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1.
Cell ; 184(24): 5886-5901.e22, 2021 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-34822784

RESUMO

Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936-a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Desenho de Fármacos , Receptor Muscarínico M1/agonistas , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Sequência de Aminoácidos , Animais , Pressão Sanguínea/efeitos dos fármacos , Células CHO , Inibidores da Colinesterase/farmacologia , Cricetulus , Cristalização , Modelos Animais de Doenças , Cães , Donepezila/farmacologia , Eletroencefalografia , Feminino , Células HEK293 , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos C57BL , Modelos Moleculares , Simulação de Dinâmica Molecular , Degeneração Neural/complicações , Degeneração Neural/patologia , Primatas , Ratos , Receptor Muscarínico M1/química , Transdução de Sinais , Homologia Estrutural de Proteína
2.
J Antibiot (Tokyo) ; 69(12): 850-857, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27189121

RESUMO

NVB333 is a novel semisynthetic lantibiotic derived from the amide coupling of 3,5-dichlorobenzylamine to the C-terminal of deoxyactagardine B. The in vitro activity of NVB333 includes efficacy against clinically relevant pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp. NVB333 shows no cross-resistance with other antibiotics tested and a very low propensity for resistance development. After intravenous dosing NVB333 has high exposure in mouse plasma and shows generally improved in vivo activity compared with vancomycin in mouse infection models despite modest MIC values. In thigh infection models, promising efficacy was demonstrated against several strains of S. aureus including methicillin-resistant S. aureus (MRSA) and vancomycin-intermediate S. aureus (VISA) strains, and against Enterococcus faecalis UNT126-3. Area under the concentration curve (AUC)/MIC was shown to be the best predictor of efficacy against S. aureus UNT103-3 with an AUC/MIC of 138 (uncorrected for protein binding) achieving a static effect. NVB333 was also effective in a disseminated infection model where it conferred complete survival from the MRSA strain ATCC 33591. NVB333 showed rather modest lung penetration after intravenous dosing (AUC in lung 2-3% of plasma AUC), but because of very high plasma exposure, therapeutic levels of compound were achieved in the lung. Efficacy at least equal to vancomycin was demonstrated against an MRSA strain (UNT084-3) in a bronchoalveolar infection model. The impressive in vivo efficacy of NVB333 and strong resistance prognosis makes this compound an interesting candidate for development for treating systemic Gram-positive infections.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacocinética , Bacteriocinas/síntese química , Bacteriocinas/farmacocinética , Animais , Área Sob a Curva , Modelos Animais de Doenças , Farmacorresistência Bacteriana Múltipla , Farmacoeconomia , Enterococcus faecalis/efeitos dos fármacos , Feminino , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pneumopatias/tratamento farmacológico , Pneumopatias/microbiologia , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Enterococos Resistentes à Vancomicina/efeitos dos fármacos
3.
Heart Surg Forum ; 19(6): E262-E264, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28054892

RESUMO

A 55-year-old man with autoimmune deficiency syndrome presented with an infected left ventricular pseudoaneurysm and sepsis. The aneurysmectomy consisted of a Dor-style pericardial patch plus debridement of the abscess cavities. The infected pseudoaneurysm recurred, much larger, within five months due to persistent infected abscess cavities. The second repair was done without a Dor-style patch and with an omental flap. No recurrence has occurred one year after the second repair, but the patient has asymptomatic, partial gastric herniation inside the pericardium. This is the first description of a primary infected left ventricular pseudoaneurysm. The omental flap contributed to the successful treatment.


Assuntos
Falso Aneurisma/cirurgia , Aneurisma Infectado/cirurgia , Procedimentos Cirúrgicos Cardíacos/métodos , Aneurisma Cardíaco/cirurgia , Omento/transplante , Retalhos Cirúrgicos , Falso Aneurisma/diagnóstico , Aneurisma Infectado/diagnóstico , Ecocardiografia , Aneurisma Cardíaco/diagnóstico , Ventrículos do Coração , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X
4.
Nurs Econ ; 29(5): 265-72, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22372083

RESUMO

An implementation project was conducted to introduce a structure for telehealth nursing practice (TNP) which would address the specific needs of complex endocrinology patients in a hospital-based clinic. Outcomes of the pilot study include analysis of 727 advice calls, survey responses from a sample of 101 patients, and feedback from 9 providers. Results support current evidence that disease management needs of chronically ill patients include prescription refills, medication and symptom management, lab results, and patient education. 81.2% of patients rated satisfaction with telehealth nursing services as very high or high. A statistically significant relationship was found between timeliness of response and patient satisfaction. A focus on care coordination provided through telehealth nursing services may emerge as an important element in the care of chronically ill patient populations.


Assuntos
Linhas Diretas/organização & administração , Doenças Metabólicas/enfermagem , Telenfermagem/organização & administração , Feminino , Custos de Cuidados de Saúde , Implementação de Plano de Saúde , Linhas Diretas/economia , Linhas Diretas/estatística & dados numéricos , Humanos , Masculino , Satisfação do Paciente , Projetos Piloto , Avaliação de Programas e Projetos de Saúde , Telenfermagem/economia , Estados Unidos
5.
Eur J Neurosci ; 24(11): 3063-72, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17156367

RESUMO

Axonal injury is a hallmark of traumatic brain injury (TBI) and is associated with a poor clinical outcome. Following central nervous system injury, axons regenerate poorly, in part due to the presence of molecules associated with myelin that inhibit axonal outgrowth, including myelin-associated glycoprotein (MAG). The involvement of MAG in neurobehavioral deficits and tissue loss following experimental TBI remains unexplored and was evaluated in the current study using an MAG-specific monoclonal antibody (mAb). Anesthetized rats (n=102) were subjected to either lateral fluid percussion brain injury (n=59) or sham injury (n=43). In surviving animals, beginning at 1 h post-injury, 8.64 microg anti-MAG mAb (n=33 injured, n=21 sham) or control IgG (n=26 injured, n=22 sham) was infused intracerebroventricularly for 72 h. One group of these rats (n=14 sham, n=11 injured) was killed at 72 h post-injury for verification of drug diffusion and MAG immunohistochemistry. All other animals were evaluated up to 8 weeks post-injury using tests for neurologic motor, sensory and cognitive function. Hemispheric tissue loss was also evaluated at 8 weeks post-injury. At 72 h post-injury, increased immunoreactivity for MAG was seen in the ipsilateral cortex, thalamus and hippocampus of brain-injured animals, and anti-MAG mAb was detectable in the hippocampus, fimbria and ventricles. Brain-injured animals receiving anti-MAG mAb showed significantly improved recovery of sensorimotor function at 6 and 8 weeks (P<0.01) post-injury when compared with brain-injured IgG-treated animals. Additionally, at 8 weeks post-injury, the anti-MAG mAb-treated brain-injured animals demonstrated significantly improved cognitive function and reduced hemispheric tissue loss (P<0.05) when compared with their brain-injured controls. These results indicate that MAG may contribute to the pathophysiology of experimental TBI and treatment strategies that target MAG may be suitable for further evaluation.


Assuntos
Anticorpos Monoclonais/farmacologia , Lesões Encefálicas/tratamento farmacológico , Doenças Desmielinizantes/tratamento farmacológico , Glicoproteína Associada a Mielina/antagonistas & inibidores , Recuperação de Função Fisiológica/efeitos dos fármacos , Degeneração Walleriana/tratamento farmacológico , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Axônios/efeitos dos fármacos , Axônios/imunologia , Axônios/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Encéfalo/fisiopatologia , Lesões Encefálicas/imunologia , Lesões Encefálicas/fisiopatologia , Doenças Desmielinizantes/imunologia , Doenças Desmielinizantes/fisiopatologia , Modelos Animais de Doenças , Imuno-Histoquímica , Masculino , Glicoproteína Associada a Mielina/imunologia , Regeneração Nervosa/efeitos dos fármacos , Regeneração Nervosa/imunologia , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/imunologia , Resultado do Tratamento , Degeneração Walleriana/imunologia , Degeneração Walleriana/fisiopatologia
6.
Mol Cell Biol ; 26(4): 1549-57, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16449664

RESUMO

Sialoadhesin (Sn, also called Siglec-1 or CD169) is a transmembrane receptor and the prototypic member of the Siglec family of sialic acid binding immunoglobulin-like lectins. It is expressed on specialized subsets of resident macrophages in hematopoietic and lymphoid tissues and on inflammatory macrophages. In order to investigate its function, we generated Sn-deficient mice and confirmed that these mice are true nulls by fluorescence-activated cell sorter analysis and immunohistochemistry. Mice deficient in Sn were viable and fertile and showed no developmental abnormalities. Analysis of cell populations revealed no differences in bone marrow, peritoneal cavity, and thymus, but there was a small increase in CD8 T cells and a decrease in B220-positive cells in spleens and lymph nodes of Sn-deficient mice. Furthermore, in spleen there was a slight decrease in follicular B cells with an increase in numbers of marginal zone B cells. B- and T-cell maturation as well as responses to stimulation with thioglycolate were only slightly affected by Sn deficiency. Immunoglobulin titers in Sn-deficient mice were significantly decreased for immunoglobulin M (IgM) but similar for IgG subclasses. These results suggest a role for sialoadhesin in regulating cells of the immune system rather than in influencing steady-state hematopoiesis.


Assuntos
Subpopulações de Linfócitos B/imunologia , Imunoglobulina M/sangue , Glicoproteínas de Membrana/deficiência , Receptores Imunológicos/deficiência , Subpopulações de Linfócitos T/imunologia , Animais , Subpopulações de Linfócitos B/citologia , Sequência de Bases , Células da Medula Óssea/citologia , DNA/genética , Feminino , Expressão Gênica , Marcação de Genes , Hematopoese/imunologia , Masculino , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Cavidade Peritoneal/citologia , Gravidez , Receptores Imunológicos/genética , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico , Subpopulações de Linfócitos T/citologia , Tioglicolatos/toxicidade
7.
J Cereb Blood Flow Metab ; 25(1): 98-107, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15678116

RESUMO

The inhibitory activity of myelin-associated glycoprotein (MAG) on neurons is thought to contribute to the lack of regenerative capacity of the CNS after injury. The interaction of MAG and its neuronal receptors mediates bidirectional signaling between neurons and oligodendrocytes. The novel finding that an anti-MAG monoclonal antibody not only possesses the ability to neutralise the inhibitory effect of MAG on neurons but also directly protects oligodendrocytes from glutamate-mediated oxidative stress-induced cell death is reported here. Furthermore, administration of anti-MAG antibody (centrally and systemically) starting 1 hour after middle cerebral artery occlusion in the rat significantly reduced lesion volume at 7 days. This neuroprotection was associated with a robust improvement in motor function compared with animals receiving control IgG1. Together, these data highlight the potential for the use of anti-MAG antibodies as therapeutic agents for the treatment of stroke.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Encéfalo/fisiologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Glicoproteína Associada a Mielina , Fármacos Neuroprotetores/administração & dosagem , Regeneração/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Encéfalo/patologia , Morte Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ácido Glutâmico/metabolismo , Imunoglobulina G/administração & dosagem , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Masculino , Camundongos , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia , Glicoproteína Associada a Mielina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Regeneração/fisiologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
8.
Mol Cell Neurosci ; 22(3): 344-52, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12691736

RESUMO

The interaction between myelin-associated glycoprotein (MAG), expressed at the periaxonal membrane of myelin, and receptors on neurons initiates a bidirectional signalling system that results in inhibition of neurite outgrowth and maintenance of myelin integrity. We show that this involves a lipid-raft to lipid-raft interaction on opposing cell membranes. MAG is exclusively located in low buoyancy Lubrol WX-insoluble membrane fractions isolated from whole brain, primary oligodendrocytes, or MAG-expressing CHO cells. Localisation within these domains is dependent on cellular cholesterol and occurs following terminal glycosylation in the trans-Golgi network, characteristics of association with lipid rafts. Furthermore, a recombinant form of MAG interacts specifically with lipid-raft fractions from whole brain and cultured cerebellar granule cells, containing functional MAG receptors GT1b and Nogo-66 receptor and molecules required for transduction of signal from MAG into neurons. The localisation of both MAG and MAG receptors within lipid rafts on the surface of opposing cells may create discrete areas of high avidity multivalent interaction, known to be critical for signalling into both cell types. Localisation within lipid rafts may provide a molecular environment that facilitates the interaction between MAG and multiple receptors and also between MAG ligands and molecules involved in signal transduction.


Assuntos
Microdomínios da Membrana/metabolismo , Bainha de Mielina/metabolismo , Glicoproteína Associada a Mielina/metabolismo , Neurônios/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Células CHO , Cricetinae , Detergentes/farmacologia , Camundongos , Neurônios/citologia , Polietilenoglicóis/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Células-Tronco/citologia
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