ABSTRACT
OBJECTIVE: The short and long-term outcomes of children with anti-Ro/La-related congenital heart block treated with a combined maternal-neonatal therapy protocol were compared with those of controls treated with other therapies. STUDY DESIGN: Sixteen mothers were treated during pregnancy with a therapy consisting of daily oral fluorinated steroids, weekly plasma exchange and fortnightly intravenous immunoglobulins and their neonates with intravenous immunoglobulins (study group); 19 mothers were treated with fluorinated steroids alone or associated to intravenous immunoglobulins or plasma exchange (control group). RESULT: The combined-therapy children showed a significantly lower progression rate from 2nd to 3rd degree block at birth, a significant increase in heart rate at birth and a significantly lower number of pacemaker implants during post-natal follow-up with respect to those treated with the other therapies. CONCLUSION: The combined therapy produced better short and long term outcomes with respect to the other therapies studied.
Subject(s)
Heart Block , Immunoglobulins, Intravenous , Betamethasone , Child , Female , Heart Block/congenital , Heart Block/therapy , Humans , Immunoglobulins, Intravenous/therapeutic use , Infant, Newborn , Pregnancy , Steroids, FluorinatedSubject(s)
Immunosuppressive Agents/therapeutic use , Lichen Planus/drug therapy , Mycophenolic Acid/therapeutic use , Aged , Drug Evaluation , Drug Substitution , Drug Tapering , Drug Therapy, Combination , Female , Humans , Male , Middle Aged , Recurrence , Retrospective Studies , Steroids, Fluorinated/therapeutic use , Treatment OutcomeABSTRACT
OBJECTIVES: Fluorinated steroids are largely the therapeutic approach of autoimmune mediated congenital heart block (CHB). We performed a meta-analysis to assess the efficacy of fluorinated steroids for the treatment of CHB. METHODS: Studies evaluating the efficacy of fluorinated steroids versus no treatment in CHB patients were identified in electronic databases. Random-effects model was used to pool odds ratio (OR) (with 95% CI) of live births as the primary outcome. ORs of CHB progression, pacemaker implantation and extranodal disease were the secondary outcome. Subgroup analysis according to CHB grade and study type was performed. RESULTS: Data from nine studies involving 747 patients were analysed. The overall live birth rates were 86.8% and 86.7%, respectively, in the fluorinated steroids exposed foetuses and in the non-exposed ones. Fluorinated steroids did not ameliorate overall survival in CHB (OR 1.02; 95% CI: 0.65-1.61) with any significant statistical heterogeneity between studies (I2 0%, p=0.45). No significant differences for the progression of CHB, the pacing and the presence of extranodal disease were observed. Subgroup analysis revealed a significant protective role of fluorinated steroids for survival in 3rd degree CHB and for pacing in monocentric studies, OR 4.07; 95% CI: 1.10-15.08 and OR 0.15; 95% CI: 0.02-0.99, respectively. CONCLUSIONS: This meta-analysis shows that fluorinated steroids are not superior to any treatment in patients with CHB in terms of live birth, prevention of progression of incomplete CHB, pacemaker implantation and extranodal disease. Thus, considering their side effects, their use in CHB patients should be discouraged.
Subject(s)
Heart Block , Steroids, Fluorinated , Glucocorticoids , Heart Block/congenital , HumansABSTRACT
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.
Subject(s)
Conservative Treatment/methods , Nasal Obstruction/therapy , Nasal Septum/surgery , Nose Deformities, Acquired/complications , Rhinoplasty/methods , Administration, Intranasal , Adult , Clinical Decision-Making/methods , Clinical Trials, Phase III as Topic , Conservative Treatment/economics , Cost-Benefit Analysis , Endoscopy , England , Female , Humans , Male , Multicenter Studies as Topic , Nasal Obstruction/diagnosis , Nasal Obstruction/etiology , Nasal Septum/diagnostic imaging , Nasal Septum/injuries , Nose Deformities, Acquired/therapy , Patient Selection , Quality of Life , Randomized Controlled Trials as Topic , Rhinoplasty/economics , Saline Solution/administration & dosage , Scotland , Self Report/statistics & numerical data , Severity of Illness Index , Steroids, Fluorinated/administration & dosage , Treatment Outcome , WalesABSTRACT
INTRODUCTION: To explore the effect of maternal fluorinated steroid therapy on fetuses affected by immune-mediated complete atrio-ventricular block (CAVB) in utero. MATERIAL AND METHODS: Pubmed, Embase, Cinahl, and ClinicalTrials.gov databases were searched. Only studies reporting the outcome of fetuses with immune CAVB diagnosed on prenatal ultrasound without any cardiac malformations and treated with fluorinated steroids compared to those not treated were included. The primary outcome observed was the regression of CAVB; secondary outcomes were need for pacemaker insertion, overall mortality, defined as the occurrence of either intrauterine (IUD) or neonatal (NND) death, IUD, NND, termination of pregnancy (TOP). Furthermore, we assessed the occurrence of all these outcomes in hydropic fetuses compared to those without hydrops at diagnosis. Meta-analyses of proportions using random effect model and meta-analyses using individual data random-effect logistic regression were used to combine data. RESULTS: Eight studies (162 fetuses) were included. The rate of regression was 3.0% (95%CI 0.2-9.1) in fetuses treated and 4.3% (95%CI 0.4-11.8) in those not treated, with no difference between the two groups (odds ratio (OR): 0.9, 95%CI 0.1-15.1). Pacemaker at birth was required in 71.5% (95%CI 56.0-84.7) of fetuses-treated and 57.8% (95%CI 40.3-74.3) of those not treated (OR: 9, 95%CI 0.4-3.4). There was no difference in the overall mortality rate (OR: 0.5, 95%CI 0.9-2.7) between the two groups; in hydropic fetuses, mortality occurred in 76.2% (95%CI 48.0-95.5) of the treated and in 23.8% (95%CI 1.2-62.3) of the untreated group, while in those without hydrops the corresponding figures were 8.9% (95%CI 2.0-20.3) and 12% (95%CI 8.7-42.2), respectively. Improvement or resolution of hydrops during pregnancy occurred in 76.2% (95%CI 48.0-95.5) of cases treated and in 23.3% (95%CI 1.2-62.3) of those nontreated with fluorinated steroids. CONCLUSIONS: The findings from this systematic review do not suggest a potential positive contribution of antenatal steroid therapy in improving the outcome of fetuses with immune CAVB.
Subject(s)
Atrioventricular Block/drug therapy , Hydrops Fetalis/drug therapy , Steroids, Fluorinated/therapeutic use , Atrioventricular Block/complications , Atrioventricular Block/immunology , Atrioventricular Block/mortality , Female , Humans , Hydrops Fetalis/immunology , PregnancyABSTRACT
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.
Subject(s)
Atrioventricular Block/diagnostic imaging , Atrioventricular Block/drug therapy , Fetal Heart/drug effects , Fetal Heart/diagnostic imaging , Steroids, Fluorinated/administration & dosage , Adult , Atrioventricular Block/epidemiology , Female , Follow-Up Studies , Humans , Netherlands/epidemiology , Pregnancy , Prenatal Diagnosis/methods , Prospective Studies , Treatment OutcomeABSTRACT
OBJECTIVES: Extension of disease beyond the atrioventricular (AV) node is associated with increased mortality in cardiac neonatal lupus (NL). Treatment of isolated heart block with fluorinated steroids to prevent disease progression has been considered but published data are limited and discordant regarding efficacy. This study evaluated whether fluorinated steroids given to manage isolated advanced block prevented development of disease beyond the AV node and conferred a survival benefit. METHODS: In this retrospective study of cases enrolled in the Research Registry for NL, inclusion was restricted to anti-SSA/Ro-exposed cases presenting with isolated advanced heart block in utero who either received fluorinated steroids within 1â week of detection (N=71) or no treatment (N=85). Outcomes evaluated were: development of endocardial fibroelastosis, dilated cardiomyopathy and/or hydrops fetalis; mortality and pacemaker implantation. RESULTS: In Cox proportional hazards regression analyses, fluorinated steroids did not significantly prevent development of disease beyond the AV node (adjusted HR=0.90; 95% CI 0.43 to 1.85; p=0.77), reduce mortality (HR=1.63; 95% CI 0.43 to 6.14; p=0.47) or forestall/prevent pacemaker implantation (HR=0.87; 95% CI 0.57 to 1.33; p=0.53). No risk factors for development of disease beyond the AV node were identified. CONCLUSIONS: These data do not provide evidence to support the use of fluorinated steroids to prevent disease progression or death in cases presenting with isolated heart block.
Subject(s)
Antibodies, Antinuclear/blood , Fetal Diseases/drug therapy , Heart Block/drug therapy , Steroids, Fluorinated/therapeutic use , Adult , Disease Progression , Female , Fetal Diseases/diagnostic imaging , Fetal Diseases/mortality , Heart Block/congenital , Heart Block/diagnostic imaging , Heart Block/etiology , Heart Block/mortality , Humans , Infant, Newborn , Kaplan-Meier Estimate , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/congenital , Male , Pacemaker, Artificial , Prenatal Care/methods , Registries , Retrospective Studies , Ultrasonography, Prenatal , United States/epidemiologyABSTRACT
Transplacental transfer of maternal anti-Ro and/or anti-La autoantibodies can result in fetal cardiac disease, including congenital heart block and cardiomyopathy, called cardiac neonatal lupus (NL). Thousands of women are faced with the risk of cardiac NL in their offspring, which is associated with significant morbidity and mortality. There are no known therapies to permanently reverse third-degree heart block in NL, although several treatments have shown some effectiveness in incomplete heart block and disease beyond the atrioventricular node. Fluorinated steroids taken during pregnancy have shown benefit in these situations, although adverse effects may be concerning. Published data are discordant on the efficacy of fluorinated steroids in the prevention of mortality in cardiac NL. ß-agonists have been used to increase fetal heart rates in utero. The endurance of ß-agonist effect and its impact on mortality are in question, but when used in combination with other therapies, they may provide benefit. No controlled experiments regarding the use of plasmapheresis in cardiac NL have been performed, despite its theoretical benefits. Intravenous immunoglobulin was not shown to prevent cardiac NL at a dose of 400 mg/kg, although it has shown effectiveness in the treatment of associated cardiomyopathy both in utero and after birth. Retrospective studies have shown that hydroxychloroquine may prevent the recurrence of cardiac NL in families with a previously affected child, and a prospective open-label trial is currently recruiting patients in order to fully evaluate this relationship.
Subject(s)
Heart Block/congenital , Lupus Erythematosus, Systemic/congenital , Adrenergic beta-Agonists/therapeutic use , Female , Heart Block/etiology , Heart Block/prevention & control , Heart Block/therapy , Humans , Hydroxychloroquine/therapeutic use , Immunoglobulins, Intravenous/therapeutic use , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/prevention & control , Lupus Erythematosus, Systemic/therapy , Plasmapheresis/methods , Pregnancy , Prenatal Care/methods , Prenatal Diagnosis/methods , Secondary Prevention , Steroids, Fluorinated/therapeutic useABSTRACT
Solid-state {(1)H}(13)C cross-polarization/magic angle spinning (CP/MAS) NMR spectroscopy was performed to analyze two fluorinated steroids, i.e., betamethasone (BMS) and fludrocortisone acetate (FCA), that have fluorine attached to C9, as well as two non-fluorinated analogs, i.e., prednisolone (PRD) and hydrocortisone 21-acetate (HCA). The (13)C signals of BMS revealed multiplet patterns with splittings of 16-215Hz, indicating multiple ring conformations, whereas the (13)C signals of FCA, HCA, and PRD exhibited only singlet patterns, implying a unique conformation. In addition, BMS and FCA exhibited substantial deviation (>3.5ppm) in approximately half of the (13)C signals and significant deviation (>45ppm) in the (13)C9 signal compared to PRD and HCA, respectively. In this study, we demonstrate that fluorinated steroids, such as BMS and FCA, have steroidal ring conformation(s) that are distinct from non-fluorinated analogs, such as PRD and HCA.
Subject(s)
Steroids, Fluorinated/chemistry , Magnetic Resonance Spectroscopy , Molecular Conformation , Reference StandardsABSTRACT
The human steroidogenic cytochromes P450 CYP17A1 (P450c17, 17α-hydroxylase/17,20-lyase) and CYP21A2 (P450c21, 21-hydroxylase) are required for the biosynthesis of androgens, glucocorticoids, and mineralocorticoids. Both enzymes hydroxylate progesterone at adjacent, distal carbon atoms and show limited tolerance for substrate modification. Halogenated substrate analogs have been employed for many years to probe cytochrome P450 catalysis and to block sites of reactivity, particularly for potential drugs. Consequently, we developed efficient synthetic approaches to introducing one or more halogen atom to the 17- and 21-positions of progesterone and pregnenolone. In particular, novel 21,21,21-tribromoprogesterone and 21,21,21-trichloroprogesterone were synthesized using the nucleophilic addition of either bromoform or chloroform anion onto an aldehyde precursor as the key step to introduce the trihalomethyl moieties. When incubated with microsomes from yeast expressing human CYP21A2 or CYP17A1 with P450-oxidoreductase, CYP21A2 metabolized 17-fluoroprogesterone to a single product, whereas incubations with CYP17A1 gave no products. Halogenated steroids provide a robust system for exploring the substrate tolerance and catalytic plasticity of human steroid hydroxylases.
Subject(s)
Microsomes/enzymology , Pregnanes/chemical synthesis , Steroid 17-alpha-Hydroxylase/chemistry , Steroid 21-Hydroxylase/chemistry , Steroids, Brominated/chemical synthesis , Steroids, Chlorinated/chemical synthesis , Steroids, Fluorinated/chemical synthesis , Cholesterol Oxidase/chemistry , Chromatography, High Pressure Liquid , Enzyme Assays , Humans , Microsomes/chemistry , Oxidation-Reduction , Pregnanes/chemistry , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , Steroid 17-alpha-Hydroxylase/metabolism , Steroid 21-Hydroxylase/metabolism , Steroids, Brominated/chemistry , Steroids, Chlorinated/chemistry , Steroids, Fluorinated/chemistry , Substrate Specificity , YeastsSubject(s)
Dermatitis, Contact/diagnosis , Dermatitis, Contact/therapy , Administration, Oral , Administration, Topical , Adult , Algorithms , Anti-Allergic Agents/administration & dosage , Anti-Inflammatory Agents/administration & dosage , Child , Child, Preschool , Cosmetics/adverse effects , Dermatitis, Allergic Contact/diagnosis , Dermatitis, Allergic Contact/therapy , Dermatitis, Contact/physiopathology , Diagnosis, Differential , Disease Susceptibility , Female , Glucocorticoids/adverse effects , Histamine H1 Antagonists/administration & dosage , Humans , Immunosuppressive Agents/administration & dosage , Male , Patch Tests , Plants/adverse effects , Plants/chemistry , Prognosis , Prostheses and Implants/adverse effects , Steroids, Fluorinated/administration & dosage , Steroids, Fluorinated/therapeutic useABSTRACT
Complete congenital atrio-ventricular (AV) heart block develops in 2-5% of fetuses of Ro/SSA and La/SSB autoantibody-positive pregnant women. During pregnancy, the Ro/SSA and La/SSB antibodies are transported across the placenta and affect the fetus. Emerging data suggest that this happens by a two-stage process. In the first step, maternal autoantibodies bind fetal cardiomyocytes, dysregulate calcium homestasis and induce apoptosis in affected cells. This step might clinically correspond to a first-degree heart block, and be reversible. La/SSB antibodies can bind apoptotic cardiomyocytes and thus increase Ig deposition in the heart. The tissue damage could, as a second step, lead to spread of inflammation in genetically pre-disposed fetuses, progressing to fibrosis and calcification of the AV-node and subsequent complete congenital heart block. Early intrauterine treatment of an incomplete AV-block with fluorinated steroids has been shown to prevent progression of the heart block, making it clinically important to find specific markers to identify the high-risk pregnancies.
Subject(s)
Autoantibodies/immunology , Autoantigens/immunology , Fetal Diseases/immunology , Heart Block/congenital , Heart Block/immunology , Animals , Female , Fetal Therapies , Heart Block/prevention & control , Humans , Myocytes, Cardiac/immunology , Myocytes, Cardiac/pathology , Pregnancy , Steroids, Fluorinated/therapeutic useABSTRACT
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.
Subject(s)
Cholanes/pharmacology , Cholestasis/prevention & control , Deoxycholic Acid/analogs & derivatives , Ethinyl Estradiol/toxicity , Steroids, Fluorinated/pharmacology , Animals , Bile/chemistry , Bile/drug effects , Bile Ducts/drug effects , Bile Ducts/metabolism , Cholanes/administration & dosage , Cholanes/chemistry , Cholestasis/chemically induced , Cholestasis/metabolism , Cholesterol 7-alpha-Hydroxylase/genetics , Cholesterol 7-alpha-Hydroxylase/metabolism , Chromatography, High Pressure Liquid , Deoxycholic Acid/administration & dosage , Deoxycholic Acid/chemistry , Deoxycholic Acid/pharmacology , Dose-Response Relationship, Drug , Ethinyl Estradiol/antagonists & inhibitors , Gas Chromatography-Mass Spectrometry , Male , Micelles , Molecular Structure , Phospholipids/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Steroid 12-alpha-Hydroxylase/genetics , Steroid 12-alpha-Hydroxylase/metabolism , Steroids, Fluorinated/administration & dosage , Steroids, Fluorinated/chemistry , Ursodeoxycholic Acid/administration & dosage , Ursodeoxycholic Acid/pharmacologyABSTRACT
BACKGROUND: Mothers with anti-SSA/Ro antibodies who have had a previous fetus with congenital heart block (CHB) have a risk of recurrence estimated to be up to 16%. OBJECTIVE: To improve the management of these "high risk patients" by determining (a) whether or not prophylactic treatment is efficient; (b) whether or not fluorinated steroids (betametasone and dexamethasone) that do cross the placenta in an active form are safe for the fetus; and (c) which prophylactic treatment should be used. METHODS: Retrospective study performed on seven mothers sent to a university hospital owing to a past history of one (six mothers) or two children (one mother) with CHB. RESULTS: 13 subsequent pregnancies occurred. No CHB was observed. All four pregnancies in women treated with 10 mg/day prednisone were uneventful. Three pregnancies in women receiving no steroids resulted in two early spontaneous abortions and one live birth. The six pregnancies in women treated with dexamethasone (4-5 mg/day) ended in one early and one late spontaneous abortion, two stillbirths, and two live births with intrauterine growth restriction and mild adrenal insufficiency. A histological study of one stillbirth disclosed intrauterine growth restriction and marked adrenal hypoplasia. CONCLUSION: Adverse obstetric outcomes were often seen here and major concerns have been raised by paediatricians about the safety of fluorinated steroids, owing to the results of animals studies, retrospective data, and randomised trials. Because fluorinated steroids have not been shown to improve prophylactic treatment of CHB in pregnant women at high risk, their use is questionable.
Subject(s)
Antibodies, Antinuclear/blood , Dexamethasone/adverse effects , Heart Block/congenital , Heart Block/prevention & control , Pregnancy, High-Risk/immunology , Steroids, Fluorinated/adverse effects , Adrenal Insufficiency/etiology , Dexamethasone/therapeutic use , Female , Fetal Growth Retardation/etiology , Heart Block/immunology , Humans , Infant, Newborn , Prednisolone/therapeutic use , Pregnancy , Retrospective Studies , Steroids, Fluorinated/therapeutic use , Treatment FailureABSTRACT
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.
Subject(s)
Asthma/drug therapy , Fluocinolone Acetonide/analogs & derivatives , Acute Disease , Administration, Inhalation , Adrenergic beta-Agonists/administration & dosage , Adult , Albuterol/administration & dosage , Bronchodilator Agents/administration & dosage , Double-Blind Method , Drug Therapy, Combination , Female , Fluocinolone Acetonide/administration & dosage , Forced Expiratory Volume , Humans , Ipratropium/administration & dosage , Male , Prospective Studies , Steroids, Fluorinated/administration & dosageABSTRACT
Novel 21,21-difluorovinyl steroids, designed as difluorinated C20(21) enol mimics of pregnenolone, were targeted as potential mechanism-based inhibitors of C17(20) lyase, a crucial enzyme in the biosynthesis of testosterone. Addition of (difluoromethyl)diphenylphosphine oxide reagent to 17-acetyl steroids was the approach chosen for the construction of these compounds. Of particular interest were the abnormal Wittig products which formed during attempted preparation of the triene 9. The target difluoroolefin 3 was found to be a moderately potent, time-dependent inhibitor of the enzyme.
Subject(s)
Pregnenolone/chemistry , Pregnenolone/pharmacology , Steroid 17-alpha-Hydroxylase/antagonists & inhibitors , Steroids, Fluorinated/chemistry , Steroids, Fluorinated/pharmacology , Animals , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Macaca fascicularis , Male , Structure-Activity Relationship , Testis/enzymology , Time FactorsABSTRACT
Cysteinyl leukotrienes (cys-LTs; LTC4, LTD4, and LTE4) are generated predominantly by mast cells and eosinophils and induce airway smooth muscle contraction, microvascular leakage, and mucous hypersecretion whereas leukotriene B4 (LTB4) is a potent chemoattractant of neutrophils. We measured cys-LTs and LTB4 in exhaled breath condensate from children aged 7-14 years including healthy nonatopic children (n = 11) and children with mild intermittent asthma (steroid naive, n = 11), mild persistent asthma (low-dose inhaled steroid treatment, n = 13), or moderate to severe persistent asthma (high-dose inhaled steroid treatment, n = 13). Exhaled LTB4 levels were increased in patients with mild and moderate to severe persistent asthma compared with patients with mild intermittent asthma (126.0 +/- 8.8 and 131.9 +/- 7.1 versus 52.7 +/- 3.8 pg/ml, p < 0.001 and p < 0.0001) and normal subjects (126.0 +/- 8.8 and 131.9 +/- 7.1 versus 47.9 +/- 4.1 pg/ml, p < 0.0001). Elevated exhaled cys-LT levels were found in patients with mild and moderate to severe persistent asthma compared with normal subjects (27.9 +/- 2.8 and 31.5 +/- 4.5 versus 18.5 +/- 0.5 pg/ml, p < 0.01 and p < 0.05). There was an inverse correlation between exhaled cys-LTs and LTB4 in patients with mild persistent asthma. We conclude that exhaled cys-LTs and LTB4 may be noninvasive markers of airway inflammation in pediatric asthma.
Subject(s)
Asthma/metabolism , Breath Tests , Cysteine/metabolism , Leukotriene B4/metabolism , Leukotrienes/metabolism , Respiration , Adolescent , Asthma/drug therapy , Biomarkers , Child , Child Welfare , Female , Forced Expiratory Volume/physiology , Humans , Male , Nitric Oxide/metabolism , Respiration/drug effects , Severity of Illness Index , Statistics as Topic , Steroids, Fluorinated/therapeutic use , Treatment Outcome , United KingdomABSTRACT
20-fluoro-17(20)-pregnenolone derivatives were designed as enol mimics of pregnenolone. All of the targeted, novel fluoroolefins were potent inhibitors of C17(20) lyase.