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1.
Artigo em Inglês | MEDLINE | ID: mdl-33558292

RESUMO

Global infections by non-tuberculous mycobacteria (NTM) are steadily rising. New drugs are needed to treat NTM infections, but the NTM drug pipeline remains poorly populated and focused on repurposing or reformulating approved antibiotics. We sought to accelerate de novo NTM drug discovery by testing advanced compounds with established activity against Mycobacterium tuberculosis 3-aminomethyl 4-halogen benzoxaboroles, a novel class of leucyl-tRNA synthetase inhibitors, were recently discovered as active against M. tuberculosis Here, we report that the benzoxaborole EC/11770 is not only a potent anti-tubercular agent but is active against the M. abscessus and M. avium complexes. Focusing on M. abscessus, which causes the most difficult-to-cure NTM disease, we show that EC/11770 retained potency against drug-tolerant biofilms in vitro and was effective in a mouse lung infection model. Resistant mutant selection experiments showed a low frequency of resistance and confirmed leucyl-tRNA synthetase as the target. This work establishes the benzoxaborole EC/11770 as a novel preclinical candidate for the treatment of NTM lung disease and tuberculosis and validates leucyl-tRNA synthetase as an attractive target for the development of broad-spectrum anti-mycobacterials.

2.
Antimicrob Agents Chemother ; 65(12): e0151421, 2021 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-34606340

RESUMO

Fluoroquinolones-the only clinically used DNA gyrase inhibitors-are effective against tuberculosis (TB) but are in limited clinical use for nontuberculous mycobacteria (NTM) lung infections due to intrinsic drug resistance. We sought to test alternative DNA gyrase inhibitors for anti-NTM activity. Mycobacterium tuberculosis gyrase inhibitors (MGIs), a subclass of novel bacterial topoisomerase inhibitors (NBTIs), were recently shown to be active against the tubercle bacillus. Here, we show that the MGI EC/11716 not only has potent anti-tubercular activity but is active against M. abscessus and M. avium in vitro. Focusing on M. abscessus, which causes the most difficult to cure NTM disease, we show that EC/11716 is bactericidal, active against drug-tolerant biofilms, and efficacious in a murine model of M. abscessus lung infection. Based on resistant mutant selection experiments, we report a low frequency of resistance to EC/11716 and confirm DNA gyrase as its target. Our findings demonstrate the potential of NBTIs as anti-M. abscessus and possibly broad-spectrum anti-mycobacterial agents.


Assuntos
Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Mycobacterium tuberculosis , Animais , Camundongos , Testes de Sensibilidade Microbiana , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Micobactérias não Tuberculosas , Tioinosina/análogos & derivados , Inibidores da Topoisomerase II/farmacologia
3.
J Pharmacokinet Pharmacodyn ; 44(2): 133-141, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28205025

RESUMO

The Multistate Tuberculosis Pharmacometric (MTP) model, a pharmacokinetic-pharmacodynamic disease model, has been used to describe the effects of rifampicin on Mycobacterium tuberculosis (M. tuberculosis) in vitro. The aim of this work was to investigate if the MTP model could be used to describe the rifampicin treatment response in an acute tuberculosis mouse model. Sixty C57BL/6 mice were intratracheally infected with M. tuberculosis H37Rv strain on Day 0. Fifteen mice received no treatment and were sacrificed on Days 1, 9 and 18 (5 each day). Twenty-five mice received oral rifampicin (1, 3, 9, 26 or 98 mg·kg-1·day-1; Days 1-8; 5 each dose level) and were sacrificed on Day 9. Twenty mice received oral rifampicin (30 mg·kg-1·day-1; up to 8 days) and were sacrificed on Days 2, 3, 4 and 9 (5 each day). The MTP model was linked to a rifampicin population pharmacokinetic model to describe the change in colony forming units (CFU) in the lungs over time. The transfer rates between the different bacterial states were fixed to estimates from in vitro data. The MTP model described well the change in CFU over time after different exposure levels of rifampicin in an acute tuberculosis mouse model. Rifampicin significantly inhibited the growth of fast-multiplying bacteria and stimulated the death of fast- and slow-multiplying bacteria. The data did not support an effect of rifampicin on non-multiplying bacteria possibly due to the short duration of the study. The pharmacometric modelling framework using the MTP model can be used to perform investigations and predictions of the efficacy of anti-tubercular drugs against different bacterial states.


Assuntos
Antibióticos Antituberculose/farmacologia , Antibióticos Antituberculose/farmacocinética , Mycobacterium tuberculosis/efeitos dos fármacos , Rifampina/farmacologia , Rifampina/farmacocinética , Tuberculose/tratamento farmacológico , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL
4.
J Med Chem ; 63(5): 2557-2576, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31922409

RESUMO

Decaprenylphosphoryl-ß-d-ribose 2'-epimerase (DprE1) is an essential enzyme in Mycobacterium tuberculosis and has recently been studied as a potential drug target, with inhibitors progressing to clinical studies. Here we describe the identification of a novel series of morpholino-pyrimidine DprE1 inhibitors. These were derived from a phenotypic high-throughput screening (HTS) hit with suboptimal physicochemical properties. Optimization strategies included scaffold-hopping, synthesis, and evaluation of fragments of the lead compounds and property-focused optimization. The resulting optimized compounds had much improved physicochemical properties and maintained enzyme and cellular potency. These molecules demonstrated potent efficacy in an in vivo tuberculosis murine infection model.


Assuntos
Oxirredutases do Álcool/antagonistas & inibidores , Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Pirimidinas/farmacologia , Tuberculose/tratamento farmacológico , Oxirredutases do Álcool/metabolismo , Animais , Antituberculosos/química , Antituberculosos/uso terapêutico , Proteínas de Bactérias/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Humanos , Masculino , Camundongos , Morfolinas/química , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Mycobacterium tuberculosis/enzimologia , Pirimidinas/química , Pirimidinas/uso terapêutico , Tuberculose/microbiologia
5.
J Med Chem ; 63(9): 4732-4748, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32275415

RESUMO

Screening of a GSK-proprietary library against intracellular Mycobacterium tuberculosis identified 1, a thioalkylbenzoxazole hit. Biological profiling and mutant analysis revealed that this compound is a prodrug that is bioactivated by the mycobacterial enzyme MymA. A hit-expansion program including design, synthesis, and profiling of a defined set of analogues with optimized drug-like properties led to the identification of an emerging lead compound, displaying potency against intracellular bacteria in the low micromolar range, high in vitro solubility and permeability, and excellent microsomal stability.


Assuntos
Antituberculosos/farmacologia , Proteínas de Bactérias/metabolismo , Benzoxazóis/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Oxigenases/metabolismo , Pró-Fármacos/farmacologia , Animais , Antituberculosos/síntese química , Antituberculosos/metabolismo , Benzoxazóis/síntese química , Benzoxazóis/metabolismo , Linhagem Celular Tumoral , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/efeitos dos fármacos , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/metabolismo , Relação Estrutura-Atividade
6.
Health Care Women Int ; 30(8): 720-7, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19575323

RESUMO

The prevalence of Human immunodeficiency virus (HIV) antibodies in pregnant women varies widely between industrialized and developing countries. There is a lack of information about the status of HIV-infected pregnant women with increased risk for AIDS. Our objective was to determine the prevalence of HIV antibodies in pregnant women with increased risk at the Hospital of Obstetrics and Gynecology of the Mexican Institute of Social Security, Leon, Mexico, from December 18, 2003, through February 28, 2006. In a cross-sectional study, 2,257 pregnant women with at least one risk factor for AIDS were recruited. In these women, a sample of blood to determine HIV antibodies was taken. There were two women with positive HIV antibodies; therefore, the HIV seroprevalence was 0.8 per 1,000. Of the two HIV-positive women, one of them had a history of chronic sexually transmitted diseases; she was married to a man who was working outside of our country for about 10 months, and also he had tattoos. The other HIV-positive woman had a history of chronic sexually transmitted diseases, and her husband had intercourse with different women. The risk factors of use of tattoos, migration to foreign countries, and use of injectable drugs were more frequent among the male partners than in the pregnant women (P < .001). We concluded that in our country as well as in other developing countries, the prevalence of HIV antibodies in pregnant women with risk factors is low but still present. Because a significant number of risk factors for AIDS also were found in their male partners, HIV testing should be performed in all pregnant women as well as in their male partners.


Assuntos
Anticorpos Anti-HIV/sangue , Infecções por HIV/diagnóstico , Infecções por HIV/epidemiologia , Complicações Infecciosas na Gravidez/epidemiologia , Saúde da Mulher , Adulto , Estudos Transversais , Feminino , HIV-1/imunologia , Humanos , México/epidemiologia , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico , Prevalência , Estudos Retrospectivos , Fatores de Risco , Parceiros Sexuais , Adulto Jovem
7.
J Med Chem ; 61(24): 11327-11340, 2018 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-30457865

RESUMO

Society urgently needs new, effective medicines for the treatment of tuberculosis. To kick-start the required hit-to-lead campaigns, the libraries of pharmaceutical companies have recently been evaluated for starting points. The GlaxoSmithKline (GSK) library yielded many high-quality hits, and the associated data were placed in the public domain to stimulate engagement by the wider community. One such series, the spiro compounds, are described here. The compounds were explored by a combination of traditional in-house research and open source methods. The series benefits from a particularly simple structure and a short associated synthetic chemistry route. Many members of the series displayed striking potency and low toxicity, and highly promising in vivo activity in a mouse model was confirmed with one of the analogues. Ultimately the series was discontinued due to concerns over safety, but the associated data remain public domain, empowering others to resume the series if the perceived deficiencies can be overcome.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Compostos de Espiro/síntese química , Relação Estrutura-Atividade , Tuberculose/tratamento farmacológico , Administração Intravenosa , Administração Oral , Animais , Antituberculosos/efeitos adversos , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Canal de Potássio ERG1/antagonistas & inibidores , Feminino , Coração/efeitos dos fármacos , Humanos , Dose Máxima Tolerável , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/efeitos dos fármacos , Coelhos
8.
CPT Pharmacometrics Syst Pharmacol ; 6(11): 787-797, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28657202

RESUMO

The aim of this study was to investigate pharmacodynamic (PD) interactions in mice infected with Mycobacterium tuberculosis using population pharmacokinetics (PKs), the Multistate Tuberculosis Pharmacometric (MTP) model, and the General Pharmacodynamic Interaction (GPDI) model. Rifampicin, isoniazid, ethambutol, or pyrazinamide were administered in monotherapy for 4 weeks. Rifampicin and isoniazid showed effects in monotherapy, whereas the animals became moribund after 7 days with ethambutol or pyrazinamide alone. No PD interactions were observed against fast-multiplying bacteria. Interactions between rifampicin and isoniazid on killing slow and non-multiplying bacteria were identified, which led to an increase of 0.86 log10 colony-forming unit (CFU)/lungs at 28 days after treatment compared to expected additivity (i.e., antagonism). An interaction between rifampicin and ethambutol on killing non-multiplying bacteria was quantified, which led to a decrease of 2.84 log10 CFU/lungs at 28 days after treatment (i.e., synergism). These results show the value of pharmacometrics to quantitatively assess PD interactions in preclinical tuberculosis drug development.


Assuntos
Antituberculosos/administração & dosagem , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Animais , Antituberculosos/farmacologia , Quimioterapia Combinada , Etambutol/administração & dosagem , Etambutol/farmacologia , Feminino , Humanos , Isoniazida/administração & dosagem , Isoniazida/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Pirazinamida/administração & dosagem , Pirazinamida/farmacologia , Rifampina/administração & dosagem , Rifampina/farmacologia , Tuberculose/microbiologia
9.
J Med Chem ; 60(19): 8011-8026, 2017 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-28953378

RESUMO

There is an urgent need to develop new and safer antitubercular agents that possess a novel mode of action. We synthesized and evaluated a novel series of 3-aminomethyl 4-halogen benzoxaboroles as Mycobacterium tuberculosis (Mtb) leucyl-tRNA synthetase (LeuRS) inhibitors. A number of Mtb LeuRS inhibitors were identified that demonstrated good antitubercular activity with high selectivity over human mitochondrial and cytoplasmic LeuRS. Further evaluation of these Mtb LeuRS inhibitors by in vivo pharmacokinetics (PK) and murine tuberculosis (TB) efficacy models led to the discovery of GSK3036656 (abbreviated as GSK656). This molecule shows potent inhibition of Mtb LeuRS (IC50 = 0.20 µM) and in vitro antitubercular activity (Mtb H37Rv MIC = 0.08 µM). Additionally, it is highly selective for the Mtb LeuRS enzyme with IC50 of >300 µM and 132 µM for human mitochondrial LeuRS and human cytoplasmic LeuRS, respectively. In addition, it exhibits remarkable PK profiles and efficacy against Mtb in mouse TB infection models with superior tolerability over initial leads. This compound has been progressed to clinical development for the treatment of tuberculosis.


Assuntos
Antituberculosos/síntese química , Antituberculosos/farmacologia , Compostos de Boro/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos com 2 Anéis/farmacologia , Leucina-tRNA Ligase/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Animais , Antituberculosos/farmacocinética , Compostos de Boro/síntese química , Compostos de Boro/farmacocinética , Descoberta de Drogas , Inibidores Enzimáticos/farmacocinética , Feminino , Compostos Heterocíclicos com 2 Anéis/síntese química , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/enzimologia , Relação Estrutura-Atividade , Especificidade por Substrato
10.
Eur J Pharm Sci ; 93: 319-33, 2016 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-27473307

RESUMO

The current first-line therapy for drug-susceptible tuberculosis consists of rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA) and ethambutol (EMB). In this study, we determined the population pharmacokinetics (PopPK) of RIF, INH, EMB and PZA using original experimental sampling designs for single-dose intravenous (IV) and single- and multiple-dose oral administration studies in the mouse model, and used these PopPK models to develop and evaluate new, more informative sampling designs with the aim of reducing the number of animals required for each drug. The RIF, INH, EMB and PZA blood concentrations after single oral and IV doses and multiple-dose oral administrations based on the original designs were used in the PopPK analysis using NONMEM software. The final PopPK models described the data well. Stochastic simulation and estimation were used to optimise the designs. The relative bias and relative imprecision of each pharmacokinetic parameter for each drug were derived and assessed to choose the final designs. The final single-dose IV and oral designs included up to eight samples per mouse with a total of 24 mice required for RIF and EMB and 33 mice for INH and PZA. In the new multiple-dose (zipper) oral designs, the mice were divided into two groups of three per dose, and four samples were taken from each mouse to cover all seven or eight sampling time points. The final number of mice required for the multiple-dose oral designs was 30 for RIF, INH and EMB, 36 for PZA. The number of mice required in the new designs for RIF, INH and EMB was decreased by up to 7-fold and the relative bias and relative imprecision in the parameter estimates were at least similar to those in the original designs.


Assuntos
Antibióticos Antituberculose/farmacocinética , Modelos Biológicos , Animais , Antibióticos Antituberculose/sangue , Modelos Animais de Doenças , Etambutol/sangue , Etambutol/farmacocinética , Isoniazida/sangue , Isoniazida/farmacocinética , Camundongos Endogâmicos C57BL , Pirazinamida/sangue , Pirazinamida/farmacocinética , Rifampina/sangue , Rifampina/farmacocinética , Tamanho da Amostra
11.
ChemMedChem ; 11(7): 687-701, 2016 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-26934341

RESUMO

Isoniazid (INH) remains one of the cornerstones of antitubercular chemotherapy for drug-sensitive strains of M. tuberculosis bacteria. However, the increasing prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains containing mutations in the KatG enzyme, which is responsible for the activation of INH into its antitubercular form, have rendered this drug of little or no use in many cases of drug-resistant tuberculosis. Presented herein is a novel family of antitubercular direct NADH-dependent 2-trans enoyl-acyl carrier protein reductase (InhA) inhibitors based on an N-benzyl-4-((heteroaryl)methyl)benzamide template; unlike INH, these do not require prior activation by KatG. Given their direct InhA target engagement, these compounds should be able to circumvent KatG-related resistance in the clinic. The lead molecules were shown to be potent inhibitors of InhA and showed activity against M. tuberculosis bacteria. This new family of inhibitors was found to be chemically tractable, as exemplified by the facile synthesis of analogues and the establishment of structure-activity relationships. Furthermore, a co-crystal structure of the initial hit with the enzyme is disclosed, providing valuable information toward the design of new InhA inhibitors for the treatment of MDR/XDR tuberculosis.


Assuntos
Antituberculosos/farmacologia , Benzamidas/farmacologia , Inibidores Enzimáticos/farmacologia , Inibinas/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , NAD/metabolismo , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Animais , Antituberculosos/síntese química , Antituberculosos/química , Benzamidas/síntese química , Benzamidas/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Inibinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/enzimologia , Relação Estrutura-Atividade , Tuberculose Resistente a Múltiplos Medicamentos/enzimologia
12.
EBioMedicine ; 8: 291-301, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27428438

RESUMO

Despite being one of the first antitubercular agents identified, isoniazid (INH) is still the most prescribed drug for prophylaxis and tuberculosis (TB) treatment and, together with rifampicin, the pillars of current chemotherapy. A high percentage of isoniazid resistance is linked to mutations in the pro-drug activating enzyme KatG, so the discovery of direct inhibitors (DI) of the enoyl-ACP reductase (InhA) has been pursued by many groups leading to the identification of different enzyme inhibitors, active against Mycobacterium tuberculosis (Mtb), but with poor physicochemical properties to be considered as preclinical candidates. Here, we present a series of InhA DI active against multidrug (MDR) and extensively (XDR) drug-resistant clinical isolates as well as in TB murine models when orally dosed that can be a promising foundation for a future treatment.


Assuntos
Antituberculosos/farmacologia , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Animais , Antituberculosos/química , Sítios de Ligação , Domínio Catalítico , Modelos Animais de Doenças , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/genética , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/metabolismo , Inibidores Enzimáticos/química , Feminino , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Microssomos , Modelos Moleculares , Mutação , Mycobacterium tuberculosis/genética , Ligação Proteica , Conformação Proteica , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Tuberculose/mortalidade , Tuberculose Resistente a Múltiplos Medicamentos
13.
ACS Infect Dis ; 1(12): 604-14, 2015 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-26771003

RESUMO

Antifolates are widely used to treat several diseases but are not currently used in the first-line treatment of tuberculosis, despite evidence that some of these molecules can target Mycobacterium tuberculosis (Mtb) bacilli in vitro. To identify new antifolate candidates for animal-model efficacy studies of tuberculosis, we paired knowledge and tools developed in academia with the infrastructure and chemistry resources of a large pharmaceutical company. Together we curated a focused library of 2508 potential antifolates, which were then tested for activity against live Mtb. We identified 210 primary hits, confirmed the on-target activity of potent compounds, and now report the identification and characterization of 5 hit compounds, representative of 5 different chemical scaffolds. These antifolates have potent activity against Mtb and represent good starting points for improvement that could lead to in vivo efficacy studies.

14.
PLoS Negl Trop Dis ; 8(10): e3253, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25340575

RESUMO

In the interest of identification of new kinase-targeting chemotypes for target and pathway analysis and drug discovery in Trypanosomal brucei, a high-throughput screen of 42,444 focused inhibitors from the GlaxoSmithKline screening collection was performed against parasite cell cultures and counter-screened against human hepatocarcinoma (HepG2) cells. In this way, we have identified 797 sub-micromolar inhibitors of T. brucei growth that are at least 100-fold selective over HepG2 cells. Importantly, 242 of these hit compounds acted rapidly in inhibiting cellular growth, 137 showed rapid cidality. A variety of in silico and in vitro physicochemical and drug metabolism properties were assessed, and human kinase selectivity data were obtained, and, based on these data, we prioritized three compounds for pharmacokinetic assessment and demonstrated parasitological cure of a murine bloodstream infection of T. brucei rhodesiense with one of these compounds (NEU-1053). This work represents a successful implementation of a unique industrial-academic collaboration model aimed at identification of high quality inhibitors that will provide the parasitology community with chemical matter that can be utilized to develop kinase-targeting tool compounds. Furthermore these results are expected to provide rich starting points for discovery of kinase-targeting tool compounds for T. brucei, and new HAT therapeutics discovery programs.


Assuntos
Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Animais , Feminino , Células Hep G2 , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Trypanosoma brucei brucei/crescimento & desenvolvimento , Tripanossomíase Africana/tratamento farmacológico
15.
PLoS One ; 8(2): e56980, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23437287

RESUMO

1,5-Diphenyl pyrroles were previously identified as a class of compounds endowed with high in vitro efficacy against M. tuberculosis. To improve the physical chemical properties and drug-like parameters of this class of compounds, a medicinal chemistry effort was undertaken. By selecting the optimal substitution patterns for the phenyl rings at N1 and C5 and by replacing the thiomorpholine moiety with a morpholine one, a new series of compounds was produced. The replacement of the sulfur with oxygen gave compounds with lower lipophilicity and improved in vitro microsomal stability. Moreover, since the parent compound of this family has been shown to target MmpL3, mycobacterial mutants resistant to two compounds have been isolated and characterized by sequencing the mmpL3 gene; all the mutants showed point mutations in this gene. The best compound identified to date was progressed to dose-response studies in an acute murine TB infection model. The resulting ED(99) of 49 mg/Kg is within the range of commonly employed tuberculosis drugs, demonstrating the potential of this chemical series. The in vitro and in vivo target validation evidence presented here adds further weight to MmpL3 as a druggable target of interest for anti-tubercular drug discovery.


Assuntos
Antibióticos Antituberculose/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Piperazinas/farmacologia , Pirróis/farmacologia , Tuberculose/metabolismo , Animais , Antibióticos Antituberculose/química , Antibióticos Antituberculose/toxicidade , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Linhagem Celular , Feminino , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Microssomos/metabolismo , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo , Piperazinas/química , Piperazinas/toxicidade , Pirróis/química , Pirróis/toxicidade , Tuberculose/tratamento farmacológico
16.
Pharm Res ; 22(11): 1769-82, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16158214

RESUMO

PURPOSE: The twofold aim of this study was to characterize in vivo in rats the pharmacokinetics (PK) and pharmacodynamics (PD) of L6-OH, a metabolite of lerisetron with in vitro pharmacological activity, and evaluate the extent to which L6-OH contributes to the overall effect. METHODS: The PK of L6-OH was determined directly postmetabolite i.v. dose (PK-1), and also simultaneously for L (lerisetron concentration) and for generated L6-OH after lerisetron dose (200 microg kg(-1), i.v.), using Nonlinear Mixed Effects Modeling with an integrated parent-metabolite PK model (PK-2). Surrogate effect was measured by inhibition of serotonin-induced bradycardia. Protein binding was assayed via ultrafiltration and all quantification was performed via liquid chromatography-electrospray ionization-mass spectrometry. RESULTS: L6-OH showed elevated plasma and renal clearances, and volume of distribution (PK-1). The in vivo potency (PD) of L6-OH was high (EC(50) = 0.098 ng mL(-1) and EC(50unbound) = 0.040 ng mL(-1)). Total clearance for L (PK-2) in the presence of generated L6-OH (CL(L) = CL(-->L6-OH) + CL(n)) was 0.0139 L min(-1). Most of this clearance was L6-OH formation (F(c) = 99.6%), but only an 8.6% fraction of L6-OH was released into the bloodstream. The remainder undergoes biliar and fecal elimination. The parameters estimated from PK-2 were used to predict concentrations of L6-OH (Cp(L6)) generated after a lerisetron therapeutic dose (10 microg kg(-1)) in the rat. These concentrations are needed for the PD model and are below the quantification limit. Cp(L6max) was less than the EC(50) of L6-OH. CONCLUSIONS: We conclude that after lerisetron administration, L6-OH is extensively formed in the rat but it is quickly eliminated; therefore, besides being equipotent with the parent drug, the L6-OH metabolite does not influence the effect of lerisetron.


Assuntos
Benzimidazóis/metabolismo , Piperidinas/metabolismo , Antagonistas da Serotonina/metabolismo , Animais , Benzimidazóis/farmacologia , Relação Dose-Resposta a Droga , Frequência Cardíaca/efeitos dos fármacos , Hidroxilação , Masculino , Modelos Biológicos , Piperidinas/farmacologia , Ratos , Ratos Sprague-Dawley
17.
Gac. méd. Caracas ; 110(3): 347-349, jul.-sept. 2002.
Artigo em Espanhol | LILACS | ID: lil-401994

RESUMO

La historia clínica es un instrumento valioso en el ejercicio de la medicina. Un registro adecuado de los datos permite tomar decisiones atinadas y resulta útil en la creación de bases de datos, proyectos de investigación, docencia, control de recursos hospitalarios. Desarrollar una nueva metodología en el registro de los datos de las historias clínicas, utilizando un formato tabular de filas y columnas. Tener nota de ingreso a sala de hospitalización, hoja para las evoluciones con formato uniforme. Las hojas para el registro de los datos tienen formato tabular. En la primera columna se van registrando los signos y síntomas individualmente y en la fila respectiva se indica con un dígito (cero o uno) ausencia o su presencia a lo largo de los días de hospitalización. Se consideraron los días hospitalizados, días válidos para las evoluciones, total de hojas utilizadas para escribir las evoluciones, seguimiento de cada signo y/o síntomas registrados en la nota de ingreso a sala y días subsiguientes. Se evaluaron un total de 40 historias clínicas, 42,50 por ciento de los pacientes eran de sexo masculino,25 por ciento del servicio de medicina interna y 75 por ciento del servicio de cardiología. Edad promedio de los pacientes 58,33 ± 15,82 años. Total de días evaluados por los médicos se corresponde en un 80 por ciento sobre el total de días considerados como válidos. Total de items (signos y síntomas), resultó de 8,45 ± 2,73. Cada item fue registrado en promedio sólo en un 35 por ciento sobre el total de días válidos. Promedio de área de escritura de las hojas de las historias y as protocolo fue de 2 231,25 cm² y 63,3 cm² respectivamente. Al establecer un formato tabular de filas y columnas para el registro de las evaluaciones en las historias clínicas, se evita la repetición innecesaria y se tiene un modelo gráfico y cronológico en el registro de cada signo y/o síntomas, que a su vez facilita la creación de una base de datos


Assuntos
Coleta de Dados , Prontuários Médicos , Métodos , Venezuela
18.
Salus militiae ; 25(1): 31-38, ene.-jun. 2000. tab, graf
Artigo em Espanhol | LILACS | ID: lil-310617

RESUMO

A propósito de una revisión de los archivos de anatomía patológica del Hospital "Miguel Pérez Carreño", de un universo de 71.978 biopsias, se encontraron 716 biopsias de médula ósea; de estas 228 corresponden a casos de patologías no clonales (31,84 por ciento) distribuidas de la siguiente forma: anemias 116 casos (50,88 por ciento), leucopenia 47 casos (20,61 por ciento), trombocitopenia 43 casos (18,86 por ciento) e hipoplasia 22 casos (9,65 por ciento). Se encontraron 36 casos relacionados con la exposición a agentes externos, correspondiendo a un 15,78 por ciento. La patología que se encontró más asociada fue la anemia con 13 casos (36,11 por ciento); siendo la anemia megaloblástica la más frecuente con 7 casos (53,84 por ciento). La leucopenia ocupó el segundo lugar en frecuencia con 12 casos (33,33 por ciento), seguida por la trombocitopenia con 7 casos (19,44 por ciento) y la hipoplasia con 4 casos (11,11 por ciento). El sexo y grupo etario más relacioando con las patologías no clonales, en función de los agentes externos, fue el femenino con 20 casos (55,55 por ciento); siendo la quinta década más afectada con 8 casos. El agente terapeútico de mayor asociación con dichas patologías, fueron los antihipertensivos con 5 casos. El agente químico con mayor número de casos, fueron los insecticidas con 6 casos (16,66 por ciento) seguido por el alcohol con 5 casos (13,88 por ciento); el agente físico más relacionado con las patologías no clonales fue la exposición a los rayos X con 3 casos (8,33 por ciento). En la anemia, el agente externo que coincidió con mayor frecuencia fue el alcohol con 3 casos (8,33 por ciento), en la leucopenia, fue el insecticida con 4 casos (11,11 por ciento); en cuanto a la trombocitopenia fueron los antihipertensivos y la aspirina con 2 casos cada uno (5,55 por ciento respectivamente); con relación a la hipoplasia fueron los antibióticos con 2 casos (5,55 por ciento). se comparan estos hallazgos con lo descrito en la literatura nacional e internacional


Assuntos
Humanos , Masculino , Feminino , Trombocitopenia , Biópsia , Anemia , Leucopenia , Anti-Hipertensivos , Células Clonais/patologia , Medula Óssea/patologia , Venezuela , Medicina
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