RESUMO
BACKGROUND: It is well-known that a neurologically favorable outcome of out-of-hospital cardiac arrest (OHCA) is associated with the presence of bystander-initiated cardiopulmonary resuscitation (bystander CPR) and use of an automated external defibrillator. However, little is known about the effect of the presence of pre-existing conditions, prior activity, and locations on the outcome of pediatric OHCA. METHODS: We analyzed the data from questionnaires about pediatric patients with OHCA aged from 3 days to 19 years in the Kyushu area in Japan between 2012 and 2016. RESULTS: A total of 594 OHCA cases were collected. The numbers of OHCA cases and the rate of 1 month survival with a favorable neurological outcome during sleeping, swimming / bathing, and exercise were 192 (1.0%), 83 (32.5%), and 44 (65.9%), respectively. When an OHCA occurred at school (n = 56), 88% of children / adolescents received bystander CPR, but when it occurred at home (n = 390), 15% received bystander CPR. Cardiovascular (n = 61), suicide (n = 61), and neurological / neuromuscular (n = 44) diseases were three major pre-existing conditions. The OHCA of cardiovascular disease was associated with exercise (24/61) and mainly occurred at school (22/61). The OHCA of neurological / neuromuscular disease was associated with swimming/bathing (15/44) and mainly occurred during bathing at home (12/44). Multivariate regression analysis showed that the presence of bystander CPR (P < 0.001) and occurrence of OHCA at school (P < 0.001) were independently predictive of a favorable outcome in pediatric OHCA. CONCLUSION: The outcome was different among pre-existing conditions, prior activity, and location of OHCA. These findings might be useful for preventing OHCA and improving the outcome of pediatric OHCA.
Assuntos
Reanimação Cardiopulmonar , Serviços Médicos de Emergência , Parada Cardíaca Extra-Hospitalar , Adolescente , Criança , Desfibriladores , Exercício Físico , Humanos , Japão/epidemiologia , Parada Cardíaca Extra-Hospitalar/epidemiologia , Parada Cardíaca Extra-Hospitalar/terapia , Sistema de RegistrosRESUMO
SM-295291 and SM-369926 are new parenteral 2-aryl carbapenems with strong activity against major causative pathogens of community-acquired infections such as methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (including penicillin-resistant strains), Streptococcus pyogenes, Enterococcus faecalis, Klebsiella pneumoniae, Moraxella catarrhalis, Haemophilus influenzae (including ß-lactamase-negative ampicillin-resistant strains), and Neisseria gonorrhoeae (including ciprofloxacin-resistant strains), with MIC(90)s of ≤ 1 µg/ml. Unlike tebipenem (MIC(50), 8 µg/ml), SM-295291 and SM-369926 had no activity against hospital pathogens such as Pseudomonas aeruginosa (MIC(50), ≥ 128 µg/ml). The bactericidal activities of SM-295291 and SM-369926 against penicillin-resistant S. pneumoniae and ß-lactamase-negative ampicillin-resistant H. influenzae were equal or superior to that of tebipenem and greater than that of cefditoren. The therapeutic efficacies of intravenous administrations of SM-295291 and SM-369926 against experimentally induced infections in mice caused by penicillin-resistant S. pneumoniae and ß-lactamase-negative ampicillin-resistant H. influenzae were equal or superior to that of tebipenem and greater than that of cefditoren, respectively, reflecting their in vitro activities. SM-295291 and SM-369926 showed intravenous pharmacokinetics similar to those of meropenem in terms of half-life in monkeys (0.4 h) and were stable against human dehydropeptidase I. SM-368589 and SM-375769, which are medoxomil esters of SM-295291 and SM-369926, respectively, showed good oral bioavailability in rats, dogs, and monkeys (4.2 to 62.3%). Thus, 2-aryl carbapenems are promising candidates that show an ideal broad spectrum for the treatment of community-acquired infections, including infections caused by penicillin-resistant S. pneumoniae and ß-lactamase-negative ampicillin-resistant H. influenzae, have low selective pressure on antipseudomonal carbapenem-resistant nosocomial pathogens, and allow parenteral, oral, and switch therapies.
Assuntos
Antibacterianos , Carbapenêmicos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Animais , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Disponibilidade Biológica , Carbapenêmicos/farmacocinética , Carbapenêmicos/farmacologia , Carbapenêmicos/uso terapêutico , Infecções Comunitárias Adquiridas/tratamento farmacológico , Dipeptidases , Cães , Estabilidade de Medicamentos , Proteínas Ligadas por GPI , Bactérias Gram-Negativas/patogenicidade , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Bactérias Gram-Positivas/patogenicidade , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Coelhos , Ratos , Ratos Sprague-DawleyRESUMO
A unique hydrolysis method using a two-layer solution, consisting of diluted hydrochloric acid and toluene was developed to isolate whole arabinose mycolates from the cell wall skeleton of Mycobacterium bovis BCG Tokyo 172 (SMP-105) in order to reveal its pivotal role in enhancing immune responses against tumors.
Assuntos
Arabinose/análogos & derivados , Esqueleto da Parede Celular/química , Mycobacterium bovis/química , Ácidos Micólicos , Adjuvantes Imunológicos/química , Arabinose/química , Ácido Clorídrico/química , Hidrólise , Estrutura Molecular , Ácidos Micólicos/química , Ácidos Micólicos/isolamento & purificação , Tóquio , Tolueno/químicaRESUMO
Familial hypercholesterolemia (FH) is characterized by a high level of LDL-cholesterol (LDL-C) and a high prevalence of atherosclerotic coronary heart disease; however, hypercholesterolemia is usually the only clinical finding in children with heterozygous FH in their first decade of life. We report a case of FH in an 11-year-old boy who presented with multiple xanthomas at both elbows, thickened Achilles tendons, and hyperplasia of the intima-media complex of the carotid artery. Echocardiogram revealed partial calcification of the aortic and mitral valves, but no stenosis of the coronary arteries was detected on 3D-computed tomography. The activity of LDL receptors was reduced to 32% by lymphocyte assay. The family history showed vertical transmission of hypercholesterolemia from father to son, thereby suggesting dominant inheritance. After 12 months of treatment with statin and resin, his LDL-C decreased from 446 to 220 mg/dL, thickening of the Achilles tendons decreased from 1618 mm to 13 mm, and hyperplasia of the intima-media complex decreased from 1.3 mm to 0.7 mm. These findings suggest that our patient had heterozygous FH. However, based on his advanced atherosclerosis, we cannot exclude the possibility that our patient may be accompanying dyslipidemia due to causes in addition to heterozygous FH.
Assuntos
Aterosclerose/complicações , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Xantomatose/complicações , Criança , Humanos , Hiperlipoproteinemia Tipo II/complicações , MasculinoRESUMO
Mycobacterial cell wall consists of rigid cell wall skeleton (CWS), a mycoloyl arabinogalactan peptidiglycan complex, in which mycoloyl structure varies by the mycobacterial species diversely, whereas the arabinogalactan peptidoglycan structure is consistent comparatively. The CWS of Mycobacterium bovis BCG has long been expected as a potent adjuvant for immunotherapy of malignant tumor. Although the chemical structure of CWS has been established in the last few decades, the physicochemical properties of CWS having highly amphipathic micelle structure with very long mycoloyl and carbohydrate chains are not unveiled. In this study, the ultrastructure of CWS of M. bovis BCG Tokyo 172 (SMP-105), suspended in several solvents with different polarity, was investigated with a particle size analyzer, a transmission electron microscope (TEM) and other techniques. As a result, the particle size was about 4.7 to 67.8 microm in physiological saline, but it became smaller and more compact when suspended in hydrophobic solvents. TEM images showed two different morphological forms distinctively: double folded sheet structure in hydrophilic conditions and multilayered rolled sheet structure in hydrophobic conditions. These studies have revealed characteristic surface features of SMP-105, the hydrophobic moiety occupying dominant space and the hydrophilic moiety smaller space, respectively, which may lead to the acceleration of immunological studies on this product.
Assuntos
Esqueleto da Parede Celular , Mycobacterium bovis/química , Mycobacterium bovis/ultraestrutura , Esqueleto da Parede Celular/química , Esqueleto da Parede Celular/ultraestrutura , Interações Hidrofóbicas e Hidrofílicas , Imuno-Histoquímica , Microscopia Eletrônica , Tamanho da Partícula , Conformação Proteica , Solventes/químicaRESUMO
Since mycolic acids, the most characteristic major lipid component in mycobacterial cell envelopes, play pivotal roles in the cell surface-based host immune responses, normal-phase HPLC has been developed to quantify and identify mycolic acids of the cell wall skeleton from Mycobacterium bovis BCG Tokyo 172 (SMP-105).
Assuntos
Esqueleto da Parede Celular/química , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Espectrometria de Massas/métodos , Mycobacterium bovis/química , Ácidos Micólicos/químicaRESUMO
The mycobacterial cell envelope consists of a characteristic cell wall skeleton (CWS), a mycoloyl arabinogalactan peptidoglycan complex, and related hydrophobic components that contribute to the cell surface properties. Since mycolic acids have recently been reported to play crucial roles in host immune response, detailed molecular characterization of mycolic acid subclasses and sub-subclasses of CWS from Mycobacterium bovis BCG Tokyo 172 (SMP-105) was performed. Mycolic acids were liberated by alkali hydrolysis from SMP-105, and their methyl esters were separated by silica gel TLC into three subclasses: alpha-, methoxy-, and keto-mycolates. Each mycolate subclass was further separated by silver nitrate (AgNO(3))-coated silica gel TLC into sub-subclasses. Molecular weights of individual mycolic acid were determined by MALDI-TOF mass spectrometry. alpha-Mycolates were sub-grouped into cis, cis-dicyclopropanoic (alpha1), and cis-monocyclopropanoic-cis-monoenoic (alpha2) series; methoxy-mycolates were sub-grouped into cis-monocyclopropanoic (m1), trans-monocyclopropanoic (m2), trans-monoenoic (m3), cis-monocyclopropanoic-trans-monoenoic (m4), cis-monoenoic (m5), and cis-monocyclopropanoic-cis-monoenoic (m6) series; and keto-mycolates were sub-grouped into cis-monocyclopropanoic (k1), trans-monocyclopropanoic (k2), trans-monoenoic (k3), cis-monoenoic (k4), and cis-monocyclopropanoic-cis-monoenoic (k5) series. The position of each functional group, including cyclopropane rings and methoxy and keto groups, was determined by analysis of the meromycolates with fast atom bombardment (FAB) mass spectrometry and FAB mass-mass spectrometry, and the cis/trans ratio of cyclopropane rings and double bonds were determined by NMR analysis of methyl mycolates. Mycolic acid subclass and molecular species composition of SMP-105 showed characteristic features including newly-identified cis-monocyclopropanoic-trans-monoenoic mycolic acid (m4).
Assuntos
Esqueleto da Parede Celular/química , Mycobacterium bovis/química , Ácidos Micólicos/química , Esqueleto da Parede Celular/isolamento & purificação , Cromatografia em Camada Fina , Hidrogênio/metabolismo , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Ácidos Micólicos/isolamento & purificação , Sílica Gel , Dióxido de Silício/análise , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
Mycobacterial cell walls have diverse adjuvant activities, and in particular, cell wall skeleton (CWS) of Mycobacterium bovis BCG has been expected as a drug for tumor immunotherapy. However, its molecular structure-biological activity relationship has not been fully elucidated despite more than 30 years of intensive research. Since it is important to secure purified CWS for such investigation, we established a preparation method of CWS from M. bovis BCG Tokyo 172 (SMP-105) and developed accurate, precise, and reliable analytical methods, based on previous reports. Furthermore, we confirmed that SMP-105 is composed of mycolic acids; arabinogalactan consisting of arabinose, galactose, and rhamnose; and peptidoglycan consisting of alanine, glutamic acid, diaminopimeric acid, muramic acid, glucosamine, and galactosamine. We also determined the levels of potential impurities that might be contaminated in the original bacterium or arise during the manufacturing process, such as glucose, mannose, non-constituted amino acids, as well as nucleic acid, trehaolse di-mycolate, and bacterial endotoxins. These results demonstrated that the prepared SMP-105 was of sufficient quality for research into the chemistry, bioactivity, and structure-activity relationship of CWS.
Assuntos
Parede Celular/química , Mycobacterium bovis/química , Cromatografia Líquida de Alta Pressão , Corantes Fluorescentes , Ácidos Micólicos/análise , Fósforo/análiseRESUMO
To establish the structure biological activity relationship of cord factor (trehalose 6,6'-dimycolate, TDM), we compared the molecular or supra-molecular structure of TDM micelles with toxicity, thymic atrophy and granulomatogenicity in lungs and spleen of BALB/c mice. According to the difference in the mycolyl subclass composition, TDM was divided into two groups, one possessing alpha-, methoxy- and keto-mycolates in M. tuberculosis H37Rv, M. bovis BCG and M. kansasii (group A) and the other having alpha-, keto- and wax ester-mycolates in M. avium serotype 4, M. phlei and M. flavescens (group B), although mycolic acid molecular species composition differed in each group considerably. Supra-molecular structure of TDM micelle differed species to species substantially and the micelle size of TDM from M. bovis BCG Connaught was the largest. The highest toxicity was shown with TDM from M. tuberculosis H37Rv which possessed the highest amount of alpha- (47.3%) and methoxy-mycolates (40.8%), while TDM from M. phlei having the low amount of alpha-mycolate (11.6%) showed almost no toxicity with the given doses. The thymic atrophy was observed with TDM from group A, but not with TDM from group B. On the other hand, TDM from group B showed massive lung granulomatogenic activity based on the histological observations and organ indices. Taken together, group A TDM showed a wide variety of micelle sizes and specific surface areas, high to low toxicity and marked to moderate granulomatogenicity, while group B TDM showed smaller sizes of micelles and larger specific surface areas, lower toxicity but higher granulomatogenicity in lungs. Existence of higher amount of longer chain alpha-mycolates in TDM appeared to be essential for high toxicity and thymic apoptotic activity, whereas TDM possessing wax ester-mycolate with smaller sized micelles seemed to be less toxic, but more granulomatogenic in lungs in mice. Thus, the mycolic acid subclass and molecular species composition of TDM affect critically the micelle forms, toxicity and granulomatogenicity in mice, while the relative abundances and carbon chain length of alpha-mycolate affected the toxicity in mice.
Assuntos
Fatores Corda/química , Fatores Corda/toxicidade , Mycobacterium/química , Animais , Apoptose , Atrofia , Peso Corporal/efeitos dos fármacos , Fatores Corda/classificação , Fatores Corda/imunologia , Feminino , Granuloma/induzido quimicamente , Histocitoquímica , Pulmão/patologia , Linfócitos/citologia , Camundongos , Camundongos Endogâmicos BALB C , Micelas , Modelos Animais , Estrutura Molecular , Organismos Livres de Patógenos Específicos , Baço/patologia , Relação Estrutura-Atividade , Timo/patologiaRESUMO
The mode of action of a series of 2-(4-dihydropyrrolylthiazol-2-ylthio) and 2-(4-tetrahydropyridinylthiazol-2-ylthio)-1beta-methylcarbapenem analogues against Pseudomonas aeruginosa was investigated with regard to contributions of the affinity for penicillin binding proteins (PBPs), the outer membrane permeability, and the effect of the MexAB-OprM efflux system. In this series of carbapenems, the introduction of a substituent in C-2 side chain with a change in physicochemical properties affected the antipseudomonal activity depending on the molecular weight. However, these structural modifications did not affect the affinity for pseudomonal PBPs significantly. It was confirmed that the affinity for PBPs was not an important determinant of the antipseudomonal activity of this series of carbapenems. OprD porin-deficiency did not affect antipseudomonal activity either. On the other hand, the MIC of these carbapenems against P. aeruginosa significantly decreased in the presence of outer membrane permeabilizer. This result strongly suggests that the cause of the relatively low antipseudomonal activity of these carbapanems is their low permeability through the outer membrane of P. aeruginosa. And also, in the presence of outer membrane permeabilizer, the MICs against MexAB-OprM deficient mutants remarkably decreased and were very close to the value of the IC(50) for pseudomonal PBPs. From this result, it was clear that the effect of the MexAB-OprM efflux system was also an important determinant of antipseudomonal activity of these carbapenems. In conclusion, the major determinants of the antipseudomonal activity of the 2-(thiazol-2-ylthio)-1beta-methylcarbapenems are the outer membrane permeability and the effect of the MexAB-OprM efflux system, not the affinity for pseudomonal PBPs.
Assuntos
Antibacterianos/farmacologia , Proteínas da Membrana Bacteriana Externa/antagonistas & inibidores , Carbapenêmicos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/metabolismo , Tiazóis/farmacologia , Proteínas da Membrana Bacteriana Externa/genética , Proteínas da Membrana Bacteriana Externa/metabolismo , Fenômenos Químicos , Físico-Química , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Membranas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Proteínas de Ligação às Penicilinas/metabolismo , Permeabilidade/efeitos dos fármacos , Pseudomonas aeruginosa/genética , Relação Estrutura-AtividadeRESUMO
TiCl4-Lewis base (AcOEt, CH3NO2) complexes smoothly deprotected tert-butyldimethylsilyl (TBDMS) ethers. The reaction velocity with these complexes, which seemed less reactive due to the influence of Lewis bases, was considerably greater than that with TiCl4 alone. Selective desilylations between aliphatic and aromatic TBDMS ethers (1 and 5), between 1 and benzyl, allyl, tosyl, methoxyphenyl, and chloroacetyl ethers (13, 14, 15, 16, and 17), and between TBDMS and TBDPS ethers (18 and 19) were successfully performed. Desilylation of TBDMS-aldol, acyloin, and beta-lactam analogues 9-12 proceeded smoothly due to anchimeric assistance by the neighboring carbonyl groups. The present method was successfully applied to the practical synthesis of 1beta-methylcarbapenems 20a'-f'.
Assuntos
Carbapenêmicos/síntese química , Éteres/química , Nitritos/química , Compostos de Organossilício/química , Titânio/química , Carbapenêmicos/química , Estrutura Molecular , EstereoisomerismoRESUMO
BACKGROUND: C-Reactive protein (CRP) is an independent risk factor for atherosclerotic coronary heart diseases (ACHD) in adults. To help prevent ACHD, it may be useful to understand risk factors during childhood. OBJECTIVE: The objective of this study was to investigate serum CRP and its relation to other risk factors for ACHD and adipocytokines (adiponectin, IL-6, and TNF-alpha) in Japanese children. METHODS: CRP, conventional risk factors for ACHD, and adipocytokines were determined in 568 children (340 boys and 228 girls, aged 7-10 yr). Serum concentrations of adipocytokines were measured by sandwich ELISA. RESULTS: Children with high CRP concentrations (highest tertile) had higher body mass index (BMI) sd scores, insulin, insulin resistance, uric acid, and adipocytokines and had more atherogenic lipoprotein profiles than other children. However, after being corrected by BMI sd, only high-density lipoprotein cholesterol, apolipoprotein A-I, IL-6, and TNF-alpha for boys and high-density lipoprotein cholesterol, apolipoprotein B, uric acid, IL-6, and TNF-alpha for girls were significantly correlated with CRP. IL-6 was the strongest predictive variable for CRP and accounted for 26.2 and 27.7% of the variability in serum concentrations of CRP in boys and girls, respectively. Serum concentrations of IL-6 were partly dependent on BMI sd and TNF-alpha in both boys and girls. CONCLUSION: Although serum concentrations of CRP are partly regulated by adipocytokines and conventional risk factors for ACHD, high CRP levels were associated with atherogenic profiles of cardiovascular risk factors in children. Our findings suggest that it may be important to control body weight to prevent an increase in serum CRP in children.
Assuntos
Proteína C-Reativa/análise , Doença da Artéria Coronariana/etiologia , Adiponectina/sangue , Apolipoproteína A-I/sangue , Índice de Massa Corporal , Criança , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Humanos , Interleucina-6/sangue , Masculino , Fatores de Risco , Caracteres Sexuais , Fator de Necrose Tumoral alfa/análiseRESUMO
The extract of the cell wall skeleton of Bacillus Calmette-Guérin (BCG-CWS) from Mycobacterium bovis is known to be an activator of innate immunity. Synthesis of pentaarabinofuranoside as part of the arabinan moiety of BCG-CWS was achieved by double alpha-arabinofuranosylation followed by double beta-arabinofuranosylation with orthogonally protected donors. Mycolic esters of the arabinan in the terminal lipo-arabinan motif of BCG-CWS were synthesized through alkylation of unprotected mycolic acid with bis- and tetra-tosylates of pentaarabinofuranoside. A series of compounds were subjected to a tumor necrosis factor alpha (TNF-alpha) secretion-inducing assay, disclosing aspects of the structure-activity relationship which should be useful in finding the site of the activity.
Assuntos
Parede Celular/química , Parede Celular/metabolismo , Mycobacterium bovis/química , Mycobacterium bovis/metabolismo , Polissacarídeos/biossíntese , Polissacarídeos/química , Fator de Necrose Tumoral alfa/metabolismo , Animais , Configuração de Carboidratos , Linhagem Celular , Esterificação , Espectrometria de Massas , Camundongos , Ácidos Micólicos/químicaRESUMO
SM-216601 is a novel parenteral 1beta-methylcarbapenem. In agar dilution susceptibility testing, the MIC of SM-216601 for 90% of the methicillin-resistant Staphylococcus aureus (MRSA) strains tested (MIC(90)) was 2 microg/ml, which was comparable to those of vancomycin and linezolid. SM-216601 was also very potent against Enterococcus faecium, including vancomycin-resistant strains (MIC(90) = 8 microg/ml). SM-216601 exhibited potent activity against penicillin-resistant Streptococcus pneumoniae, ampicillin-resistant Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, with MIC(90)s of less than 0.5 microg/ml, and intermediate activity against Citrobacter freundii, Enterobacter cloacae, Serratia marcescens, and Pseudomonas aeruginosa. The therapeutic efficacy of SM-216601 against experimentally induced infections in mice caused by S. aureus, E. faecium, E. coli, and P. aeruginosa reflected its in vitro activity and plasma level. Thus, SM-216601 is a promising candidate for nosocomial bacterial infections caused by a wide range of gram-positive and gram-negative bacteria, including multiresistant pathogens.
Assuntos
Antibacterianos/farmacologia , Carbapenêmicos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Bactérias Gram-Positivas/efeitos dos fármacos , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Abscesso/tratamento farmacológico , Abscesso/microbiologia , Abscesso/patologia , Animais , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Área Sob a Curva , Carbapenêmicos/administração & dosagem , Carbapenêmicos/sangue , Carbapenêmicos/química , Carbapenêmicos/farmacocinética , Carbapenêmicos/uso terapêutico , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecalis/patogenicidade , Bactérias Gram-Negativas/isolamento & purificação , Infecções por Bactérias Gram-Negativas/microbiologia , Bactérias Gram-Positivas/isolamento & purificação , Infecções por Bactérias Gram-Positivas/microbiologia , Infusões Parenterais , Cinética , Masculino , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Estrutura Molecular , Padrões de ReferênciaRESUMO
It has been reported that 2-(4-substituted thiazol-2-ylthio)-1beta-methyl-carbapenems exhibit potent activity against methicillin-resistant staphylococci (MRS) and vancomycin-resistant enterococci (VRE). In order to develop a novel broad-spectrum carbapenem, the structure-activity relationships of a series of 2-(4-tetrahydropyridinylthiazol-2-ylthio)-1beta-methylcarbapenems and 4-dihydropyrrolyl thiazole analogs were investigated with regard to their activity against Gram-positive and especially Gram-negative bacteria and also their convulsant activity, which is a major side effect concern of carbapenems. The introduction of substituent(s) on the dihydropyrrole moiety did not cause remarkable changes in anti-MRS and VRE activities, but tended to lower the anti-Gram-negative bacterial activity except in some cases of methyl group introduction. These substitutions did however cause a reduction of the convulsant activity, which was affected by the size and also the configuration of the substituent. In the case of SM-216601 (6), introduction of a methyl group brought about significant reduction in neurotoxicity while maintaining favorable anti-Gram-negative bacterial activity.
Assuntos
Bactérias/efeitos dos fármacos , Carbapenêmicos/farmacologia , Convulsivantes/farmacologia , Animais , Carbapenêmicos/química , Carbapenêmicos/toxicidade , Convulsivantes/química , Convulsivantes/toxicidade , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Convulsões/induzido quimicamente , Espectrofotometria Infravermelho , Espectroscopia de Infravermelho com Transformada de Fourier , Relação Estrutura-AtividadeRESUMO
In order to design orally active carbapenem antibiotics effective against beta-lactam-resistant pathogens, such as penicillin-resistant Streptococcus pneumoniae (PRSP) and beta-lactamase non-producing ampicillin-resistant Haemophilus influenzae (BLNAR), a series of novel 2-phenylcarbapenems and some 2-thienyl derivatives were synthesized and tested for antibacterial activities. These compounds were highly active against PRSP, BLNAR, and major Gram-positive and Gram-negative bacteria that cause community-acquired infections. Their pivaloyloxymethylester-type prodrug exhibited good oral absorption in mice, suggesting that this series of carbapenems were promising as a prototype of novel orally active beta-lactams.
Assuntos
Antibacterianos/farmacologia , Antibacterianos/farmacocinética , Carbapenêmicos/farmacologia , Carbapenêmicos/farmacocinética , Tiofenos/farmacologia , Tiofenos/farmacocinética , Animais , Bactérias/efeitos dos fármacos , Dipeptidases/metabolismo , Humanos , Hidrólise , Indicadores e Reagentes , Absorção Intestinal , Cinética , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Espectrofotometria Infravermelho , Relação Estrutura-AtividadeRESUMO
Small low-density lipoprotein (LDL) particles are more atherogenic than larger LDL particles. To help prevent atherosclerotic coronary heart diseases, it may be useful to understand risk factors during childhood. In the present study, we evaluated LDL size and its relationship to other risk factors for atherosclerotic coronary heart disease. LDL size was measured by 2-15% gradient gel electrophoresis in 586 Japanese children (316 boys and 270 girls). Plasma lipids, apolipoproteins (apo), glucose, and insulin were also determined by conventional methods. Pattern B (LDL size < 25.5 nm) was found in 10.8% of boys and 4.4% of girls. Children with pattern B had a higher body mass index (BMI) and insulin resistance and a more atherogenic lipoprotein profile [higher triglycerides, higher apoB, and lower high-density lipoprotein cholesterol (HDL-C)] than children with pattern A (LDL size > or = 25.5 nm). BMI, insulin resistance, and plasma concentrations of triglycerides, glucose, and insulin decreased and plasma concentrations of HDL-C and apoA-I increased as LDL size increased. HDL-C and insulin in boys, and BMI, HDL-C, and apoA-I in girls predicted 22.9 and 28.1% of the variability of LDL size, respectively. LDL size was correlated with BMI and plasma concentrations of HDL-C, apoA-I, and insulin. Although the contribution of these parameters to LDL size in children was less than that in adults, improvement of these parameters by changes in lifestyle might be important for preventing the development of atherosclerosis even in children.
Assuntos
Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/metabolismo , Lipoproteínas LDL/metabolismo , Obesidade/epidemiologia , Obesidade/metabolismo , Índice de Massa Corporal , Criança , Feminino , Humanos , Japão , Masculino , Tamanho da Partícula , Análise de Regressão , Fatores de RiscoRESUMO
SM-197436, SM-232721, and SM-232724 are new 1beta-methylcarbapenems with a unique 4-substituted thiazol-2-ylthio moiety at the C-2 side chain. In agar dilution susceptibility testing these novel carbapenems were active against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) with a MIC(90) of =4 micro g/ml. Furthermore, SM-232724 showed strong bactericidal activity against MRSA, in contrast to linezolid, which was bacteriostatic up to four times the MIC. SM-232724 showed good therapeutic efficacy comparable to those of vancomycin and linezolid against systemic infections of MRSA in cyclophosphamide-treated mice. The MICs of SM-197436, SM-232721, and SM-232724 for streptococci, including penicillin-intermediate and penicillin-resistant Streptococcus pneumoniae strains, ranged from =0.063 to 0.5 micro g/ml. These drugs were the most active beta-lactams tested against Enterococcus faecium, and the MIC(90) s for ampicillin-resistant E. faecium ranged between 8 and 16 micro g/ml, which were slightly higher than the value for linezolid. However, time-kill assays revealed the superior bactericidal activity of SM-232724 compared to those of quinupristin-dalfopristin and linezolid against an E. faecium strain with a 4-log reduction in CFU at four times the MIC after 24 h of exposure to antibiotics. In addition, SM-232724 significantly reduced the numbers of bacteria in a murine abscess model with the E. faecium strain: its efficacy was superior to that of linezolid, although the MICs (2 micro g/ml) of these two agents are the same. Among gram-negative bacteria, these three carbapenems were highly active against Haemophilus influenzae (including ampicillin-resistant strains), Moraxella catarrhalis, and Bacteroides fragilis, and showed antibacterial activity equivalent to that of imipenem for Escherichia coli, Klebsiella pneumoniae, and Proteus spp. Thus, these new carbapenems are promising candidates for agents to treat nosocomial bacterial infections by gram-positive and gram-negative bacteria, especially multiresistant gram-positive cocci, including MRSA and vancomycin-resistant enterococci.
Assuntos
Proteínas de Bactérias , Carbapenêmicos/farmacologia , Proteínas de Transporte , Bactérias Gram-Positivas/efeitos dos fármacos , Muramilpentapeptídeo Carboxipeptidase , Abscesso/tratamento farmacológico , Abscesso/microbiologia , Acetamidas/farmacologia , Resistência a Ampicilina , Animais , Antibacterianos/farmacologia , Dipeptidases/metabolismo , Farmacorresistência Bacteriana Múltipla , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Positivas/microbiologia , Hexosiltransferases/metabolismo , Rim/enzimologia , Linezolida , Masculino , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Complexos Multienzimáticos/metabolismo , Oxazolidinonas/farmacologia , Proteínas de Ligação às Penicilinas , Peptidil Transferases/metabolismo , Vancomicina/farmacologia , Resistência a Vancomicina , beta-Lactamases/metabolismoRESUMO
Discovery of novel antimicrobial agents effective against infections caused by drug-resistant pathogens is an important objective. In order to find a new parenteral carbapenem antibiotic, which has potent antibacterial activity especially against methicillin-resistant staphylococci, vancomycin-resistant enterococci and penicillin-resistant Streptococcus pneumoniae, a series of 1beta-methylcarbapenems with thiazol-2-ylthio groups at the C-2 position have been synthesized. Structure-activity relationships were investigated which led to SM-197436 (27), SM-232721 (44) and SM-232724 (41), being selected for further evaluation.