New prophylaxis regimen for SARS-CoV-2 infection in health professionals with low doses of hydroxychloroquine and bromhexine: a randomised, double-blind placebo clinical trial (ELEVATE Trial).

INTRODUCTION: SARS-CoV-2 infection in Mexico has caused ~2.7 million confirmed cases; around 20%-25% of health workers will be infected by the virus at their workplace, with approximately 4.4% of mortality. High infectivity of SARS-CoV-2 is related with cell entry mechanism, through the ACE receptor. SARS-CoV-2 requires transmembrane protease serine 2 to cleave its spike glycoprotein and ensure fusion of host cell and virus membrane. We propose studying prophylactic treatment with hydroxychloroquine (HCQ) and bromhexine (BHH), which have been shown to be effective in preventing SARS-CoV-2 infection progression when administered in early stages. The aim of this study is to assess the efficacy of HCQ and BHH as prophylactic treatments for SARS-CoV-2 infection in healthy health workers exposed to the virus. METHODS AND ANALYSIS: Double-blind randomised clinical trial, with parallel allocation at a 1:1 ratio with placebo, of low doses of HCQ plus BHH, for 60 days. Study groups will be defined as follows: (1) HCQ 200 mg/day+BHH 8 mg/8 hours versus (2) HCQ placebo plus BHH placebo. Primary endpoint will be efficacy of both interventions for the prevention of SARS-CoV-2 infection, determined by the risk ratio of infected personnel and the absolute risk. At least a 16% reduction in absolute risk is expected between the intervention and placebo groups; a minimum of 20% infection is expected in the placebo group. The sample size calculation estimated a total of 214 patients assigned: two groups of 107 participants each. ETHICS AND DISSEMINATION: This protocol has been approved by the local Medical Ethics Committee (National Institute of Rehabilitation 'Luis Guillermo Ibarra Ibarra', approval number INRLGII/25/20) and by the Federal Commission for Protection against Sanitary Risks (COFEPRIS, approval number 203 300 410A0058/2020). The results of the study will be submitted for publication in peer-reviewed journals and disseminated through conferences. TRIAL REGISTRATION NUMBER: NCT04340349.

Acetilcisteína: Una actualización clínica y farmacológica sobre su efecto mucolítico. Estudio de revisión / Acetylcisteine. A clinical and pharmacological actualization with special. Reference to its mucolytic efect

The authors present a clinical and farmacological evaluation of the effect and safety of N-acetylcysteine in chronic obstructive diseases. The N-actylcysteine (NAC) is a sulphorated amino acid employed as an mucolytic agent. The efficacy and tolerability of oral NAC as compared with other agents was determined, in the mucolytic treatment on mucus hypersecretion and in the management of respiratory tract fluids and sputums from cigarette smokers, and also as a bronchial mucus fluidifying agent. A sistematic review and analysis of the effect of NAC and its effectiveness. In the treatment of acute respiratory disorders in children was determined

Biotransformation of bromhexine by Cunninghamella elegans, C. echinulata and C. blakesleeana

Fungi is a well-known model used to study drug metabolism and its production in in vitro condition. We aim to screen the most efficient strain of Cunninghamella sp. among C. elegans, C. echinulata and C. blakesleeana for bromhexine metabolites production. We characterized the metabolites produced using various analytical tools and compared them with mammalian metabolites in Rat liver microsomes (RLM). The metabolites were collected by two-stage fermentation of bromhexine with different strains of Cunninghamella sp. followed by extraction. Analysis was done by thin layer chromatography, high performance thin layer chromatography, Fourier transform infrared spectroscopy, high performance liquid chromatography and Liquid chromatography-mass spectrometry. The role of Cytochrome P3A4 (CYP3A4) enzymes in bromhexine metabolism was studied. Fungal incubates were spiked with reference standard clarithromycin to confirm the role of CYP3A4 enzyme in bromhexine metabolism. Three metabolites appeared at 4.7, 5.5 and 6.4 min retention time in HPLC. Metabolites produced by C. elegans and RLM were concluded to be similar based on their retention time, peak area and peak response of 30.05%, 21.06%, 1.34%, and 47.66% of three metabolites and bromhexine in HPLC. The role of CYP3A4 enzyme in metabolism of bromhexine and the presence of these enzymes in Cunninghamella species was confirmed due to absence of peaks at 4.7, 5.4 and 6.7 min when RLM were incubated with a CYP3A4 enzyme inhibitor - clarithromycin.(AU)

Biotransformation of bromhexine by Cunninghamella elegans, C. echinulata and C. blakesleeana

Abstract Fungi is a well-known model used to study drug metabolism and its production in in vitro condition. We aim to screen the most efficient strain of Cunninghamella sp. among C. elegans, C. echinulata and C. blakesleeana for bromhexine metabolites production. We characterized the metabolites produced using various analytical tools and compared them with mammalian metabolites in Rat liver microsomes (RLM). The metabolites were collected by two-stage fermentation of bromhexine with different strains of Cunninghamella sp. followed by extraction. Analysis was done by thin layer chromatography, high performance thin layer chromatography, Fourier transform infrared spectroscopy, high performance liquid chromatography and Liquid chromatography–mass spectrometry. The role of Cytochrome P3A4 (CYP3A4) enzymes in bromhexine metabolism was studied. Fungal incubates were spiked with reference standard – clarithromycin to confirm the role of CYP3A4 enzyme in bromhexine metabolism. Three metabolites appeared at 4.7, 5.5 and 6.4 min retention time in HPLC. Metabolites produced by C. elegans and RLM were concluded to be similar based on their retention time, peak area and peak response of 30.05%, 21.06%, 1.34%, and 47.66% of three metabolites and bromhexine in HPLC. The role of CYP3A4 enzyme in metabolism of bromhexine and the presence of these enzymes in Cunninghamella species was confirmed due to absence of peaks at 4.7, 5.4 and 6.7 min when RLM were incubated with a CYP3A4 enzyme inhibitor – clarithromycin.

Biotransformation of bromhexine by Cunninghamella elegans, C. echinulata and C. blakesleeana.

Fungi is a well-known model used to study drug metabolism and its production in in vitro condition. We aim to screen the most efficient strain of Cunninghamella sp. among C. elegans, C. echinulata and C. blakesleeana for bromhexine metabolites production. We characterized the metabolites produced using various analytical tools and compared them with mammalian metabolites in Rat liver microsomes (RLM). The metabolites were collected by two-stage fermentation of bromhexine with different strains of Cunninghamella sp. followed by extraction. Analysis was done by thin layer chromatography, high performance thin layer chromatography, Fourier transform infrared spectroscopy, high performance liquid chromatography and Liquid chromatography-mass spectrometry. The role of Cytochrome P3A4 (CYP3A4) enzymes in bromhexine metabolism was studied. Fungal incubates were spiked with reference standard - clarithromycin to confirm the role of CYP3A4 enzyme in bromhexine metabolism. Three metabolites appeared at 4.7, 5.5 and 6.4min retention time in HPLC. Metabolites produced by C. elegans and RLM were concluded to be similar based on their retention time, peak area and peak response of 30.05%, 21.06%, 1.34%, and 47.66% of three metabolites and bromhexine in HPLC. The role of CYP3A4 enzyme in metabolism of bromhexine and the presence of these enzymes in Cunninghamella species was confirmed due to absence of peaks at 4.7, 5.4 and 6.7min when RLM were incubated with a CYP3A4 enzyme inhibitor - clarithromycin.

Parotiditis crónica recurrente en el niño / Chronic recurrent parotiditis in children

La Parotiditis crónica recurrente (PCR) en niños es una enfermedad de etiología desconocida y evolución autolimitada caracterizada por episodios de aumento de volumen parotídeos dolorosos asociados a sialectacia parotidea no obstructiva. Su estudio y tratamiento no obedece a criterio único. El objetivo del presente trabajo es revisar nuestra experiencia con el uso de mucolíticos como tratamiento sintomático en los periodos agudos de la enfermedad. Pacientes y MÚtodo: Se estudiaron en forma retrospectiva las características clínicas, estudio de imágenes y respuesta clínica al uso de mucolítico (Bromhexina) en 25 pacientes tratados por parotiditis crónica recurrente entre 1993 y 1999, en el policlínico de cirugía del Hospital Roberto del Río. Resultados: La distribución por gÚnero del grupo en estudio fue de 16 hombres y 9 mujeres, con una relación de 1,8:1. El 92 por ciento se tenía entre 4 a 10 años. El aumento de volumen como síntoma estuvo presente en el total de los casos y al momento de la primera consulta todos los pacientes habían presentado por lo menos 1 episodio antes. Hubo respuesta clínica favorable al uso de mucolíticos en el 100 por ciento de los casos, manifestada como disminución del dolor entre 48 y 96 h luego de comenzada la administración del mucolítico. La Parotiditis crónica inespecífica, como todas las enfermedades crónicas con periodos de reagudización ofrece algunas dificultades para su evaluación y tratamiento. El uso de mucolíticos disminuye el periodo sintomático en relación a los descrito en la literatura y puede ser una buena alternativa terapÚutica.

Síndrome de Sjögren / Sjögren's syndrome

El síndrome de Sjögren es una inflamación crónica de las glándulas salivales y lagrimales, las que presentan una infiltración linfoplasmocitaria. Clínicamente se manifiesta por xeroftalmia y xerostomía. Se reconocen formas primarias y secundarias asociadas a algunas mesenquimopatías (lupus, esclerosis sistémica o artritis reumatoídea). Además del compromiso de las glándulas lagrimales y salivales, la afección tiene manifestaciones sistémicas especialmente pulmonares, renales y articulares. El diagnóstico es clínico y se confirma mediante sialografía parotídea, ecotomografía, cintigrafía salival y biopsia. El tratamiento es básicamente sintomático y está dirigido a disminuir la sequedad ocular y bucal

Determination of the minor component bromhexine in cotrimoxazole-containing tablets by absorption spectrophotometry and partial least-squares (PLS-1) multivariate calibration.

The mucolitic bromhexine [N-(2-amino-3,5-dibromobenzyl)-N-methylcyclohexylamine] has been determined in cotrimoxazole-containing tablets by partial least-squares (PLS-1) multivariate of spectrophotometric calibration data in the spectral range 310-350 nm. In the studied commercial tablets, cotrimoxazole is present in large excess (ca. 100:1 in weight) with respect to bromhexine, and a high degree of spectral overlapping exists among bromhexine and cotrimoxazole components. However, the obtained recoveries are reasonably good with the presently discussed technique.

Síndrome Sj÷gren asociado a colagenopatías: presentación de un caso / Sj÷grens syndrome associated to collagenophaties

Se describe un Síndrome Sicca en una mujer de 53 años de edad, internada en el Hospital Zenón Santillán, asociado a enfermedades del colágeno tales como: Artritis Reumatoidea, Vasculitis Leucocitoclástica y probable Tiroiditis. Los resultados de sus análisis bioquímicos, Rx de glándulas salivales, gammagrafía y la biopsia del labio inferior, confirman el diagnóstico. Se instituyó tratamiento con Bromhexina y gotas de Pilocarpina (medicación no habitual), obteniendo resultados satisfactorios. (AU)

Síndrome Sjögren asociado a colagenopatías: presentación de un caso / Sjögren's syndrome associated to collagenophaties

Se describe un Síndrome Sicca en una mujer de 53 años de edad, internada en el Hospital Zenón Santillán, asociado a enfermedades del colágeno tales como: Artritis Reumatoidea, Vasculitis Leucocitoclástica y probable Tiroiditis. Los resultados de sus análisis bioquímicos, Rx de glándulas salivales, gammagrafía y la biopsia del labio inferior, confirman el diagnóstico. Se instituyó tratamiento con Bromhexina y gotas de Pilocarpina (medicación no habitual), obteniendo resultados satisfactorios.

Evaluación comparativa del tratamiento con yodo y bromhexina en la queratoconjuntivitis sicca / A comparative evaluation of the keratoconjuntivitis sicca treatment between iodine and bromhexine

Presentamos aqui los resultados de un estudio clinico, con la administracion de yodo en pacientes con Queratoconjuntivitis Sicca (QCS) o Sindrome de Sjogren (SS), con el fin de estimular su secreción lagrimal, más del 80%respondieron al tratamiento satisfactoriamente, asi como el 71%de los tratados con bromhexina (grupo control), conocida ya como lacrimoestimulantes. Ambos tratamientos mejoraron la xerostomia en la mayoria de pacientes son (SS)

Influence of ambroxol on lung tissue penetration of amoxicillin.

Lung amoxicillin levels were assessed in tissue obtained from 16 patients who underwent lung resection due to different pulmonary diseases. In this double-blind placebo controlled study patients were allocated to two groups in randomized order; one group received amoxicillin 1000 mg t.i.d. (n = 8) and the other amoxicillin 1000 mg + ambroxol 60 mg t.i.d. (n = 8). A trend towards higher antibiotic lung tissue levels was observed in patients who received the antibiotic together with the mucolytic agent. The ratio pulmonary tissue/serum amoxicillin levels reached a significant difference being higher in the amoxicillin plus ambroxol group than in the other one (0.411 +/- 0.04 vs 0.672 +/- 0.07; p less than 0.01), even if the amoxicillin plasma levels were lower. A possible effect of ambroxol on lung tissue penetration of amoxicillin is suggested and discussed.

Influence of ambroxol on amoxicillin levels in bronchoalveolar lavage fluid.

Amoxicillin levels were measured in bronchoalveolar lavage (BAL) fluid samples obtained from patients who after randomization were treated in double-blind fashion either with amoxicillin 1000 mg p.o.t.i.d. or with amoxicillin 1000 mg + ambroxol 60 mg p.o.t.i.d. Antibiotic levels were higher in the group receiving ambroxol (0.32 +/- 0.02 micrograms/ml; n = 8) than in the other one (0.19 +/- 0.02 micrograms/ml; n = 6). This difference was statistically significant (p less than 0.001). Comparisons of protein concentrations in BAL fluid samples and of amoxicillin plasma levels did not show significant differences in the two groups. These results seem to prove that ambroxol is able to increase the antibiotics concentration in the lungs, although the mechanism of action is still unclear. In addition it could be shown that the BAL technique is suitable for exploring the lung concentration of antibiotics.

Ambroxol plus amoxicillin in the treatment of exacerbations of chronic bronchitis.

Twenty-three patients with exacerbations of chronic bronchitis were divided in two groups in a randomized fashion receiving either amoxicillin 1500 mg/d (n = 13) or amoxicillin 1500 mg/d associated with the mucolytic drug ambroxol 90 mg/d (n = 10). The improvement in cough, expectoration difficulties and sputum purulence was statistically more evident and occurred earlier in the ambroxol + amoxicillin group than in the amoxicillin only group. Although amoxicillin plasma and sputum levels were similar in both groups, the differences in daily sputum volume, which was also statistically greater in patients receiving ambroxol, suggests that this drug favours the bronchial mucus clearance of the antibiotic which could be related to the more favourable clinical evolution. No changes were observed in lung function tests and blood gases.

Uma associaçäo farmacológica em infecçöes respiratórias / A pharmacological combination in respiratory tract infections

Foram estudados, do ponto de vista clínico e bacteriológico, 32 pacientes, 29 com infecçöes broncopulmonares e 3 com infecçöes de vias aéreas altas, que foram tratados por via oral com a associaçäo Amoxicilina 500 mg + Bromexina 8 mg cada 8 horas, durante pelo menos 7 dias. A eficácia terapêutica foi muito boa, proporcionando cura e melhora clínica em 90,4% dos pacientes e cura bacteriológica em 90,6%. Em 7 pacientes registraram-se efeitos secundários a nível do tubo gastrintestinal (epigastralgia e diarréia), que näo levaram à interrupçäo do tratamento. Consideramos que esta associaçäo farmacológica é muito eficaz para o tratamento das infecçöes bacterianas provocadas por germes Gram-positivos e Gram-negativos mais freqüentemente identificados no aparelho respiratório

Influência da bromohexine sobre os níveis de lisozima da secreçäo lacrimal, o teste de rosa bengala e os sintomas oculares na síndrome de Sjögren / Influence of bromohexine on tear lysozyme level, rose-bengal test and ocular symptoms in Sjogren's syndrome

Foram estados, em 21 pacientes portadoras de Síndrome de Sjögren primária ou secundária, a influência da bromohexine sobre os níveis de lisozima da secreçäo lacrimal, teste de rosa bengala e sintomas oculares. Realizamos estudo cego com administraçäo de placebo (um comprimido por dia) e bromohexine (um comprimido de 48 mg por dia), durante 2 períodos consecutivos de 3 semanas (21 dias), com avaliaçöes do nível de lisozima lacrimal, sintomas oculares e teste de rosa bengala no dia antecedente ao ínicio do tratamento e após o uso de placebo (22§) e de bromohexine (44§ dia). Näo houve influência estatisticamente significante da bromohexine sobre os parâmetros analisados

Avaliaçäo crítica ao uso de Bromexine / Critical evaluation of the bromhexine use

Faz-se uma revisäo sobre mucolíticos, principalmente, sobre a Bromexine. Discute-se suas propriedades farmacológicas e seu perfil de prescriçäo em nosso meio

Ambroxol, nuevo broncosecretolitico en afecciones broncopulmonares en pediatria. / Cambroxol, new bronchosecretolytic in bronchopulmonary disesases in pediatrics

Se presentan los resultados de un estudio clinico multicentrico nacional del tipo abierto no comparativo. Fue realizado en tres centros hospitalarios, en un total de 74 ninos con afecciones agudas y cronicas de las vias respiratorias, cuya manifestacion mas importante era la retencion de secreciones. Como secretolitico, el ambroxol modifico favorablemente el curso del padecimiento en 83.7% de los casos.Solo se uso medicacion antibiotica y/o broncodilatadora cuando se considero necesario. La tolerancia al medicamento fue excelente