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1.
J Perinatol ; 42(9): 1161-1168, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35717457

RESUMO

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.


Assuntos
Bloqueio Cardíaco , Imunoglobulinas Intravenosas , Betametasona , Criança , Feminino , Bloqueio Cardíaco/congênito , Bloqueio Cardíaco/terapia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Recém-Nascido , Gravidez , Esteroides Fluorados
3.
Clin Exp Rheumatol ; 38(4): 783-791, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32573408

RESUMO

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.


Assuntos
Bloqueio Cardíaco , Esteroides Fluorados , Glucocorticoides , Bloqueio Cardíaco/congênito , Humanos
4.
Trials ; 21(1): 179, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32054508

RESUMO

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.


Assuntos
Tratamento Conservador/métodos , Obstrução Nasal/terapia , Septo Nasal/cirurgia , Deformidades Adquiridas Nasais/complicações , Rinoplastia/métodos , Administração Intranasal , Adulto , Tomada de Decisão Clínica/métodos , Ensaios Clínicos Fase III como Assunto , Tratamento Conservador/economia , Análise Custo-Benefício , Endoscopia , Inglaterra , Feminino , Humanos , Masculino , Estudos Multicêntricos como Assunto , Obstrução Nasal/diagnóstico , Obstrução Nasal/etiologia , Septo Nasal/diagnóstico por imagem , Septo Nasal/lesões , Deformidades Adquiridas Nasais/terapia , Seleção de Pacientes , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Rinoplastia/economia , Solução Salina/administração & dosagem , Escócia , Autorrelato/estatística & dados numéricos , Índice de Gravidade de Doença , Esteroides Fluorados/administração & dosagem , Resultado do Tratamento , País de Gales
5.
J Matern Fetal Neonatal Med ; 32(11): 1884-1892, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29251180

RESUMO

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.


Assuntos
Bloqueio Atrioventricular/tratamento farmacológico , Hidropisia Fetal/tratamento farmacológico , Esteroides Fluorados/uso terapêutico , Bloqueio Atrioventricular/complicações , Bloqueio Atrioventricular/imunologia , Bloqueio Atrioventricular/mortalidade , Feminino , Humanos , Hidropisia Fetal/imunologia , Gravidez
7.
Int J Cardiol ; 225: 167-171, 2016 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-27728859

RESUMO

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.


Assuntos
Bloqueio Atrioventricular/diagnóstico por imagem , Bloqueio Atrioventricular/tratamento farmacológico , Coração Fetal/efeitos dos fármacos , Coração Fetal/diagnóstico por imagem , Esteroides Fluorados/administração & dosagem , Adulto , Bloqueio Atrioventricular/epidemiologia , Feminino , Seguimentos , Humanos , Países Baixos/epidemiologia , Gravidez , Diagnóstico Pré-Natal/métodos , Estudos Prospectivos , Resultado do Tratamento
8.
Ann Rheum Dis ; 75(6): 1161-5, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26835701

RESUMO

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 1 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.


Assuntos
Anticorpos Antinucleares/sangue , Doenças Fetais/tratamento farmacológico , Bloqueio Cardíaco/tratamento farmacológico , Esteroides Fluorados/uso terapêutico , Adulto , Progressão da Doença , Feminino , Doenças Fetais/diagnóstico por imagem , Doenças Fetais/mortalidade , Bloqueio Cardíaco/congênito , Bloqueio Cardíaco/diagnóstico por imagem , Bloqueio Cardíaco/etiologia , Bloqueio Cardíaco/mortalidade , Humanos , Recém-Nascido , Estimativa de Kaplan-Meier , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/congênito , Masculino , Marca-Passo Artificial , Cuidado Pré-Natal/métodos , Sistema de Registros , Estudos Retrospectivos , Ultrassonografia Pré-Natal , Estados Unidos/epidemiologia
9.
Cardiol Rev ; 22(6): 263-7, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25050975

RESUMO

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.


Assuntos
Bloqueio Cardíaco/congênito , Lúpus Eritematoso Sistêmico/congênito , Agonistas Adrenérgicos beta/uso terapêutico , Feminino , Bloqueio Cardíaco/etiologia , Bloqueio Cardíaco/prevenção & controle , Bloqueio Cardíaco/terapia , Humanos , Hidroxicloroquina/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/prevenção & controle , Lúpus Eritematoso Sistêmico/terapia , Plasmaferese/métodos , Gravidez , Cuidado Pré-Natal/métodos , Diagnóstico Pré-Natal/métodos , Prevenção Secundária , Esteroides Fluorados/uso terapêutico
10.
Steroids ; 80: 64-70, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24316163

RESUMO

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.


Assuntos
Esteroides Fluorados/química , Espectroscopia de Ressonância Magnética , Conformação Molecular , Padrões de Referência
11.
J Steroid Biochem Mol Biol ; 128(1-2): 38-50, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22001566

RESUMO

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.


Assuntos
Microssomos/enzimologia , Pregnanos/síntese química , Esteroide 17-alfa-Hidroxilase/química , Esteroide 21-Hidroxilase/química , Esteroides Bromados/síntese química , Esteroides Clorados/síntese química , Esteroides Fluorados/síntese química , Colesterol Oxidase/química , Cromatografia Líquida de Alta Pressão , Ensaios Enzimáticos , Humanos , Microssomos/química , Oxirredução , Pregnanos/química , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Esteroide 17-alfa-Hidroxilase/metabolismo , Esteroide 21-Hidroxilase/metabolismo , Esteroides Bromados/química , Esteroides Clorados/química , Esteroides Fluorados/química , Especificidade por Substrato , Leveduras
12.
Curr Opin Immunol ; 18(6): 690-6, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17011766

RESUMO

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.


Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Doenças Fetais/imunologia , Bloqueio Cardíaco/congênito , Bloqueio Cardíaco/imunologia , Animais , Feminino , Terapias Fetais , Bloqueio Cardíaco/prevenção & controle , Humanos , Miócitos Cardíacos/imunologia , Miócitos Cardíacos/patologia , Gravidez , Esteroides Fluorados/uso terapêutico
14.
Toxicol Appl Pharmacol ; 214(2): 199-208, 2006 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-16487557

RESUMO

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.


Assuntos
Colanos/farmacologia , Colestase/prevenção & controle , Ácido Desoxicólico/análogos & derivados , Etinilestradiol/toxicidade , Esteroides Fluorados/farmacologia , Animais , Bile/química , Bile/efeitos dos fármacos , Ductos Biliares/efeitos dos fármacos , Ductos Biliares/metabolismo , Colanos/administração & dosagem , Colanos/química , Colestase/induzido quimicamente , Colestase/metabolismo , Colesterol 7-alfa-Hidroxilase/genética , Colesterol 7-alfa-Hidroxilase/metabolismo , Cromatografia Líquida de Alta Pressão , Ácido Desoxicólico/administração & dosagem , Ácido Desoxicólico/química , Ácido Desoxicólico/farmacologia , Relação Dose-Resposta a Droga , Etinilestradiol/antagonistas & inibidores , Cromatografia Gasosa-Espectrometria de Massas , Masculino , Micelas , Estrutura Molecular , Fosfolipídeos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Esteroide 12-alfa-Hidroxilase/genética , Esteroide 12-alfa-Hidroxilase/metabolismo , Esteroides Fluorados/administração & dosagem , Esteroides Fluorados/química , Ácido Ursodesoxicólico/administração & dosagem , Ácido Ursodesoxicólico/farmacologia
15.
Ann Rheum Dis ; 62(10): 1010-2, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12972484

RESUMO

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.


Assuntos
Anticorpos Antinucleares/sangue , Dexametasona/efeitos adversos , Bloqueio Cardíaco/congênito , Bloqueio Cardíaco/prevenção & controle , Gravidez de Alto Risco/imunologia , Esteroides Fluorados/efeitos adversos , Insuficiência Adrenal/etiologia , Dexametasona/uso terapêutico , Feminino , Retardo do Crescimento Fetal/etiologia , Bloqueio Cardíaco/imunologia , Humanos , Recém-Nascido , Prednisolona/uso terapêutico , Gravidez , Estudos Retrospectivos , Esteroides Fluorados/uso terapêutico , Falha de Tratamento
16.
Chest ; 123(6): 1908-15, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12796167

RESUMO

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.


Assuntos
Asma/tratamento farmacológico , Fluocinolona Acetonida/análogos & derivados , Doença Aguda , Administração por Inalação , Agonistas Adrenérgicos beta/administração & dosagem , Adulto , Albuterol/administração & dosagem , Broncodilatadores/administração & dosagem , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Fluocinolona Acetonida/administração & dosagem , Volume Expiratório Forçado , Humanos , Ipratrópio/administração & dosagem , Masculino , Estudos Prospectivos , Esteroides Fluorados/administração & dosagem
18.
Bioorg Med Chem ; 11(3): 427-31, 2003 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-12517438

RESUMO

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.


Assuntos
Pregnenolona/química , Pregnenolona/farmacologia , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Esteroides Fluorados/química , Esteroides Fluorados/farmacologia , Animais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Macaca fascicularis , Masculino , Relação Estrutura-Atividade , Testículo/enzimologia , Fatores de Tempo
19.
Am J Respir Crit Care Med ; 166(10): 1345-9, 2002 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-12406853

RESUMO

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.


Assuntos
Asma/metabolismo , Testes Respiratórios , Cisteína/metabolismo , Leucotrieno B4/metabolismo , Leucotrienos/metabolismo , Respiração , Adolescente , Asma/tratamento farmacológico , Biomarcadores , Criança , Proteção da Criança , Feminino , Volume Expiratório Forçado/fisiologia , Humanos , Masculino , Óxido Nítrico/metabolismo , Respiração/efeitos dos fármacos , Índice de Gravidade de Doença , Estatística como Assunto , Esteroides Fluorados/uso terapêutico , Resultado do Tratamento , Reino Unido
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