Alsinol, an arylamino alcohol derivative active against Plasmodium, Babesia, Trypanosoma, and Leishmania: past and new outcomes.

Malaria, babesiosis, trypanosomosis, and leishmaniasis are some of the most life-threatening parasites, but the range of drugs to treat them is limited. An effective, safe, and low-cost drug with a large activity spectrum is urgently needed. For this purpose, an aryl amino alcohol derivative called Alsinol was resynthesized, screened in silico, and tested against Plasmodium, Babesia, Trypanosoma, and Leishmania. In silico Alsinol follows the Lipinski and Ghose rules. In vitro it had schizontocidal activity against Plasmodium falciparum and was able to inhibit gametocytogenesis; it was particularly active against late gametocytes. In malaria-infected mice, it showed a dose-dependent activity similar to chloroquine. It demonstrated a similar level of activity to reference compounds against Babesia divergens, and against promastigotes, and amastigotes stages of Leishmania in vitro. It inhibited the in vitro growth of two African animal strains of Trypanosoma but was ineffective in vivo in our experimental conditions. It showed moderate toxicity in J774A1 and Vero cell models. The study demonstrated that Alsinol has a large spectrum of activity and is potentially affordable to produce. Nevertheless, challenges remain in the process of scaling up synthesis, creating a suitable clinical formulation, and determining the safety margin in preclinical models.

Primaquine-quinoxaline 1,4-di-N-oxide hybrids with action on the exo-erythrocytic forms of Plasmodium induce their effect by the production of reactive oxygen species.

BACKGROUND: The challenge in anti-malarial chemotherapy is based on the emergence of resistance to drugs and the search for medicines against all stages of the life cycle of Plasmodium spp. as a therapeutic target. Nowadays, many molecules with anti-malarial activity are reported. However, few studies about the cellular and molecular mechanisms to understand their mode of action have been explored. Recently, new primaquine-based hybrids as new molecules with potential multi-acting anti-malarial activity were reported and two hybrids of primaquine linked to quinoxaline 1,4-di-N-oxide (PQ-QdNO) were identified as the most active against erythrocytic, exoerythrocytic and sporogonic stages. METHODS: To further understand the anti-malarial mode of action (MA) of these hybrids, hepg2-CD81 were infected with Plasmodium yoelii 17XNL and treated with PQ-QdNO hybrids during 48 h. After were evaluated the production of ROS, the mitochondrial depolarization, the total glutathione content, the DNA damage and proteins related to oxidative stress and death cell. RESULTS: In a preliminary analysis as tissue schizonticidals, these hybrids showed a mode of action dependent on peroxides production, but independent of the activation of transcription factor p53, mitochondrial depolarization and arrest cell cycle. CONCLUSIONS: Primaquine-quinoxaline 1,4-di-N-oxide hybrids exert their antiplasmodial activity in the exoerythrocytic phase by generating high levels of oxidative stress which promotes the increase of total glutathione levels, through oxidation stress sensor protein DJ-1. In addition, the role of HIF1a in the mode of action of quinoxaline 1,4-di-N-oxide is independent of biological activity.

Novel antimalarial chloroquine- and primaquine-quinoxaline 1,4-di-N-oxide hybrids: Design, synthesis, Plasmodium life cycle stage profile, and preliminary toxicity studies.

Emergence of drug resistance and targeting all stages of the parasite life cycle are currently the major challenges in antimalarial chemotherapy. Molecular hybridization combining two scaffolds in a single molecule is an innovative strategy for achieving these goals. In this work, a series of novel quinoxaline 1,4-di-N-oxide hybrids containing either chloroquine or primaquine pharmacophores was designed, synthesized and tested against both chloroquine sensitive and multidrug resistant strains of Plasmodium falciparum. Only chloroquine-based compounds exhibited potent blood stage activity with compounds 4b and 4e being the most active and selective hybrids at this parasite stage. Based on their intraerythrocytic activity and selectivity or their chemical nature, seven hybrids were then evaluated against the liver stage of Plasmodium yoelii, Plasmodium berghei and Plasmodium falciparum infections. Compound 4b was the only chloroquine-quinoxaline 1,4-di-N-oxide hybrid with a moderate liver activity, whereas compound 6a and 6b were identified as the most active primaquine-based hybrids against exoerythrocytic stages, displaying enhanced liver activity against P. yoelii and P. berghei, respectively, and better SI values than primaquine. Although both primaquine-quinoxaline 1,4-di-N-oxide hybrids slightly reduced the infection of mosquitoes, they inhibited sporogony of P. berghei and compound 6a showed 92% blocking of transmission. In vivo liver efficacy assays revealed that compound 6a showed causal prophylactic activity affording parasitaemia reduction of up to 95% on day 4. Absence of genotoxicity and in vivo acute toxicity were also determined. These results suggest the approach of primaquine-quinoxaline 1,4-di-N-oxide hybrids as new potential dual-acting antimalarials for further investigation.

Pediatric asthma treatment: What to do when international guideline recommendations do not agree.

BACKGROUND: There was a need for a solid asthma guideline in Mexico to update and unify asthma management. Because high-quality asthma guidelines exist worldwide, in which the latest evidence on asthma management is summarized, the ADAPTE approach allows for the development of a national asthma guideline based on evidence from already existing guidelines, adapted to national needs. OBJECTIVE: To fuse evidence from the best asthma guidelines and adapt it to local needs with the ADAPTE approach. METHODS: The Appraisal of Guidelines for Research and Evaluation (AGREE) II asthma guidelines were evaluated by a core group to select 3 primary guidelines. For each step of asthma management, clinical questions were formulated and replied according to (1) evidence in the primary guidelines, (2) safety, (3) Cost, and (4) patient preference. The Guidelines Development Group, composed of a broad range of experts from medical specialties, primary care physicians, and methodologists, adjusted the draft questions and replies in several rounds of a Delphi process and 3 face-to-face meetings, taking into account the reality of the situation in Mexico. We present the results of the pediatric asthma treatment part. RESULTS: Selected primary guidelines are from the British Thoracic Society and Scottish Intercollegiate Guidelines Network (BTS/SIGN), Global Initiative for Asthma (GINA), and Spanish Guidelines on the Management of Asthma (GEMA) 2015, with 2016 updates. Recommendations or suggestions were made for asthma treatment in Mexico. In this article, the detailed analysis of the evidence present in the BTS/SIGN, GINA, and GEMA sections on the (non) pharmacologic treatment of pediatric asthma, education, and devices are presented for 2 age groups: children 5 years or younger and children 6 to 11 years old with asthma. CONCLUSION: For the pediatric treatment and patient education sections, applying the AGREE II and Delphi methods is useful to develop a scientifically sustained document, adjusted to the Mexican situation, as is the Mexican Guideline on Asthma.

[Mexican Asthma Guidelines: GUIMA 2017]. / Guía Mexicana del Asma: GUIMA 2017.

BACKGROUND: The need for a national guideline, with a broad basis among specialists and primary care physicians was felt in Mexico, to try unifying asthma management. As several high-quality asthma guidelines exist worldwide, it was decided to select the best three for transculturation. METHODS: Following the internationally recommended methodology for guideline transculturation, ADAPTE, a literature search for asthma guidelines, published 1-1-2007 through 31-12-2015 was conducted. AGREE-II evaluations yielded 3/40 most suitable for transculturation. Their compound evidence was fused with local reality, patient preference, cost and safety considerations to draft the guideline document. Subsequently, this was adjusted by physicians from 12 national medical societies in several rounds of a Delphi process and 3 face-to-face meetings to reach the final version. RESULTS: Evidence was fused from British Thoracic Society Asthma Guideline 2014, Global Initiative on Asthma 2015, and Guía Española del Manejo del Asma 2015 (2016 updates included). After 3 Delphi-rounds we developed an evidence-based document taking into account patient characteristics, including age, treatment costs and safety and best locally available medication. CONCLUSIONS: In cooperation pulmonologists, allergists, ENT physicians, paediatricians and GPs were able to develop an evidence-based document for the prevention, diagnosis and treatment of asthma and its exacerbations in Mexico.

Antecedentes: Con el objetivo de unificar el manejo del asma en México se estructuró una guía clínica que conjunta el conocimiento de diversas especialidades y la atención en el primer nivel de contacto. Se seleccionaron 3 guías publicadas en el ámbito internacional para su transculturación. Métodos: Conforme a la metodología ADAPTE se usó AGREE II después de la búsqueda bibliográfica de guías sobre asma publicadas entre 2007 y 2015. Se fusionó la realidad local con la evidencia de 3/40 mejores guías. El documento inicial fue sometido a la revisión de representantes de 12 sociedades médicas en varias rondas Delphi hasta llegar a la versión final. Resultados: Las guías base fueron la British Thoracic Society Asthma Guideline 2014, la Global Initiative on Asthma 2015 y la Guía Española del Manejo del Asma 2015. Después de 3 rondas Delphi se desarrolló un documento en el que se consideraron las características de los pacientes según edad, costos de los tratamientos y perfiles de seguridad de los fármacos disponibles en México. Conclusión: Con la cooperación de neumólogos, alergólogos, otorrinolaringólogos, pediatras y médicos generales se llegó a un consenso basado en evidencia, en el que se incluyeron recomendaciones sobre prevención, diagnóstico y tratamiento del asma y sus crisis.

The in vivo antimalarial activity of methylene blue combined with pyrimethamine, chloroquine and quinine.

The effectiveness of methylene blue (MB) combined with pyrimethamine (PYR), chloroquine (CQ) or quinine (Q) was examined in a classical four-day suppressive test against a causative agent of rodent malaria, Plasmodium berghei. A marked potentiation was observed when MB was administered at a non-curative dose of 15 mg/kg/day in combination with PYR (0.19 mg/kg/day) or Q (25 mg/kg/day). No synergy was found between MB (15 mg/Kg) and CQ (0.75 mg/Kg). Our results suggest that the combination of MB with PYR or Q may improve the efficacy of these currently used antimalarial drugs.

The in vivo antimalarial activity of methylene blue combined with pyrimethamine, chloroquine and quinine

The effectiveness of methylene blue (MB) combined with pyrimethamine (PYR), chloroquine (CQ) or quinine (Q) was examined in a classical four-day suppressive test against a causative agent of rodent malaria, Plasmodium berghei. A marked potentiation was observed when MB was administered at a non-curative dose of 15 mg/kg/day in combination with PYR (0.19 mg/kg/day) or Q (25 mg/kg/day). No synergy was found between MB (15 mg/Kg) and CQ (0.75 mg/Kg). Our results suggest that the combination of MB with PYR or Q may improve the efficacy of these currently used antimalarial drugs.

3-Trifluoromethylquinoxaline N,N'-dioxides as anti-trypanosomatid agents. Identification of optimal anti-T. cruzi agents and mechanism of action studies.

For a fourth approach of quinoxaline N,N'-dioxides as anti-trypanosomatid agents against T. cruzi and Leishmania, we found extremely active derivatives. The present study allows us to state the correct requirements for obtaining optimal in vitro anti-T. cruzi activity. Derivatives possessing electron-withdrawing substituents in the 2-, 3-, 6-, and 7-positions were the most active compounds. With regard to these features and taking into account their mammal cytotoxicity, some trifluoromethylquinoxaline N,N'-dioxides have been proposed as candidates for further clinical studies. Consequently, mutagenicity and in vivo analyses were performed with the most promising derivatives. In addition, with regard to the mechanism of action studies, it was demonstrated that mitochondrial dehydrogenases are involved in the anti-T. cruzi activity of the most active derivatives.

Synthesis, trypanocidal activity and docking studies of novel quinoxaline-N-acylhydrazones, designed as cruzain inhibitors candidates.

In this paper, we report the structural design, synthesis, trypanocidal activity and docking studies of novel quinoxaline-N-acylhydrazone (NAH) derivatives, planned as cruzain inhibitors candidates, a cysteine protease essential for the survival of Trypanosoma cruzi within the host cell. The salicylaldehyde N-acylhydrazones 7a and 8a presented IC(50) values of the same magnitude order than the standard drug nifurtimox (Nfx), when tested in vitro against epimastigote forms of Trypanosoma cruzi (Tulahuen 2 strain) and were non-toxic at the highest assayed doses rendering selectivity indexes (IC(50) (macrophages)/IC(50) (Trypanosoma cruzi)) of >25 for 7a and >20 for 8a, with IC(50) values in macrophages >400 microM.

Anti-leishmanial and structure-activity relationship of ring substituted 3-phenyl-1-(1, 4-di-N-oxide quinoxalin-2-yl)-2-propen-1-one derivatives

A series of ring substituted 3-phenyl-1-(1,4-di-N-oxide quinoxalin-2-yl)-2-propen-1-one derivatives were synthesized and tested for in vitro leishmanicidal activity against amastigotes of Leishmania amazonensis in axenical cultures and murine infected macrophages. Structure-activity relationships demonstrated the importance of a radical methoxy at position R3', R4' and R5'. (2E)-3-(3,4,5-trimethoxy-phenyl)-1-(3,6,7-trimethyl-1,4-dioxy-quinoxalin-2-yl)-propenone was the most active. Cytotoxicity on macrophages revealed that this product was almost six times more active than toxic.

Anti-leishmanial and structure-activity relationship of ring substituted 3-phenyl-1-(1,4-di-N-oxide quinoxalin-2-yl)-2-propen-1-one derivatives.

A series of ring substituted 3-phenyl-1-(1,4-di-N-oxide quinoxalin-2-yl)-2-propen-1-one derivatives were synthesized and tested for in vitro leishmanicidal activity against amastigotes of Leishmania amazonensis in axenical cultures and murine infected macrophages. Structure-activity relationships demonstrated the importance of a radical methoxy at position R3', R4' and R5'. (2E)-3-(3,4,5-trimethoxy-phenyl)-1-(3,6,7-trimethyl-1,4-dioxy-quinoxalin-2-yl)-propenone was the most active. Cytotoxicity on macrophages revealed that this product was almost six times more active than toxic.

Antiplasmodial activity of 3-trifluoromethyl-2-carbonylquinoxaline di-N-oxide derivatives

The in vitro antiplasmodial activity of some 3-trifluoromethyl-2-carbonylquinoxaline di-N-oxide derivatives is reported. The evaluation was performed on cultures of FcB1 strain (chloroquine-resistant) of P. falciparum and the most interesting compounds were then evaluated on MCF7 tumor cells in order to evaluate an index of selectivity. The 7-methyl (2b, 4b, 5b, 6b) and nonsubstituted (3c, 4c, 5c) quinoxaline 1,4-dioxide derivatives presented the best level of activity.

Neste artigo descreve-se a atividade anti-Plasmodium falciparum de derivados 3-trifluorometil-2-carbonilquinoxalinas di-N-óxidos (2a-6g). A avaliação das propriedades farmacológicas dos derivados 2a-6g foi realizada em modelo in vitro de inibição de cepas P. falciparum FcB1 (cloroquina resistente) em cultura celular, e sobre culturas de células tumorais MCF7, com a finalidade de estabelecer o índice de seletividade para os compostos mais promissores. Os derivados 7-metil (2b, 4b, 5b, 6b) e não-substituído (3c, 4c, 5c) apresentaram o melhor perfil de atividade.

Quinoxaline N,N'-dioxide derivatives and related compounds as growth inhibitors of Trypanosoma cruzi. Structure-activity relationships.

Quinoxaline derivatives presented good inhibitor activity of growth of Trypanosoma cruzi in in vitro assays. The 50% inhibitory doses were of the same order of that of Nifurtimox. Derivative 13, a quinoxaline N,N'-dioxide derivative, and the reduced derivatives 19 and 20 were the most cytotoxic compounds against the protozoan. Structural requirements for optimal activity were studied by computational methods. From statistical analysis we could establish a multiple correlation between activity and lipophilic properties and LUMO energy.

Benzo[1,2-c]1,2,5-oxadiazole N-oxide derivatives as potential antitrypanosomal drugs. Structure-activity relationships. Part II.

The preparation of new derivatives of benzo[1,2-c]1,2,5-oxadiazole N-oxide is described. These derivatives were chosen in order to investigate and confirm previous structural features found necessary to display an adequate antitrypanosomal activity. The compounds synthesized were tested in vitro against epimastigote forms of Trypanosoma cruzi. The presence of a bromine atom in the benzo system produced compounds less active than the corresponding de-halo analogues. However, 5-(bromomethyl)-7-bromobenzo[1,2-c]oxadiazole N-oxide (23) was the most cytotoxic compound against T. cruzi. For this, the 50% inhibitory dose (ID50) was determined, it was of the same order as that of Nifurtimox. From statistical analysis we could establish a relationship between lipophilic-hydrophilic balance of the derivatives with their effectiveness as antichagasic compounds.

Levocabastina contra cetirizina en niños con rinitis alérgica perenne / Compare efficacy and safety of levocabastine vs cetirizine in allergic rhinitis children

Objetivo: comparar la eficacia y la seguridad de la levocabastina en aerosol nasal contra la cetrizina por vía oral para el tratamiento de la rinitis alérgica perenne en niños: Material y método: se realizó un estudio al azar, prospectivo, experimental, en el cual se estudiaron 30 niños con edades entre 6 y 16 años y con diagnóstico de rinitis alérgica perenne. El grupo 1, compuesto por 17 pacientes (siete mujeres, 10 hombres), recibió cetirizina una vez al día, 5 mg en niños con peso menor de 30 kg y 10 mg en niños con peso mayor de 30 kg y 10 mg en niños con peso mayor de 30 kg durante 15 días. El grupo 2, compuesto por 13 pacientes (siete hombres, seis mujeres) recibió levocabastina, dos inhalaciones en cada fosa nasal cada 12 horas durante el mismo tiempo. Se realizó una calificación de los síntomas, una determinación del flujo, nasal máximo y la cuantificación de eosinófilos en el moco nasal antes y después del tratamiento. Resultados: no hubo diferencias significativas entre ellos (intergrupo); las eosinófilos en el moco nasal permanecieron sin cambios. Encontramos diferencias estadísticas pre y postratamiento dentro de cada grupo (intragrupo): Grupo 1, congestión nasal p= 0.002, prurito ocular p= 0.01, estornudos p= 0.001, secreción nasal p= 0.01, prurito nasal P0 0.009, puntos totales p= 0.0005. Grupos 2, congestión nasal p= 0.02, prurito ocular p= 0.05, estornudos p= 0.01, secreción nasal p= 0.01, prurito nasal p= 0.04, puntos totales p = 0.005. Encontramos diferencias significativas en el flujo nasal máximo en el Grupo 1 (p 0.01) pero no hubo diferencias en el número de eosinófilos entre los dos grupos. Efectos secundarios: 3 sujetos en el grupo 1 (1 somnolencia, 1 aumento del apetito y 1 rinorrea con epistaxis) y uno en el grupo 2 sensación de edema facial. Conclusión. ambos medicamentos son efectivos en la mejoría clínica de los síntomas de rinitis alérgica perenne en niños y la levocabastina ocasiona menos efectos secundarios

Saturación arterial de oxígeno contra flujo espiratorio máxima como valores predictivos en la evolución de la crisis asmática en niños / The value of arterial oxygen saturation versus peak expiratory flow rate measurements as predictors of the outcome of the asthmatic crisis in children

Estudio prospectivo, longitudinal, observacional, comparativo, en 50 niños de uno y otro sexo (30 masculino y 20 femeninos), con edades entre 6 y 18 años, con crisis asmática moderada. Se determinó la saturación arterial de oxigeno (SaO2) y el flujo espiratorio máximo (FFM) al momento de su llegada a urgencias y a los 30 minutos, 2, 4 y 24 horas después de la administración de salbutamol en aerosol (100 mcg/dosis), con el propósito de relacionar el valor de ambas mediciones con el pronóstico de dichos pacientes. De los 50 pacientes evaluados 48 se trataron en forma ambulatoria y dos requirieron hospitalización. Se observaron diferencias estadisticamente significativas en la SaO2, basal y los registros tomados a las 2, 4 y 24 horas postratamiento (p < 0.01), y sólo se observaron diferencias estadisticamente significativas entre el FEM basal y el registro tomado a las 24 horas postratamiento. En conclusión la SaO2 tiene un mejor valor predictivo que el FEM en la evolución de la crisis asmática en niños

Rinitis alérgica y no alérgica / Allergic and non-allergic rhinitis

La rinitis alérgica es una enfermedad crónica muy común que afecta de 10-20 por ciento de la población general. Puede llegar a desaparecer hasta en un 20 por ciento de los casos en edades avanzadas, pero muchos de estos pacientes pueden desarrollar asma. De aquí deriva la importancia de un diagnóstico temprano y manejo adecuado con medidas de control del medio ambiente, uso de antihistamínicos y de inmunoterapia ya que con éstos se puede lograr disminuir el desarrollo de asma hasta en 5 por ciento

Factores de riesgo para el desarrollo de enfermedades atópicas / Risk factors for the development of atopic diseases

Los factores de riesgo para desarrollar enfermedades atópicas son multifactoriales; dentro de los que juegan un papel importante se encuentran los genéticos, la exposición temprana a alergenos e infecciones. Pueden llevarse a cabo múltiples estrategias para disminuir la incidencia de enfermedades atópicas como son: Evitar sensibilización intrauterina, tabaquismo, manipulación dietética durante la lactancia, e iniciar ablactación y alimentos sólidos entre los cuatro y los seis meses