New and repurposed drugs to treat multidrug- and extensively drug-resistant tuberculosis / Novos fármacos e fármacos repropostos para o tratamento da tuberculose multirresistente e extensivamente resistente

ABSTRACT Multidrug-resistant and extensively drug-resistant tuberculosis (MDR-TB and XDR-TB, respectively) continue to represent a challenge for clinicians and public health authorities. Unfortunately, although there have been encouraging reports of higher success rates, the overall rate of favorable outcomes of M/XDR-TB treatment is only 54%, or much lower when the spectrum of drug resistance is beyond that of XDR-TB. Treating M/XDR-TB continues to be a difficult task, because of the high incidence of adverse events, the long duration of treatment, the high cost of the regimens used, and the drain on health care resources. Various trials and studies have recently been undertaken (some already published and others ongoing), all aimed at improving outcomes of M/XDR-TB treatment by changing the overall approach, shortening treatment duration, and developing a universal regimen. The objective of this review was to summarize what has been achieved to date, as far as new and repurposed drugs are concerned, with a special focus on delamanid, bedaquiline, pretomanid, clofazimine, carbapenems, and linezolid. After more than 40 years of neglect, greater attention has recently been paid to the need for new drugs to fight the "white plague", and promising results are being reported.

RESUMO A tuberculose multirresistente (TB-MDR, do inglês multidrug-resistant) e a extensivamente resistente (TB-XDR, do inglês extensively drug-resistant) continuam representando um desafio para os clínicos e as autoridades de saúde pública. Infelizmente, embora haja relatos encorajadores de taxas de sucesso maiores, a taxa global de desfechos favoráveis do tratamento da TB-MDR/XDR é de apenas 54%, ou muito menor quando o espectro de resistência aos fármacos vai além do da TB-XDR. O tratamento da TB-MDR/XDR continua sendo uma tarefa difícil, em razão da alta incidência de eventos adversos, do longo tempo de tratamento, do alto culto dos esquemas utilizados e da drenagem dos recursos de saúde. Diversos ensaios e estudos foram realizados recentemente (alguns já publicados e outros em andamento), todos visando a melhorar os desfechos do tratamento da TB-MDR/XDR por meio da alteração da abordagem geral, redução do tempo de tratamento e desenvolvimento de um esquema universal. O objetivo desta revisão foi resumir o que se conseguiu até o momento, no que se refere a novos fármacos e fármacos repropostos, dando foco especial para delamanid, bedaquilina, pretomanida, clofazimina, carbapenêmicos e linezolida. Após mais de 40 anos de negligência, recentemente foi dada mais atenção á necessidade de novos fármacos para se combater a "praga branca", e resultados promissores estão sendo relatados.

In vitro susceptibility of methicillin-resistant Staphylococcus aureus isolates from skin and soft tissue infections to vancomycin, daptomycin, linezolid and tedizolid

Abstract Introduction Treatment of multidrug-resistant Gram-positive infections caused by Staphylococcus aureus remains as a clinical challenge due to emergence of new resistance mechanisms. Tedizolid is a next-generation oxazolidinone, recently approved for skin and soft tissues infections. We conducted a study to determine in vitro susceptibility to vancomycin, daptomycin, linezolid and tedizolid in MRSA clinical isolates from adult patients with skin and soft tissue infections. Material and methods Methicillin-resistant S. aureus isolates were collected in three tertiary-care hospitals of Medellin, Colombia, from February 2008 to June 2010 as part of a previous study. Clinical characteristics were assessed by medical records and MIC values were determined by Epsilometer test. Genotypic analysis included spa typing, MLST, and SCCmec typing. Results A total of 150 MRSA isolates were evaluated and tedizolid MIC values obtained showed higher in vitro activity than other antimicrobials, with MIC values ranging from 0.13 µg/mL to 0.75 µg/mL and lower values of MIC50 and MIC90 (0.38 µg/mL and 0.5 µg/mL). In contrast, vancomycin and linezolid had higher MIC values, which ranged from 0.5 µg/mL to 2.0 µg/mL and from 0.38 µg/mL to 4.0 µg/mL, respectively. Tedizolid MICs were 2- to 5-fold lower than those of linezolid. Clinical characteristics showed high previous antimicrobial use and hospitalization history. The majority of the strains belong to the CC8 harboring the SCCmec IVc and were associated with the spa t1610 (29.33%, n = 44). Conclusion In vitro effectiveness of tedizolid was superior for isolates from skin and soft tissue infections in comparison with the other antibiotics evaluated. The above added to its less toxicity, good bioavailability, daily dose and unnecessity of dosage adjustment, make tedizolid in a promising alternative for the treatment of infections caused by MRSA.

Avances en el tratamiento de la tuberculosis multirresistente / Advances in the treatment of multi-drug resistant tuberculosis

Resumen El tratamiento de las tuberculosis multidrogorresistentes (TBC-MDR) se basa en esquemas de fármacos con diseños muy variables, en pacientes con patrones de resistencia heterogéneos y seguimientos no estandarizados, lo que hace dificil plantear recomendaciones con fuerte nivel de evidencia. Además, sólo una minoría de estos enfermos recibe tratamiento a nivel mundial y con los actuales esquemas menos del 50% de los que logran ser tratados curan. Afortunadamente, durante los últimos años han aparecido nuevos medicamentos, (bedaquilina, delamanid y pretomanid), que están demostrando ser de real utilidad para estos pacientes en ensayos con mejor diseño y seguimiento, donde se puede establecer con mayor precisión la eficacia, toxicidad y grado de recaídas. Además, algunos fármacos ya conocidos, (fluoroquinolonas, linezolid, clofazimina) están siendo introducidos dentro de los nuevos esquemas de tratamiento.

Abstract Therapy of multi-drug resistant tuberculosis (MDR TB) is based on trials with drugs with highly variable patterns of resistance and non-standardized follow-ups that make it difficult to provide recommendations with strong levels of evidence. Also, the vast majority of MDR-TB patients fail to receive therapy and those who receive it, only achieve around 50% of good results. Fortunately new drugs have emerged (bedaquiline, delamanid, pretomanid) that are being useful for these patients with better designed trials and monitoring, in which the efficacy, toxicity and degree of relapses can be evaluated more accurately. Some drugs already known (fluorquinolones, linezolid and clofazimine) are also being introduced in new schemes of therapy.

Efficacy, safety, tolerability and population pharmacokinetics of tedizolid, a novel antibiotic, in Latino patients with acute bacterial skin and skin structure infections

Abstract Acute bacterial skin and skin structure infections are caused mainly by Gram-positive bacteria which are often treated with intravenous vancomycin, daptomycin, or linezolid, with potential step down to oral linezolid for outpatients. Tedizolid phosphate 200 mg once daily treatment for six days demonstrated non-inferior efficacy, with a favourable safety profile, compared with linezolid 600 mg twice daily treatment for 10 days in the Phase 3 ESTABLISH-1 and -2 trials. The objective of the current post-hoc analysis of the integrated dataset of ESTABLISH-1 and -2 was to evaluate the efficacy and safety of tedizolid (N = 182) vs linezolid (N = 171) in patients of Latino origin enrolled into these trials. The baseline demographic characteristics of Latino patients were similar between the two treatment groups. Tedizolid demonstrated comparable efficacy to linezolid at 48–72 h in the intent-to-treat population (tedizolid: 80.2% vs linezolid: 81.9%). Sustained clinical success rates were comparable between tedizolid- and linezolid-treated Latino patients at end-of-therapy (tedizolid: 86.8% vs linezolid: 88.9%). Tedizolid phosphate treatment was well tolerated by Latino patients in the safety population with lower abnormal platelet counts at end-of-therapy (tedizolid: 3.4% vs linezolid: 11.3%, p = 0.0120) and lower incidence of gastrointestinal adverse events (tedizolid: 16.5% vs linezolid: 23.5%). Population pharmacokinetic analysis suggested that estimated tedizolid exposure measures in Latino patients vs non-Latino patients were similar. These findings demonstrate that tedizolid phosphate 200 mg, once daily treatment for six days was efficacious and well tolerated by patients of Latino origin, without warranting dose adjustment.

Isolation of an aryloxyphenoxy propanoate (AOPP) herbicide-degrading strain Rhodococcus ruber JPL-2 and the cloning of a novel carboxylesterase gene (feh)

The strain JPL-2, capable of degrading fenoxaprop-P-ethyl (FE), was isolated from the soil of a wheat field and identified as Rhodococcus ruber. This strain could utilize FE as its sole carbon source and degrade 94.6% of 100 mg L−1 FE in 54 h. Strain JPL-2 could also degrade other aryloxyphenoxy propanoate (AOPP) herbicides. The initial step of the degradation pathway is to hydrolyze the carboxylic acid ester bond. A novel esterase gene feh, encoding the FE-hydrolyzing carboxylesterase (FeH) responsible for this initial step, was cloned from strain JPL-2. Its molecular mass was approximately 39 kDa, and the catalytic efficiency of FeH followed the order of FE > quizalofop-P-ethyl > clodinafop-propargyl > cyhalofop-butyl > fluazifop-P-butyl > haloxyfop-P-methyl > diclofop-methy, which indicated that the chain length of the alcohol moiety strongly affected the hydrolysis activity of the FeH toward AOPP herbicides.

Serological detection of Toxoplasma gondii, Leishmania infantum and Neospora caninum in cats from an area endemic for leishmaniasis in Brazil / Detecção sorológica de Toxoplasma gondii, Leishmania infantum e Neospora caninum em gatos de uma área endêmica para leishmaniose no Brasil

An investigation was made into the occurrence of antibodies to Toxoplasma gondii, Leishmania infantum and Neospora caninum in 151 domestic cats, based on the indirect fluorescent antibody test (IFAT). Serum samples were collected from 151 domestic cats (65 free-roaming and 86 domiciled cats; 55 males and 96 females) in Campo Grande, Mato Grosso do Sul, Brazil between January and April 2013. IgG antibodies to T. gondii, L. infantum and N. caninum were found, respectively, in 49 (32.5%), 34 (22.5%) and 10 (6.6%) sampled cats. A positive correlation was found between T. gondii and N. caninum, T. gondii and L. infantum, and N. caninum and L. infantum (p <0.05) infections. Also, a significant interaction was identified between gender and area of activity on the probability of T. gondii (p = 0.0324) infection. However, no significant interaction was observed between gender and area of activity on infections by either N. caninum or L. infantum. This study showed that cats from an area endemic for visceral leishmaniasis in Brazil are exposed to three different protozoans, two of which are causal agents of important zoonosis.

O presente estudo teve como objetivo investigar a ocorrência de anticorpos anti-Toxoplasma gondii, Leishmania infantum e Neospora caninum, em 151 gatos, por meio da Reação de Imunofluorescência Indireta (RIFI). Entre os meses de janeiro e abril de 2013, amostras de soro foram coletadas de 151 gatos domésticos (65 gatos errantes e 86 gatos domiciliados; 55 machos e 96 fêmeas), de Campo Grande, Mato Grosso do Sul, Brasil. Anticorpos IgG anti-T. gondii, anti-L. infantum e anti-N. caninum foram encontrados em 49 (32,5%), 34 (22,5%) e 10 (6,6%) gatos amostrados, respectivamente. Verificou-se uma associação estatisticamente significativa entre as infecções por T. gondii e N. caninum, T. gondii e L. infantum e N. caninum e Leishmania infantum (p <0,05). Além disso, foi observada uma interação significativa entre sexo, área de atividade na probabilidade de infecção por T. gondii (p = 0,0324). No entanto, não foi observada interação significativa entre sexo e área de atividade nas infecções por N. caninum e L. infantum. Este estudo mostrou que os gatos de uma área endêmica brasileira para leishmaniose visceral são expostos a três diferentes protozoários, sendo dois deles importantes agentes zoonóticos.

Vascular O-GlcNAcylation augments reactivity to constrictor stimuli by prolonging phosphorylated levels of the myosin light chain

O-GlcNAcylation is a modification that alters the function of numerous proteins. We hypothesized that augmented O-GlcNAcylation levels enhance myosin light chain kinase (MLCK) and reduce myosin light chain phosphatase (MLCP) activity, leading to increased vascular contractile responsiveness. The vascular responses were measured by isometric force displacement. Thoracic aorta and vascular smooth muscle cells (VSMCs) from rats were incubated with vehicle or with PugNAc, which increases O-GlcNAcylation. In addition, we determined whether proteins that play an important role in the regulation of MLCK and MLCP activity are directly affected by O-GlcNAcylation. PugNAc enhanced phenylephrine (PE) responses in rat aortas (maximal effect, 14.2±2 vs 7.9±1 mN for vehicle, n=7). Treatment with an MLCP inhibitor (calyculin A) augmented vascular responses to PE (13.4±2 mN) and abolished the differences in PE-response between the groups. The effect of PugNAc was not observed when vessels were preincubated with ML-9, an MLCK inhibitor (7.3±2 vs 7.5±2 mN for vehicle, n=5). Furthermore, our data showed that differences in the PE-induced contractile response between the groups were abolished by the activator of AMP-activated protein kinase (AICAR; 6.1±2 vs 7.4±2 mN for vehicle, n=5). PugNAc increased phosphorylation of myosin phosphatase target subunit 1 (MYPT-1) and protein kinase C-potentiated inhibitor protein of 17 kDa (CPI-17), which are involved in RhoA/Rho-kinase-mediated inhibition of myosin phosphatase activity. PugNAc incubation produced a time-dependent increase in vascular phosphorylation of myosin light chain and decreased phosphorylation levels of AMP-activated protein kinase, which decreased the affinity of MLCK for Ca2+/calmodulin. Our data suggest that proteins that play an important role in the regulation of MLCK and MLCP activity are directly affected by O-GlcNAcylation, favoring vascular contraction.

1, 4- Addition of diazomethane to a heterodiene: a direct preparation of the oxazolic ring

The reaction of naphthoquinone-oximes (3) and (4) with diazomethane yields directly, in one step, the oxazoles (5) and (6), respectively.

A reação das naphthoquinona-oximas (3) e (4) com diazometano fornece diretamente, em uma etapa, os oxazóis (5) e (6), respectivamente.

Caracterización neurofarmacológica de la 2-fenil-4, 4-bis-(hidroximetil)-2-oxazolina obtenida bajo irradiación de microondas / Neuropharmachological characterization of 2-phenyl-4, 4-bis-(hydroxymethyl)-2-oxazoline obtained under microwaves irradiation

Algunas aril-oxazolinas han sido descritas como sustancias activas sobre el sistema nervioso central, con efectos y aplicaciones diversas como depresoras, anestésicos, anticonvulsivantes, etc. En el presente trabajo se realizó la caracterización neurofarmacológica primaria de la 2-fenil-4,4-bis-(hidroximetil)-2-oxazolina, obtenida por un método de síntesis bajo radiación de microondas como fuente energética. La realización de la prueba de Irwin mostró que este compuesto presenta un efecto depresor sobre el sistema nervioso central, con una notable inhibición de la actividad motora y del tono muscular, con pérdida de los reflejos posturales. A dosis moderadas estos efectos se acompañaron de signos de excitación central. Estas características sugirieron una acción de tipo periférica, confirmado por el efecto bloqueador de las contorsiones en la prueba de irritación peritoneal por ácido acético al 0,8 por ciento y la disminución de la amplitud del potencial de acción neuromuscular compuesto durante la estimulación supramáxima del nervio ciático, pruebas que evidenciaron una acción anestésica local para la 2-fenil-4,4-bis-(hidroximetil)-2-oxazolina

Bloqueo de las crisis audiogénicas y del choque electroconvulsivo por la 2-fenil-4, 4-bis-(hidroximetil)-2-oxazolina / Block of the audiogenic seizures and of the electroconvulsive shock by 2-phenyl-4, 4-bis-(hydroxymethyl)-2-oxazoline

Algunas aril-oxazolinas han sido descritas como sustancias activas sobre el sistema nervioso central, con efectos y aplicaciones diversas como depresoras, anestésicos, anticonvulsivos, etc. El presente trabajo se trazó como objetivo fundamental estudiar el posible efecto de la 2-fenil-4,4-bis (hidroximetil)-2-oxazolina (OX) obtenida por síntesis química bajo microondas, en 2 modelos experimentales de epilepsia: el choque electroconvulsivo por estimulación repetitiva en ratones y el de inducción de crisis convulsiva por estímulo audiogénico en el gerbo mongol. La dosis de 150 mg/kg de OX redujo el número de pulsos eléctricos necesarios para inducir la crisis tónica producida por el choque eléctrico, así como su duración. Esta misma dosis bloqueó las crisis inducidas por el estímulo audiogénico en el gerbo, y disminuyó significativamente su severidad (grados de crisis) y ocurrencia. Estos resultados permiten afirmar que OX presenta un efecto antiepiléptico relacionado posiblemente con una inhibición de la sinapsis glutamatérgica en el hipocampo

Protective effects of centrally acting sympathomodulatory drugs on myocardial ischemia induced by sympathetic overactivity in rabbits

It is recognized that an imbalance of the autonomic nervous system is involved in the genesis of ventricular arrhythmia and sudden death during myocardial ischemia. In the present study we investigated the effects of clonidine and rilmenidine, two centrally acting sympathomodulatory drugs, on an experimental model of centrally induced sympathetic hyperactivity in pentobarbital-anesthetized New Zealand albino rabbits of either sex (2-3 kg, N = 89). We also compared the effects of clonidine and rilmenidine with those of propranolol, a á-blocker, known to induce protective cardiovascular effects in patients with ischemic heart disease. Central sympathetic stimulation was achieved by intracerebroventricular injection of the excitatory amino acid L-glutamate (10 æmol), associated with inhibition of nitric oxide synthesis with L-NAME (40 mg/kg, iv). Glutamate triggered ventricular arrhythmia and persistent ST-segment shifts in the ECG, indicating myocardial ischemia. The intracisternal administration of clonidine (1 æg/kg) and rilmenidine (30 æg/kg) or of a nonhypotensive dose of rilmenidine (3 æg/kg) decreased the incidence of myocardial ischemia (25, 14 and 25 percent, respectively, versus 60 percent in controls) and reduced the mortality rate from 40 percent to 0.0, 0.0 and 12 percent, respectively. The total number of ventricular premature beats per minute fell from 30 ± 9 in the control group to 7 ± 3, 6 ± 3 and 2 ± 2, respectively. Intravenous administration of clonidine (10 æg/kg), rilmenidine (300 æg/kg) or propranolol (500 æg/kg) elicited similar protective effects. We conclude that clonidine and rilmenidine present cardioprotective effects of central origin, which can be reproduced by propranolol, a lipophilic á-blocking agent

Toloxatona y depresión / Toloxatone and depression

Los autores informan la experiencia recogida con la utilización, en 101 pacientes deprimidos, de un antidepressivo de segunda generación, la toloxatona: molécula original dotada de una actividad inhibidora específica y reversible de la MAO A. Al momento de la admisión, los 101 pacientes con enfermedad depresiva presentaban un score mínimo de 20 puntos en al Escala de Hamilton y un puntaje no inferior a 4 en el Test del índice de endogeneidad de Fischer, Fernández Labriola y Rodríguez Casanova. En 57 de ellos se dispuso de perfiles biológicos: Fenil-etilamina, NA y MHPG. Asimismo, en el momento de la admisión ningún paciente estaba ingiriendo antidepresivos. El estudio fue un doble ciego vs. placebo; la edad promedio de los pacientes era de 46 años. El experimento duró 6 semanas. La dosis diaria total se estandardizó en 400mg de toloxatona. Hubo modificaciones significativas en 51 pacietnes. De los 50 casos que recibieron principio activo, 37 obtuvieron un resultado "escelente" o "bueno". Los marcadores biológicos señalaron el perfil de pacientes que mejor responden a la molécula: los de actividad noradrenérgica disminuida. Las depresiones sin ansiedad y las depresiones inhibidas son las patologías de elección para la utilización