RESUMEN
Malaria remains a global health concern as drug resistance threatens treatment programs. We identified a piperidine carboxamide (SW042) with anti-malarial activity by phenotypic screening. Selection of SW042-resistant Plasmodium falciparum (Pf) parasites revealed point mutations in the Pf_proteasome ß5 active-site (Pfß5). A potent analog (SW584) showed efficacy in a mouse model of human malaria after oral dosing. SW584 had a low propensity to generate resistance (minimum inoculum for resistance [MIR] >109) and was synergistic with dihydroartemisinin. Pf_proteasome purification was facilitated by His8-tag introduction onto ß7. Inhibition of Pfß5 correlated with parasite killing, without inhibiting human proteasome isoforms or showing cytotoxicity. The Pf_proteasome_SW584 cryoelectron microscopy (cryo-EM) structure showed that SW584 bound non-covalently distal from the catalytic threonine, in an unexplored pocket at the ß5/ß6/ß3 subunit interface that has species differences between Pf and human proteasomes. Identification of a reversible, species selective, orally active series with low resistance propensity provides a path for drugging this essential target.
Asunto(s)
Antimaláricos , Piperidinas , Plasmodium falciparum , Inhibidores de Proteasoma , Piperidinas/química , Piperidinas/farmacología , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/enzimología , Animales , Antimaláricos/farmacología , Antimaláricos/química , Humanos , Ratones , Inhibidores de Proteasoma/farmacología , Inhibidores de Proteasoma/química , Inhibidores de Proteasoma/síntesis química , Administración Oral , Complejo de la Endopetidasa Proteasomal/metabolismo , Malaria/tratamiento farmacológico , Malaria/parasitología , Amidas/química , Amidas/farmacología , Amidas/síntesis química , Malaria Falciparum/tratamiento farmacológico , Femenino , Estructura MolecularRESUMEN
Chagas disease is a neglected tropical disease caused by Trypanosoma cruzi. Because current treatments present several limitations, including long duration, variable efficacy and serious side effects, there is an urgent need to explore new antitrypanosomal drugs. The present study describes the hit-to-lead optimization of a 2-aminobenzimidazole hit 1 identified through in vitro phenotypic screening of a chemical library against intracellular Trypanosoma cruzi amastigotes, which focused on optimizing potency, selectivity, microsomal stability and lipophilicity. Multiparametric Structure-Activity Relationships were investigated using a set of 277 derivatives. Although the physicochemical and biological properties of the initial hits were improved, a combination of low kinetic solubility and in vitro cytotoxicity against mammalian cells prevented progression of the best compounds to an efficacy study using a mouse model of Chagas disease.
Asunto(s)
Enfermedad de Chagas , Tripanocidas , Trypanosoma cruzi , Animales , Tripanocidas/química , Enfermedad de Chagas/tratamiento farmacológico , Relación Estructura-Actividad , MamíferosRESUMEN
A series of 5-aryl-2-amino-imidazothiadiazole (ITD) derivatives were identified by a phenotype-based high-throughput screening using a blood stage Plasmodium falciparum (Pf) growth inhibition assay. A lead optimization program focused on improving antiplasmodium potency, selectivity against human kinases, and absorption, distribution, metabolism, excretion, and toxicity properties and extended pharmacological profiles culminated in the identification of INE963 (1), which demonstrates potent cellular activity against Pf 3D7 (EC50 = 0.006 µM) and achieves "artemisinin-like" kill kinetics in vitro with a parasite clearance time of <24 h. A single dose of 30 mg/kg is fully curative in the Pf-humanized severe combined immunodeficient mouse model. INE963 (1) also exhibits a high barrier to resistance in drug selection studies and a long half-life (T1/2) across species. These properties suggest the significant potential for INE963 (1) to provide a curative therapy for uncomplicated malaria with short dosing regimens. For these reasons, INE963 (1) was progressed through GLP toxicology studies and is now undergoing Ph1 clinical trials.
Asunto(s)
Antimaláricos , Antagonistas del Ácido Fólico , Malaria Falciparum , Malaria , Animales , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Antagonistas del Ácido Fólico/uso terapéutico , Malaria/tratamiento farmacológico , Malaria Falciparum/tratamiento farmacológico , Ratones , Ratones SCID , Plasmodium falciparumRESUMEN
The functions of the bromodomain and extra terminal (BET) family of proteins have been implicated in a wide range of diseases, particularly in the oncology and immuno-inflammatory areas, and several inhibitors are under investigation in the clinic. To mitigate the risk of attrition of these compounds due to structurally related toxicity findings, additional molecules from distinct chemical series were required. Here we describe the structure- and property-based optimization of the in vivo tool molecule I-BET151 toward I-BET282E, a molecule with properties suitable for progression into clinical studies.
Asunto(s)
Antiinflamatorios/uso terapéutico , Artritis/tratamiento farmacológico , Imidazoles/uso terapéutico , Proteínas Nucleares/antagonistas & inhibidores , Quinolinas/uso terapéutico , Factores de Transcripción/antagonistas & inhibidores , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/metabolismo , Artritis/inducido químicamente , Colágeno , Cristalografía por Rayos X , Perros , Femenino , Imidazoles/síntesis química , Imidazoles/metabolismo , Masculino , Ratones , Estructura Molecular , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Unión Proteica , Dominios Proteicos , Quinolinas/síntesis química , Quinolinas/metabolismo , Ratas Endogámicas Lew , Ratas Wistar , Relación Estructura-Actividad , Factores de Transcripción/química , Factores de Transcripción/metabolismoRESUMEN
The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria.
Asunto(s)
Antimaláricos , Malaria Falciparum , Malaria , Parásitos , Animales , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Endocitosis , Malaria/tratamiento farmacológico , Malaria Falciparum/tratamiento farmacológico , Plasmodium falciparumRESUMEN
Leishmaniasis is a major infectious disease with hundreds of thousands of new cases and over 20,000 deaths each year. The current drugs to treat this life-threatening infection have several drawbacks such as toxicity and long treatment regimens. A library of 1.8 million compounds, from which the hits reported here are publicly available, was screened against Leishmania infantum as part of an optimization program; a compound was found with a 2-aminobenzimidazole functionality presenting moderate potency, low metabolic stability and high lipophilicity. Several rounds of synthesis were performed to incorporate chemical groups capable of reducing lipophilicity and clearance, leading to the identification of compounds that are active against different parasite strains and have improved in vitro properties. As a result of this optimization program, a group of compounds was further tested in anticipation of in vivo evaluation. In vivo tests were carried out with compounds 29 (L. infantum IC50: 4.1 µM) and 39 (L. infantum IC50: 0.5 µM) in an acute L. infantum VL mouse model, which showed problems of poor exposure and lack of efficacy, despite the good in vitro potency.
Asunto(s)
Bencimidazoles/farmacología , Descubrimiento de Drogas , Leishmania infantum/efectos de los fármacos , Leishmaniasis/tratamiento farmacológico , Animales , Antiprotozoarios/farmacología , Bencimidazoles/química , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Microsomas HepáticosRESUMEN
A series of benzene sulphonamides with good potency and selectivity against Leishmania spp. intracellular amastigotes was identified by high-throughput screening. Approximately 200 compounds were synthesized as part of a hit-to-lead optimization program. The potency of the series appears to be strongly dependent on lipophilicity, making the identification of suitable orally available candidates challenging due to poor pharmacokinetics. Despite not identifying a clinical candidate, a likely solvent exposed area was found, best exemplified in compound 29. Ongoing detailed mode-of-action studies may provide an opportunity to use target-based medicinal chemistry to overcome the issues with the current series.
RESUMEN
Herein we describe the optimization of a phenotypic hit against Plasmodium falciparum based on an aminoacetamide scaffold. This led to N-(3-chloro-4-fluorophenyl)-2-methyl-2-{[4-methyl-3-(morpholinosulfonyl)phenyl]amino}propanamide (compound 28) with low-nanomolar activity against the intraerythrocytic stages of the malaria parasite, and which was found to be inactive in a mammalian cell counter-screen up to 25â µm. Inhibition of gametes in the dual gamete activation assay suggests that this family of compounds may also have transmission blocking capabilities. Whilst we were unable to optimize the aqueous solubility and microsomal stability to a point at which the aminoacetamides would be suitable for inâ vivo pharmacokinetic and efficacy studies, compound 28 displayed excellent antimalarial potency and selectivity; it could therefore serve as a suitable chemical tool for drug target identification.
Asunto(s)
Acetamidas/farmacología , Antimaláricos/farmacología , Acetamidas/síntesis química , Acetamidas/farmacocinética , Animales , Antimaláricos/síntesis química , Antimaláricos/farmacocinética , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Plasmodium berghei/efectos de los fármacos , Plasmodium cynomolgi/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
BACKGROUND: Many translational MR biomarkers derive from measurements of the water proton longitudinal relaxation rate R1, but evidence for between-site reproducibility of R1 in small-animal MRI is lacking. OBJECTIVE: To assess R1 repeatability and multi-site reproducibility in phantoms for preclinical MRI. METHODS: R1 was measured by saturation recovery in 2% agarose phantoms with five nickel chloride concentrations in 12 magnets at 5 field strengths in 11 centres on two different occasions within 1-13â¯days. R1 was analysed in three different regions of interest, giving 360 measurements in total. Root-mean-square repeatability and reproducibility coefficients of variation (CoV) were calculated. Propagation of reproducibility errors into 21 translational MR measurements and biomarkers was estimated. Relaxivities were calculated. Dynamic signal stability was also measured. RESULTS: CoV for day-to-day repeatability (Nâ¯=â¯180 regions of interest) was 2.34% and for between-centre reproducibility (Nâ¯=â¯9 centres) was 1.43%. Mostly, these do not propagate to biologically significant between-centre error, although a few R1-based MR biomarkers were found to be quite sensitive even to such small errors in R1, notably in myocardial fibrosis, in white matter, and in oxygen-enhanced MRI. The relaxivity of aqueous Ni2+ in 2% agarose varied between 0.66â¯s-1â¯mM-1 at 3â¯T and 0.94â¯s-1â¯mM-1 at 11.7T. INTERPRETATION: While several factors affect the reproducibility of R1-based MR biomarkers measured preclinically, between-centre propagation of errors arising from intrinsic equipment irreproducibility should in most cases be small. However, in a few specific cases exceptional efforts might be required to ensure R1-reproducibility.
Asunto(s)
Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética , Fantasmas de Imagen , Sefarosa/química , Agua/química , Animales , Biomarcadores , Simulación por Computador , Ratones , Níquel/química , Oxígeno , Protones , Ratas , Análisis de Regresión , Reproducibilidad de los ResultadosRESUMEN
Combination therapy drugs are considered a fundamental way to control malaria as it mimimizes the risk of emergence of resistance to the individual partner drugs. Consequently, this type of therapy constitutes a driving force for the discovery of new drugs with different modes of action, since this will provide options for combining different drugs to achieve the optimum antimalarial treatment. In this context, a 2,3,8-trisubstitued quinoline compound was found in a high throughput screen (HTS) to show an excellent inhibition of P. falciparum NF54 (IC50 = 22 nM) and low cytotoxicity. We performed a detailed evaluation of the substituents to improve the metabolic stability and solubility liabilities of the original hit and identified derivatives with enhanced physicochemical and/or PK properties and that maintained biological activity. However the high potency was not retained on testing against drug resistant plasmodium strains.
Asunto(s)
Antimaláricos/farmacología , Plasmodium falciparum/efectos de los fármacos , Quinolinas/farmacología , Animales , Antimaláricos/síntesis química , Antimaláricos/química , Diseño de Fármacos , Humanos , Pruebas de Sensibilidad Parasitaria , Quinolinas/síntesis química , Quinolinas/química , RatasRESUMEN
K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives.
Asunto(s)
Antimaláricos/farmacología , Artemisininas/farmacología , Resistencia a Medicamentos/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Plasmodium vivax/efectos de los fármacos , Proteínas Protozoarias/metabolismo , Tetraoxanos/química , Tetraoxanos/farmacología , Animales , Antimaláricos/química , Perros , Relación Dosis-Respuesta a Droga , Resistencia a Medicamentos/genética , Eritrocitos/parasitología , Femenino , Semivida , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Mutación , Plasmodium falciparum/genética , Plasmodium vivax/genética , Ratas , Ratas Sprague-Dawley , Tetraoxanos/farmacocinética , TransgenesRESUMEN
Phenotypic HTS campaigns with a blood stage malaria assay have been used to discover novel chemotypes for malaria treatment with potential alternative mechanisms of action compared to existing agents. N1-(5-(3-Chloro-4-fluorophenyl)furan-2-yl)-N3,N3-dimethylpropane-1,3-diamine, 1 was identified as a modest inhibitor of P. falciparum NF54 (IC50 = 875 nM) with an apparent long plasma half-life after high dose oral administration to mice, although the compound later showed poor metabolic stability in liver microsomes through ring- and side chain-oxidation and N-dealkylation. We describe here the synthesis of derivatives of 1, exploring the influence of substitution patterns around the aromatic ring, variations on the alkyl chain and modifications in the core heterocycle, in order to probe potency and metabolic stability, where 4k showed a long half-life in rats.
Asunto(s)
Antimaláricos/química , Antimaláricos/farmacología , Diseño de Fármacos , Furanos/química , Furanos/farmacología , Plasmodium falciparum/efectos de los fármacos , Aminas/química , Animales , Antimaláricos/metabolismo , Estabilidad de Medicamentos , Furanos/metabolismo , Semivida , Humanos , Ratones , Pruebas de Sensibilidad Parasitaria , Ratas , Relación Estructura-ActividadRESUMEN
The antiplasmodial activity, DMPK properties, and efficacy of a series of quinoline-4-carboxamides are described. This series was identified from a phenotypic screen against the blood stage of Plasmodium falciparum (3D7) and displayed moderate potency but with suboptimal physicochemical properties and poor microsomal stability. The screening hit (1, EC50 = 120 nM) was optimized to lead molecules with low nanomolar in vitro potency. Improvement of the pharmacokinetic profile led to several compounds showing excellent oral efficacy in the P. berghei malaria mouse model with ED90 values below 1 mg/kg when dosed orally for 4 days. The favorable potency, selectivity, DMPK properties, and efficacy coupled with a novel mechanism of action, inhibition of translation elongation factor 2 (PfEF2), led to progression of 2 (DDD107498) to preclinical development.
Asunto(s)
Antimaláricos/farmacología , Descubrimiento de Drogas , Malaria/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Quinolinas/farmacología , Animales , Antimaláricos/síntesis química , Antimaláricos/química , Modelos Animales de Enfermedad , Ratones , Estructura Molecular , Quinolinas/síntesis química , Quinolinas/química , Relación Estructura-ActividadRESUMEN
In this paper we describe the optimization of a phenotypic hit against Plasmodium falciparum, based on a trisubstituted pyrimidine scaffold. This led to compounds with good pharmacokinetics and oral activity in a P. berghei mouse model of malaria. The most promising compound (13) showed a reduction in parasitemia of 96% when dosed at 30 mg/kg orally once a day for 4 days in the P. berghei mouse model of malaria. It also demonstrated a rapid rate of clearance of the erythrocytic stage of P. falciparum in the SCID mouse model with an ED90 of 11.7 mg/kg when dosed orally. Unfortunately, the compound is a potent inhibitor of cytochrome P450 enzymes, probably due to a 4-pyridyl substituent. Nevertheless, this is a lead molecule with a potentially useful antimalarial profile, which could either be further optimized or be used for target hunting.
Asunto(s)
Antimaláricos/química , Antimaláricos/uso terapéutico , Malaria/tratamiento farmacológico , Plasmodium berghei/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Pirimidinas/química , Pirimidinas/uso terapéutico , Animales , Antimaláricos/farmacocinética , Antimaláricos/farmacología , Humanos , Malaria/parasitología , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/parasitología , Ratones SCID , Parasitemia/tratamiento farmacológico , Parasitemia/parasitología , Pirimidinas/farmacocinética , Pirimidinas/farmacologíaRESUMEN
BACKGROUND: Up to 60% of patients with Crohn's disease need intestinal resection within the first 10 years of diagnosis, and postoperative recurrence is common. We investigated whether mercaptopurine can prevent or delay postoperative clinical recurrence of Crohn's disease. METHODS: We did a randomised, placebo-controlled, double-blind trial at 29 UK secondary and tertiary hospitals of patients (aged >16 years in Scotland or >18 years in England and Wales) who had a confirmed diagnosis of Crohn's disease and had undergone intestinal resection. Patients were randomly assigned (1:1) by a computer-generated web-based randomisation system to oral daily mercaptopurine at a dose of 1 mg/kg bodyweight rounded to the nearest 25 mg or placebo; patients with low thiopurine methyltransferase activity received half the normal dose. Patients and their carers and physicians were masked to the treatment allocation. Patients were followed up for 3 years. The primary endpoint was clinical recurrence of Crohn's disease (Crohn's Disease Activity Index >150 plus 100-point increase in score) and the need for anti-inflammatory rescue treatment or primary surgical intervention. Primary and safety analyses were by intention to treat. Subgroup analyses by smoking status, previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis were also done. This trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN89489788) and the European Clinical Trials Database (EudraCT number 2006-005800-15). FINDINGS: Between June 6, 2008, and April 23, 2012, 240 patients with Crohn's disease were randomly assigned: 128 to mercaptopurine and 112 to placebo. All patients received at least one dose of study drug, and no randomly assigned patients were excluded from the analysis. 16 (13%) of patients in the mercaptopurine group versus 26 (23%) patients in the placebo group had a clinical recurrence of Crohn's disease and needed anti-inflammatory rescue treatment or primary surgical intervention (adjusted hazard ratio [HR] 0·54, 95% CI 0·27-1·06; p=0·07; unadjusted HR 0·53, 95% CI 0·28-0·99; p=0·046). In a subgroup analysis, three (10%) of 29 smokers in the mercaptopurine group and 12 (46%) of 26 in the placebo group had a clinical recurrence that needed treatment (HR 0·13, 95% CI 0·04-0·46), compared with 13 (13%) of 99 non-smokers in the mercaptopurine group and 14 (16%) of 86 in the placebo group (0·90, 0·42-1·94; pinteraction=0·018). The effect of mercaptopurine did not significantly differ from placebo for any of the other planned subgroup analyses (previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis). The incidence and types of adverse events were similar in the mercaptopurine and placebo groups. One patient on placebo died of ischaemic heart disease. Adverse events caused discontinuation of treatment in 39 (30%) of 128 patients in the mercaptopurine group versus 41 (37%) of 112 in the placebo group. INTERPRETATION: Mercaptopurine is effective in preventing postoperative clinical recurrence of Crohn's disease, but only in patients who are smokers. Thus, in smokers, thiopurine treatment seems to be justified in the postoperative period, although smoking cessation should be strongly encouraged given that smoking increases the risk of recurrence. FUNDING: Medical Research Council.
Asunto(s)
Enfermedad de Crohn/prevención & control , Enfermedad de Crohn/cirugía , Inmunosupresores/uso terapéutico , Mercaptopurina/uso terapéutico , Prevención Secundaria/métodos , Administración Oral , Adolescente , Adulto , Anciano , Enfermedad de Crohn/diagnóstico , Método Doble Ciego , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Fumar/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
Regulatory T (Treg) cells play a pivotal role in suppressing self-harmful T cell responses, but how Treg cells mediate suppression to maintain immune homeostasis and limit responses during inflammation is unclear. Here we show that effector Treg cells express high amounts of the integrin αvß8, which enables them to activate latent transforming growth factor-ß (TGF-ß). Treg-cell-specific deletion of integrin αvß8 did not result in a spontaneous inflammatory phenotype, suggesting that this pathway is not important in Treg-cell-mediated maintenance of immune homeostasis. However, Treg cells lacking expression of integrin αvß8 were unable to suppress pathogenic T cell responses during active inflammation. Thus, our results identify a mechanism by which Treg cells suppress exuberant immune responses, highlighting a key role for effector Treg-cell-mediated activation of latent TGF-ß in suppression of self-harmful T cell responses during active inflammation.
Asunto(s)
Inflamación/inmunología , Integrinas/metabolismo , Linfocitos T Reguladores/inmunología , Factor de Crecimiento Transformador beta/inmunología , Animales , Proliferación Celular , Colitis/inmunología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/inmunología , Humanos , Mediadores de Inflamación/inmunología , Integrinas/genética , Ratones , Modelos Inmunológicos , Linfocitos T Reguladores/citologíaRESUMEN
PURPOSE: Asthma is associated with reversible airway obstruction, leucocyte infiltration, airways hyperresponsiveness (AHR), and airways remodeling. Fluid accumulation causes pulmonary edema contributing to airways obstruction. We examined the temporal relationship between the late asthmatic response (LAR) following allergen challenge of sensitized guinea-pigs and pulmonary edema measured by magnetic resonance imaging (MRI). MATERIALS AND METHODS: Ovalbumin (OVA) sensitized guinea-pigs received either a single OVA inhalation (acute) or nine OVA inhalations at 48 h intervals (chronic). Airways obstruction was measured as specific airways conductance (sG(aw)) by whole body plethysmography. AHR to inhaled histamine and bronchoalveolar lavage for leucocyte counts were measured 24 h after a single or the final chronic ovalbumin challenges. MRI was performed at intervals after OVA challenge and high-intensity edemic signals were quantified. RESULTS: Ovalbumin caused early bronchoconstriction, followed at 7 h by an LAR and at 24 h AHR and leucocyte influx. The bright-intensity MRI edema signal, peaking at 7 h, was significantly (P < .05) greater after chronic (9.0 ± 0.7 × 10(3) mm(3)) than acute OVA (7.6 ± 0.2 × 10(3) mm(3)). Dexamethasone treatment before acute OVA abolished the AHR and LAR and significantly reduced eosinophils and the bright-intensity MRI edema from 9.1 ± 1.0 to 6.4 ± 0.3 × 10(3) mm(3). CONCLUSION: We show a temporal relationship between edema and the LAR and their parallel reduction, along with eosinophils and AHR, by dexamethasone. This suggests a close causative association between pulmonary edema and impaired airways function.
Asunto(s)
Alérgenos , Asma/patología , Pulmón/patología , Imagen por Resonancia Magnética , Ovalbúmina , Edema Pulmonar/patología , Animales , Antiasmáticos/farmacología , Asma/inducido químicamente , Asma/inmunología , Asma/fisiopatología , Asma/prevención & control , Líquido del Lavado Bronquioalveolar/inmunología , Broncoconstricción , Quimiotaxis de Leucocito , Dexametasona/farmacología , Modelos Animales de Enfermedad , Cobayas , Pulmón/efectos de los fármacos , Pulmón/fisiopatología , Masculino , Valor Predictivo de las Pruebas , Edema Pulmonar/inducido químicamente , Edema Pulmonar/inmunología , Edema Pulmonar/prevención & control , Eosinofilia Pulmonar/inducido químicamente , Eosinofilia Pulmonar/inmunología , Eosinofilia Pulmonar/patología , Eosinofilia Pulmonar/prevención & control , Factores de TiempoRESUMEN
PURPOSE: Despite the significant impact of Crohn's disease (CD) on patients' physical and emotional well-being, no CD-specific patient-reported outcome (PRO) measure is available for determining the efficacy of interventions. The objective of the study was to develop and validate the Crohn's Life Impact Scale (CLIQ), the first such measure. METHODS: Questionnaire content was derived from qualitative interviews with CD patients and face and content validity assessed by cognitive debriefing interviews (CDIs) with patients. A postal survey was conducted to identify the final scale, confirm its unidimensionality and determine reproducibility and construct validity. A subset of the respondents was sent a second questionnaire package 2 weeks after the first. The survey included the CLIQ, Nottingham Health Profile (NHP) and Unidimensional Fatigue Impact Scale (U-FIS). RESULTS: Content analysis was conducted on the 30 interview transcripts and a draft scale produced. The CDIs indicated that the draft scale was relevant, clear and easy to use. The questionnaire package was completed by 273 CD patients (65.6 % male; aged 16-79 (mean 43.9; SD 15.1) years). Of these, 104 also completed the second package. Rasch analysis confirmed a 27-item unidimensional QoL scale (p < 0.05). Both internal consistency and test-retest reliability were high (0.91). Scores on the CLIQ were related to both physical and emotional impairments (NHP) and to fatigue (U-FIS). CONCLUSION: The CLIQ, the first CD-specific PRO, is unidimensional and has excellent psychometric properties. It should prove to be a valuable tool for evaluating the impact of CD and its treatment from the patients' perspective.
Asunto(s)
Enfermedad de Crohn/psicología , Emociones , Calidad de Vida/psicología , Adolescente , Adulto , Anciano , Fatiga/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Psicometría , Reproducibilidad de los Resultados , Encuestas y Cuestionarios , Adulto JovenRESUMEN
BACKGROUND: Ulcerative colitis is a lifelong, chronic, relapsing-remitting disease. OBJECTIVE: To assess the relationship between ulcerative colitis disease status and patient quality of life, and to determine the impact of ulcerative colitis on healthcare costs and work productivity, in the UK. METHODS: Clinicians assessed 173 adult patients' current disease status at a single study visit using the partial Mayo (pMayo) instrument. Patients completed the Euro Quality of Life 5-dimension, 5-level (EQ-5D-5L) questionnaire, the Work Productivity and Activity Impairment (WPAI) questionnaire. Healthcare resource use was determined from questionnaires and from patients' medical charts. RESULTS: Patients in remission had a significantly higher EQ-5D-5L scores (mean (SD) 0.86 (0.15)) than patients with active disease (0.71 (0.20); p<0.001). Patients with mild disease had significantly higher mean (SD) EQ-5D-5L scores than patients with moderate/severe disease: 0.77 (0.11) and 0.66 (0.24), respectively (p<0.001). The mean percent productivity impairment was greater for patients with active disease than for patients in remission on all items of the WPAI questionnaire: 24.6% vs 1.8% for work time missed, 34.1% vs 12.9% for impairment while working, 40.8% vs 14.4% for overall work impairment and 42.7% vs 13.0% for activity impairment (p<0.001 for all comparisons). The mean (SD) total cost of healthcare for ulcerative colitis in the prior 3â months was £1211 (1588). CONCLUSIONS: When compared with patients in remission, patients with active ulcerative colitis have significantly worse quality of life and significantly more work impairment. The healthcare costs of ulcerative colitis are considerable.