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A Prospective, Randomized Trial of Povidone-Iodine 0.6% and Dexamethasone 0.1% Ophthalmic Suspension for Acute Bacterial Conjunctivitis.
Ta, CN, Raizman, MB, Gross, RD, Joshi, S, Mallick, S, Wang, Y, Segal, B
American journal of ophthalmology. 2020;:56-65
Abstract
PURPOSE To evaluate the efficacy and safety of a topical ophthalmic suspension combination of povidone-iodine 0.6% (PVP-I) and dexamethasone 0.1% (DEX) for infectious and inflammatory components of bacterial conjunctivitis. DESIGN Randomized, double-masked, multicenter, phase 3 clinical trial. METHODS Subjects of all ages (those <3 months had to be full-term) with a diagnosis of bacterial conjunctivitis were randomized 3:1:3 to either PVP-I/DEX, PVP-I alone, or placebo. The primary endpoint was clinical resolution in the study eye, and the key secondary efficacy endpoint was bacterial eradication, both at the day 5 visit. Adverse events (AEs) were documented at all visits. RESULTS Overall, 753 subjects were randomized (intent-to-treat [ITT] population; PVP-I/DEX [n = 324]; PVP-I [n = 108]; placebo [n = 321]); mean and standard deviation (SD) age was 44.3 (22.9) years, and most were female (61.2%) and white (78.1%). In all treatment groups, mean treatment compliance was >98%. The modified ITT population for the efficacy analysis comprised 526 subjects. In the study eye at the day 5 visit, clinical resolution was achieved by 50.5% (111/220) subjects in the PVP-I/DEX group vs 42.8% (95/222) in the placebo group (P = .127), and bacterial eradication was achieved by 43.3% (94/217) and 46.8% (102/218), respectively (P = .500). Treatment-emergent AEs were experienced by 32.8% (106/323), 39.8% (43/108), and 19.0% (61/321) of subjects in the safety population treated with PVP-I/DEX, PVP-I, and placebo, respectively (most mild in severity). CONCLUSION In this study, PVP-I/DEX did not demonstrate additional benefit in clinical efficacy compared with placebo in subjects with bacterial conjunctivitis.
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Randomized Safety and Feasibility Trial of Ultra-Rapid Cooling Anesthesia for Intravitreal Injections.
Besirli, CG, Smith, SJ, Zacks, DN, Gardner, TW, Pipe, KP, Musch, DC, Shah, AR
Ophthalmology. Retina. 2020;(10):979-986
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PURPOSE To test the safety and preliminary efficacy of rapid, nonpharmacologic anesthesia via cooling for intravitreal injections. DESIGN Single-center, randomized phase 1 dose-ranging safety study (ClinicalTrials.gov identifier, NCT02872012). PARTICIPANTS Adults 18 years of age or older with a diagnosis of exudative macular degeneration or diabetic macular edema requiring bilateral anti-vascular endothelial growth factor therapy were included. METHODS A handheld device was developed to provide anesthesia via cooling to a focal area on the surface of the eye before intravitreal treatment (IVT). In 22 patients undergoing bilateral IVT, 1 eye was randomized to receive standard of care (SOC) lidocaine-based anesthesia and the other eye received cooling-anesthesia at 1 of 5 different temperatures and cooling times. Subjective pain was assessed via the visual analog scale (VAS; range, 1-10) at 2 time points: (1) immediately after IVT and (2) 4 hours after IVT. Treated eyes were assessed for ocular safety 24 hours after IVT. MAIN OUTCOME MEASURES We determined the occurrence of adverse events in eyes treated with cooling anesthesia. Mean VAS pain scores immediately after IVT and 4 hours after IVT in eyes receiving cooling anesthesia were compared with eyes receiving SOC. RESULTS A total of 44 eyes were treated, 22 with cooling anesthesia and 22 with SOC. No dose-related toxicity was found with cooling anesthesia. Mild, transient adverse events were recorded in 32% of patients treated with cooling anesthesia versus 44% of patients receiving SOC. The mean±standard error of the mean (SEM) VAS pain scores immediately after intravitreal injection were 2.3 ± 0.4 for patients receiving SOC and 2.2 ± 0.6 in patients receiving -10° C cooling anesthesia (P = 0.8). Mean±SEM pain scores 4 hours after injection were 1.6 ± 0.4 for SOC and 1.2 ± 0.5 in the combined -10° C arms (P = 0.56). Total mean±SEM procedure time was 124 ± 5 seconds for patients treated with cooling anesthesia versus 395 ± 40 seconds for SOC (P < 0.0001). CONCLUSIONS Ultra-rapid cooling of the eye for anesthesia was well tolerated, with -10° C treatment resulting in comparable levels of anesthesia to SOC with a reduction in procedure time.
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Study protocol for efficacy and safety of steroid-containing mouthwash to prevent chemotherapy-induced stomatitis in women with breast cancer: a multicentre, open-label, randomised phase 2 study.
Kuba, S, Yamanouchi, K, Matsumoto, M, Maeda, S, Hatachi, T, Sakiko, S, Kawashita, Y, Morita, M, Sakimura, C, Inamasu, E, et al
BMJ open. 2020;(2):e033446
Abstract
INTRODUCTION Stomatitis is a frequent adverse event in patients undergoing chemotherapy for breast cancer. Stomatitis can hamper oral nutrition resulting in malnutrition, reduce quality of life and introduce the need for dose reductions and interruption of chemotherapy; however, there is currently no standard approach for preventing chemotherapy-induced stomatitis. We aimed to assess the safety and efficacy of a dexamethasone-based elixir mouthwash for preventing chemotherapy-induced stomatitis in patients with early breast cancer. METHODS AND ANALYSIS In this multicenter, randomised, controlled phase 2 trial, we will randomly assign 120 women with early breast cancer undergoing chemotherapy to use of a dexamethasone-based elixir or standard oral care, to compare their preventive effects on chemotherapy-induced stomatitis. Patients will be assigned in a 1:1 ratio. Patients in the intervention group will receive chemotherapy, oral care and a dexamethasone-based elixir (10 mL 0.1 mg/mL; swish for 2 min and spit, four times daily for 9 weeks), and patients in the control group will receive chemotherapy and oral care. The primary endpoint is the difference in incidence of stomatitis between the two groups. The sample size allows for the detection of a minimum difference of 20% in the incidence of stomatitis between the two groups. Secondary endpoints are severity of stomatitis, duration of stomatitis, completion rate of chemotherapy and adverse events. ETHICS AND DISSEMINATION All participants signed a written consent form, and the study protocol has been reviewed and approved by the Clinical Research Review Board of Nagasaki University (CRB7180001). TRIAL REGISTRATION NUMBER UMIN Clinical Trials Registry (UMIN000030489).
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HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma.
Zein, J, Gaston, B, Bazeley, P, DeBoer, MD, Igo, RP, Bleecker, ER, Meyers, D, Comhair, S, Marozkina, NV, Cotton, C, et al
Proceedings of the National Academy of Sciences of the United States of America. 2020;(4):2187-2193
Abstract
Asthma resistance to glucocorticoid treatment is a major health problem with unclear etiology. Glucocorticoids inhibit adrenal androgen production. However, androgens have potential benefits in asthma. HSD3B1 encodes for 3β-hydroxysteroid dehydrogenase-1 (3β-HSD1), which catalyzes peripheral conversion from adrenal dehydroepiandrosterone (DHEA) to potent androgens and has a germline missense-encoding polymorphism. The adrenal restrictive HSD3B1(1245A) allele limits conversion, whereas the adrenal permissive HSD3B1(1245C) allele increases DHEA metabolism to potent androgens. In the Severe Asthma Research Program (SARP) III cohort, we determined the association between DHEA-sulfate and percentage predicted forced expiratory volume in 1 s (FEV1PP). HSD3B1(1245) genotypes were assessed, and association between adrenal restrictive and adrenal permissive alleles and FEV1PP in patients with (GC) and without (noGC) daily oral glucocorticoid treatment was determined (n = 318). Validation was performed in a second cohort (SARP I&II; n = 184). DHEA-sulfate is associated with FEV1PP and is suppressed with GC treatment. GC patients homozygous for the adrenal restrictive genotype have lower FEV1PP compared with noGC patients (54.3% vs. 75.1%; P < 0.001). In patients with the homozygous adrenal permissive genotype, there was no FEV1PP difference in GC vs. noGC patients (73.4% vs. 78.9%; P = 0.39). Results were independently confirmed: FEV1PP for homozygous adrenal restrictive genotype in GC vs. noGC is 49.8 vs. 63.4 (P < 0.001), and for homozygous adrenal permissive genotype, it is 66.7 vs. 67.7 (P = 0.92). The adrenal restrictive HSD3B1(1245) genotype is associated with GC resistance. This effect appears to be driven by GC suppression of 3β-HSD1 substrate. Our results suggest opportunities for prediction of GC resistance and pharmacologic intervention.
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Denosumab Versus Risedronate in Glucocorticoid-Induced Osteoporosis: Final Results of a Twenty-Four-Month Randomized, Double-Blind, Double-Dummy Trial.
Saag, KG, Pannacciulli, N, Geusens, P, Adachi, JD, Messina, OD, Morales-Torres, J, Emkey, R, Butler, PW, Yin, X, Lems, WF
Arthritis & rheumatology (Hoboken, N.J.). 2019;(7):1174-1184
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OBJECTIVE Clinical trial results have shown that, in glucocorticoid-treated patients, treatment with denosumab 60 mg subcutaneously once every 6 months (Q6M) increased spine and hip bone mineral density (BMD) at month 12 significantly more than treatment with risedronate 5 mg orally once daily (QD). The present analysis was performed to compare efficacy and characterize safety through month 24. METHODS This phase III study enrolled men and women ≥18 years old who had received ≥7.5 mg daily prednisone or equivalent for <3 months (glucocorticoid-initiating) or for ≥3 months (glucocorticoid-continuing) before screening. All patients <50 years old had a history of osteoporotic fracture. Glucocorticoid-continuing patients ≥50 years old had T scores of -2.0 or less (or -1.0 or less with fracture history). Patients were randomized (1:1) to receive denosumab 60 mg subcutaneously Q6M or risedronate 5 mg orally QD for 24 months, with daily calcium and vitamin D. RESULTS Of 795 patients, 590 (74.2%) completed the study (in the glucocorticoid-initiating group, 109 of 145 patients treated with denosumab and 117 of 145 patients treated with risedronate; in the glucocorticoid-continuing group, 186 of 253 patients treated with denosumab and 178 of 252 patients treated with risedronate). Denosumab was superior to risedronate in increasing lumbar spine and total hip BMD at all time points assessed, among glucocorticoid-initiating patients (24-month lumbar spine: BMD increase of 6.2% versus 1.7%, respectively [P < 0.001]; 24-month total hip: BMD increase of 3.1% versus 0.0% [P < 0.001]) and among glucocorticoid-continuing patients (24-month lumbar spine: BMD increase of 6.4% versus 3.2% [P < 0.001]; 24-month total hip: BMD increase of 2.9% versus 0.5% [P < 0.001]). Adverse events, serious adverse events (including infections), and fractures were similar between treatment groups. CONCLUSION Denosumab was superior to risedronate in terms of increases in spine and hip BMD through month 24, and the safety profile was similar between treatment groups. Denosumab may offer a new osteoporosis treatment option for glucocorticoid-treated patients.
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Topical fluorometholone treatment and desiccating stress change inflammatory protein expression in tears.
Nättinen, J, Jylhä, A, Aapola, U, Enríquez-de-Salamanca, A, Pinto-Fraga, J, López-Miguel, A, González-García, MJ, Stern, ME, Calonge, M, Zhou, L, et al
The ocular surface. 2018;(1):84-92
Abstract
PURPOSE It was hypothesized that tear protein biomarkers could predict the effects of topical steroid treatment and desiccating stress in patients with dry eye disease (DED). To test this concept, a randomized, double-masked, controlled clinical trial with 41 patients was conducted. METHODS The patients were treated topically with either 0.1% fluorometholone (FML) or polyvinyl alcohol (PA). Tear samples were collected using 1 μl glass capillaries at recruitment into the study and after a 3-week treatment period, both before and after 2 h exposure to desiccating stress, in a controlled environment chamber. Relative quantification of tear proteins was conducted by NanoLC-MSTOF using sequential window acquisition of all theoretical mass spectra (SWATH). Ocular surface integrity (corneal and conjunctival staining and conjunctival hyperemia) was selected as the key DED-related sign and analyzed with proteomic data. Analysis of covariance (ANCOVA) and linear models were used to analyze the data with R. RESULTS 758 proteins were identified and relatively quantified from each tear sample. Analysis revealed 9 differentially expressed proteins between FML and PA treatments after 3 weeks and 7 after desiccating stress (P < 0.05). We also identified several differentially expressed proteins at the initial collection, which could be used to predict changes of conjunctival and corneal staining and conjunctival hyperemia after FML treatment and after desiccating stress. These proteins include complement C3 (C3) and calmodulin like 5 (CALML5), which could also differentiate the severity of DED at baseline. CONCLUSIONS The identified proteins could be further used as biomarkers to identify patients most benefiting from FML treatment.
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Increased salt consumption induces body water conservation and decreases fluid intake.
Rakova, N, Kitada, K, Lerchl, K, Dahlmann, A, Birukov, A, Daub, S, Kopp, C, Pedchenko, T, Zhang, Y, Beck, L, et al
The Journal of clinical investigation. 2017;(5):1932-1943
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BACKGROUND The idea that increasing salt intake increases drinking and urine volume is widely accepted. We tested the hypothesis that an increase in salt intake of 6 g/d would change fluid balance in men living under ultra-long-term controlled conditions. METHODS Over the course of 2 separate space flight simulation studies of 105 and 205 days' duration, we exposed 10 healthy men to 3 salt intake levels (12, 9, or 6 g/d). All other nutrients were maintained constant. We studied the effect of salt-driven changes in mineralocorticoid and glucocorticoid urinary excretion on day-to-day osmolyte and water balance. RESULTS A 6-g/d increase in salt intake increased urine osmolyte excretion, but reduced free-water clearance, indicating endogenous free water accrual by urine concentration. The resulting endogenous water surplus reduced fluid intake at the 12-g/d salt intake level. Across all 3 levels of salt intake, half-weekly and weekly rhythmical mineralocorticoid release promoted free water reabsorption via the renal concentration mechanism. Mineralocorticoid-coupled increases in free water reabsorption were counterbalanced by rhythmical glucocorticoid release, with excretion of endogenous osmolyte and water surplus by relative urine dilution. A 6-g/d increase in salt intake decreased the level of rhythmical mineralocorticoid release and elevated rhythmical glucocorticoid release. The projected effect of salt-driven hormone rhythm modulation corresponded well with the measured decrease in water intake and an increase in urine volume with surplus osmolyte excretion. CONCLUSION Humans regulate osmolyte and water balance by rhythmical mineralocorticoid and glucocorticoid release, endogenous accrual of surplus body water, and precise surplus excretion. FUNDING Federal Ministry for Economics and Technology/DLR; the Interdisciplinary Centre for Clinical Research; the NIH; the American Heart Association (AHA); the Renal Research Institute; and the TOYOBO Biotechnology Foundation. Food products were donated by APETITO, Coppenrath und Wiese, ENERVIT, HIPP, Katadyn, Kellogg, Molda, and Unilever.
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Long-term safety of once-daily, dual-release hydrocortisone in patients with adrenal insufficiency: a phase 3b, open-label, extension study.
Nilsson, AG, Bergthorsdottir, R, Burman, P, Dahlqvist, P, Ekman, B, Engström, BE, Ragnarsson, O, Skrtic, S, Wahlberg, J, Achenbach, H, et al
European journal of endocrinology. 2017;(6):715-725
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OBJECTIVE To investigate the long-term safety and tolerability of a once-daily, dual-release hydrocortisone (DR-HC) tablet as oral glucocorticoid replacement therapy in patients with primary adrenal insufficiency (AI). DESIGN Prospective, open-label, multicenter, 5-year extension study of DR-HC conducted at five university clinics in Sweden. METHODS Seventy-one adult patients diagnosed with primary AI who were receiving stable glucocorticoid replacement therapy were recruited. Safety and tolerability outcomes included adverse events (AEs), intercurrent illness episodes, laboratory parameters and vital signs. Quality of life (QoL) was evaluated using generic questionnaires. RESULTS Total DR-HC exposure was 328 patient-treatment years. Seventy patients reported 1060 AEs (323 per 100 patient-years); 85% were considered unrelated to DR-HC by the investigator. The most common AEs were nasopharyngitis (70%), fatigue (52%) and gastroenteritis (48%). Of 65 serious AEs reported by 32 patients (20 per 100 patient-years), four were considered to be possibly related to DR-HC: acute AI (n = 2), gastritis (n = 1) and syncope (n = 1). Two deaths were reported (fall from height and subarachnoid hemorrhage), both considered to be unrelated to DR-HC. From baseline to 5 years, intercurrent illness episodes remained relatively stable (mean 2.6-5.4 episodes per patient per year), fasting plasma glucose (0.7 mmol/L; P < 0.0001) and HDL cholesterol (0.2 mmol/L; P < 0.0001) increased and patient-/investigator-assessed tolerability improved. QoL total scores were unchanged but worsening physical functioning was recorded (P = 0.008). CONCLUSIONS In the first prospective study evaluating the long-term safety of glucocorticoid replacement therapy in patients with primary AI, DR-HC was well tolerated with no safety concerns observed during 5-year treatment.
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Correlation between polymorphisms of the NR3C1 gene and glucocorticoid effectiveness in patients with pemphigus vulgaris.
Fang, SY, Li, CL, Liu, XS, Chen, F, Hua, H
Scientific reports. 2017;(1):11890
Abstract
Glucocorticoid (GC) resistance is the major obscule in the treatment of pemphigus vulgaris (PV) for both patients and clinicans with unclear mechanism. A hypotheis for this resistance is the mutations or polymorphisms present in the nuclear receptor subfamily 3, group C, member 1 (NR3C1) gene that encodes receptors for steroid hormones. This study aimed to investigate the association between NR3C1 gene polymorphisms and GC effectiveness in PV patients. 94 PV patients (64 GC-sensitive and 30 GC-resistant) and 100 healthy volunteers were enrolled in this case-control study. The genotyping of single nucleotide polymorphisms (SNPs) in BCL1, Arg23Lys, Asn363Ser 1548 t-insert, and le747Met, together with tag-SNP sites of the NR3C1 gene were evaluated. No significant differences were observed in genotypic and allelic frequencies of the 16 SNPs between PV patients and healthy volunteers. However, SNPs rs 11745958 C/T (OR: 8.95) and rs17209237 A/G (OR: 4.07) may be associated with an increased risk of GC resistance, while rs 33388 A/T (OR: 0.45) and rs7701443 A/G (OR: 0.51) may indicate a decreased risk of GC resistance in PV patients. NR3C1 gene variation may be associated with GC resistance in PV patients. More extensive genetic analyses and mechanistic analysis are required for further exploration.
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Incidence of Posttransplantation Diabetes Mellitus in De Novo Kidney Transplant Recipients Receiving Prolonged-Release Tacrolimus-Based Immunosuppression With 2 Different Corticosteroid Minimization Strategies: ADVANCE, A Randomized Controlled Trial.
Mourad, G, Glyda, M, Albano, L, Viklický, O, Merville, P, Tydén, G, Mourad, M, Lõhmus, A, Witzke, O, Christiaans, MHL, et al
Transplantation. 2017;(8):1924-1934
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BACKGROUND ADVANCE (NCT01304836) was a phase 4, multicenter, prospectively randomized, open-label, 24-week study comparing the incidence of posttransplantation diabetes mellitus (PTDM) with 2 prolonged-release tacrolimus corticosteroid minimization regimens. METHODS All patients received prolonged-release tacrolimus, basiliximab, mycophenolate mofetil and 1 bolus of intraoperative corticosteroids (0-1000 mg) as per center policy. Patients in arm 1 received tapered corticosteroids, stopped after day 10, whereas patients in arm 2 received no steroids after the intraoperative bolus. The primary efficacy variable was the diagnosis of PTDM as per American Diabetes Association criteria (2010) at any point up to 24 weeks postkidney transplantation. Secondary efficacy variables included incidence of composite efficacy failure (graft loss, biopsy-proven acute rejection or severe graft dysfunction: estimated glomerular filtration rate (Modification of Diet in Renal Disease-4) <30 mL/min per 1.73 m), acute rejection and graft and patient survival. RESULTS The full-analysis set included 1081 patients (arm 1: n = 528, arm 2: n = 553). Baseline characteristics and mean tacrolimus trough levels were comparable between arms. Week 24 Kaplan-Meier estimates of PTDM were similar for arm 1 versus arm 2 (17.4% vs 16.6%; P = 0.579). Incidence of composite efficacy failure, graft and patient survival, and mean estimated glomerular filtration rate were also comparable between arms. Biopsy-proven acute rejection and acute rejection were significantly higher in arm 2 versus arm 1 (13.6% vs 8.7%, P = 0.006 and 25.9% vs 18.2%, P = 0.001, respectively). Tolerability profiles were comparable between arms. CONCLUSIONS A prolonged-release tacrolimus, basiliximab, and mycophenolate mofetil immunosuppressive regimen is efficacious, with a low incidence of PTDM and a manageable tolerability profile over 24 weeks of treatment. A lower incidence of biopsy-proven acute rejection was seen in patients receiving corticosteroids tapered over 10 days plus an intraoperative corticosteroid bolus versus those receiving an intraoperative bolus only.