423 ± 72.04 microns to 345 ± 68.7 microns. Hence, there was a total of 18.4 % decrease in retinal thickness on difluprednate. Major side effects included raised intraocular pressure in 20 %. Difluprednate is a potent and strong steroid which causes a rapid decrease in persistent diabetic macular edema. However, the potential side effect of raised intraocular pressure limits its use as an adjuvant therapy in non-steroid responders.

Purpose: To describe the clinical course of uveitis-associated inflammatory papillitis and evaluate the utility and reproducibility of optic nerve spectral domain optical coherence tomography (SD-OCT)., Methods: Data on 22 eyes of 14 patients with uveitis-related papillitis and optic nerve imaging were reviewed. SD-OCT measure reproducibility was determined and parameters were compared in active vs. inactive uveitis., Results: Papillitis resolution lagged behind uveitis resolution in three patients. For SD-OCT measures, the intraclass correlation coefficients were 99.1-100% and 86.9-100% for intraobserver and interobserver reproducibility, respectively. All SD-OCT optic nerve measures except inferior and nasal peripapillary retinal thicknesses were significantly higher in active vs. inactive uveitis after correction for multiple hypotheses testing. Mean optic nerve central thickness decreased from 545.1 to 362.9 µm (p = 0.01)., Conclusions: Resolution of inflammatory papillitis can lag behind resolution of uveitis. SD-OCT assessment of papillitis is reproducible and correlates with presence vs. resolution of uveitis.

Purpose: To identify changes in intraocular pressure (IOP) after vitreoretinal surgical procedures in eyes that received either difluprednate ophthalmic emulsion 0.05% (DP) or prednisolone acetate ophthalmic suspension 1% (PA)., Methods: A retrospective chart review compared a consecutive series of 100 patients who received DP with 100 patients who received PA after vitreoretinal surgery. Data were collected for a 3-month period from the time of surgery., Results: A significantly higher number of patients treated with DP (35%, n = 35) developed increased IOP (>21 mmHg with a change from baseline of >10 mmHg) compared with those receiving PA (22%, n = 22) (P = 0.042). The mean maximum IOP in the DP cohort (26.7 mmHg) was significantly higher than that in the PA cohort (22.8 mmHg) (P = 0.0027). Additionally, the rise in IOP from baseline was significantly higher in the DP-treated cohort (9.0 mmHg) than that in the PA-treated cohort (6.0 mmHg) (P = 0.027)., Conclusion: Eyes treated with DP after vitreoretinal surgery were at increased risk for developing clinically significant increases in IOP compared with those receiving PA.

Hypokalemia occurs commonly in lactating dairy cows. The objectives of this study were to determine (1) whether a 24-h oral KCl dose of 0.4 g/kg of body weight (BW) was effective and safe in hypokalemic cattle; (2) whether potassium was best administered as 2 large doses or multiple smaller doses over a 24-h period; and (3) the effect of oral KCl administration on plasma Mg concentration and urine Mg excretion in fasted lactating dairy cattle. Plasma K and Cl concentrations were decreased, and blood pH increased, in 15 lactating Holstein-Friesian cows by administering 2 intramuscular (i.m.) 10-mg injections of isoflupredone acetate 24h apart followed by 2 i.m. injections of furosemide (1mg/kg of BW) 8h apart and by decreasing feed intake. Cows were randomly assigned to 1 of 3 treatment groups with 5 cows/group: untreated control (group C); oral administration of KCl at 0.05 g/kg of BW 8 times at 3-h intervals (group K3); and oral administration of KCl at 0.2g/kg of BW twice at 12-h intervals (group K12). A 24-h KCl dose rate of 0.4 g/kg of BW increased plasma and milk K concentration and plasma Cl concentration, and corrected the metabolic alkalosis and alkalemia, with no clinically significant difference between 2 large doses (group K12) or multiple small doses (group K3) of KCl over 24 h. Oral KCl administration decreased peripheral fat mobilization in cattle with experimentally induced hypokalemia, as measured by changes in plasma nonesterified fatty acid concentration, and slightly augmented the fasting-induced decrease in plasma Mg concentration. Our findings support recommendations for a 24-h oral KCl dose of 0.4 g/kg of BW for treating moderately hypokalemic cattle. Additional Mg may need to be administered to inappetant lactating dairy cattle being treated with oral KCl to minimize K-induced decreases in magnesium absorption., (Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the clinical effect of topical difluprednate in pediatric patients for treatment of noninfectious uveitis., Design: Retrospective, observational case series., Methods: Twenty-six eyes of 14 pediatric patients with noninfectious uveitis who were treated with topical difluprednate were evaluated. Anterior and posterior cell grade, visual acuity, intraocular pressure (IOP), and cystoid macular edema (CME) were recorded at each visit. Main outcome measures were changes in anterior segment cell, CME, visual acuity, and IOP and development of a visually significant cataract., Results: A significant (≥ 2-grade decrease or decrease to 0 in anterior segment cell) reduction in anterior segment inflammation was observed during treatment with topical difluprednate in 88% of eyes (22/25) when used as an adjuvant to systemic immunomodulatory therapy. In addition, improvement in CME associated with uveitis was seen in response to topical therapy with difluprednate in 78% of eyes with CME (7/9). A significant IOP response (IOP increase of ≥ 10 mm Hg from baseline and IOP ≥ 24 mm Hg) was seen in 50% of eyes (13/26) and in 50% of patients (7/14); 3 eyes of 2 patients required glaucoma surgery. Cataract formation or progression was observed in 39% of eyes (10/26) and in 43% of patients (6/14); 5 eyes of 3 patients required cataract surgery., Conclusions: Difluprednate is an effective agent for both control of anterior segment inflammation and reduction of CME in pediatric patients with uveitis when used as an adjuvant to systemic immunomodulatory therapy. A high rate of steroid-induced IOP elevation and cataract formation is seen in this population. Close monitoring of pediatric patients receiving difluprednate is recommended., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Uveitis is the third leading cause of preventable blindness in the U.S. Topical administration of corticosteroids remains the mainstay in the management of acute autoimmune anterior uveitis. Difluprednate 0.05% ophthalmic emulsion is a potent new topical corticosteroid that exhibits enhanced penetration, better bioavailability, rapid local metabolism and strong efficacy, with a low incidence of adverse effects. In June 2008, difluprednate ophthalmic emulsion 0.05% gained FDA approval in the U.S. for the treatment of postoperative ocular inflammation and pain. Recently, a multicenter, randomized clinical trial showed difluprednate to be noninferior to prednisolone acetate 1% dosed twice as often, the current standard of care for the acute management of endogenous uveitis in the U.S. Furthermore, difluprednate proved to have a comparable safety profile. Here, we review difluprednate pharmacokinetics, ocular indications, animal studies, as well as the results of the clinical trials conducted to date in the U.S., (Copyright 2011 Prous Science, S.A.U. or its licensors. All rights reserved.)

Purpose: To report the effects of twice-daily difluprednate in a child with pars planitis (PP)., Design/methods: Case report., Results: PP was controlled with topical difluprednate for 1 year. Then an atypical pattern of steroid response--delayed, relatively sudden onset of recalcitrant ocular hypertension (OHT)--and posterior subcapsular cataract (PSC) formation necessitated alternative treatment., Conclusion: Although not a standard treatment, in select cases of PP topical difluprednate therapy could be a useful short-term treatment option while alternative treatments are considered or immunosuppressive agents build to therapeutic levels. Ophthalmologists must be aware of the potential for delayed onset of serious complications when using difluprednate.

Introduction: Difluprednate ophthalmic emulsion 0.05% (Durezol™, Alcon, Fort Worth, Texas) is a topical difluorinated derivative of prednisolone with potent anti-inflammatory activity. Difluprednate 0.05% has a reported associated increase in intraocular pressure (IOP) in 3% of patients. Although the occurrence may be low, the possible elevation in IOP may be substantially higher than commonly encountered with other topical steroids., Case Reports: A 49-year-old black man presented with a traumatic anterior uveitis recalcitrant to traditional prednisolone acetate 1% treatment. The patient was switched to difluprednate 0.05% in an attempt to better control the ocular inflammation. Although the patient did not exhibit an IOP response after 4 weeks of treatment with prednisolone acetate 1%, he did experience a pressure response within 2 weeks of initiating difluprednate treatment, resulting in an IOP increase from 9 mmHg to 48 mmHg with subsequent microcystic edema. A 44-year-old black woman presented with recurrent scleritis resistant to topical prednisolone acetate, loteprednol etabonate, and oral nonsteroidal anti-inflammatory therapy. Topical loteprednol 0.5% was replaced by difluprednate 0.05%. All evidence of ocular inflammation was eradicated with the changed therapy. IOP rose in the difluprednate-treated eye from 18 mmHg to 34 mmHg over the course of 18 days. In both cases, the IOP elevation was managed rapidly with the discontinuation of difluprednate and temporary use of IOP-reducing agents with no lasting adverse effects., Conclusion: Difluprednate 0.05% is a new topical therapeutic option indicated for the treatment of inflammation and pain management associated with ocular surgery with an off-label potential for treatment of other anterior segment inflammatory conditions. However, clinicians need to be aware of the potential risk for significant and potentially rapid onset of IOP increase with this medication and manage patients accordingly., (Copyright © 2010 American Optometric Association. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the efficacy of treatment of refractory diabetic macular edema (DME) after vitrectomy with difluprednate ophthalmic emulsion 0.05% (Durezol(TM)), and to compare this treatment with sub-Tenon's injection of triamcinolone (STTA)., Methods: This study enrolled patients with refractory diabetic macular edema that persisted despite pars plana vitrectomy in our clinic. In all subjects, more than 3 months had passed since prior treatment. Eleven eyes in ten subjects were treated with STTA (STTA group), and 11 eyes in seven subjects were treated with difluprednate ophthalmic emulsion 0.05% (Durezol(TM), Sirion Therapeutics Inc., USA) 4 times daily for the first month and then twice daily for 2 months (eye drop group)., Results: In the eye drop group, mean VA (+/- SD) was 0.67 +/- 0.35 logMAR and mean retinal thickness was 500.6 +/- 207.7 mum at baseline. After 3 months of treatment, mean VA was 0.67 +/- 0.29 and mean retinal thickness had decreased to 341.2 +/- 194.8 mum. The mean minimum value of RT during the treatment period was 300.6 +/- 123.2 mum, and significantly lower than that at baseline (Mann-Whitney U test: P = 0.003). In the STTA group, mean VA (+/- SD) was 0.67 +/- 0.35 logMAR, and mean retinal thickness was 543.3 +/- 132.6 mum at baseline. After 3 months of treatment, mean VA was 0.49 +/- 0.67, and mean retinal thickness had decreased to 378.6 +/- 135 mum. The mean minimum value of RT during the treatment period was 349.9 +/- 113.8 mum, and significantly lower than at baseline (Mann-Whitney U test: P = 0.003). The rate of effective improvement in RT did not differ between the eye drop group (73%) and STTA group (84%) (Fisher's exact test: P = 1)., Conclusions: Comparable improvements of retinal thickness were observed in the STTA and eye drop groups. Instillation of difluprednate ophthalmic emulsion 0.05% is a safe and effective treatment that does not require surgical intervention and does not produce severe side-effects.

Purpose: To assess the efficacy and safety of difluprednate ophthalmic emulsion 0.05% (Durezol) 2 or 4 times a day compared with those of a placebo in the treatment of inflammation and pain associated with ocular surgery., Setting: Twenty-six clinics in the United States., Methods: One day after unilateral ocular surgery, patients who had an anterior chamber cell grade of 2 or higher (>10 cells) were treated with 1 drop of difluprednate 2 times or 4 times a day or with a placebo (vehicle) 2 times or 4 times a day in the study eye for 14 days. This was followed by a 14-day tapering period and a 7-day safety evaluation. Outcome measures included cleared anterior chamber inflammation (grade 0, or=10 mm Hg and >or=21 mm Hg from baseline, respectively) versus 1% in the placebo group., Conclusions: Difluprednate given 2 or 4 times a day cleared postoperative inflammation and reduced pain rapidly and effectively. There were no serious ocular adverse events. Fewer adverse events were reported in the difluprednate-treated groups than in the placebo group.

Glucocorticoids are commonly used to treat cows with clinical ketosis and fatty liver disease, but their use is controversial. The objectives of the present study were to investigate the effects of isoflupredone acetate alone or with insulin on the energy metabolism of dairy cows in early lactation in a large double-blind, randomized clinical trial. A total of 1,162 Holstein cows and first-lactation heifers were randomly assigned to receive 1 of 3 treatments between the day of parturition and 8 DIM: group A, 20-mg i.m. injection of isoflupredone and 100 units of insulin; group B, 20-mg i.m. injection of isoflupredone; group C (control group), 10-mL i.m. injection of sterile water. Treatments were randomized across 24 dairy farms located near Guelph, Ontario, Canada. Serum samples obtained at the time of treatment and at wk 1 and 2 following treatment were analyzed for beta-hydroxybutyrate, nonesterified fatty acids, glucose, calcium, potassium, sodium, and chloride. Cows were assigned a body condition score at the time of enrollment. Data were analyzed using a repeated-measures mixed model that accounted for the effects of parity and body condition score, and the random effects of cow and farm. Cows that received isoflupredone with insulin and isoflupredone alone had higher beta-hydroxybutyrate and nonesterified fatty acid concentrations 1 wk after treatment compared with control cows. Cows that received isoflupredone acetate plus insulin had lower glucose concentrations at 1 wk after treatment. Calcium concentrations 1 wk after treatment were lower for cows that received isoflupredone and insulin or isoflupredone only compared with control cows. Serum sodium, potassium, and chloride concentrations were not influenced by treatment. The effect of treatment on the proportion of cows with subclinical ketosis was evaluated with a logistic regression model. Over the 2 wk following treatment, a significant increase in the prevalence of subclinical ketosis was observed in the isoflupredone plus insulin group relative to the control group. Among 972 cows that were not ketotic at enrollment, cows that received isoflupredone acetate plus insulin or isoflupredone acetate only were, respectively, 1.72 and 1.59 times more likely than control cows to develop subclinical ketosis 1 wk after treatment. There were no treatment effects on test-day milk production, milk fat and protein percentages, or the intervals from calving to first insemination or pregnancy.

Objective: To determine whether administration of isoflupredone acetate (ISO) to healthy cows increases the frequency of severe hypokalemia and whether dexamethasone (DEX) has detectable mineralocorticoid properties., Animals: 33 cows at 20 to 25 days of lactation., Procedures: Cows were randomly allocated to 5 treatment groups and received 2 IM injections (on days 0 and 2) of sterile saline (0.9% NaCl) solution (10 mL each), an injection of ISO (20 mg) or DEX (20 mg) followed by 10 mL of saline solution, or 2 injections of ISO or DEX. Milk production was measured, physical examinations were performed, and blood and urine samples were collected daily on days 0 through 7., Results: Physical examination parameters did not differ among groups; however, 1 cow developed atrial fibrillation on day 4. Both corticosteroids significantly increased plasma glucose concentrations, and ISO significantly decreased plasma potassium concentrations and increased total carbon dioxide concentrations with time. One dose of ISO decreased mean plasma potassium concentration by 25% on day 2, compared with day 0, and severe hypokalemia (serum potassium concentration < 2.3 mEq/L) developed in 1 of 6 cows. Mean plasma potassium concentration was 46% lower on day 3 than on day 0 in cows receiving 2 doses of ISO, and 5 of 7 cows became severely hypokalemic. Mean urinary fractional excretion of potassium significantly increased from that on day 0 in cows receiving 2 doses of ISO., Conclusions and Clinical Relevance: Both corticosteroids had glucocorticoid activity; however, only ISO had mineralocorticoid activity. Compared with saline solution, administration of 2 doses of ISO significantly increased the frequency of severe hypokalemia.

Reasons for Performing Study: Corticosteroids are currently the most effective drugs for the control of 'heaves' in horses. However, there is limited information concerning the comparative efficacy and tolerability of the various corticosteroids when used for treatment., Objectives: To compare the therapeutic and side effects of isoflupredone acetate to those of dexamethasone., Methods: A parallel design to compare the effects of 2 corticosteroids by evaluating lung function, serum cortisol and electrolyte concentrations, response to ACTH stimulation and haematology sequentially during a 14 day control period (no treatment), followed by 14 day treatment with either isoflupredone acetate (0.03 mg/kg i.m. s.i.d., n = 6) or dexamethasone (0.04 mg/kg i.v. s.i.d., n = 6) and 7 days of wash-out., Results: Both drugs were well tolerated clinically and resulted in a significant improvement in lung function that started on Day 3 and lasted for the treatment and wash-out periods. Blood cortisol levels were significantly decreased during the treatment period in both groups of horses, but a normal response to ACTH stimulation was preserved. Serum electrolytes concentration of horses receiving dexamethasone was not affected by the treatment, but horses treated with isoflupredone demonstrated a significant decrease in serum potassium level. Both treatments induced stress changes in haematology., Conclusions and Potential Relevance: Isoflupredone is as effective as dexamethasone in the treatment of 'heaves'-affected horses but associated with hypokalaemia. Even if clinical signs of hypokalaemia were not observed, this is a side effect that deserves further investigation.

We performed this prospective, randomised, investigator-masked, parallel-group study to compare Fluorometholone-Gentamicin eye drops with Maxitrol (dexamethasone, neomycin, polymyxin B) eye drops in the reduction of ocular bacterial flora and control of ocular inflammation after cataract surgery. One hundred and twelve (FML-Genta 54, Maxitrol 58) patients of both sexes undergoing cataract and posterior chamber lens implant surgery for visually disabling cataract were enrolled in the study and examined pre-operatively and post-operatively on days 1, 6-8 and 24-34. The baseline parameters were similar in the two study groups. The conjunctival bacterial colony count on day 6-8 post-operatively was significantly less on FML-Genta compared with Maxitrol (p = 0.033). There was no statistically significant difference between the two treatments in the degree of intra-ocular inflammation as assessed by flare and cells in the anterior chamber. Both treatments were judged to be equal in the global assessment of the success of therapy and local tolerance by the study patients and doctors. Fluorometholone-gentamicin eye drops were more effective than Maxitrol eye drops in the reduction of ocular bacterial flora while being as well-tolerated and as effective as Maxitrol in the control of ocular inflammation after cataract surgery.

The effects of four days' treatment with topical Maxitrol (neomycin sulphate 3500 IU/mL, polymyxin-B sulphate 6000 IU/mL with dexamethasone 0.1%) were compared with those of Maxidex (dexamethasone 0.1% alone) in a double-masked study in 111 patients with bacterial blepharitis or conjunctivitis, 95 of whom were evaluable for efficacy. The majority of patients (N = 80) had chronic blepharitis. Maxitrol treatment resulted in a significantly greater reduction (90%) in bacterial counts and bacterial eradication (50%) compared with Maxidex (34% and 17% respectively). Maxitrol treatment also produced a significantly greater reduction in conjunctival discharge than did Maxidex, while the treatments were equally effective in alleviating other ocular signs and symptoms. It was concluded that use of a fixed dose combination steroid-antibiotic product was more effective for bacterial control and therapeutic efficacy in the treatment of chronic blepharitis and conjunctivitis patients than treatment with steroid alone. However, in the long-term treatment of chronic blepharitis the well-known toxic problems of neomycin sulphate have to be taken into account.

In an effort to test the hypothesis that 9 alpha-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 11 beta, 21-dihydroxy- 3,20-dioxo-1,4-pregnadiene-16 alpha-carboxylate (DP16CM, 1) was synthesized and evaluated. In the acute rat croton oil-induced ear edema bioassay, 10 was found to be twice as potent as 1. This increase in topical potency was consistent with enhanced binding affinity of 10, relative to 1. The IC50 values for displacement of [3H]dexamethasone from glucocorticoid receptors of rat hepatoma tissue culture cells were 0.16, 1.2, and 0.03 microM for 10, 1, and prednisolone, respectively. Following multiple topical ID50 applications of predniosolone, 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 fluroination of 1 enhanced 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.

The presence of hypokalaemia in hypertensive patient must prompt a search for increased mineralocorticoid activity. We describe and discuss the observation of a patient with biological markers of hypermineralocorticoidism, despite low plasma and urinary aldosterone levels, and suppressed plasma renin activity. This typical syndrome of apparent mineralocorticoid excess was secondary, in our patient, to prolonged administration of a mineralocorticoid-containing nasal spray.

In a clinical case of arterial hypertension with hypopotassiaemia and hyporeninaemic hypoaldosteronism due to the use of a dermatological cream containing 9-alpha-fluoroprednisolone, late identification of the iatrogenic cause forced attention on the differential diagnosis of the less frequent hyporeninaemic hypoaldosteronism.

Among the various syndromes caused by excess mineralocorticoids, the factitious syndrome produced by excessive 9-alpha-fluorprednisolone inhalations is more common than might be expected, especially in places where the drug is easily obtained without a doctor's prescription. A fairly typical case of addiction to a nasal spray containing ephedrine hydrochloride and an imidazoline compound as well as the steroid is described. The diagnosis of the case is analysed with details of certain differences from similar cases reported in the literature and the modifications to clinical and instrumental parameters achieved after over two months' treatment with spironolactone are described.

A 2-month-old breast-fed baby is described, who, admitted for a prolongation of the QT interval on ECG, was found to be severely hypokalemic, alkalotic and hypertensive (blood pressure 200/100 mm Hg). Marked generalized hypotonia was present, and length was less than 3% for age. The results of endocrinological evaluation showed profound suppression of the pituitary-adrenal function and of the renin-aldosterone mechanism. CT scan, cavography and pyelography were normal. A pharmacological cause for the symptoms was sought and found: the mother had been using for the care of bruised nipples a cream containing 1% 9-alpha-fluoroprednisolone-21-acetate. Blood pressure remained elevated for 6 months, but became normal after one year, and growth has resumed normally. The possible differential diagnoses are considered, and the risks presented by topical steroids are emphasized.

A patient is reported who presented with severe arterial hypertension and pronounced hypokalemic metabolic alkalosis along with suppression of 17-hydroxicorticoids, plasma renin activity and urinary aldosterone excretion, in relation to topical application of 9-alpha-fluoroprednisolone, 300 mg weekly. The clinical picture changed after discontinuation of the steroid preparation. Whenever topical steroids are prescribed for extensive chronic skin the development of systemic side-effects must be watched. Depending on the type of steroid employed, Cushing's syndrome or a hypermineralcorticism state may appear. The differential diagnosis of a hypermineralcorticism syndrome without aldosteronism should include the possible topical application of fluorated steroids.

We report the case of a 9-year-old boy suffering from exzematous dermatitis who was treated for 6 years with a daily dose of 100 mg of a dermatological ointment containing 9 alpha-fluoroprednisolone-21-acetate. At examination the patient's blood pressure was persistently 230/160 mm Hg and was considered essential in origin after secondary forms of arterial hypertension had been excluded. Treatment with nifedipine and labetalol lowered the blood pressure to 150/100 mm Hg. When we became aware of the dermatological treatment, we advised its discontinuance. In the subsequent 7 days, the blood pressure fell to hypotensive levels (75/40 mm Hg) and then became normal a few days after discontinuance of the antihypertensive therapy. This case suggests that prolonged use of topical steroids, commonly prescribed for skin diseases, may cause hypertension, especially in childhood.

Iatrogenic pathology due to treatment with steroid drugs used by systemic route is well known. On the contrary iatrogenic pathology due to topical use of these drugs is rarely reported. Two cases of abuse of 9-alpha- fluor-prednisolone and kanamycin administered by endonasal route are reported. The same treatment has been carried out in patients and rabbits. Clinical and bio-humoral data in patients and anatomo-pathological findings in rabbits are reported. The risks, sometimes underestimated, of an overdose of corticosteroid and antibiotic drugs used by endonasal route are pointed out.

The finding of hypokalemia and of low plasma renin activity (PRA) in a hypertensive patient suggests a diagnosis of primary hypermineralocorticoidism. Medications containing compounds with mineralocorticoid-like activity (licorice, carbenexolone) may also cause the same syndrome. Recently, we carried out detailed studies on 10 patients with severe hypertension and hypokalemic alkalosis, suppressed PRA and low aldosterone levels. Plasma levels of cortisol and ACTH were suppressed in most of the cases. Measurement of deoxycorticosterone and corticosterone (and in some patient of 18-hydroxydeoxycorticosterone and 18-hydroxycorticosterone) was not significantly higher than normal. Therapeutic trials of dexamethasone and aminoglutethimide were ineffective. In contrast, spironolactone and amiloride treatment resulted in substantial but incomplete amelioration of both hypertension and hypokalemia. All of the patients share a common history of chronic rhinitis and habitual use of large doses of nasal spray containing 9 alpha-fluoroprednisolone and vasoconstrictor agents. Withdrawal resulted in a complete remission of hypokalemia in one to two weeks in all patients. The hypertension and depressed levels of PRA, aldosterone and cortisol took longer to return to normal, varying from case to case; in all but one patient, the values returned to normal within two months. This report reveals another cause of factitious mineralocorticoid excess which may be considered in the differential diagnosis of hypokalemic hypertensive syndromes.

Three cases of rhabdomyolysis secondary to hypopotassaemia caused respectively by excess liquorice intake, the use of a nasal spray containing fluoroprednisolone acetate and a kidney tubular condition identified as distal tubular acidosis (ATR) are described. The aetiology of each case is discussed with a description of the clinical course and laboratory tests and particular emphasis on variations in the renin-angiotensin-aldosterone system.

Three cases of arterial hypertension and severe hypokaliemia are reported; in two cases an acute rhabdomyolisis was also observed. The syndrome was iatrogenic in two cases depending on the licorice eating and the combined use of diuretics and a 9-alpha-fluoroprednisolone-containing nasal spray in one patient, and on a long-term use of the same nasal decongestant in the other. In the patient 2 the persistence of low PRA and aldosterone levels seems to indicate an excess of mineralcorticoid activity other than aldosterone. The syndrome of factitious mineralcorticoid excess should, therefore, be considered in the differential diagnosis of arterial hypertension with hypokaliemia; the risks of a long-term administration of steroid-containing nasal sprays, responsible of serious side effects, should also be stressed.