Nasal Airway Obstruction Study (NAIROS): a phase III, open-label, mixed-methods, multicentre randomised controlled trial of septoplasty versus medical management of a septal deviation with nasal obstruction.

BACKGROUND: Septoplasty (surgery to straighten a deviation in the nasal septum) is a frequently performed operation worldwide, with approximately 250,000 performed annually in the US and 22,000 in the UK. Most septoplasties aim to improve diurnal and nocturnal nasal obstruction. The evidence base for septoplasty clinical effectiveness is hitherto very limited. AIMS: To establish, and inform guidance for, the best management strategy for individuals with nasal obstruction associated with a deviated septum. METHODS/DESIGN: A multicentre, mixed-methods, open label, randomised controlled trial of septoplasty versus medical management for adults with a deviated septum and a reduced nasal airway. Eligible patients will have septal deflection visible at nasendoscopy and a nasal symptom score ≥ 30 on the NOSE questionnaire. Surgical treatment comprises septoplasty with or without reduction of the inferior nasal turbinate on the anatomically wider side of the nose. Medical management comprises a nasal saline spray followed by a fluorinated steroid spray daily for six months. The recruitment target is 378 patients, recruited from up to 17 sites across Scotland, England and Wales. Randomisation will be on a 1:1 basis, stratified by gender and severity (NOSE score). Participants will be followed up for 12 months post randomisation. The primary outcome measure is the total SNOT-22 score at 6 months. Clinical and economic outcomes will be modelled against baseline severity (NOSE scale) to inform clinical decision-making. The study includes a recruitment enhancement process, and an economic evaluation. DISCUSSION: The NAIROS trial will evaluate the clinical effectiveness and cost-effectiveness of septoplasty versus medical management for adults with a deviated septum and symptoms of nasal blockage. Identifying those individuals most likely to benefit from surgery should enable more efficient and effective clinical decision-making, and avoid unnecessary operations where there is low likelihood of patient benefit. TRIAL REGISTRATION: EudraCT: 2017-000893-12, ISRCTN: 16168569. Registered on 24 March 2017.

Fluorinated steroids do not improve outcome of isolated atrioventricular block.

INTRODUCTION: Congenital atrioventricular block (CAVB) is a rare disorder with a significant morbidity and mortality. Consensus regarding the prescription and efficacy of prenatal corticosteroids is lacking. This nationwide study was initiated to evaluate the effects of prenatal treatment with corticosteroids on the outcome of CAVB in The Netherlands. METHODS: All fetuses identified with isolated congenital AVB-II° or AVB-III° in any of the eight academic fetal heart centers of The Netherlands between 2003 and 2013 were included and reviewed. RESULTS: Fifty-six fetuses were included. Fourteen (25%) fetuses were treated with dexamethasone. We found no differences between the steroid-treated and untreated cases regarding in utero progression of the AVB (63% vs 67% respectively), survival to birth (86% vs 84%), pacemaker implantations (74% vs 58%) or long-term dilated cardiomyopathy (13% vs 17%). Steroid treated fetuses demonstrated more in utero growth restriction (38% vs 11%). CONCLUSION: No benefit from prenatal corticosteroid treatment was demonstrated for fetuses with isolated CAVB in this study. However, we found negative side effects. Our data provide no evidence to support the routine administration of corticosteroids for the treatment of fetal CAVB.

Synthesis and topical antiinflammatory properties of 17,21-bis(acetyloxy)-6beta,9-difluoro-11beta-hydroxypregna-1,4-diene-3,20-dione and related 2-halogenated compounds.

Introduction of a halogen atom at C-2 of steroid 3-ketofluorohydrins, obtained from the corresponding 5alpha,6alpha-epoxides by trans-diaxial opening with hydrofluoric acid, prevents the 6beta-fluorine atom from undergoing rearrangement to the more stable 6alpha configuration when the 5-tert-hydroxyl is split off to yield to yield a conjugated double bond. Two processes were investigated for the synthesis of 17,21-bis(acetyloxy)-6beta-fluoro-1,4,9(11)-triene-3,20-dione (24a) and the related 2-bromo compound 24b starting from the known 21-(acetyloxy)-6beta-fluoro-5alpha,11alpha,17-trihydroxypregnane-3,20-dione (13). Successive reaction with hypobromous acid, epoxidation, and fluorination converted 24a and 24b into the title compound 27a and the analogue 2-bromo compound 27b. In addition, a synthesis of 17,21-bis(acetyloxy)-2-chloro-6beta,9-difluoropregna-1,4-diene-3,20-dione (27c) is reported. The antiinflammatory activity of 17,21-bis-(acetyloxy)-6beta,9-difluoropregna-1,4-diene-3,20-dione (27a) and its 2-halogenated analogues 27b and 27c in comparison with the corresponding 6alpha,9-difluoro epimers was studied. Some 6beta-fluoro compounds displayed high topical antiinflammatory activity without systemic effects.

Triple inhaled drug protocol for the treatment of acute severe asthma.

STUDY OBJECTIVE: This study tests the hypothesis that the administration of multiple doses of inhaled albuterol (A), ipratropium bromide (IB), and flunisolide (F) provides an additional benefit to adults with acute severe asthma compared with the administration of A plus IB (A/IB) or A plus F (A/F). DESIGN: Randomized, double-blind, prospective trial. PATIENTS AND INTERVENTIONS: One hundred seventy-two patients who presented to an emergency department were assigned to receive A, IB, and F (ie, triple drug treatment [TDG]; 56 patients), A/IB (60 patients), or A/F (56 patients). All drugs were administered through a metered-dose inhaler and spacer at 10-min intervals for 3 h. RESULTS: Patients who received TDG had an overall 64% greater improvement (95% confidence interval [CI], 24 to 103%; p = 0.002) in FEV(1) (mean [+/- SD], 2.1 +/- 0.6 L) than those who received A/F (mean, 1.7 +/- 0.6 L), and a 41% greater improvement (95% CI, 1 to 80%; p = 0.04) than those who received A/IB (mean, 1.8 +/- 0.6 L). Differences between groups increased with time (p = 0.001). At 3 h, there was a trend toward a reduction in hospital admission rates (A/IB group, 25%; A/F group, 20%; and TDG group, 11%). The patients who were the most likely to benefit (ie, those with a greater improvement in pulmonary function and a significant reduction in the hospitalization rate) from TDG were those with more severe obstruction (ie, FEV(1), < 30% of predicted). The benefit of TDG was equally evident independent of the patient's previous use of corticosteroids. CONCLUSIONS: The data suggest that there was a therapeutic benefit from the addition of IB and F to A administered in high doses, particularly in those patients in whom the FEV(1) was < 30% of the predicted value.

Topical steroids: a guide for use in the elderly patient.

Topical steroids are indicated for the treatment of a number of skin disorders affecting the elderly, including several forms of dermatitis and psoriasis. Proper selection of a topical steroid is based on several factors, including the disorder and anatomical site being treated, the potency, dosage form, and application technique of the steroid, potential side effects, and the presence of coexisting factors such as infection and preexisting atrophy. This review outlines guidelines for the safe, efficacious selection and administration of these commonly prescribed agents in the elderly patient.

The topical administration of steroids in the treatment of typical vulvar dystrophies.

Sixty-eight patients with histologically diagnosed typical vulvar dystrophies were treated with local administration of steroids. Twenty-three patients with hyperplastic dystrophies received topical fluorinated corticosteroids twice a day for 4 weeks and once a day for another 2 weeks. Thirty-five patients with lichen sclerosus were given local 2% testosterone propionate in vaseline twice a day for 8 weeks, once a day for another 8 weeks and then 3 times a week for another 8 weeks. Ten patients with mixed dystrophy first received topical fluorinated corticosteroids twice a day for 4 weeks and once a day for another 2 weeks, and then local 2% testosterone propionate in vaseline twice a day for 4 weeks and once a day for another 4 weeks. A relief of symptomatology and a regression of gross appearance were obtained in 82.6% and 69.6% of patients respectively with hyperplastic dystrophy, in 82.9% and 65.7% of those with lichen sclerosus and in 80% and 40% of those with mixed dystrophy. A recurrence of symptomatology often occurred at various times after the end of therapy.

3alpha-6alpha-Dihydroxy-7alpha-fluoro-5beta-cholanoate (UPF-680), physicochemical and physiological properties of a new fluorinated bile acid that prevents 17alpha-ethynyl-estradiol-induced cholestasis in rats.

3alpha-6alpha-Dihydroxy-7alpha-fluoro-5beta-cholanoate (UPF-680), the 7alpha-fluorine analog of hyodeoxycholic acid (HDCA), was synthesized to improve bioavailability and stability of ursodeoxycholic acid (UDCA). Acute rat biliary fistula and chronic cholestasis induced by 17alpha-ethynyl-estradiol (17EE) models were used to study and compare the effects of UPF-680 (dose range 0.6-6.0 micromol/kg min) with UDCA on bile flow, biliary bicarbonate (HCO(3)(-)), lipid output, biliary bile acid composition, hepatic enzymes and organic anion pumps. In acute infusion, UPF-680 increased bile flow in a dose-related manner, by up to 40.9%. Biliary HCO(3)(-) output was similarly increased. Changes were observed in phospholipid secretion only at the highest doses. Treatment with UDCA and UPF-680 reversed chronic cholestasis induced by 17EE; in this model, UDCA had no effect on bile flow in contrast to UPF-680, which significantly increased bile flow. With acute administration of UPF-680, the biliary bile acid pool became enriched with unconjugated and conjugated UPF-680 (71.7%) at the expense of endogenous cholic acid and muricholic isomers. With chronic administration of UPF-680 or UDCA, the main biliary bile acids were tauro conjugates, but modification of biliary bile acid pool was greater with UPF-680. UPF-680 increased the mRNA for cytochrome P450 7A1 (CYP7A1) and cytochrome P450 8B (CYP8B). Both UDCA and UPF-680 increased the mRNA for Na(+) taurocholate co-transporting polypeptide (NCTP). In conclusion, UPF-680 prevented 17EE-induced cholestasis and enriched the biliary bile acid pool with less detergent and cytotoxic bile acids. This novel fluorinated bile acid may have potential in the treatment of cholestatic liver disease.

Steroid-induced rosacea.

The excessive, regular use of topical fluorinated corticosteroids on the face often produces an array of skin complications, including an eruption clinically indistinguishable from rosacea ("iatrosacea"). Treatment involves discontinuation of the steroid and administration of oral tetracycline and nonsteroidal topical preparations. Once therapy is begun, clearing of the lesions may take several months.

Effect of topical administration of antiinflammatory drugs to rats with adjuvant arthritis.

Oral or intramuscular administration of antiinflammatory agents produces numerous undesirable side effects. This work explores the hypothesis that topical administration of such agents directly to the site of inflammation would have beneficial antiinflammatory effects. Topical administration of steroidal and nonsteroidal antiinflammatory drugs to rats with adjuvant arthritis was as effective as oral or intramuscular administration. Peak blood levels of radioactivity following administration of equal doses of hydrocortisone-3H were considerably lower after topical administration than after oral administration.

Do excoriations in psoriasis delay or prevent the effect of topical treatment?

Topical treatment of a number of out-patients with psoriasis vulgaris resulted in reduced induration and diminished thickness of the layer of scales but complete involution was not obtained. A sequential photographic study of the macroscopic appearance of the lesions over a 3-month period of treatment revealed that artificially produced excoriations and a horny layer without scales were prominent features. The view is put forward that the cutaneous reaction to the injury probably elicited by the excoriations, together with an unsatisfactory treatment, may give rise to tissue changes which counteract the effect of topical treatment.

[Toxicological examination of pure diflucortolone valerate and its formulations as ointment, fatty ointment and cream in animal experiments (author's transl)]. / Tierexperimentelle Verträglichkeitsprüfung von Diflucortolonvalerianat als reiner Wirkstoff und als Salbe, Fettsalbe und Creme

On the basis of absolute DL50 values 6alpha,9-difluor-11beta-hydroxy-16alpha-methyl-21-valeryloxy-1,4-pregnadiene-3,20-dione (diflucortolone valerate, Nerisona) is virtually non-toxic after single oral administration (mouse greater than 4 g/kg, rat ca. 3.1 g/kg, dog greater than 1 g/kg). Given s.c. (LD50 mouse ca. 180 mg/kg, rat ca. 13 mg/kg) and i.p. (LD50 mouse ca. 450 mg/kg, rat ca. 98 mg/kg) it is highly active and therefore produces also toxic effects. The formulations Nerisona ointment, fatty ointment and cream have proven practically non-toxic in rats after single oral gavage (LD50 greater than 33 g/kg). The daily s.c. administration over 6 weeks revealed systemic glucocorticoid effects in rats at 0.0004 mg/kg and in dogs at 0.04 mg/kg. Similar effects were seen in dogs after daily dermal treatment for 13-14 weeks with Nerisona ointment at 100 mg/kg body weight. On the skin of rabbits and dogs there were no differences in the reaction at the application site between Nerisona ointment, fatty ointment and cream and the corresponding ointment, or cream bases by daily dermal administration for 28 days. However, the 13-14 week dermal study in dogs with Nerisona ointment revealed atrophy of the epidermis at the application site in several cases. The daily dermal application of Nerisona ointment during organogenetic phases of pregnancy caused embryotoxic effects in rats at 500 mg/kg and in rabbits at 50 mg/kg. All of these findings are discusses as well-known glucocorticosteroid effects.

[Adrenal function in topic corticotherapy]. / La función suprarrenal en la corticoterapia tópica.

It has been shown that corticosteroids for dermatological use produce an inhibition of the adrenal function, and it is considered that in our milieu these products are used without any precise indication. In this study, 29 ambulatory children from 3 to 15 years of age were selected, who were suffering from dermatoses with different degrees of extension, on whom urinary 17-ketosteroids, 17-ketogenicsteroids and serum cortisol were measured before and after non-occlusive treatment of two weeks, using 0.01 percent fluorocorticoids and controls after 24 hours and 8 days. A significant drop of the 17-keratogenicsteroids was found in patients studied at the end of the treatment, with immediate recovery. Additionally it was observed, in patients who had over 30 percent of skin area involved, that there was a decrease in serum cortisol, which persisted even 24 hours after discontinuing treatment, with normal levels in a measurement taken eight days later. It is therefore concluded that glucocorticoids applied topically are capable of inhibiting adrenal function.

Response of mononuclear leukocyte cyclic adenosine monophosphate-phosphodiesterase activity to treatment with topical fluorinated steroid ointment in atopic dermatitis.

Our studies of mononuclear leukocyte peripheral blood homogenates demonstrate significantly increased cyclic adenosine monophosphate-specific phosphodiesterase activity in patients with atopic dermatitis who were untreated for 1 week, compared with normal adult nonatopic control subjects. Phosphodiesterase activity is not related to the extent or activity of the patient's disease or the presence or absence of allergic respiratory disease. Enzyme kinetic studies showed a triphasic plot in normal mononuclear leukocytes but a biphasic plot in atopic dermatitis. This may be interpreted as an absence of an enzyme with a low (0.080) Michaelis Menton constant (Km) in atopic dermatitis samples. One week of therapy with a topical fluorinated steroid ointment caused a significant reduction in disease activity. Although a slight reduction in mean total phosphodiesterase activity occurred, it did not reach statistical significance. One week's treatment, however, caused the abnormal biphasic kinetic plot to revert to a triphasic plot with return of the low Km enzyme form in those patients who showed a fall in phosphodiesterase activity. This finding suggests that the elevated phosphodiesterase activity in atopic dermatitis may be responsive in a limited degree to topical steroid therapy.