Simultaneous determination of 6 kinds of N-nitrosamines genotoxic impurities in losartan potassium raw material and its formulations by GC-MS/MS / 中国药房

OBJECTIVE To establish a method for simultaneous determination of the contents of 6 kinds of N-nitrosamines genotoxic impurities in losartan potassium raw material and its formulations. METHODS GC-MS/MS was adopted to determine 6 kinds of N-nitrosamines genotoxic impurities in losartan potassium raw material， Losartan potassium tablet， Losartan potassium capsule and Losartan potassium hydrochlorothiazide tablets， such as N-nitrosodimethylamine （NDMA）， N-nitrosodiethylamine （NDEA）， N-ethyl-N-nitroso-2-propanamine （NEiPA）， N-nitrosodiisopropylamine （NDiPA）， N-nitrosodipropylamine （NDPA） and N-nitrosodibutylamine （NDBA）. The separation was performed on SHIMADZU SH-L-17Sil MS capillary column by temperature- programmed GC， with injector temperature of 250 ℃ ， sample size of 1 μL， carrier gas of helium， and carrier flow rate of 1 mL/min. Electron ionization and multiple reaction monitoring （MRM） data acquisition mode were used， with an ion source temperature of 250 ℃ and solvent delay time of 3.1 min. RESULTS The separation among NDMA， NDEA， NEiPA， NDiPA， NDPA， NDBA and adjacent chromatographic peaks was good， and the separation rate was higher than 3.8； the linear ranges of them were 4.9-486.0， 4.9-488.5， 4.5-451.5， 6.8-683.5， 5.2-525.0 and 5.2-520.0 ng/mL（all r≥0.999 8）. The limits of quantitation were 4.86， 4.88， 4.52， 6.84， 5.25 and 5.20 ng/mL； the limits of detection were 0.97， 0.98， 0.90， 1.37， 1.05 and 1.04 ng/mL. RSDs of repeatability tests were 2.2%-5.6%（n＝6）， those of precision tests were 0.5%-1.4%（n＝6）， and those of stability tests were 1.5%-3.4%（n＝5）， respectively. Average recoveries of low-， medium- and high-concentration solution were 83.4%-103.0% （RSDs were 1.2%-6.3%， n＝3）， respectively. No one among the 6 kinds of N-nitrosamines genotoxic impurities was detected in both losartan potassium raw material and formulations. CONCLUSIONS The method is good in separation effect， highly accurate， sensitive and simple. It can be used in the determination of the 6 kinds of N-nitrosamines genotoxic impurities.

Choque vasopléjico por envenenamiento con amlodipino y losartán

RESUMEN El choque vasodilatado o también llamado distributivo ocurre cuando las arteriolas presentan una pérdida de contractibilidad por diferentes mecanismos en donde la hipoxia y acidosis suelen ser los principales. La causa más común de este tipo de choque es la sepsis. Sin embargo, existen otras causas como las intoxicaciones con fármacos. Presentamos el manejo en la unidad de cuidados intensivos de un caso de intoxicación con fines de autoeliminación con dosis elevadas de antihipertensivos bloqueantes de canales calcio y antagonistas del receptor de angiotensina II, que requirió soporte hemodinámico y respiratorio.

ABSTRACT Vasodilated or also called distributive shock occurs when the arterioles present a loss of contractility due to different mechanisms in which hypoxia and acidosis are usually the main events. The most common cause of this type of shock is sepsis. However, there are other causes such as drug poisoning. We present the management in the intensive care unit of a case of poisoning for self-elimination purposes with high doses of antihypertensive calcium channel blockers and angiotensin II receptor antagonists, which required hemodynamic and respiratory support.

Caracterización de pacientes con prescripción de losartán en dosis superior a la dosis máxima diaria, su problemática e intervención

Introducción: La hipertensión arterial es una de las enfermedades con mayor preva-lencia en nuestro país. La prescripción de antagonistas del receptor de angiotensina tipo II, es uno los tratamientos más comunes; sin embargo, su dosis máxima efectiva es controversial. Objetivo: El objetivo del estudio fue caracterizar una población de una entidad promotora de salud en Colombia, que recibía para el manejo de la hipertensión arterial, una dosis de losartán mayor a 100 mg/día. Metodología: Se incluyó una base de prescripción de 3816 casos con hipertensión arterial, en manejo con losartán potásico a dosis superiores a 100 mg/día, con una muestra proporcional de 300 casos; en quienes se aplicó una alerta de dosis máxima (100 mg/día) en la prescripción. Se describió el perfil farmacoterapéutico, interacciones farmacológicas, cambios de dosificación y en las cifras de presión arterial. Para confirmar el efecto terapéutico de losartán potásico en control de cifras de presión arterial, se realizaron pruebas estadísticas (Tukey, Bonferroni). Resultados: De los 300 pacientes, 224 (74,6%) contaban con registro de presión arterial al inicio de la prescripción de losartán potásico a 100 mg/día; después de la intervención se logró reducción de dosis en 70 casos (23,3%). 76 casos (25,3%) no contaban con ningún paraclínico de seguimiento. Conclusión: No se encontró evidencia clínica o científica que justifique la prescripción de losartán con dosis mayores a 100 mg/día para el manejo de la hipertensión arterial esencial en nuestra población descrita.

SUMMARY Introduction: Hypertension is one of the most prevalent diseases in our country. Type II angiotensin receptor antagonists are one of the most common treatments; however, its maximum effective dose is controversial. Aim: The objective of study to characterize a population of a health promoting entity in Colombia, which received a dose of losartan greater than 100 mg/day for management of arterial hypertension. Methodology: The study included a prescription base of 3816 cases with arterial hypertension, in management with losartan potassium at doses higher than 100 mg/day, with a proportional sample of 300 cases; in whom a maximum dose alert (100 mg/day) was applied in prescription. Pharmacotherapeutic profile, drug interactions, dosage changes, and changes in blood pressure figures were described. To confirm therapeutic effect of losartan potassium in controlling blood pressure figures, statistical tests were performed (Tukey, Bonferroni). Results: Of the 300 patients, 224 (74.6%) had a blood pressure record at beginning of prescription of losartan potassium at 100 mg/day; after the intervention, a dose reduction was achieved in 70 cases (23.3%). 76 cases (25.3%) did not have any follow-up paraclinical. Conclusion: It was concluded that losartan potassium at doses greater than 100 mg/day did not show statistically significant differences for blood pressure control. We found insufficient clinical and scientific evidence to support the treatment with losartan more than 100 mg/day for hypertension in our population.

Introdução: A hipertensão arterial é uma das doenças mais prevalentes em nosso país. Os antagonistas do receptor de angiotensina tipo II são um dos tratamentos mais comuns; entretanto, sua dose máxima efetiva é controversa. Objetivo: Caracterizar uma população de uma entidade promotora de saúde na Colômbia, que receberam uma dose de losartana superior a 100 mg/dia para tratamento de hipertensão. Metodologia: O estudo incluiu uma base de prescrição de 3816 casos com hipertensão arterial, em manejo com losartana potássica em doses maiores superior a 100 mg/ dia, com amostra proporcional de 300 casos; em quem um máximo alerta de dose (100 mg/dia) foi aplicado na prescrição. Perfil farmacoterapêutico, interações medicamentosas, alterações de dosagem e alterações nos valores da pressão arterial foram descrito. Para confirmar o efeito terapêutico da losartana potássica no controle do sangue valores pressóricos, foram realizados testes estatísticos (Tukey, Bonferroni). Resultados: De dos 300 pacientes, 224 (74,6 %) tinham registro de pressão arterial no início da prescrição de losartana potássica a 100 mg/dia; após a intervenção, uma redução da dose foi alcançada em 70 casos (23,3 %). 76 casos (25,3 %) não tiveram seguimento paraclínico. Conclusão: Concluiuse que a losartana potássica em doses maiores superior a 100 mg/dia não apresentou diferenças estatisticamente significativas para a pressão arterial ao controle. Encontramos evidências clínicas e científicas insuficientes para apoiar o tratamento com losartana mais de 100 mg/dia para hipertensão em nossa população.

Endothelial expression of the receptor for advanced glycation end products in experimental diabetes / Expresión endotelial del receptor para productos finales de glicación avanzada en diabetes experimental

The receptor for advanced glycation end products (RAGE) is implicated in the pathogenesis of several chronic diseases including diabetes. The interaction between RAGE and advanced glycation end products (AGEs) promotes gene expression, enhances the release of proinflammatory molecules and causes the generation of oxidative stress in numerous cell types. The aim of this investigation was to evaluate the effect of enalapril and losartan on RAGE expression in abdominal aortic endothelium of rats with experimentally induced diabetes. Male Sprague-Dawley rats, weighing approximately 150 - 200 g, were used. Diabetes was induced in 30 rats by intravenous administration of a single dose of 55 mg/kg body weight of streptozotocin (ETZ). The following groups were studied: control (n=10), diabetic (n=10), losartan-treated diabetic (n=10) and enalapril-treated diabetic (n=10) rats. RAGE expression in aortic endothelium was determined by indirect immunofluorescence. A significant increase in RAGE expression was observed in diabetic animals versus controls (p<0.001), there was a decrease in RAGE expression, in animals treated with losartan versus controls (p<0.01) and in those treated with enalapril (p<0.05) versus control and versus diabetes + vehicle. In conclusion, in the experimental model of ETZ-induced diabetes, there is an increase in RAGE expression at the level of the abdominal aortic endothelium, which can be reversed by treatment with losartan and/or enalapril, two drugs that block the renin-angiotensin system, suggesting its involvement in the molecular events related to vascular damage during diabetes.

El receptor para productos finales de glicación avanzada (RAGE) está implicado en la patogénesis de varias enfermedades crónicas incluyendo la diabetes. La interacción entre RAGE y los productos finales de glicación avanzada (AGEs), promueve la expresión génica, potencia la liberación de moléculas proinflamatorias y provoca la generación de estrés oxidativo en numerosos tipos de células. El objetivo de esta investigación fue evaluar el efecto del enalapril y el losartán sobre la expresión de RAGE en el endotelio de la aorta abdominal de ratas con diabetes inducida experimentalmente. Se utilizaron ratas Sprague-Dawley machos, con un peso aproximado de entre 150 - 200 g. La diabetes se indujo en 30 ratas mediante la administración intravenosa de una sola dosis de 55 mg/Kg de peso corporal de estreptozotocina (ETZ). Se estudiaron los siguientes grupos: ratas control (n=10), diabéticas (n=10), diabéticas tratadas con losartán (n=10) y diabéticas tratadas con enalapril (n=10). La expresión de RAGE en el endotelio aórtico se determinó por inmunofluorescencia indirecta. Se observó un incremento significativo en la expresión de RAGE en los animales diabéticos versus los controles (p<0.001), hubo una disminución en la expresión de RAGE, en los animales tratados con losartán versus los controles (p<0.01) y en los tratados con enalapril (p<0.05) versus control y versus diabetes + vehículo. En conclusión, en el modelo experimental de diabetes inducida por ETZ, existe un incremento en la expresión de RAGE a nivel del endotelio de la aorta abdominal, la cual puede revertirse mediante el tratamiento con losartán y/o enalapril, dos fármacos bloqueadores del sistema renina-angiotensina, lo cual sugiere la participación del mismo en los acontecimientos moleculares relacionados con el daño vascular durante la diabetes.

Losartan: Benefits Beyond Hypertension

Losartan was the first angiotensin AT1 receptor blocker (ARB) approved by US Food and Drug Administration (FDA) for the treatment of hypertension. In addition to its established antihypertensive and end organ effects, several benefits of losartan beyond its antihypertensive effect have been demonstrated in clinical trials. Apart from its class effects of ARBs, losartan has pharmacokinetic and pharmacodynamic properties that are unique to it. It has shown considerable benefits as uricosuric agent, in erectile dysfunction and in prevention of stroke in hypertension patients with left ventricular hypertrophy. This review presents the benefits of losartan beyond being a hypertensive agent and associated clinical outcomes.

Sustained release matrix tablet of 100 mg losartan potassium: Formulation development and in vitro characterization

Abstract Sustained release matrix tablets of 100 mg losartan potassium HCl were fabricated with two release retarding polymers namely HPMC K100 M and affinisol by direct compression method. Nine trial formulations were prepared by varying content of these polymers, each from 50 mg to 100 mg; keeping the total weight of the tablet 310 mg. The best formulation was selected based on in vitro drug release profile for 12 hours conducted in Type II dissolution apparatus at 50 rpm and water as dissolution medium. Pre-compression parameters such as bulk density, tap density, Carr's index and Hausner ratio were evaluated for the selected tablet. The tablets were subjected to thickness, weight variation test, drug content, hardness and friability. Drug release kinetics, surface morphology and accelerated stability study were investigated for that selected formulation. Formulation F4 with the composition of 75 mg HPMC K100M and 100 mg affinisol was selected as the best formulation that extended the drug release up to 12 hours. Pre-compression parameters and other tableting properties were within the Pharmacopoeia limit. Release kinetics analysis proved non-fickian zero-order drug release and that was further confirmed by surface morphology of the tablets before and after dissolution study visualized by SEM. The developed formulation was found to be stable for one month stored at 60 ○C.

Effect of Haikunshenxi capsule combined with losartan potassium tablets on renal function and inflammatory factors in patients with chronic kidney disease / 中国医师进修杂志

Objective:To investigate the curative effect of Haikunshenxi capsule combined with losartan potassium tablets on chronic kidney disease (CKD) and its effect on renal function and inflammatory factors.Methods:One hundred patients with chronic kidney disease in Shaoxing Central Hospital from January 2018 to December 2019 were selected and randomly divided into observation group (50 cases) and control group (50 cases). The control group was treated with losartan potassium tablets based on conventional therapy, and the observation group was treated with Haikunshenxi capsulebase on control group. The treatment course of the two groups was 12 weeks. The curative effect, renal function, inflammatory factors, 24h urinary protein (24 h Upro) and glomerular filtration rate (GFR) were compared between the two groups before and after treatment.Results:The total effective rate in the observation group was higher than that in the control group: 90.0%(45/50) vs. 72.0%(36/50), χ2 = 5.26, P<0.05. After treatment, the levels of serum creatinine (Scr) and blood urea nitrogen (BUN) in the two groups were decreased and the levels of Scr and BUN in the observation group were lower than those in the control group: (63.27 ± 2.89) μmol/L vs. (67.89 ± 2.35) μmol/L, (5.23 ± 0.19) mmol/L vs. (5.56 ± 0.16) mmol/L, the differences were statistically significant ( P<0.05). After treatment, the levels of serum C-reactive protein (CRP) , interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in the two groups were decreased and the levels of CRP, IL-6 and TNF-α in the observation group were lower than those in the control group: (2.97 ± 0.34) mg/L vs. (3.58 ± 0.42) mg/L, (3.64 ± 0.68) ng/L vs. (4.97 ± 0.96) ng/L, (14.32 ± 2.17) ng/L vs. (17.86 ± 2.06) ng/L, the differences were statistically significant ( P<0.05). After treatment, the level of 24 h Upro in two groups was decreased, while the level of GFR was increased, and the level of 24 h Upro in the observation group was lower than that in the control group: (0.87 ± 0.09) g vs. (1.15 ± 0.13) g , but the level of GFR in the observation group was higher than that in the control group: (101.73 ± 3.12) ml/(min·m 2) vs. (96.75 ± 2.35) ml/(min·m 2), the differences were statistically significant ( P<0.05). Conclusions:Haikunshenxi capsule combined with losartan potassium tablets has obvious curative effect on patients with chronic kidney disease, and can improve renal function and micro inflammation.

Comparación de los perfiles de disolución de los comprimidos de Losartán potásico 100mg nacionales e importados vs precio, Paraguay (2019)

RESUMEN La hipertensión arterial es el principal factor de riesgo cardiovascular, y su prevalencia en Paraguay es la mayor de América Latina. El objetivo del presente trabajo fue comparar productos de losartán de 100 mg comprimidos de producción nacional e importada a través de los perfiles de disolución versus su precio. Se tomaron 8 marcas de losartán potásico comercializadas durante el 2017, realizándose los controles de calidad de acuerdo a lo establecido en la Farmacopea Americana (USP 38). Se determinó el porcentaje de principio activo liberado en el medio de disolución establecido por la USP 38, por medio de los perfiles de disolución. Las determinaciones se realizaron por HPLC y espectrofotometría UV/V. Los controles realizados cumplieron con las especificaciones establecidas por la USP 38. No se encontraron diferencias significativas en el análisis estadístico de los perfiles de disolución de las diferentes marcas analizadas. Los resultados demostraron que los precios de las marcas analizadas no afectaban la calidad de los productos, pero sí en el costo del tratamiento de la población de escasos recursos, debido al mayor costo de los productos importados con respecto a los de producción nacional.

ABSTRACT Hypertension is the main cardiovascular risk factor, and its prevalence in Paraguay is the highest in Latin America. The objective of the present work was to compare products of 100 mg losartan tablets made in Paraguay and imported products, through dissolution profiles versus price. Eight brands of potassic losartan commercialized during 2017 were subjected to quality controls in accordance with the provisions of the American Pharmacopoeia (USP 38). The percentage of active principle released in the dissolution medium established by USP 38 was determined by means of dissolution profiles. The determinations were made by HPLC and UV/V spectrophotometry. The controls carried out complied with the specifications established by USP 38. No significant differences were found in the statistical analysis of the dissolution profiles of the different brands analyzed. The results showed that the prices of the brands analyzed did not affect the quality of the products, but they affected the cost of treatment of the low-income population due to the higher cost of imported products compared to those of national production.

Losartan-induced DRESS syndrome

Abstract Introduction: drug reactions with eosinophilia and systemic symptoms, known as DRESS syndrome, are a hypersensitivity reaction to medications which can lead to skin lesions and internal organ involvement. This syndrome has typically been associated with a wide variety of medications, including aromatic anticonvulsants, allopurinol and antibiotics as the main culprits. Objective: we present the case of a patient with DRESS syndrome secondary to losartan, manifesting skin symptoms and mild hepatic involvement. Up until now, there have been no reports of losartan as the cause of this condition. Prompt treatment was instated including the withdrawal of the offending medication and initiation of oral systemic steroids, with a satisfactory response. Conclusion: caregivers should be alert to the appearance of skin lesions with the use of different groups of medications, not just those typically reported, since any medication could potentially cause a hypersensitivity reaction. (Acta Med Colomb 2021; 46. DOI:https://doi.org/10.36104/amc.2021.2081).

Caracterização do tecido ósseo peri-implantar em ratas hipertensas e com deficiência de estrógeno, após ação sinérgica de losartan e alendronato de sódio / Characterization of peri-implant bone tissue in hypertensive and estrogen-deficient rats after the synergistic action of losartan and alendronate sodium

Introdução: Este estudo visou caracterizar morfológica e estruturalmente o tecido produzido na interface osso-implante em ratas espontaneamente hipertensas ovariectomizadas com implantes instalados em suas tíbias, e analisou como o tratamento associado de losartan sistêmico e alendronato de sódio local influenciou no reparo ósseo peri-implantar. Material e Métodos: Foram utilizadas ratas espontaneamente hipertensas (SHR) que receberam losartan (30 mg/kg, p.o.). Após uma semana, implantes de titânio tratados (Medens, Ribeirão Preto, São Paulo, Brazil) ou não com alendronato de sódio (ALE) foram instalados nas tíbias. Sessenta dias após a implantação, a estabilidade do implante foi avaliada pela medição de torque reverso, considerado como desfecho primário. A microtomografia computadorizada e a análise por confocal foram parâmetros secundários. Resultados: A ação sinérgica do losartan e do alendronato de sódio na superfície do implante aumentou o torque reverso no grupo SHR SHAM ALE. Enquanto a microtomografia também revelou maior extensão de contato entre osso e implante, volume ósseo e espessura trabecular nos animais SHR SHAM ALE. Por último, o losartan e o alendronato de sódio não alterou significativamente os parâmetros de osseointegração nas ratas ovariectomizadas. Conclusões: Os resultados apresentados sugerem que a ação sistêmica do losartan somada à atuação local do alendronato de sódio na superfície dos implantes melhoram os parâmetros de osseointegração em tíbias de ratas hipertensas e não ovariectomizadas(AU)

Background: This study aims to characterize morphologically and structurally the tissue produced at the bone-implant interface in spontaneously hypertensive ovariectomized rats that will have implants placed in their tibiae, and to analyze how the associated treatment of systemic losartan and local sodium alendronate might influence the peri-implant bone healing. Methods: They are used spontaneously hypertensive (SHR) rats that received losartan (30 mg/kg, p.o.). After one week, titanium implants treated (Medens, Ribeirão, São Paulo, Brazil) or not with sodium alendronate (ALE) were installed in the tibiae. Sixty days after implantation, implant stability was assessed by measuring the removal torque considered the primary end point. Computed tomography and confocal analysis were secondary parameters. Results: The synergistic action of losartan and sodium alendronate on the implant surface increased the reverse torque in the SHR SHAM ALE group. While microtomography also revealed a greater extent of contact between bone and implant, bone volume and trabecular thickness in SHR SHAM ALE animals. Finally, losartan and sodium alendronate did not significantly alter osseointegration parameters in ovariectomized rats. Conclusions: The results presented suggest that systemic losartan plus the local action of sodium alendronate on implants surface improves osseointegration parameters in tibias of hypertensives and non-ovariectomized rats(AU)

Effect of Modified Fuyuanwan Combined with Auricular Acupressure Bean on Stage Ⅱ， Ⅲ Diabetic Nephropathy and Its Effect on Serum JAK/STAT Signaling Pathway / 中国实验方剂学杂志

Objective:To observe the therapeutic effect of modified Fuyuanwan combined with auricular acupressure bean on stage Ⅱ， Ⅲ diabetic nephropathy and its effect on serum janus kinase （JAK）/ signal transducer and activator of tranions （STAT） signaling pathway. Method:A total of 180 cases were randomly divided into control group and observation group， 90 cases in each group. Losartan potassium， modified Fuyuanwan combined with auricular acupressure bean were given respectively for 12 weeks. Renal function indexes ［blood urea nitrogen （BUN）， serum creatinine （SCr）， urinary albumin excretion rate （UAER）， 24 h urinary protein quantitative （24 h Upor）］， relative abundance of intestinal flora （verruca microflora， scleriobacteriae， deferribacter， proteobacteria）， oxidative stress indicators ［advanced oxidation protein products （AOPPs）， reactive oxygen species （ROS）， glutathione peroxidase （GSH-Px）， total superoxide dismutase （TSOD）］， renal blood flow index ［end-diastolic blood flow velocity （EDV）， peak systolic value （PSV）， pulse index （PI）， blood flow resistance index （RI）］， JAK/STAT signaling pathway ［JAK， phosphorylated JAK （p-JAK）， STAT， phosphorylated STAT （p-STAT） were observed before and after treatment. The safety indexes of two groups were evaluated after treatment. The efficacy was observed after treatment and followed up for 1 years and 2 years. Result:After treatment and follow-up for 1， 2 years， the total effective rates of patients in observation group were 97.8% （87/89）， 81.6% （71/87）， 59.8% （49/82）， respectively， observation group which were significantly higher than those in control group of 79.3%（69/87），57.8%（48/83），37.2%（29/78） （<italic>χ</italic>²=4.016， <italic>χ</italic>²=4.503， <italic>χ</italic>²=4.769， <italic>P</italic><0.05）. Compared with control group after treatment， UAER， BUN， SCr， 24 h Upor， firmicutes， actinobacillus， proteobacteria， AOPPs， ROS， PI， RI， p-JAK， p-STAT3 in observation group were significantly decreased （<italic>P</italic><0.05，<italic>P</italic><0.01）， microflora verruca， GSH-PX， TSOD， JAK， STAT3 were significantly increased （<italic>P</italic><0.05，<italic>P</italic><0.01）， EDV and PSV were significantly accelerated （<italic>P</italic><0.05，<italic>P</italic><0.01）. The incidence of adverse reactions was 1.1% （1/89） in observation group， lower than 13.8% （12/87） in control group （<italic>χ</italic>²=5.127， <italic>P</italic><0.05）. Conclusion:Modified Fuyuanwan combined with auricular acupressure bean can significantly improve the curative effect of stage Ⅱ， Ⅲ diabetic nephropathy， and its mechanism of action may be related to the serum JAK/STAT signaling pathway.

Síndrome de piel indurada en un paciente pediátrico: un desafío terapéutico. Presentación de un caso / Stiff skin syndrome in a pediatric patient: a therapeutic challenge. Clinical case

El síndrome de la piel indurada es un trastorno esclerosante crónico, infrecuente, que se presenta en la infancia, caracterizado por la induración progresiva de la piel. Esta afección puede provocar restricciones torácicas y dificultad respiratoria, limitaciones en la movilidad articular y trastornos en la marcha, con importante deterioro de la calidad de vida. Debido a que sus opciones terapéuticas son escasas y poco eficaces, es fundamental que el paciente inicie precozmente una terapia física para prevenir estas complicaciones y que se continúe estudiando esta enfermedad a fin de poder ofrecer a los pacientes más y mejores tratamientos. Se presenta el caso de una paciente de 9 años con síndrome de la piel indurada y su desafío terapéutico.

Stiff skin syndrome is a chronic, rare sclerosing disorder that occurs in childhood, characterized by progressive induration of the skin that can cause thoracic restrictions and respiratory distress, limitations in joint mobility and gait difficulties, with significant deterioration of the quality of life. Because their therapeutic options are scarce and ineffective it is essential to start an early physical therapy to prevent these complications and to continue studying this condition to be able to offer patients more and better treatments. We present the case of a 9-year-old patient with indurated skin syndrome and its therapeutic challenge.

COVID-19 y su asociación con los inhibidores de la enzima convertidora de angiotensina y los antagonistas de los receptores para angiotensina II / COVID-19 and its Association with Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Antagonists

Resumen En la pandemia de COVID-19 que se ha presentado en México y en el mundo, y que ya ha infectado alrededor de 7 millones de personas, las comorbilidades que se han asociado a esta enfermedad en orden de importancia son: hipertensión, diabetes mellitus, obesidad, enfermedad pulmonar obstructiva crónica, enfermedad cardiovascular, insuficiencia renal crónica, tabaquismo e inmunosupresión, y la hipertensión arterial es un rasgo característico en todas ellas. La enzima convertidora de angiotensina-2 (ACE2), es el receptor funcional para el SARS-CoV-2. Este virus, tiene una proteína llamada espiga (proteína S) que reconoce a la ACE2 como su receptor para ingresar a las células. La ACE2 es una proteína de la membrana plasmática y se encuentra expresada en las células alveolares tipo I y II, células epiteliales, fibroblastos, células endoteliales y macrófagos. El tratamiento con inhibidores de la enzima convertidora de angiotensina (ACEi) o con antagonistas del receptor a angiotensina II (ARBs) aumentan notablemente la expresión de ACE2. Por lo tanto, en pacientes con estas patologías y tratados con estos medicamentos, se podría incrementar el riesgo de desarrollar la COVID-19 en forma severa y fatal. Cabe destacar que los pacientes con mayor mortalidad por la COVID-19 en México son los que presentan hipertensión, diabetes mellitus, obesidad y los mayores de 65 años. Por todo lo anterior, podríamos sugerir que, durante la etapa crítica de la pandemia por SARS-CoV-2, a los pacientes, particularmente en personas de edad avanzada, con hipertensión o con diabetes mellitus y obesidad que cursan con hipertensión y si su tratamiento es con ACEi o con ARBs, se les debería modificar a medicamentos alternativos como los bloqueadores de los canales de Ca2+ tipo L (amlodipino), que hasta el momento no han sido asociados con la ACE2.

Abstract Worldwide, over 7 million people have been infected due to the pandemic of COVID-19. The comorbidities associated to this disease are: hypertension, diabetes mellitus, obesity, obstructive pulmonary disease (COPD), cardiovascular disease, chronic renal failure, smoking, immunosuppression, and hypertension. Angiotensin-converting enzyme 2 (ACE2) is the functional receptor for SARS-CoV-2. This virus has an S protein that recognizes ACE2 as its receptor to enter the cell. ACE2 is a plasmatic protein expressed in alveolar cells type I, II, fibroblasts, endothelial cells and macrophages. Treatment with inhibitors of the angiotensin-converting enzyme (ACEi) or the receptor antagonist for angiotensin II (ARBs) notably increase the expression of ACE2. Therefore, in patients with these pathologies and treated with these medicines, the risk of developing the COVID-19 in a severe and fatal way could be increased. In Mexico, the major mortality due to COVID-19 is related to hypertension, diabetes mellitus, obesity and being over 65 years of age. Therefore, we suggest that during the SARS-CoV-2 pandemic, patients with hypertension treated with ACEi or ARBs, should receive alternative treatments such as L-type Ca2+ channel blockers (amlodipine) that have not been associated with ACE2 until now.

Bloqueio de Receptores AT1 Melhora o Desempenho Funcional Miocárdico na Obesidade / AT1Receptor Blockade Improves Myocardial Functional Performance in Obesity

Resumo Fundamento A obesidade tem sido associada com ativação crônica do sistema renina-angiotensina-aldosterona e importantes alterações no desempenho cardíaco. Objetivo Avaliar a influência do bloqueio de receptores de angiotensina-II do tipo 1 (AT1) sobre a morfologia e desempenho cardíaco de ratos obesos por dieta Métodos Ratos Wistar (n=48) foram submetidos a dieta controle (2,9 kcal/g) ou hiperlipídica (3,6 kcal/g) durante 20 semanas. Após a 16ª semana, foram distribuídos em quatro grupos: Controle (CO), Obeso (OB), Controle Losartan (CL) e Obeso Losartan (OL). CL e OL receberam losartan (30 mg/kg/dia) na água durante quatro semanas. Posteriormente, foram analisadas composição corporal, pressão arterial sistólica (PAS) e ecocardiograma. A função de músculos papilares foi avaliada em situação basal com concentração de cálcio ([Ca2+]o) de 2,50 mM e após manobras inotrópicas: potencial pós-pausa (PPP), elevação da [Ca2+]o e durante estimulação beta-adrenérgica com isoproterenol. A análise dos resultados foi feita por meio de Two-Way ANOVA e teste de comparações apropriado. O nível de significância considerado foi de 5%. Resultados Embora a alteração da PAS não tenha se mantido ao final do experimento, a obesidade se associou com hipertrofia cardíaca e maior velocidade de encurtamento da parede posterior do ventrículo esquerdo.No estudo de músculos papilares em condição basal, CL mostrou menor velocidade máxima de variação negativa da tensão desenvolvida (-dT/dt) do que CO. O PPP de 60s promoveu menor -dT/dt e pico de tensão desenvolvida (TD) em OB e CL, comparados ao CO, e maior variação relativa de TD e velocidade máxima de variação positiva (+dT/dt) no OL em relação a CL e OB. Sob 1,5, 2,0 e 2,5mM de [Ca2+]o, o grupo OL exibiu maior -dT/dt do que CL. Conclusão Losartan melhora a função miocárdica de ratos com obesidade induzida por dieta. (Arq Bras Cardiol. 2020; 115(1):17-28)

Abstract Background Obesity has been associated with chronic activation of the renin-angiotensin-aldosterone system and with significant changes in cardiac performance. Objective To assess the impact of a blockade of angiotensin-II receptor type 1 (AT1receptor) on morphology and on myocardial functional performance in rats with high-fat diet- induced obesity. Methods Wistar rats (n=48) were submitted to control (2.9 kcal/g) or high-fat (3.6 kcal/g) diet for 20 weeks. After the 16thweek they were divided into four groups: Control (CO), Obese (OB), Control Losartan (CL) and Obese Losartan (OL). CL and OL received losartan (30 mg/kg/day) in drinking water for four weeks. Subsequently, body composition, systolic blood pressure (SBP) and echocardiographic variables were analyzed. Papillary muscle function was assessed at baseline with 2.50 mM calcium concentration ([Ca2+]o) and after inotropic maneuvers: post-pause potentiation (PPP), [Ca2+]oelevation, and during beta-adrenergic stimulation with isoproterenol. Analysis of the results was performed by the Two-Way ANOVA and by the appropriate comparison test. The level of significance was set at 5%. Results Although SBP change had been not maintained at the end of the experiment, obesity was associated with cardiac hypertrophy and with increased left ventricle posterior wall shortening velocity. In the study of papillary muscles in basal condition, CL showed lower developed tension maximum negative variation velocity (-dT/dt) than CO. The 60s PPP promoted lower -dT/dt and maximum developed tension (DT) in OB and CL compared with CO, and higher relative DT variation and maximum positive variation velocity (+dT/dt) in OL compared with CL and OB. Under 1.5, 2.0, and 2.5mM [Ca2+]o, the OL group showed higher -dT/dt than CL. Conclusion Losartan improves myocardial function in high-fat diet-induced obesity. (Arq Bras Cardiol. 2020;115(1):17-28)

Determination of N-Nitroso-N-Methyl-4-Aminobutyric Acid in Losartan Potassium Using High Performance Liquid Chromatography Triple Quadrupole Mass Spectrometry / 中国药学杂志

OBJECTIVE: To establish a method to determine the genotoxic impurity, N-nitroso-N-methyl-4-aminobytyric acid, in losartan potassium using high performance liquid chromatography triple quadrupole mass spectrometry (HPLC-MS/MS). METHODS: The method was developed by using Shimadzu Shim-pack XR-ODS II column (2.0 mm×150 mm, 2.2 μm). Time program was conducted with mobile phase consisting of water (0.1% formic acid, A) and methanol (B). The flow rate was 0.3 mL•min-1, and the column oven temperature was maintained at 40 ℃. The samples were ionized by electrospray ionization (ESI) with multi reaction monitoring (MRM) data acquisition mode. The collision energies were -11, -13, and -13 V, CID gas was argon with pressure of 270 kPa.3 pairs of precursor, and product ions (m/z) of NMBA were 147.15→117.10, 147.15→87.10, and 147.15→44.10, respectively. RESULTS: The genotoxic impurity NMBA showed linearity between 1 and 100 ng•mL-1 with correlation coefficient of 0.999 9. The intra-day and inter-day repeatability was examined by relative standard deviations (RSDs) of retention time and peak area (RSD<1.10%, n=6 for intra-day repeatability and n=18 for inter-day repeatability). The accuracy was examined by percent recovery at three concentration levels, and the average percent recovery was between 94.40% and 98.04%. CONCLUSION: The established LC-MS/MS method is efficient for limit test and quantitation of NMBA in losartan potassium bulk drug.

The effect of losartan on the inflammatory damage through HMGB1 in the hepatocytes stimulated by heat stress / 解放军医学杂志

Objective To explore the function of losartan on heat-stress induced high-mobility group protein B1 (HMGB1) mediated inflammatory damage in the hepatocytes. Methods Rats were randomized into three groups: sham group (without heat stress), heatstroke group (heatstroke induction followed by i.p. injection of normal saline) and heatstroke+losartan group (heatstroke induction followed by i.p. injection of 50 mg/kg losartan). The serum and liver tissue were harvested nine hours after heatstroke to invest the serum alanine aminotransferase (ALT) levels, liver myeloperoxidase (MPO) levels, liver pathological morphology, serum HMGB1 levels as well as the expression of interleukin(IL)-1β and IL-18 in the liver. In vitro, the HBL3A hepatocyte cell lines were divided into the sham group (without heat stress), heat stress group and heat stress +losartan group (10 μmol/L losartan added into the supernatant after heat stress). Nine hours after heat stress, the cell viability and the levels of supernatant lactate dehydrogenase, supernatant HMGB, cytoplasm and total HMGB1 were all examined. Besides, the level of activated caspase-1 in hepatocytes, supernatant IL-1β and IL-18, as well as the cellular level of reactive oxygen species (ROS), were detected. The effects of recombinant HMGB1 with concentration gradients and 0.2 mmol/L hydrogen peroxide on the levels of IL-1β, IL-18 and HMGB1 in the heat stress hepatocytes treated by losartan were observed. Results In vivo, liver damage occurred in the rats of the heatstroke group. Compared with the heatstroke group, the levels of serum ALT, liver MPO, serum HMGB1, liver tissue IL-1β and IL-18 decreased in the heatstroke+losartan group (P<0.05). In vitro, hepatocytes in the heat stress group were apparently damaged. Compared with the heat stress, the levels of cytoplasmic HMGB1, supernatant HMGB1, IL-1β and IL-18 decreased in the heat stress+losartan group, and the cell survival rate increased (P<0.05). In addition, the HMGB1 inhibitor also reduced the levels of IL-1β and IL-18 in heat stress group hepatocytes. And the supplementation with HMGB1 increased the levels of IL-1β and IL-18 in heat stress hepatocytes treated by losartan (P<0.05). Losartan reduced the level of reactive oxygen species in heat stress hepatocytes, and the supplementation with hydrogen peroxide increased the level of HMGB1 in heat stress hepatocytes treated by losartan (P<0.05). Conclusion Losartan decreased the heat-stress induced HMGB1 mediated inflammatory damage in the hepatocytes.

Efecto de las variantes de CYP2C9 sobre la dosis de losartán en hipertensos chilenos / Association between cytochrome p4502c9 polymorphisms and losartan dosing in hypertensive patients

Background Losartan is widely used in many clinicals settings. Its dosage is related to the genetic characteristics of CYP2C9 enzymatic activity, which metabolizes losartan to its active form E-3174, responsible for the antihypertensive effect. Aims To identify the frequency of allelic variants CYP2C9*2 and CYP2C9*3 in hypertensive patients and to compare genotypes with a healthy Chilean population. To relate polymorphisms with the losartan dosing to obtain an optimal blood pressure. Material and Methods We studied 30 patients with controlled essential hypertension using losartan with normal liver function, and 202 healthy people. Peripheral blood DNA genotyping was performed by polymerase chain reaction to identify the polymorphisms. Allelic and genotypic frequencies were compared. Results In hypertensive patients, allelic frequencies were 0.85 (CYP2C9*1), 0.05 (CYP2C9*2) and 0.1 (CYP2C9*3). Genotypic frequencies were 73.3% (CYP2C9*1/*1), 6.7% (CYP2C9*1/*2), 16.7% (CYP2C9*1/*3) and 3.3% (CYP2C9*2/3); observing a significantly higher frequency of the allele CYP2C9*3 (p=0.041) and CYP2C9*1/*3 genotype (p=0.04). A non-significant tendency to need a larger dose of losartan was observed with the CYP2C9 * 3 allele, with an odds ratio (OR) of 1.46 (95% confidence intervals (CI) 0.01-18.64). The same tendency was observed with the need to use losartan twice a day, obtaining an OR of 5.88 (CI 0.54 -62.14). Conclusions There could be a relationship between the presence of CYP2C9 polymorphisms and the pathogenesis of hypertension. The presence of CYP2C9*3 is associated with the need for higher doses of losartan, possibly due to a decrease in the conversion of losartan to E-3174.

Evaluation of losartan plus hydrochlorothiazide combination therapy against amlodipine monotherapy in patients of hypertension

Background: Microalbuminuria has been shown to predict cardiovascular disease (CVD) in patients with hypertension. Recently the FDC of losartan and hydrochlorothiazide (HCTZ) has been reported to be effective for achieving a target BP level and also improvement in cardiovascular prognosis. The present study was conducted to compare effect of losartan plus hydrochlorothiazide combination therapy and high dose amlodipine monotherapy on blood pressure and microalbuminuria.Methods: Total 184 patients with hypertension were randomly allocated to two groups. The patients in group 1 received Amlodipine 5 mg orally for first 4 weeks. The patients from group 2 received losartan 50 mg orally for first 4 weeks. Patients in group 1 were titrated to amlodipine 10 mg orally for next 4 weeks. The patients in group 2 were titrated to FDC of losartan (50 mg) plus HCTZ (12.5 mg) for next 4 weeks. Follow杣p visits were scheduled at 4 weeks and 8 weeks. Pulse rate, sSBP and sDBP were estimated at each follow杣p. Microalbuminuria was estimated at 8 weeks.Results: There was no significant difference in mean change in sSBP, sDBP and pulse rate between two treatment groups (p>0.05). There was greater reduction in microalbuminuria in group 2 patients (p<0.0001). The adverse effects such as flushing and lower extremity oedema were significantly more in amlodipine group (p<0.05).Conclusions: Losartan plus HCTZ has similar effect on BP, better safety profile and superior effect on microalbuminuria level reduction.

Development and evaluation of liquid oral controlled release systems for Losartan potassium

Losartan potassium is a water soluble antihypertensive agent with short half-life. Controlling its release will improvepatient compliance. The benefit will be extended for geriatric patients if the developed system was liquid. The objectiveof this work was to develop controlled release oral liquid losartan potassium. This employed a combination of in situgelation and coating drug particles with pH-dependent polymer (Eudragit® L100). Solid dispersion (SD) prepared at1:1, 1:1.5, and 1:2 drug : polymer ratios, respectively. Sodium alginate solution was loaded with either pure drug orSD, in presence and absence of 1% w/v chitosan. These systems were evaluated for the drug release using continuouspH variation study. Alginate formulation with pure drug underwent in situ gelation in the gastric conditions but lost thegelling strength in the intestinal phase with burst drug release. Loading the formulation with SD resulted in controlleddrug release both in the gastric and intestinal phases. Increasing eudragit concentration in SD decreased the drugreleased with total release efficiency of 62.1%, 53.0%, and 41.7%. Incorporation of chitosan at reduced further drugrelease rate reaching 21% at the higher eudragit concentration. The study provided the formulator with a range of oralliquid formulations for controlled release of losartan potassium.

Control adecuado de la presión arterial en adultos con medicación antihipertensiva de dos Unidades de Salud Familiar de Luque y Fernando de la Mora, Paraguay, 2018

RESUMEN Introducción: la reducción de la presión arterial es una meta en el tratamiento de la hipertensión arterial primaria. Objetivos: determinar la frecuencia de control adecuado de la hipertensión arterial en adultos en tratamiento antihipertensivo de las Unidades de Salud Familiar de Luque y Fernando de la Mora, Paraguay. Metodología: estudio observacional, transversal, prospectivo, con componentes analíticos realizado en pacientes adultos hipertensos tratados en dos Unidades de Salud Familiar durante agosto y septiembre 2018. Se evaluaron variables sociodemográficas y clínicas. Se consideró presión arterial adecuada a todo valor <140/90 mm Hg. Resultados: se incluyeron 149 sujetos, con edad media 60±12 años, 68% del sexo femenino, 42% con sobrepeso-obesidad, 32% eran portadores de diabetes mellitus. Todos recibían tratamiento farmacológico antihipertensivo. El control adecuado de la hipertensión arterial se observó en 55%. Conclusiones: el control adecuado de la hipertensión arterial en pacientes adultos de dos Unidades de Salud Familiar fue 55%. Los antihipertensivos más usados fueron los inhibidores de enzima convertidora de angiotensina y los antagonistas de los receptores de angiotensina II.

ABSTRACT Introduction: The reduction of blood pressure is a goal in the treatment of primary arterial hypertension. Objectives: To determine the frequency of adequate control of arterial hypertension in adults under antihypertensive treatment at the Family Health Units of Luque and Fernando de la Mora, Paraguay. Methodology: Observational, cross-sectional, prospective study with analytical components performed in adult hypertensive patients treated in two Family Health Units during August and September 2018. Sociodemographic and clinical variables were evaluated. Adequate blood pressure was considered at any value <140/90 mm Hg. Results: One hundred forty nine subjects were included, with a average age of 60±12 years, 68% were women, 42% with overweight-obesity, and 32% were carriers of diabetes mellitus. All were receiving antihypertensive drug treatment. Adequate control of arterial hypertension was observed in 55%. Conclusions: The adequate control of hypertension in adult patients of two Family Health Units was 55%. The most commonly used antihypertensives were angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists.