Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 39
Filtrar
Mais filtros











Base de dados
Intervalo de ano de publicação
1.
Sci Rep ; 12(1): 2488, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35169194

RESUMO

In vitro fertilization is typically associated with high failure rates per transfer, leading to an acute need for the identification of embryos with high developmental potential. Current methods are tailored to specific times after fertilization, often require expert inspection, and have low predictive power. Automatic methods are challenged by ambiguous labels, clinical heterogeneity, and the inability to utilize multiple developmental points. In this work, we propose a novel method that trains a classifier conditioned on the time since fertilization. This classifier is then integrated over time and its output is used to assign soft labels to pairs of samples. The classifier obtained by training on these soft labels presents a significant improvement in accuracy, even as early as 30 h post-fertilization. By integrating the classification scores, the predictive power is further improved. Our results are superior to previously reported methods, including the commercial KIDScore-D3 system, and a group of eight senior professionals, in classifying multiple groups of favorable embryos into groups defined as less favorable based on implantation outcomes, expert decisions based on developmental trajectories, and/or genetic tests.


Assuntos
Implantação do Embrião , Transferência Embrionária/métodos , Desenvolvimento Embrionário , Fertilização in vitro/métodos , Feminino , Humanos
2.
Proc Math Phys Eng Sci ; 476(2235): 20200066, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32269494

RESUMO

[This corrects the article DOI: 10.1098/rspa.2016.0425.].

3.
Pediatr Cardiol ; 39(4): 705-708, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29453682

RESUMO

Persistent pulmonary hypertension (PPHN) of the newborn is one of the most challenging acute disorders of postnatal transition with substantial morbidity and mortality. The aim of the study was to find if there is an association between persistent pulmonary hypertension and histologic chorioamnionitis in preterm infants. 27 preterm infants with echocardiographic evidence of PPHN within the first 3 days of life were eligible for the study. A matched control group of 27 patients was chosen according to gestational age, date of birth, and gender. Data collection included the need for respiratory support, use of nitric oxide oxygen supplementation, duration of rupture of membranes, blood culture, blood count, and C-reactive protein levels at birth and 12 h. Maternal clinical and laboratory data suggesting clinical chorioamnionitis Placentas of both groups were examined. Differences between groups were analyzed using two-tail t test, Kolmogorov-Smirnov test, Chi-square test. No statistically differences were found in all parameters compared between groups, except for a higher number of patients in the PPHN group who were treated by oxygen supplementation. An association was not found between the incidence of HCA and echocardiographic PPHN in preterm infants in the first 3 days of life.


Assuntos
Corioamnionite/epidemiologia , Hipertensão Pulmonar/etiologia , Displasia Broncopulmonar/complicações , Ecocardiografia/métodos , Feminino , Idade Gestacional , Humanos , Incidência , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Óxido Nítrico/uso terapêutico , Placenta/patologia , Gravidez , Respiração Artificial/estatística & dados numéricos , Estudos Retrospectivos
4.
Proc Math Phys Eng Sci ; 472(2192): 20160425, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27616929

RESUMO

This work studies the motion of Purcell's three-link microswimmer in viscous flow, by using perturbation expansion of its dynamics under small-amplitude strokes. Explicit leading-order expressions and next-order correction terms for the displacement of the swimmer are obtained for the cases of a square or circular gait in the plane of joint angles. The correction terms demonstrate the reversal in movement direction for large stroke amplitudes, which has previously only been shown numerically. In addition, asymptotic expressions for Lighthill's energetic efficiency are obtained for both gaits. These approximations enable calculating optimal stroke amplitudes and swimmer's geometry (i.e. ratio of links' lengths) for maximizing either net displacement or Lighthill's efficiency.

5.
Reproduction ; 149(1): 75-85, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25349438

RESUMO

A decade ago, we first reported that endometrial biopsy significantly improves the success of pregnancy in IVF patients with recurrent implantation failure, an observation that was later confirmed by others. Recently, we have demonstrated that this treatment elevated the levels of endometrial pro-inflammatory cytokines and increased the abundance of macrophages (Mac) and dendritic cells (DCs). We therefore hypothesised that the biopsy-related successful pregnancy is secondary to an inflammatory response, and aimed at deciphering its mechanism of action. Supporting our hypothesis, we found that the pro-inflammatory TNFα stimulated primary endometrial stromal cells to express cytokines that attracted monocytes and induced their differentiation into DCs. These monocyte-derived DCs stimulated endometrial epithelial cells to express the adhesive molecule SPP1 (osteopontin (OPN)) and its receptors ITGB3 and CD44, whereas MUC16, which interferes with adhesion, was downregulated. Other implantation-associated genes, such as CHST2, CCL4 (MIP1B) and GROA, were upregulated by monocyte-derived Mac. These findings suggest that uterine receptivity is mediated by the expression of molecules associated with inflammation. Such an inflammatory milieu is not generated in some IVF patients with recurrent implantation failure in the absence of local injury provoked by the biopsy treatment.


Assuntos
Implantação do Embrião , Perda do Embrião/imunologia , Embrião de Mamíferos/imunologia , Endométrio/imunologia , Endométrio/lesões , Mediadores da Inflamação/metabolismo , Inflamação/imunologia , Adulto , Biópsia , Western Blotting , Diferenciação Celular , Células Cultivadas , Citocinas/metabolismo , Células Dendríticas/citologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Perda do Embrião/patologia , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Endométrio/citologia , Feminino , Fertilização in vitro , Humanos , Infertilidade Feminina/imunologia , Infertilidade Feminina/prevenção & controle , Inflamação/metabolismo , Inflamação/patologia , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos/metabolismo , Gravidez , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Estromais , Adulto Jovem
6.
Eur Phys J E Soft Matter ; 35(8): 78, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22907616

RESUMO

One of the few possible mechanisms for self-propulsion at low Reynolds number is undulations of a passive elastic tail, as proposed in the classical work of Purcell (1977). This effect is studied here by investigating a variant of Purcell's three-link swimmer model where the front joint angle is periodically actuated while the rear joint is driven by a passive torsional spring. The dynamic equations of motion are formulated and explicit expressions for the leading-order solution are derived by using perturbation expansion. The dependence of the motion on the actuation amplitude and frequency is analyzed, and optimization with respect to the swimmer's geometry is conducted.


Assuntos
Elasticidade , Microbiologia , Modelos Biológicos , Movimento
7.
IEEE Trans Image Process ; 17(4): 443-57, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18390354

RESUMO

This paper suggests a discriminative approach for wavelet denoising where a set of mapping functions (MFs) are applied to the transform coefficients in an attempt to produce a noise free image. As opposed to the descriptive approaches, modeling image or noise priors is not required here and the MFs are learned directly from an ensemble of example images using least-squares fitting. The suggested scheme generates a novel set of MFs that are essentially different from the traditional soft/hard thresholding in the over-complete case. These MFs are demonstrated to obtain comparable performance to the state-of-the-art denoising approaches. Additionally, this framework enables a seamless customization of the shrinkage operation to a new set of restoration problems that were not addressed previously with shrinkage techniques, such as deblurring, JPEG artifact removal, and various types of additive noise that are not necessarily Gaussian white noise.


Assuntos
Algoritmos , Artefatos , Gráficos por Computador , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Processamento de Sinais Assistido por Computador , Análise Discriminante , Armazenamento e Recuperação da Informação/métodos , Análise Numérica Assistida por Computador , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
8.
Ann Hum Genet ; 67(Pt 2): 153-64, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12675690

RESUMO

The Samaritan community is a small, isolated, and highly endogamous group numbering some 650 members who have maintained extensive genealogical records for the past 13-15 generations. We performed mutation detection experiments on mitochondrial DNAs and Y chromosomes from confirmed maternal and paternal lineages to estimate mutation rates in these two haploid compartments of the genome. One hundred and twenty four DNA samples from different pedigrees (representing 200 generation links) were analyzed for the mtDNA hypervariable I and II regions, and 74 male samples (comprising 139 links) were typed for 12 Y-STRs mapping to the non-recombining portion of the Y chromosome (NRY). Excluding two somatic heteroplasmic substitutions and several length variants in the homopolymeric C run in the HVII region, no mutations were found in the Samaritans' maternal lineages. Based on mutations found in Samaritan paternal lineages, an estimate of a mutation rate of 0.42% (95% confidence interval of 0.22%-0.71%) across 12 Y-STRs was obtained. This estimate is slightly higher than those obtained in previous pedigree studies in other populations. The haplotypes identified in Samaritan paternal lineages that belong to the same haplogroup were used to estimate the number of generations elapsed since their most recent common ancestor (MRCA). The estimate of 80 generations corresponds with accepted traditions of the origin of this sect.


Assuntos
Mutação , Evolução Biológica , Cromossomos Humanos Y/genética , DNA Mitocondrial , Pai , Feminino , Haploidia , Haplótipos , Humanos , Masculino , Modelos Teóricos , Mães , Filogenia , Mutação Puntual , Reação em Cadeia da Polimerase , Polimorfismo Genético , Polimorfismo Conformacional de Fita Simples , Fatores de Tempo
9.
J Med Chem ; 44(24): 4137-56, 2001 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-11708916

RESUMO

A novel series of erythromycin derivatives has been discovered with potent activity against key respiratory pathogens, including those resistant to erythromycin. These compounds are characterized by having an aryl group tethered to the C-6 position of the erythronolide skeleton. Extensive structural modification of the C-6 moiety led to the discovery of several promising compounds with potent activity against both mef- and erm-mediated resistant Streptoccoccus pneumoniae. Preliminary mechanistic studies indicated that the new macrolides are potent protein synthesis inhibitors, which interact with methylated ribosomes isolated from resistant organisms. In experimental animal models, these compounds exhibited excellent in vivo efficacy and balanced pharmacokinetic profiles.


Assuntos
Antibacterianos/síntese química , Carbamatos/síntese química , Eritromicina/análogos & derivados , Eritromicina/síntese química , Cetolídeos , Inibidores da Síntese de Proteínas/síntese química , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Carbamatos/química , Carbamatos/farmacologia , Sistema Livre de Células , Resistência a Múltiplos Medicamentos , Eritromicina/química , Eritromicina/farmacologia , Haemophilus influenzae/efeitos dos fármacos , Pulmão/microbiologia , Camundongos , Modelos Moleculares , Biossíntese de Proteínas , Inibidores da Síntese de Proteínas/química , Inibidores da Síntese de Proteínas/farmacologia , Ratos , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/microbiologia , Infecções Respiratórias/mortalidade , Ribossomos/efeitos dos fármacos , Ribossomos/genética , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/ultraestrutura , Streptococcus pyogenes/efeitos dos fármacos , Relação Estrutura-Atividade , Transcrição Gênica
10.
Antimicrob Agents Chemother ; 45(9): 2585-93, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11502533

RESUMO

ABT-773 is a novel ketolide effective against antibacterial-resistant respiratory tract pathogens. The pharmacokinetic profile of ABT-773 was studied in rats and consisted of a mean peak concentration in plasma of 1.07 microg/ml and an area under the concentration-time curve (AUC) of 12.03 microg. h/ml when the compound was delivered at a dose of 25 mg/kg of body weight. It concentrated in rat lung tissue, with a lung tissue-to-plasma ratio of 29 based on the AUC. In acute systemic infections in mice, ABT-773 showed efficacy against macrolide-susceptible strains of Staphylococcus aureus, Streptococcus pneumoniae, S. pyogenes, and Listeria monocytogenes. Additionally, ABT-773 improved the survival of mice infected with resistant S. pneumoniae containing either the ermB gene, the mefE gene, or altered penicillin binding protein genes. In a rat lung model of infection, ABT-773 demonstrated 50% effective doses lower than those of comparator macrolides when evaluated against the following strains of S. pneumoniae: a macrolide-lincosamide-streptogramin B-susceptible strain, an ermB strain, and an mefE strain. ABT-773 was also effective against Haemophilus influenzae lung infections in rats. Thus, ABT-773 may prove to be a useful new antibacterial agent for the treatment of respiratory tract infections.


Assuntos
Infecções Bacterianas/tratamento farmacológico , Eritromicina/análogos & derivados , Eritromicina/uso terapêutico , Cetolídeos , Animais , Infecções Bacterianas/metabolismo , Modelos Animais de Doenças , Resistência Microbiana a Medicamentos , Eritromicina/farmacocinética , Feminino , Infecções por Haemophilus/tratamento farmacológico , Infecções por Haemophilus/metabolismo , Haemophilus influenzae/efeitos dos fármacos , Listeriose/tratamento farmacológico , Listeriose/metabolismo , Pneumopatias/tratamento farmacológico , Pneumopatias/metabolismo , Pneumopatias/microbiologia , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Doenças Respiratórias/tratamento farmacológico , Doenças Respiratórias/metabolismo , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/metabolismo , Infecções Estreptocócicas/tratamento farmacológico , Infecções Estreptocócicas/metabolismo , Streptococcus pneumoniae/efeitos dos fármacos , Resultado do Tratamento
11.
Antimicrob Agents Chemother ; 45(7): 2163-8, 2001 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-11408246

RESUMO

The in vitro activities of ABT-773, erythromycin, clarithromycin, and azithromycin were compared. ABT-773 was the most active compound against macrolide-susceptible Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, Staphylococcus epidermidis, Listeria monocytogenes, and Enterococcus spp. and multidrug-resistant Streptococcus pneumoniae. It also had good activity against gram-negative and atypical respiratory tract pathogens and Helicobacter pylori.


Assuntos
Antibacterianos/farmacologia , Eritromicina/análogos & derivados , Eritromicina/farmacologia , Cetolídeos , Azitromicina/farmacologia , Claritromicina/farmacologia , Resistência a Múltiplos Medicamentos , Enterococcus/efeitos dos fármacos , Helicobacter pylori/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Staphylococcus/efeitos dos fármacos , Streptococcus/efeitos dos fármacos , Fatores de Tempo
12.
IEEE Trans Image Process ; 10(8): 1187-93, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-18255535

RESUMO

This paper addresses the problem of recovering a super-resolved image from a set of warped blurred and decimated versions thereof. Several algorithms have already been proposed for the solution of this general problem. In this paper, we concentrate on a special case where the warps are pure translations, the blur is space invariant and the same for all the images, and the noise is white. We exploit previous results to develop a new highly efficient super-resolution reconstruction algorithm for this case, which separates the treatment into de-blurring and measurements fusion. The fusion part is shown to be a very simple non-iterative algorithm, preserving the optimality of the entire reconstruction process, in the maximum-likelihood sense. Simulations demonstrate the capabilities of the proposed algorithm.

13.
Org Lett ; 2(19): 2951-4, 2000 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-10986080

RESUMO

A novel class of 2-fluoro-6-O-propargyl-11,12-carbamate ketolide derivatives of erythromycin has been synthesized for antibacterial SAR studies. Replacement of the C2-hydrogen by a fluorine atom allows the synthesis of 6-O-propargylic ketones and electron-deficient 6-O-propargylic aromatic derivatives by preventing intramolecular C2-enolate Michael cyclization.


Assuntos
Antibacterianos/síntese química , Eritromicina/análogos & derivados , Antibacterianos/química , Cristalografia por Raios X
14.
Bioorg Med Chem Lett ; 10(8): 815-9, 2000 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-10782693

RESUMO

A series of novel 6-O-substituted erythromycin A derivatives has been synthesized. Good in vitro antibacterial activity has been demonstrated for analogues incorporating a variety of structural features. The methodology disclosed is expected to find application in the design of future macrolide antibiotics that target the prevalent bacterial resistance problem.


Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Eritromicina/análogos & derivados , Eritromicina/síntese química , Eritromicina/farmacologia , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade
16.
Gynecol Obstet Invest ; 49(2): 102-5, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-10671816

RESUMO

Traditional management of persistent ovarian cysts in pregnancy is explorative laparotomy at 16-20 weeks of gestation and resection of the tumor. Scheduling surgery to this time of pregnancy is accepted in order to prevent abortions that are common whenever surgery is done in the first trimester, without delaying treatment of ovarian tumors which harbor a malignant potential. In the following article we report of 10 cases where simple ovarian cysts diagnosed during pregnancy were successfully treated by sonographically guided cyst aspiration. This new approach is justified with no fear of missing a malignant ovarian tumor due to strict ultrasonic characteristics of benign cysts that include unilocular simple appearing cyst with no solid echogenic parts, septations or papillary structures. For 5 of the 10 women undergoing aspiration, this constituted the definitive treatment, while the remaining 5 were later operated. We conclude that aspiration of simple cysts during pregnancy is safe, may save surgical intervention and in some cases this will be the definitive treatment.


Assuntos
Cistos Ovarianos/cirurgia , Complicações na Gravidez/cirurgia , Resultado da Gravidez , Adulto , Cesárea , Feminino , Seguimentos , Humanos , Laparotomia/métodos , Cistos Ovarianos/diagnóstico por imagem , Gravidez , Complicações na Gravidez/diagnóstico por imagem , Sucção , Resultado do Tratamento , Ultrassonografia Pré-Natal
17.
Microb Drug Resist ; 5(3): 183-8, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10566867

RESUMO

One major mechanism for resistance to macrolide antibiotics in Streptococcus pneumoniae is MLS (macrolide, lincosamide, and streptogramin B) resistance, manifested when the 23S rRNA is methylated by the product of an erm gene. This modification results in the decreased binding of all known macrolide, lincosamide, and streptogramin B antibiotics to the ribosome. More than 30 ermAM-containing clinical isolates of S. pneumoniae were examined in our lab and showed high-level resistance (MIC > or =128 microg/ml) to erythromycin, azithromycin, tylosin, clindamycin, and ketolide (macrolides that lack the cladinose sugar) TE-802. We found that the new generation of ketolides A965 and A088 displayed variable activity against the same group of resistant S. pneumoniae strains. To understand the basis of variability of the minimal inhibitory concentration (MIC) values of A965 and A088, we examined the effects of a series of macrolides and ketolides on the level of 23S rRNA methylation in five ermAM-containing resistant S. pneumoniae isolates. We show here that the basal levels of ribosomal methylation vary from strain to strain. The level of rRNA methylation can be strongly induced by erythromycin, azithromycin, and TE-802, resulting in high-level of resistance to these compounds. Ketolide A965 and A088, however, are weak inducers at sub-MIC drug concentrations, therefore showing variable activities in strains with differential methylation levels.


Assuntos
Antibacterianos/farmacologia , Macrolídeos , RNA Ribossômico 16S/metabolismo , Streptococcus pneumoniae/efeitos dos fármacos , Virginiamicina/farmacologia , Resistência Microbiana a Medicamentos , Lincosamidas , Metilação , Streptococcus pneumoniae/genética
18.
J Med Chem ; 42(21): 4456-61, 1999 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-10543889

RESUMO

C24-Deoxyascomycin was prepared in a two-step process from ascomycin and evaluated for its immunosuppressant activity relative to ascomycin and FK506. An intermediate in the synthetic pathway, Delta(23,24)-dehydroascomycin, was likewise evaluated. Despite lacking the hydrogen-bonding interactions associated with the C24-hydroxyl moiety of ascomycin, C24-deoxyascomycin was found to be equipotent to the parent compound both in its immunosuppressive potency and in its interaction with the immunophilin, FKBP12. Conversely, Delta(23,24)-dehydroascomycin which also lacks the same hydrogen-bonding interactions did not exhibit this potency. NMR studies were conducted on the FKBP12/C24-deoxyascomycin complex in an attempt to understand this phenomenon at the molecular level. The NMR structures of the complexes formed between FKBP12 and ascomcyin or C24-deoxyascomcyin were very similar, suggesting that hydrogen-bonding interactions with the C24 hydroxyl moiety are not important for complex formation.


Assuntos
Imunofilinas/metabolismo , Imunossupressores/síntese química , Peptidilprolil Isomerase/metabolismo , Tacrolimo/análogos & derivados , Sequência de Aminoácidos , Animais , Humanos , Hiperplasia , Imunofilinas/química , Imunofilinas/genética , Imunossupressores/química , Imunossupressores/metabolismo , Imunossupressores/farmacologia , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Linfonodos/patologia , Teste de Cultura Mista de Linfócitos , Espectroscopia de Ressonância Magnética , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Nucleotidiltransferases/genética , Peptidilprolil Isomerase/química , Peptidilprolil Isomerase/genética , Ligação Proteica , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Proteínas Recombinantes de Fusão/metabolismo , Tacrolimo/síntese química , Tacrolimo/química , Tacrolimo/metabolismo , Tacrolimo/farmacologia , Proteínas de Ligação a Tacrolimo
19.
J Med Chem ; 42(20): 4202-13, 1999 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-10514290

RESUMO

The antibacterial 4H-4-oxoquinolizines were introduced recently to overcome bacterial resistance to fluoroquinolones. They exhibit potent antibacterial activity against Gram-positive, Gram-negative, and anaerobic organisms and are highly active against some quinolone-resistant bacteria including quinolone-resistant MRSA. Preliminary studies indicated that oxoquinolizines possess distinct activity and toxicity profiles as compared with their parent quinolones. In order to develop a potent antibacterial agent with the desired spectrum of activity, good tolerability, and balanced pharmacokinetic profile, we synthesized and evaluated a series of oxoquinolizines with various substituents at the C-8 position. Most compounds tested in this study demonstrated better activity against Gram-positive bacteria than ciprofloxacin and exhibited good susceptibility against ciprofloxacin- and methicillin-resistant S. aureus. While maintaining potent in vitro activity, several compounds showed improved in vivo efficacy over ABT-719 as indicated by the mouse protection test. As an example, the oral ED(50) values for the cis-3-amino-4-methylpiperidine analogue 3ss against S. aureus NCTC 10649M, S. pneumoniae ATCC 6303, and E. coli JUHL were 0. 8, 2.0, and 1.4 mg/kg, compared to 3.0, 10.0, and 8.3 mg/kg for ABT-719. The current study revealed that the steric and electronic environment, conformation, and absolute stereochemistry of the C-8 group are very important to the antibacterial profiles. Structural modifications of the C-8 group provide a useful means to improve the antibacterial activities, physicochemical properties, and pharmacokinetic profiles. Manipulation of the C-8 group also allows us to generate analogues with the desired spectrum of activity, such as analogues that are selective against respiratory pathogens.


Assuntos
Antibacterianos/síntese química , Quinolizinas/síntese química , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Camundongos , Quinolizinas/química , Quinolizinas/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade
20.
J Invest Dermatol ; 112(5): 729-38, 1999 May.
Artigo em Inglês | MEDLINE | ID: mdl-10233764

RESUMO

T lymphocytes play a critical part in inflammatory skin diseases but are targeted by available therapies that have only partial efficacy, significant side-effects, or both. Because psoriasis, atopic dermatitis, and allergic contact hypersensitivity are associated with T helper type 1 (Th1), T helper type 2 (Th2), or mixed Th1-Th2 cell subsets and cytokine types, respectively, there is a need for a better broad-based inhibitor. The macrolactam ascomycin analog, ABT-281, was found to inhibit potently T cell function across species and to inhibit expression of multiple cytokines in human peripheral blood leukocytes which have been found in human skin disease cells and tissues. These included immunoregulatory Th1 (interleukin-2 and interferon-gamma) and Th2 (interleukin-4 and interleukin-5) cytokines. ABT-281 was shown to have potent topical activity (ED50 = 0.6% in acetone/olive oil) in a stringent swine model of allergic contact hypersensitivity, but its potency was markedly reduced compared with ascomycin when administered systemically due to more rapid clearance. Topical application of 3% ABT-281 in acetone/olive oil over 25% of the body surface in swine resulted in undetectable blood levels. Compared with a wide potency range of topical corticosteroids in clinical formulations, 0.3% and 1% ABT-281 ointments profoundly inhibited dinitrochlorobenzene-induced contact hypersensitivity in the pig by 78% and 90%, respectively, whereas super-potent steroids such as clobetasol propionate only inhibited in the 50% range and mild to moderate potency steroids such as fluocinolone acetonide were inactive. The potent topical activity of ABT-281 in swine, its superior efficacy, its rapid systemic clearance following uptake into the bloodstream, and its ability to inhibit cytokine biosynthesis of both Th1 and Th2 cell subsets, suggests that it will have a broad therapeutic value in inflammatory skin diseases, including psoriasis, atopic dermatitis, and allergic contact dermatitis.


Assuntos
Citocinas/antagonistas & inibidores , Dermatite de Contato/tratamento farmacológico , Lactamas/farmacologia , Células Th1/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Administração Tópica , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Divisão Celular/efeitos dos fármacos , Citocinas/biossíntese , Dermatite de Contato/imunologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Vias de Administração de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Feminino , Cobaias , Humanos , Lactamas/metabolismo , Lactamas/uso terapêutico , Masculino , Camundongos , Ratos , Suínos , Tacrolimo/análogos & derivados , Tacrolimo/farmacologia , Tacrolimo/uso terapêutico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA