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1.
BMC Ophthalmol ; 15: 129, 2015 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-26447043

RESUMO

We present a paediatric case of infectious mononucleosis in a 13-year old, manifesting with follicular conjunctivitis and a conjunctival mass in one eye with no evidence of leucocytosis on the blood count. The diagnosis was confirmed following surgical excision and biopsy. The case represented a diagnostic challenge due to its atypism and given the steady increase in the prevalence of EBV-related ocular diseases in the last years, this report can serve as an example to prompt earlier serological tests to identify the aetiology in similar cases. This is important because EBV can be treated with acyclovir early in the active viral phase.


Assuntos
Conjuntivite Viral/diagnóstico , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções Oculares Virais/diagnóstico , Adolescente , Anticorpos Antivirais/sangue , Conjuntivite Viral/cirurgia , Conjuntivite Viral/virologia , Infecções por Vírus Epstein-Barr/cirurgia , Infecções por Vírus Epstein-Barr/virologia , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Infecções Oculares Virais/cirurgia , Infecções Oculares Virais/virologia , Humanos , Imunoglobulina G/sangue , Mononucleose Infecciosa/diagnóstico , Mononucleose Infecciosa/cirurgia , Mononucleose Infecciosa/virologia , Masculino , Procedimentos Cirúrgicos Oftalmológicos
2.
J Clin Pathol ; 67(7): 614-9, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24782357

RESUMO

AIMS: To characterise patients with systemic reactions and anaphylaxis with an acute serum tryptase of ≥14 µg/L against recently published World Allergy Organisation (WAO) diagnostic criteria. To also perform a clinical audit to assess adherence to National Institute of Health and Care Excellence (NICE) guideline recommendations regarding serial tryptase measurements and specialist referral. METHODS: A systematic retrospective survey (2006-2010) was carried out (n=171; males=86; mean age±SD 48±20 years) and data were extracted from emergency department and specialist allergy clinic records. RESULTS: 34 patients (20%) had a grade 1 reaction, 61 (36%) grade 2, 46 (27%) grade 3 and 6 patients (4%) grade 4 (24 patients (13%) could not be graded due to lack of adequate clinical details) and 6% developed a biphasic response. Serial tryptase measurements were not available in 117 (69%) of the cohort. 97 (57%) patients were referred for specialist assessment, and 72 (74%) attended. 50% of cases were diagnosed with idiopathic systemic reactions/anaphylaxis and 28%, 14% and 8% triggered by drugs, foods and other allergies including disorders of mast cell overload, respectively. A weak positive correlation was detected between acute serum tryptase and severity. CONCLUSIONS: The correlation between acute serum tryptase and severity of anaphylaxis/systemic reactions is weak. A significant proportion of patients with raised acute serum tryptase had mild reactions which did not meet WAO criteria for anaphylaxis and this may reduce the specificity of the test. The commonest aetiology in this cohort was idiopathic followed by drug and food allergies. NICE guidelines relating to serial tryptase measurements and specialist referral were not followed, and there is an urgent need to raise the awareness among clinicians involved in the management of anaphylaxis.


Assuntos
Anafilaxia/diagnóstico , Ensaios Enzimáticos Clínicos/normas , Fidelidade a Diretrizes/normas , Guias de Prática Clínica como Assunto/normas , Encaminhamento e Consulta/normas , Triptases/sangue , Adulto , Idoso , Anafilaxia/sangue , Anafilaxia/etiologia , Biomarcadores/sangue , Feminino , Humanos , Masculino , Auditoria Médica , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Reino Unido , Regulação para Cima
3.
J Med Chem ; 57(1): 159-70, 2014 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-24359185

RESUMO

A series of novel, potent, and selective human ß2 adrenoceptor agonists incorporating a sulfone moiety on the terminal right-hand-side phenyl ring of (R)-salmeterol is presented. Sulfone 10b had salmeterol-like potency and selectivity profile, long duration of action on guinea pig trachea, and longer than salmeterol duration of action in vivo, suitable for once-daily dosing. It had lower than salmeterol oral absorption in rat, lower bioavailability in rat and dog, and a high turnover in human hepatocytes. It was metabolized in human hepatocytes by hydroxylation, oxidation, cleavage, and conjugation; most of the metabolites would be expected to have reduced or no ß2 activity. The 4-biphenylsulfonic acid was identified as a crystalline, non-hygroscopic salt of 10b, suitable for inhaled delivery. Furthermore, it was free of any genetic toxicity issues and was considered as a backup to vilanterol.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/síntese química , Sulfonas/síntese química , Agonistas de Receptores Adrenérgicos beta 2/metabolismo , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Cães , Esquema de Medicação , Descoberta de Drogas , Cobaias , Hepatócitos/metabolismo , Humanos , Ratos , Sulfonas/metabolismo , Sulfonas/farmacologia , Traqueia/efeitos dos fármacos
4.
Eur J Pharmacol ; 704(1-3): 49-57, 2013 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-23454522

RESUMO

Loss of function mutations in the two key proteins which constitute Calcium-Release Activated Calcium (CRAC) channels demonstrate the critical role of this ion channel in immune cell function. The aim of this study was to demonstrate that inhibition of immune cell activation could be achieved with highly selective inhibitors of CRAC channels in vitro using cell preparations from human, rat, mouse and guinea-pig. Two selective small molecule blockers of CRAC channels; GSK-5498A and GSK-7975A were tested to demonstrate their ability to inhibit mediator release from mast cells, and pro-inflammatory cytokine release from T-cells in a variety of species. Both GSK-5498A and GSK-7975A completely inhibited calcium influx through CRAC channels. This led to inhibition of the release of mast cell mediators and T-cell cytokines from multiple human and rat preparations. Mast cells from guinea-pig and mouse preparations were not inhibited by GSK-5498A or GSK-7975A; however cytokine release was fully blocked from T-cells in a mouse preparation. GSK-5498A and GSK-7975A confirm the critical role of CRAC channels in human mast cell and T-cell function, and that inhibition can be achieved in vitro. The rat displays a similar pharmacology to human, promoting this species for future in vivo research with this series of molecules. Together these observations provide a critical forward step in the identification of CRAC blockers suitable for clinical development in the treatment of inflammatory disorders.


Assuntos
Benzamidas/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/metabolismo , Mastócitos/efeitos dos fármacos , Pirazóis/farmacologia , Linfócitos T/efeitos dos fármacos , Animais , Linhagem Celular , Células Cultivadas , Citocinas/metabolismo , Feminino , Cobaias , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Mastócitos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina , Ratos , Baço/citologia , Linfócitos T/metabolismo , Traqueia/efeitos dos fármacos , Traqueia/fisiologia
5.
J Pharmacol Exp Ther ; 345(2): 260-70, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23435542

RESUMO

Activation of muscarinic subtype 3 (M3) muscarinic cholinergic receptors (mAChRs) increases airway tone, whereas its blockade improves lung function and quality of life in patients with pulmonary diseases. The present study evaluated the pharmacological properties of a novel mAChR antagonist, GSK573719 (4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane; umeclidinium). The affinity (Ki) of GSK573719 for the cloned human M1-M5 mAChRs ranged from 0.05 to 0.16 nM. Dissociation of [(3)H]GSK573719 from the M3 mAChR was slower than that for the M2 mAChR [half-life (t1/2) values: 82 and 9 minutes, respectively]. In Chinese hamster ovary cells transfected with recombinant human M3 mAChRs, GSK573719 demonstrated picomolar potency (-log pA2 = 23.9 pM) in an acetylcholine (Ach)-mediated Ca(2+) mobilization assay. Concentration-response curves indicate competitive antagonism with partial reversibility after drug washout. Using isolated human bronchial strips, GSK573719 was also potent and showed competitive antagonism (-log pA2 = 316 pM) versus carbachol, and was slowly reversible in a concentration-dependent manner (1-100 nM). The time to 50% restoration of contraction at 10 nM was about 381 minutes (versus 413 minutes for tiotropium bromide). In mice, the ED50 value was 0.02 µg/mouse intranasally. In conscious guinea pigs, intratracheal administration of GSK573719 dose dependently blocked Ach-induced bronchoconstriction with long duration of action, and was comparable to tiotropium; 2.5 µg elicited 50% bronchoprotection for >24 hours. Thus, GSK573719 is a potent anticholinergic agent that demonstrates slow functional reversibility at the human M3 mAChR and long duration of action in animal models. This pharmacological profile translated into a 24-hour duration of bronchodilation in vivo, which suggested umeclidinium will be a once-daily inhaled treatment of pulmonary diseases.


Assuntos
Pneumopatias/tratamento farmacológico , Antagonistas Muscarínicos/uso terapêutico , Quinuclidinas/uso terapêutico , Administração por Inalação , Animais , Células CHO , Cálcio/metabolismo , Carbacol/farmacologia , Antagonistas Colinérgicos/farmacologia , Cricetinae , Cricetulus , Cobaias , Cinética , Pulmão/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Agonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/administração & dosagem , Pletismografia , Quinuclidinas/administração & dosagem , Receptor Muscarínico M3/efeitos dos fármacos , Receptores Muscarínicos , Derivados da Escopolamina/farmacologia , Brometo de Tiotrópio
6.
J Pharmacol Exp Ther ; 344(1): 218-30, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23131596

RESUMO

Vilanterol trifenatate (vilanterol) is a novel, long-acting ß(2)-adrenoceptor (ß(2)-AR) agonist with 24 h activity. In this study, we describe the preclinical pharmacological profile of vilanterol using radioligand binding and cAMP studies in recombinant assays as well as human and guinea pig tissue systems to characterize ß(2)-AR binding and functional properties. Vilanterol displayed a subnanomolar affinity for the ß(2)-AR that was comparable with that of salmeterol but higher than olodaterol, formoterol, and indacaterol. In cAMP functional activity studies, vilanterol demonstrated similar selectivity as salmeterol for ß(2)- over ß(1)-AR and ß(3)-AR, but a significantly improved selectivity profile than formoterol and indacaterol. Vilanterol also showed a level of intrinsic efficacy that was comparable to indacaterol but significantly greater than that of salmeterol. In cellular cAMP production and tissue-based studies measuring persistence and reassertion, vilanterol had a persistence of action comparable with indacaterol and longer than formoterol. In addition, vilanterol demonstrated reassertion activity in both cell and tissue systems that was comparable with salmeterol and indacaterol but longer than formoterol. In human airways, vilanterol was shown to have a faster onset and longer duration of action than salmeterol, exhibiting a significant level of bronchodilation 22 h after treatment. From these investigations, the data for vilanterol are consistent, showing that it is a novel, potent, and selective ß(2)-AR receptor agonist with a long duration of action. This pharmacological profile combined with clinical data is consistent with once a day dosing of vilanterol in the treatment of both asthma and chronic obstructive pulmonary disease (COPD).


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Álcoois Benzílicos/farmacologia , Clorobenzenos/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/metabolismo , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Antagonistas de Receptores Adrenérgicos beta 3/farmacologia , Albuterol/análogos & derivados , Albuterol/farmacologia , Animais , Ligação Competitiva/efeitos dos fármacos , Células CHO , Membrana Celular/metabolismo , Células Cultivadas , Cricetinae , Cricetulus , AMP Cíclico/biossíntese , AMP Cíclico/metabolismo , Interpretação Estatística de Dados , Polarização de Fluorescência , Cobaias , Humanos , Cinética , Propanolaminas/metabolismo , Propanolaminas/farmacocinética , Propanolaminas/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Ensaio Radioligante , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Receptores Adrenérgicos beta 2/metabolismo , Xinafoato de Salmeterol
7.
J Neuroophthalmol ; 32(4): 329-31, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23196945

RESUMO

Neurofibromatosis 2 (NF2) is a rare autosomal dominant disorder associated with the development of multiple central and peripheral nervous system tumors. Patients with NF2 are often diagnosed in adulthood, with symptoms of an isolated tumor or hearing loss associated with vestibular schwannomas. Diagnosing NF2 in children is complicated by the fact that the diagnostic criteria often are not met at presentation and there is usually no family history of the disease. The authors describe the diagnostic challenge posed by a pediatric patient who developed a relapsing and remitting third nerve paresis and was later diagnosed with NF2. A mechanism for the recurrent cranial mononeuropathy is proposed.


Assuntos
Neurofibromatose 2/fisiopatologia , Doenças do Nervo Oculomotor/diagnóstico , Audiologia , Criança , Feminino , Lateralidade Funcional , Perda Auditiva/etiologia , Humanos , Imagem por Ressonância Magnética , Tomografia Computadorizada por Raios X
8.
Bioorg Med Chem ; 19(20): 6026-32, 2011 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-21925889

RESUMO

A series of novel, potent and selective human ß(2) adrenoceptor agonists incorporating a urea moiety on the terminal right-hand side phenyl ring of (R)-salmeterol is presented. Urea 9j had long duration of action in vitro on guinea pig trachea, and also in vivo similar to that of salmeterol. It had lower oral absorption and bioavailability than salmeterol in both rat and dog. It had a turnover ratio similar to salmeterol, with no evidence for formation of any aniline metabolites in human liver microsomes and hepatocytes. However no crystalline salts suitable for inhaled delivery were identified.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/síntese química , Astenia/tratamento farmacológico , Broncodilatadores/farmacologia , Ureia/análogos & derivados , Ureia/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/química , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Albuterol/análogos & derivados , Albuterol/química , Albuterol/farmacocinética , Albuterol/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Cães , Relação Dose-Resposta a Droga , Feminino , Cobaias , Humanos , Masculino , Ratos , Xinafoato de Salmeterol , Estereoisomerismo
9.
Bioorg Med Chem ; 19(14): 4192-201, 2011 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-21696967

RESUMO

A series of novel, potent and selective human ß(2) adrenoceptor agonists incorporating a hydantoin or a uracil ring on the right-hand side phenyl ring of (R)-salmeterol is presented. Hydantoin 12a had long duration of action in vitro on guinea pig trachea, and 12h in guinea pigs in vivo at its EC(90) 25 µM. It had lower oral absorption than salmeterol in rats, and lower bioavailability than salmeterol in vivo in both rats and dogs (2% and 5%, respectively). An improved method for measuring the absorbed fraction of analogues dosed to rats, which considers the glucuronidated fraction is presented. Compound 12a was metabolised in human liver microsomes and hepatocytes to the active hydantoic acid 12m.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/síntese química , Descoberta de Drogas , Hidantoínas/química , Uracila/química , Agonistas de Receptores Adrenérgicos beta 2/metabolismo , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Cães , Relação Dose-Resposta a Droga , Feminino , Cobaias , Hepatócitos/química , Hepatócitos/metabolismo , Humanos , Masculino , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ratos , Ratos Wistar , Receptores Adrenérgicos beta 2/metabolismo , Estereoisomerismo , Traqueia/efeitos dos fármacos
10.
J Med Chem ; 53(11): 4522-30, 2010 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-20462258

RESUMO

A series of saligenin beta(2) adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compounds were screened for beta(2), beta(1), and beta(3) agonist activity in CHO cells. The onset and duration of action in vitro of selected compounds were assessed on isolated superfused guinea pig trachea. Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo, low oral bioavailability in the rat, and to be rapidly metabolized. Crystalline salts of 13f (vilanterol) were identified that had suitable properties for inhaled administration. A proposed binding mode for 13f to the beta(2)-receptor is presented.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2 , Agonistas Adrenérgicos beta/química , Agonistas Adrenérgicos beta/farmacologia , Agonistas Adrenérgicos beta/síntese química , Agonistas Adrenérgicos beta/metabolismo , Animais , Álcool Benzílico/química , Álcoois Benzílicos/síntese química , Álcoois Benzílicos/química , Álcoois Benzílicos/metabolismo , Álcoois Benzílicos/farmacologia , Células CHO , Clorobenzenos/síntese química , Clorobenzenos/química , Clorobenzenos/metabolismo , Clorobenzenos/farmacologia , Cricetinae , Cricetulus , Humanos , Modelos Moleculares , Conformação Proteica , Ratos , Receptores Adrenérgicos beta 2/química , Relação Estrutura-Atividade
11.
J Med Chem ; 52(8): 2280-8, 2009 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-19317397

RESUMO

A series of saligenin alkoxyalkylphenylsulfonamide beta(2) adrenoceptor agonists were prepared by reacting a protected saligenin oxazolidinone with alkynyloxyalkyl bromides, followed by Sonogashira reaction, hydrogenation, and deprotection. The meta-substituted primary sulfonamide was more potent than the para- and the ortho-analogues. Primary sulfonamides were more potent than the secondary and tertiary analogues. The onset and duration of action in vitro of selected compounds was assessed on isolated superfused guinea pig trachea. Sulfonamide 29b had the best profile of potency, selectivity, onset, and duration of action on both guinea pig trachea and human bronchus. Furthermore, 29b was found to have low oral bioavailability in rat and dog and also to have long duration of action in an in vivo model of bronchodilation. Crystalline salts of 29b were identified that had suitable properties for inhaled administration. A proposed binding mode for 29b to the beta(2)-receptor is presented.


Assuntos
2-Hidroxifenetilamina/análogos & derivados , Agonistas de Receptores Adrenérgicos beta 2 , Sulfonamidas/síntese química , 2-Hidroxifenetilamina/síntese química , 2-Hidroxifenetilamina/química , 2-Hidroxifenetilamina/farmacologia , Administração Oral , Albuterol/análogos & derivados , Albuterol/química , Albuterol/farmacologia , Animais , Disponibilidade Biológica , Brônquios/efeitos dos fármacos , Brônquios/fisiologia , Células CHO , Cricetinae , Cricetulus , AMP Cíclico/biossíntese , Cães , Cobaias , Humanos , Técnicas In Vitro , Microssomos/metabolismo , Modelos Moleculares , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Ratos , Xinafoato de Salmeterol , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Traqueia/efeitos dos fármacos , Traqueia/fisiologia
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