RESUMO
Shigella flexneri is the main causative agent of the communicable diarrheal disease, shigellosis. It is estimated that about 80-165 million cases and > 1 million deaths occur every year due to this disease. S. flexneri causes dysentery mostly in young children, elderly and immunocompromised patients, all over the globe. Recently, due to the emergence of S. flexneri antibiotic resistance strains, it is a dire need to predict novel therapeutic drug targets in the bacterium and screen natural products against it, which could eliminate the curse of antibiotic resistance. Therefore, in current study, available antibiotic-resistant genomes (n = 179) of S. flexneri were downloaded from PATRIC database and a pan-genome and resistome analysis was conducted. Around 5059 genes made up the accessory, 2469 genes made up the core, and 1558 genes made up the unique genome fraction, with 44, 34, and 13 antibiotic-resistant genes in each fraction, respectively. Core genome fraction (27% of the pan-genome), which was common to all strains, was used for subtractive genomics and resulted in 384 non-homologous, and 85 druggable targets. Dihydroorotase was chosen for further analysis and docked with natural product libraries (Ayurvedic and Streptomycin compounds), while the control was orotic acid or vitamin B13 (which is a natural binder of this protein). Dynamics simulation of 50 ns was carried out to validate findings for top-scored inhibitors. The current study proposed dihydroorotase as a significant drug target in S. flexneri and 4-tritriacontanone & patupilone compounds as potent drugs against shigellosis. Further experiments are required to ascertain validity of our findings.
Assuntos
Antibacterianos/farmacologia , Produtos Biológicos/antagonistas & inibidores , Descoberta de Drogas/métodos , Pirimidinas/farmacologia , Shigella flexneri/enzimologia , Simulação por Computador , Farmacorresistência Bacteriana , Pirimidinas/biossíntese , Shigella flexneri/efeitos dos fármacosRESUMO
During postnatal adaptation pulmonary surfactant may be inactivated by lipopolysaccharide (LPS). We evaluated the effect of surfactant therapy in combination with antibiotic polymyxin B (PxB) in double-hit model of neonatal lung injury. Surfactant (poractant alfa, Curosurf) was exposed to smooth (S) LPS without/with PxB and tested in captive bubble surfactometer. Preterm rabbits received intratracheally saline (control) or S-LPS and were ventilated with 100% oxygen. After 30 min, LPS-treated animals received no treatment, or surfactant (200 mg/kg) without/with 3% PxB; controls received the same dose of surfactant. Animals were ventilated for further 2 h. In vitro, addition of 5% S-LPS to surfactant increased minimum surface tension (γmin) and addition of 1-3% PxB to surfactant/S-LPS mixture restored γmin to low values. Animals only given S-LPS had lower lung compliance and lung gas volume (LGV) compared to surfactant groups. Treatment with surfactant/PxB, but not with surfactant only, restored LGV. Addition of PxB to the surfactant increased the alveolar expansion. S-LPS interferes with surface activity of the pulmonary surfactant and PxB improves the resistance of surfactant to LPS-induced inactivation. In our neonatal model of respiratory distress syndrome surfactant gives positive response even in simultaneous exposure to S-LPS, when enriched with PxB.
Assuntos
Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/metabolismo , Polimixina B/farmacologia , Surfactantes Pulmonares/metabolismo , Animais , Animais Recém-Nascidos , Produtos Biológicos/administração & dosagem , Produtos Biológicos/antagonistas & inibidores , Modelos Animais de Doenças , Feminino , Humanos , Técnicas In Vitro , Recém-Nascido , Lipopolissacarídeos/toxicidade , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiopatologia , Complacência Pulmonar/efeitos dos fármacos , Lesão Pulmonar/induzido quimicamente , Masculino , Fosfolipídeos/administração & dosagem , Fosfolipídeos/antagonistas & inibidores , Polimixina B/administração & dosagem , Surfactantes Pulmonares/administração & dosagem , Surfactantes Pulmonares/agonistas , Síndrome do Desconforto Respiratório do Recém-Nascido/tratamento farmacológico , Síndrome do Desconforto Respiratório do Recém-Nascido/metabolismoRESUMO
Detection of anti-drug antibodies (ADA) that have a neutralizing capacity is an important aspect of immunogenicity evaluation during development of biotherapeutics, but developing and validating neutralizing antibody (NAb) assays that show direct interference of a biologic function is a challenging and resource-intensive activity. In particular, the need for adequate drug and target tolerance often requires extensive pre-treatment steps that limit assay sensitivity compared with a typical bridging-format assay used to detect binding ADA. Such limitations may complicate data interpretation as a positive ADA followed by a negative NAb result could be due to the presence of non-neutralizing antibodies or could be a false-negative for NAbs due to methodology differences. To address such issues, we developed a novel assay for Nanobodies® and other antibody-derived therapeutics that solely detects ADA directed against the complementarity-determining regions (CDRs) involved in drug-target interactions. This was achieved by creating a "null variant" of the therapeutic drug, which has mutated CDRs rendering it non-functional for target binding but is otherwise identical to the drug compound. Non-CDR-binding antibodies are pre-complexed with the null variant of the Nanobody leaving only CDR-binding ADA with neutralizing potential (ANP) to be detected in this assay, which is called a NAb Epitope Characterization Assay (NECA). Method qualification results confirmed highly comparable assay characteristics (sensitivity, drug tolerance, selectivity and precision) of both the NECA and a validated ADA assay for the same Nanobody. A panel of purified neutralizing and non-neutralizing antibodies as well as non-clinical and clinical samples were used to further substantiate the fit-for-purpose and advantages of this novel assay format to detect ANP. In the clinical case study, a 20 to 40-fold difference in assay sensitivity existed between the validated ADA assay and NAb assay, which complicated data interpretation. Implementation of the NECA allowed unambiguous comparison of the levels of binding ADA and ANP in study samples which enabled us to delineate the true neutralizing capacity of the responses. Depending on the risk of the therapeutic, this method could be a valuable alternative for NAb testing by enabling earlier detection of ADA with neutralizing potential and ensuring adequate immunogenicity risk assessment.
Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/sangue , Produtos Biológicos/imunologia , Imunoensaio , Anticorpos de Domínio Único/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/imunologia , Sítios de Ligação de Anticorpos , Ligação Competitiva , Produtos Biológicos/antagonistas & inibidores , Produtos Biológicos/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Regiões Determinantes de Complementaridade/imunologia , Humanos , Ligantes , Macaca mulatta , Anticorpos de Domínio Único/uso terapêuticoRESUMO
Methicillin-resistant Staphylococcus aureus (MRSA) is a major hospital-acquired infective pathogen that has developed resistance to many antibiotics. It is imperious to develop novel anti-MRSA drugs to control the emergence of drug resistance. The biosynthesis of cysteine in bacteria is catalyzed by CysE and CysK. CysE was predicted to be important for bacterial viability, it could be a potential drug target. The serine acetyltransferase activity of CysE was detected and its catalytic properties were also determined. CysE homology model was built to investigate interaction sites between CysE and substrate L-Ser or inhibitors by molecular docking. Docking data showed that residues Asp94 and His95 were essential for serine acetyltransferase activity of CysE, which were confirmed by site-directed mutagenesis. Colorimetric assay was used to screen natural products and six compounds which inhibited CysE activity (IC50 ranging from 29.83⯵M to 203.13⯵M) were found. Inhibition types of two compounds 4 (11-oxo-ebracteolatanolide B) and 30 ((4R,4aR)-dihydroxy-3-hydroxymethyl-7,7,10a-trimethyl-2,4,4a,5,6,6a,7,8,9,10,10a,l0b-dodecahydrophenanthro[3,2-b]furan-2-one) on CysE were determined. Compounds 4 and 30 showed inhibitory effect on MRSA growth (MIC at 12.5⯵g/ml and 25⯵g/ml) and mature biofilm. The established colorimetric assay will facilitate further high-throughput screening of CysE inhibitors from different compound libraries. The compounds 4 and 30 may offer structural basis for developing new anti-MRSA drugs.
Assuntos
Produtos Biológicos/antagonistas & inibidores , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/enzimologia , Serina O-Acetiltransferase/efeitos dos fármacos , Serina O-Acetiltransferase/metabolismo , Sequência de Aminoácidos , Sequência de Bases , Biofilmes/efeitos dos fármacos , Domínio Catalítico , Clonagem Molecular , Regulação Bacteriana da Expressão Gênica , Cinética , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Modelos Moleculares , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Alinhamento de Sequência , Serina O-Acetiltransferase/genéticaRESUMO
BACKGROUND: A large number of disorders and their symptoms emerge from deficiency or overproduction of specific metabolites has drawn the attention for the discovery of new therapeutic agents for the treatment of disorders. Various approaches such as computational drug design have provided the new methodology for the selection and evaluation of target protein and the lead compound mechanistically. For instance, the overproduction of xanthine oxidase causes the accumulation of uric acid which can prompt gout. OBJECTIVE: In the present study we critically discussed the various techniques such as 3-D QSAR and molecular docking for the study of the natural based xanthine oxidase inhibitors with their mechanistic insight into the interaction of xanthine oxidase and various natural leads. CONCLUSION: The computational studies of deferent natural compounds were discussed as a result the flavonoids, anthraquinones, xanthones shown the remarkable inhibitory potential for xanthine oxidase inhibition moreover the flavonoids such as hesperidin and rutin were found as promising candidates for further exploration.
Assuntos
Produtos Biológicos/antagonistas & inibidores , Produtos Biológicos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/farmacologia , Antraquinonas/química , Produtos Biológicos/química , Coenzimas/química , Simulação por Computador , Desenho Assistido por Computador , Desenho de Fármacos , Flavina-Adenina Dinucleotídeo/química , Flavonoides/química , Proteínas Ferro-Enxofre/química , Metaloproteínas/química , Simulação de Acoplamento Molecular , Cofatores de Molibdênio , Conformação Proteica , Pteridinas/química , Relação Quantitativa Estrutura-Atividade , Xantina Oxidase/biossíntese , Xantina Oxidase/química , Xantonas/químicaRESUMO
The respiratory system is constantly exposed to pathogens which enter the lungs by inhalation or via blood stream. Lipopolysaccharide (LPS), also named endotoxin, can reach the airspaces as the major component of the outer membrane of Gram-negative bacteria, and lead to local inflammation and systemic toxicity. LPS affects alveolar type II (ATII) cells and pulmonary surfactant and although surfactant molecule has the effective protective mechanisms, excessive amount of LPS interacts with surfactant film and leads to its inactivation. From immunological point of view, surfactant specific proteins (SPs) SP-A and SP-D are best characterized, however, there is increasing evidence on the involvement of SP-B and SP-C and certain phospholipids in immune reactions. In animal models, the instillation of LPS to the respiratory system induces acute lung injury (ALI). It is of clinical importance that endotoxin-induced lung injury can be favorably influenced by intratracheal instillation of exogenous surfactant. The beneficial effect of this treatment was confirmed for both natural porcine and synthetic surfactants. It is believed that the surfactant preparations have anti-inflammatory properties through regulating cytokine production by inflammatory cells. The mechanism by which LPS interferes with ATII cells and surfactant layer, and its consequences are discussed below.
Assuntos
Produtos Biológicos/antagonistas & inibidores , Produtos Biológicos/metabolismo , Lipopolissacarídeos/metabolismo , Fosfolipídeos/antagonistas & inibidores , Fosfolipídeos/metabolismo , Surfactantes Pulmonares/antagonistas & inibidores , Surfactantes Pulmonares/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Animais , Humanos , Lipopolissacarídeos/toxicidade , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , SuínosRESUMO
Covering: up to 2017History points to the bacterial cell wall biosynthetic network as a very effective target for antibiotic intervention, and numerous natural product inhibitors have been discovered. In addition to the inhibition of enzymes involved in the multistep synthesis of the macromolecular layer, in particular, interference with membrane-bound substrates and intermediates essential for the biosynthetic reactions has proven a valuable antibacterial strategy. A prominent target within the peptidoglycan biosynthetic pathway is lipid II, which represents a particular "Achilles' heel" for antibiotic attack, as it is readily accessible on the outside of the cytoplasmic membrane. Lipid II is a unique non-protein target that is one of the structurally most conserved molecules in bacterial cells. Notably, lipid II is more than just a target molecule, since sequestration of the cell wall precursor may be combined with additional antibiotic activities, such as the disruption of membrane integrity or disintegration of membrane-bound multi-enzyme machineries. Within the membrane bilayer lipid II is likely organized in specific anionic phospholipid patches that form a particular "landing platform" for antibiotics. Nature has invented a variety of different "lipid II binders" of at least 5 chemical classes, and their antibiotic activities can vary substantially depending on the compounds' physicochemical properties, such as amphiphilicity and charge, and thus trigger diverse cellular effects that are decisive for antibiotic activity.
Assuntos
Bactérias/citologia , Parede Celular/metabolismo , Uridina Difosfato Ácido N-Acetilmurâmico/análogos & derivados , Antibacterianos/química , Antibacterianos/farmacologia , Produtos Biológicos/antagonistas & inibidores , Vias Biossintéticas , Estrutura Molecular , Peptidoglicano/efeitos dos fármacos , Ligação Proteica , Uridina Difosfato Ácido N-Acetilmurâmico/metabolismoRESUMO
Enterovirus 71 (EV-A71) is a major cause of hand, foot, and mouth disease (HFMD). Infection with EV-A71 is more often associated with neurological complications in children and is responsible for the majority of fatalities, but currently there is no approved antiviral therapy for treatment. Here, we identified auraptene, formononetin, and yangonin as effective inhibitors of EV-A71 infection in the low-micromolar range from screening of a natural product library. Among them, formononetin and yangonin selectively inhibited EV-A71 while auraptene could inhibit viruses within the enterovirus species A. Time of addition studies showed that all the three inhibitors inhibit both attachment and postattachment step of entry. We found mutations conferring the resistance to these inhibitors in the VP1 and VP4 capsid proteins and confirmed the target residues using a reverse genetic approach. Interestingly, auraptene- and formononetin-resistant viruses exhibit cross-resistance to other inhibitors while yangonin-resistant virus still remains susceptible to auraptene and formononetin. Moreover, auraptene and formononetin, but not yangonin protected EV-A71 against thermal inactivation, indicating a direct stabilizing effect of both compounds on virion capsid conformation. Finally, neither biochanin A (an analog of formononetin) nor DL-Kavain (an analog of yangonin) exhibited anti-EV-A71 activity, suggesting the structural elements required for anti-EV-A71 activity. Taken together, these compounds could become potential lead compounds for anti-EV-A71 drug development and also serve as tool compounds for studying virus entry.
Assuntos
Produtos Biológicos/antagonistas & inibidores , Cumarínicos/antagonistas & inibidores , Enterovirus Humano A/efeitos dos fármacos , Infecções por Enterovirus/prevenção & controle , Ensaios de Triagem em Larga Escala/métodos , Isoflavonas/antagonistas & inibidores , Pironas/antagonistas & inibidores , Animais , Produtos Biológicos/administração & dosagem , Produtos Biológicos/química , Proteínas do Capsídeo/genética , Linhagem Celular , Chlorocebus aethiops , Cumarínicos/administração & dosagem , Cumarínicos/química , Cricetinae , Descoberta de Drogas , Farmacorresistência Viral/genética , Enterovirus/efeitos dos fármacos , Enterovirus Humano A/genética , Infecções por Enterovirus/virologia , Genisteína , Haplorrinos , Humanos , Isoflavonas/administração & dosagem , Isoflavonas/química , Mutação , Pironas/administração & dosagem , Pironas/química , Alinhamento de Sequência , Células Vero , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacosRESUMO
Unlike conventional chemical drugs where immunogenicity typically does not occur, the development of anti-drug antibodies following treatment with biologics has led to concerns about their impact on clinical safety and efficacy. Hence the elucidation of the immunogenicity of biologics is required for drug approval by health regulatory authorities worldwide. Published ADA 'incidence' rates can vary greatly between same-class products and different patient populations. Such differences are due to disparate bioanalytical methods and interpretation approaches, as well as a plethora of product-specific and patient-specific factors that are not fully understood. Therefore, the incidence of ADA and their association with clinical consequences cannot be generalized across products. In this context, the intent of this review article is to discuss the complex nature of ADA and key nuances of the methodologies used for immunogenicity assessments, and to dispel some fallacies and myths.
Assuntos
Anticorpos Neutralizantes/imunologia , Formação de Anticorpos/imunologia , Produtos Biológicos/antagonistas & inibidores , Produtos Biológicos/imunologia , Anticorpos Neutralizantes/sangue , Produtos Biológicos/uso terapêutico , Humanos , Imunoensaio/métodosRESUMO
If new scientific knowledge is to be more efficiently generated and applied toward the advancement of health, human safety must be more effectively addressed in the conduct of research. Given the present difficulties of accurately predicting biological outcomes of novel interventions in vivo, the imperative of human safety suggests the development of novel pharmaceutical products in tandem with their prospective antidotes in anticipation of possible adverse events, to render the risks of initial clinical trials more acceptable from a regulatory standpoint. Antibody-mediated immunity provides a generally applicable mechanistic basis for developing antidotes to both biologicals and small-molecule drugs (such that antibodies may serve as antidotes to pharmaceutical agents as a class including other antibodies) and also for the control and prevention of both infectious and noninfectious diseases via passive or active immunization. Accordingly, the development of prophylactic or therapeutic passive-immunization strategies using antipeptide antibodies is a plausible prelude to the development of corresponding active-immunization strategies using peptide-based vaccines. In line with this scheme, global proliferation of antibody- and vaccine-production technologies, especially those that obviate dependence on the cold chain for storage and transport of finished products, could provide geographically distributed breakout capability against emerging and future health challenges.
Assuntos
Anticorpos/isolamento & purificação , Anticorpos/farmacologia , Antídotos/isolamento & purificação , Antídotos/farmacologia , Produtos Biológicos/antagonistas & inibidores , Imunização Passiva/métodos , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Ensaios Clínicos como Assunto , Descoberta de Drogas/tendências , HumanosRESUMO
The pharmacological evidence for synergism between natural compounds is not fully elucidated. In this study, we investigated the synergistic function of one target compound in medicinal plant extract by using knock-out (KO) extract, which is one target compound-eliminated extract from whole crude extract. Licorice is the most important ingredient used in the traditional Chinese medicine (TCM) and the Japanese Kampo medicine, and one of the major active components of licorice is glycyrrhizin (GC). To identify the potential role of GC, we prepared GC-removed extract (GC-KO extract) from licorice extract (LE) using immunoaffinity column conjugated with anti-GC monoclonal antibody (MAb), which could eliminate 99.5% of GC from LE. LE inhibited nitric oxide (NO) production and inducible NO synthase (iNOS) expression in lipopolysaccharide (LPS)-stimulated RAW264 murine macrophage cells. However, treatment of GC alone could not show the suppression of NO production and iNOS expression. Interestingly, the inhibitory effect of GC-KO extract was significantly attenuated compared with LE. Furthermore, the combined treatment with GC-KO extract and GC could improve the attenuated inhibition. Taken together, our results indicate that GC may exert synergistic suppression of iNOS expression when coexisting with the other constituents contained in LE, and KO extract is a useful approach for determination of real pharmacological functions of natural compound in the phytochemical mixture.
Assuntos
Produtos Biológicos/farmacologia , Ácido Glicirrízico/farmacologia , Óxido Nítrico/antagonistas & inibidores , Extratos Vegetais/farmacologia , Animais , Anticorpos Monoclonais/imunologia , Produtos Biológicos/antagonistas & inibidores , Produtos Biológicos/imunologia , Linhagem Celular , Sinergismo Farmacológico , Glycyrrhiza , Ácido Glicirrízico/antagonistas & inibidores , Ácido Glicirrízico/imunologia , Lipopolissacarídeos , Camundongos , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/biossínteseRESUMO
Molecular recognition and chemical modification of DNA are important in medicinal chemistry, toxicology, and biotechnology. Historically, natural products have revealed many interesting and unexpected mechanisms for noncovalent DNA binding and covalent DNA modification. The studies reported here characterize the molecular mechanisms underlying the efficient alkylation of duplex DNA by the Streptomyces-derived natural product leinamycin. Previous studies suggested that alkylation of duplex DNA by activated leinamycin (2) is driven by noncovalent association of the natural product with the double helix. This is striking because leinamycin does not contain a classical noncovalent DNA-binding motif, such as an intercalating unit, a groove binder, or a polycation. The experiments described here provide evidence that leinamycin is an atypical DNA-intercalating agent. A competition binding assay involving daunomycin-mediated inhibition of DNA alkylation by leinamycin provided evidence that activated leinamycin binds to duplex DNA with an apparent binding constant of approximately 4.3 ± 0.4 × 10(3) M(-1). Activated leinamycin caused duplex unwinding and hydrodynamic changes in DNA-containing solutions that are indicative of DNA intercalation. Characterization of the reaction of activated leinamycin with palindromic duplexes containing 5'-CG and 5'-GC target sites, bulge-containing duplexes, and 5-methylcytosine-containing duplexes provided evidence regarding the orientation of leinamycin with respect to target guanine residues. The data allow construction of a model for the leinamycin-DNA complex suggesting how a modest DNA-binding constant combines with proper positioning of the natural product to drive efficient alkylation of guanine residues in the major groove of duplex DNA.
Assuntos
Produtos Biológicos/farmacologia , DNA/efeitos dos fármacos , Lactamas/farmacologia , Macrolídeos/farmacologia , Tiazóis/farmacologia , Tionas/farmacologia , Alquilação , Sítios de Ligação/efeitos dos fármacos , Produtos Biológicos/antagonistas & inibidores , Produtos Biológicos/química , DNA/química , Daunorrubicina/farmacologia , Lactamas/antagonistas & inibidores , Lactamas/química , Macrolídeos/antagonistas & inibidores , Macrolídeos/química , Modelos Moleculares , Conformação Molecular , Relação Estrutura-Atividade , Tiazóis/antagonistas & inibidores , Tiazóis/química , Tionas/antagonistas & inibidores , Tionas/químicaRESUMO
Cephalostatin 1, OSW-1, ritterazine B and schweinfurthin A are natural products that potently, and in some cases selectively, inhibit the growth of cultured human cancer cell lines. The cellular targets of these small molecules have yet to be identified. We have discovered that these molecules target oxysterol binding protein (OSBP) and its closest paralog, OSBP-related protein 4L (ORP4L)--proteins not known to be involved in cancer cell survival. OSBP and the ORPs constitute an evolutionarily conserved protein superfamily, members of which have been implicated in signal transduction, lipid transport and lipid metabolism. The functions of OSBP and the ORPs, however, remain largely enigmatic. Based on our findings, we have named the aforementioned natural products ORPphilins. Here we used ORPphilins to reveal new cellular activities of OSBP. The ORPphilins are powerful probes of OSBP and ORP4L that will be useful in uncovering their cellular functions and their roles in human diseases.
Assuntos
Produtos Biológicos/farmacologia , Colestenonas/farmacologia , Neoplasias/metabolismo , Fenazinas/farmacologia , Receptores de Esteroides/metabolismo , Saponinas/farmacologia , Compostos de Espiro/farmacologia , Esteroides/farmacologia , Produtos Biológicos/antagonistas & inibidores , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colestenonas/antagonistas & inibidores , Humanos , Hidroxicolesteróis/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fenazinas/antagonistas & inibidores , Receptores de Esteroides/genética , Saponinas/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Esfingomielinas/biossíntese , Compostos de Espiro/antagonistas & inibidores , Esteroides/antagonistas & inibidores , Estilbenos/antagonistas & inibidores , Estilbenos/farmacologiaAssuntos
Antirreumáticos/uso terapêutico , Produtos Biológicos/biossíntese , Produtos Biológicos/uso terapêutico , Pesquisa Biomédica , Projetos de Pesquisa , Doenças Reumáticas/tratamento farmacológico , Produtos Biológicos/antagonistas & inibidores , Ensaios Clínicos como Assunto , Humanos , Reumatologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/efeitos dos fármacosRESUMO
A relevant aspect in the treatment of patients with hemophilia A (HA) presenting inhibitor against factor VIII (FVIII) is the different antigenicity of FVIII used for replacement therapy. The aim of the study was to assess the effect of different products, with variable von Willebrand factor (vWF) concentration, in preventing the binding of inhibitor to FVIII. The reactivity of inhibitors from plasma of 18 patients with HA versus three commercial concentrates containing different amounts of vWF was compared. The results show that increasing amounts of vWF might have a protective effect on the transfused FVIII inactivation.
Assuntos
Produtos Biológicos/química , Inibidores dos Fatores de Coagulação Sanguínea/química , Fator VIII/química , Hemofilia A/sangue , Fator de von Willebrand/química , Adulto , Produtos Biológicos/antagonistas & inibidores , Produtos Biológicos/imunologia , Inibidores dos Fatores de Coagulação Sanguínea/sangue , Inibidores dos Fatores de Coagulação Sanguínea/imunologia , Ensaio de Imunoadsorção Enzimática , Fator VIII/antagonistas & inibidores , Fator VIII/genética , Hemofilia A/tratamento farmacológico , Hemofilia A/imunologia , Humanos , Lactente , Pessoa de Meia-Idade , Mutação , Fatores de Tempo , Fator de von Willebrand/análiseRESUMO
The high prevalence of complementary and alternative medicine use including natural health products (NHPs) in the pediatric oncology population is well established. The potential for concurrent use of NHPs with conventional chemotherapy necessitates physician awareness regarding the potential risks and benefits that might come from this coadministration. Knowledge of interactions between NHPs and chemotherapy is poorly characterized; however, an understanding of potential mechanisms of interaction by researchers and clinicians is important. Concerns regarding the use of antioxidants during chemotherapy are controversial and evidence exists to support both adherents and detractors in this debate. Our review addresses issues regarding potential interactions between NHPs and chemotherapies used in pediatric oncology from a pharmacokinetic and pharmacodynamic perspective. Examples of combinations of NHP and chemotherapies are briefly presented in addition to a strategy to avoid (or induce) a possible interaction between a NHP and chemotherapy. In conclusion, more clinical research is needed to substantiate or preclude the use of NHPs in the treatment of cancer and especially in combination with chemotherapy.
Assuntos
Produtos Biológicos , Terapias Complementares , Interações Medicamentosas , Neoplasias/tratamento farmacológico , Adolescente , Produtos Biológicos/agonistas , Produtos Biológicos/antagonistas & inibidores , Produtos Biológicos/farmacocinética , Produtos Biológicos/uso terapêutico , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Terapias Complementares/efeitos adversos , Terapias Complementares/métodos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Neoplasias/complicaçõesRESUMO
Antifungal activity of natural products has been tested by adapting methods designed for synthetic drugs. Inthis study, two methods for the determination of antifungal activity of natural products, agar diffusionand broth microdilution, the CLSI reference methods for synthetic drugs, are compared and discussed. Themicrodilution method was more sensitive. The minimal inhibitory concentrations (MIC) of crude extracts,fractions and pure substances from different species of the plant families Piperaceae, Rubiaceae, Clusiaceae, Fabaceae and Lauraceae, from the Biota project, were determined. Antifungal activities against Candida albicans, C.krusei, C.parapsilosis and Cryptococcus neoformans were produced by several samples
Atividade antifúngica de produtos naturais foi determinada após algumas adaptações de métodos preconizados para fármacos sintéticos. Neste estudo foram comparados e discutidos os métodos para determinação de atividade antifúngica de produtos naturais por duas metodologias, difusão em ágar e microdiluição em caldo, segundo método preconizado pelo CLSI para fármacos sintéticos. A concentração mínima inibitória foi determinada de extratos brutos, frações e de substâncias puras de diferentes espécies de plantas das famílias Piperaceae, Rubiaceae, Clusiaceae, Fabaceae and Lauraceae do projeto Biota. Vários apresentaram atividade antifúngica para as levedurasCandida albicans, C.krusei, C.parapsilosis and Cryptococcus neoformans.
Assuntos
Antígenos de Fungos , Candida albicans , Cryptococcus , Produtos Biológicos/antagonistas & inibidoresRESUMO
Six chain-extended analogues of the naturally occurring glycosidase inhibitor salacinol, with ring-heteroatom variation, were synthesized for structure-activity studies with different glycosidase enzymes. The syntheses involved the reaction of PMB-protected D- and L- seleno-, thio-, and iminoarabinitol with a benzylidene- and isopropylidene-protected 1,3-cyclic sulfate, derived from commercially available D-sorbitol, in 1,1,1,3,3,3-hexafluoro-2-propanol containing potassium carbonate. Deprotection of the products afforded the novel selenonium, sulfonium, and iminium analogues of salacinol containing polyhydroxylated, monosulfated, extended acyclic chains of 6-carbons, differing in stereochemistry at the stereogenic centers and ring-heteroatom constitution. Four of these compounds inhibit recombinant human maltase glucoamylase, one of the key intestinal enzymes involved in the breakdown of glucose oligosaccharides in the small intestine, with Ki values in the micromolar range, thus providing lead candidates for the treatment of Type 2 diabetes.
Assuntos
Ácidos Acíclicos/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores de Glicosídeo Hidrolases , Compostos Heterocíclicos com 1 Anel/síntese química , Compostos Heterocíclicos com 1 Anel/farmacologia , Álcoois Açúcares/química , Sulfatos/química , Produtos Biológicos/antagonistas & inibidores , Produtos Biológicos/química , Inibidores Enzimáticos/química , Compostos Heterocíclicos com 1 Anel/química , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Álcoois Açúcares/síntese química , Álcoois Açúcares/farmacologia , Sulfatos/síntese química , Sulfatos/farmacologia , alfa-Glucosidases/metabolismoRESUMO
BACKGROUND: Health care workers belong to a high risk occupational group in view of their permanent contact with biological agents. It is essential to take all available and effective technical, organizational and medical preventive measures to protect the exposed workers. METHODS AND MATERIALS: Activities aimed at protecting workers from risks related to exposure to biological agents, according to recommendations laid down in Directive 2000/54/EC, were assessed in a questionnaire survey carried out in 47 hospitals. RESULTS AND CONCLUSIONS: The following requirements were best satisfied by the hospitals under study: provision of workers exposed to biological agents with collective and personal protective measures; washing and toilet facilities; separate dinning rooms; registration of accidents involving handling of biological agents and including biological agents issues in the program of occupational training of workers. Most flaws and oversights were observed in regard to: biological agents risk assessment; appropriate marking of rooms where biohazard may occur; written procedures for safe handling of biological agents and the implementation of vaccination program against hepatitis B.
Assuntos
Produtos Biológicos/análise , Exposição Ocupacional/análise , Exposição Ocupacional/prevenção & controle , Recursos Humanos em Hospital/estatística & dados numéricos , Prevenção Primária/estatística & dados numéricos , Medição de Risco/métodos , Gestão da Segurança/métodos , Produtos Biológicos/antagonistas & inibidores , Conhecimentos, Atitudes e Prática em Saúde , Inquéritos Epidemiológicos , Humanos , Exposição Ocupacional/estatística & dados numéricos , Saúde Ocupacional , Polônia/epidemiologia , Prevenção Primária/organização & administraçãoRESUMO
The objective of this study was to apply the pertinent findings from gamma inactivation of virus infectivity to the production of high quality diagnostic reagents. A Gammacell 220 (Atomic Energy of Canada, Ltd., Ottawa, Canada) was used to subject 38 viruses grown in either susceptible tissue cultures or embryonated chicken eggs to various doses of gamma radiation from a cobalt-60 source. The radiation required to reduce viral infectivity was 0.42 to 3.7 megarads (Mrad). The effect of gamma treatment on the antigenic reactivity of reagents for the complement fixation (CF), hemagglutination (HA) and neuraminadase assays was determined. Influenza antigens inactivated with 1.7 Mrad displayed comparable potency, sensitivity, specificity and stability to those inactivated by standard procedures with beta-propiolactone (BPL). Significant inactivation of influenza N1 and B neuraminidase occurred with greater than 2.4 Mrad radiation at temperatures above 4 degrees C. All 38 viruses were inactivated, and CF or HA antigens were prepared successfully. Antigenic potency remained stable with all antigens for 3 years and with 83% after 5 years storage. Influenza HA antigens evaluated after 9 years of storage demonstrated 86% stability. Gamma radiation is safer than chemical inactivation procedures and is reliable and effective replacement for BPL in preparing diagnostic reagents.