RESUMEN
BACKGROUND: Oral propranolol is widely prescribed as first-line treatment for infantile haemangiomas (IHs). Anecdotally, prescribing practice differs widely between centres. OBJECTIVES: The Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce was founded to establish patterns of use of propranolol in IHs. METHODS: Participating centres entered data on all of their patients who had completed treatment with oral propranolol for IHs, using an online data capture tool. RESULTS: The study cohort comprised 1097 children from 39 centres in eight European countries. 76·1% were female and 92·8% had a focal IH, with the remainder showing a segmental, multifocal or indeterminate pattern. The main indications for treatment were periocular location (29·3%), risk of cosmetic disfigurement (21·1%) and ulceration and bleeding (20·6%). In total 69·2% of patients were titrated up to a maintenance regimen, which consisted of 2 mg kg(-1) per day (85·8%) in the majority of cases. 91·4% of patients had an excellent or good response to treatment. Rebound growth occurred in 14·1% upon stopping, of whom 53·9% were restarted and treatment response was recaptured in 91·6% of cases. While there was no significant difference in the treatment response, comparing a daily maintenance dose of < 2 mg kg(-1) vs. 2 mg kg(-1) vs. > 2 mg kg(-1) , the risk of adverse events was significantly higher: odds ratio (OR) 1 vs. adjusted OR 0·70, 95% confidence interval (CI) 0·33-1·50, P = 0·36 vs. OR 2·38, 95% CI 1·04-5·46, P = 0·04, Ptrend < 0·001. CONCLUSIONS: The PITCH survey summarizes the use of oral propranolol across 39 European centres, in a variety of IH phases, and could be used to inform treatment guidelines and the design of an interventional study.
Asunto(s)
Antineoplásicos/administración & dosificación , Hemangioma/tratamiento farmacológico , Propranolol/administración & dosificación , Neoplasias Cutáneas/tratamiento farmacológico , Administración Oral , Antineoplásicos/efectos adversos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Lactante , Masculino , Propranolol/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: The oxidized forms of the fragrance terpenes limonene and linalool are known to cause allergic contact dermatitis. Significant rates of contact allergy to these fragrances have been reported in European studies and in a recent worldwide study. Patch testing to oxidized terpenes is not routinely carried out either in the U.K. or in other centres internationally. OBJECTIVES: To investigate the prevalence of contact allergy to oxidized limonene and linalool in the U.K. METHODS: Between 1 August 2011 and 31 December 2012, 4731 consecutive patients in 13 U.K. dermatology departments were tested for hydroperoxides of limonene 0·3% pet., hydroperoxides of linalool 1·0% pet., stabilized limonene 10·0% pet. and stabilized linalool 10·0% pet. Doubtful (?+) and equivocal (±) reactions were grouped together as irritant reactions. RESULTS: Two hundred and thirty-seven patients (5·0%) had a positive patch test reaction to hydroperoxides of limonene 0·3% pet. and 281 (5·9%) to hydroperoxides of linalool 1·0% pet. Irritant reactions to one or both oxidized terpenes were found in 242 patients (7·3%). Eleven patients (0·2%) had a positive patch test reaction to the stabilized terpenes alone. CONCLUSIONS: This large, multicentre U.K. audit shows a significant rate of allergy to the hydroperoxides of limonene and linalool plus a high rate of irritant reactions. Testing to the oxidized forms alone captures the majority (97·0%; 411 of 422) of positive reactions; testing to nonoxidized terpenes appears to be less useful. We recommend that the hydroperoxides of limonene and linalool be added to an extended baseline patch test series.
Asunto(s)
Ciclohexenos/toxicidad , Dermatitis Alérgica por Contacto/epidemiología , Monoterpenos/toxicidad , Terpenos/toxicidad , Monoterpenos Acíclicos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alérgenos/toxicidad , Niño , Preescolar , Femenino , Humanos , Irritantes/toxicidad , Limoneno , Masculino , Persona de Mediana Edad , Pruebas del Parche , Perfumes/toxicidad , Reino Unido/epidemiología , Adulto JovenRESUMEN
The type-1 glycine transporter (GlyT1) is an important target for the development of new medications for schizophrenia. A specific and selective positron emission tomography (PET) GlyT1 ligand would facilitate drug development studies to determine whether a drug reaches this target and help establish suitable doses for clinical trials. This article describes the evaluation of three candidate GlyT1 PET radioligands (GSK931145, GSK565710, and GSK991022) selected from a library of compounds based on favorable physicochemical and pharmacological properties. Each candidate was successfully labeled using [(11)C]methyl iodide or [(11)C]methyl triflate and administered to a pig pre- and postadministration with a pharmacological dose of a GlyT1 inhibitor to determine their suitability as PET ligands in the porcine brain in vivo. All three candidate ligands were analyzed quantitatively with compartment analyses employing a plasma input function. [(11)C]GSK931145 showed good brain penetration and a heterogeneous distribution in agreement with reported GlyT1 localization. Following pretreatment with GSK565710, uptake of [(11)C]GSK931145 was reduced to homogeneous levels. Although [(11)C]GSK565710 also showed good brain penetration and a heterogeneous distribution, the apparent level of specific binding was reduced compared to [(11)C]GSK931145. In contrast, [(11)C]GSK991022 showed a much lower brain penetration and resultant signal following pretreatment with GSK565710. Based on these findings [(11)C]GSK931145 was identified as the most promising ligand for imaging GlyT1 in the porcine brain, possessing good brain penetration, specific signal, and reversible kinetics. [(11)C]GSK931145 is now being progressed into higher species.
Asunto(s)
Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Proteínas de Transporte de Glicina en la Membrana Plasmática/metabolismo , Tomografía de Emisión de Positrones/métodos , Radiofármacos , Animales , Radioisótopos de Carbono , Relación Dosis-Respuesta a Droga , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Hidrocarburos Yodados/farmacología , Ligandos , Mesilatos/farmacología , Radiofármacos/administración & dosificación , Radiofármacos/farmacocinética , Porcinos , Factores de TiempoAsunto(s)
Ciclopropanos/uso terapéutico , Inmunoterapia/métodos , Fármacos Fotosensibilizantes/uso terapéutico , Verrugas/tratamiento farmacológico , Adolescente , Adulto , Femenino , Humanos , Huésped Inmunocomprometido , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
A catalytic enantioselective inverse-electron demand hetero-Diels-Alder reaction of alpha,beta-unsaturated carbonyl compounds with electron-rich alkenes catalyzed by chiral bisoxazolines in combination with Cu(OTf)2 as the Lewis acid is presented. The reaction of gamma-substituted beta,gamma-unsaturated alpha-keto esters with vinyl ethers and various types of cis-disubstituted alkenes proceeds in good yield, high diastereoselectivity, and excellent enantioselectivity. The potential of the reaction is demonstrated by the synthesis of optically active carbohydrates such as spiro-carbohydrates, an ethyl beta-D-mannoside tetraacetate, and acetal-protected C-2-branched carbohydrates. On the basis of X-ray crystallographic data and the absolute configuration of the products, it is proposed that the alkene approaches the si-face of the reacting alpha,beta-unsaturated carbonyl functionality when coordinated to the catalyst.