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The combination of silica nanoparticles with fluorescent molecularly imprinted polymers (Si-FMIPs) prepared by a one-pot sol-gel synthesis method to act as chemical sensors for the selective and sensitive determination of captopril is described. Several analytical parameters were optimized, including reagent ratio, solvent, concentration of Si-FMIP solutions, and contact time. Fourier-transform infrared spectroscopy (FT-IR), transmission electron microscopy (TEM), and the ninhydrin assay were used for characterization. The selectivity was evaluated against molecules belonging to other drug classes, such as fluoroquinolones, nonacid nonopioids, benzothiadiazine, alpha amino acids, and nitroimidazoles. Under optimized conditions, the Si-FMIP-based sensor exhibited a working range of 1-15 µM, with a limit of detection (LOD) of 0.7 µM, repeatability of 6.4% (n = 10), and suitable recovery values at three concentration levels (98.5% (1.5 µM), 99.9% (3.5 µM), and 99.2% (7.5 µM)) for wastewater samples. The sensor provided a working range of 0.5-15 µM for synthetic urine samples, with an LOD of 0.4 µM and a repeatability of 7.4% (n = 10) and recovery values of 93.7%, 92.9%, and 98.0% for 1.0 µM, 3.5 µM, and 10 µM, respectively. In conclusion, our single-vessel synthesis approach for Si-FMIPs proved to be highly effective for the selective determination of captopril in wastewater and synthetic urine samples.

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The brain angiotensin II acting via AT1 receptors is a prominent mechanism involved in physiological and behavioral responses during aversive situations. The AT2 receptor has also been implicated in stress responses, but its role was less explored. Despite these pieces of evidence, the brain sites related to control of the changes during aversive threats by the brain renin-angiotensin system (RAS) are poorly understood. The bed nucleus of the stria terminalis (BNST) is a limbic structure related to the cardiovascular responses by stress, and components of the RAS system were identified in this forebrain region. Therefore, we investigated the role of angiotensinergic neurotransmission present within the BNST acting via local AT1 and AT2 receptors in cardiovascular responses evoked by an acute session of restraint stress in rats. For this, rats were subjected to bilateral microinjection of either the angiotensin-converting enzyme inhibitor captopril, the selective AT1 receptor antagonist losartan, or the selective AT2 receptor antagonist PD123319 before they underwent the restraint stress session. We observed that BNST treatment with captopril reduced the decrease in tail skin temperature evoked by restraint stress, without affecting the pressor and tachycardic responses. Local AT2 receptor antagonism within the BNST reduced both the tachycardia and the drop in tail skin temperature during restraint. Bilateral microinjection of losartan into the BNST did not affect the restraint-evoked cardiovascular changes. Taken together, these data indicate an involvement of BNST angiotensinergic neurotransmission acting via local AT2 receptors in cardiovascular responses during stressful situations.

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Introdução: O captopril (CP) é o medicamento de escolha para o tratamento da hipertensão arterial. Sua degradação leva à formação do dímero dissulfeto de captopril (DSCP), este associado a um odor forte no medicamento, podendo causar abandono do tratamento pelo paciente. Objetivo: Determinar DCSP, associar a percepção olfativa de odor de enxofre desprendido do produto e realizar a avaliação de bula de comprimidos de captopril 25 mg distribuídos pelos setores público e privado. Método: Foi verificado o desempenho do método de determinação do CP e DSCP pela Farmacopeia Brasileira 6a ed. por HPLC (DAD). Foram analisados 13 produtos de comprimidos de captopril 25 mg, sendo dois provenientes do setor público de lotes diferentes e mesmo fabricante e 11 do setor privado de diferentes fabricantes e lotes. Foram avaliados aspectos do comprimido quanto à percepção de odor, determinação de peso, identificação e teor de CP e de DSCP e análise do conteúdo da bula. Resultados: Dentre os 13, o medicamento vencido apresentou 4,4% de DSCP, os demais estavam de acordo com a especificação. Verificouse  correspondência do odor de enxofre perceptível com teor de DSCP acima de 0,5%. Considerando os textos de bula sobre odor de enxofre, as constatações foram: nenhuma informação (três produtos), odor característico (dois), leve odor de enxofre (um), leve odor de enxofre sem diminuir a eficácia (sete). Conclusões: As amostras apresentaram resultados satisfatórios para os ensaios realizados. Verificou-se falta de homogeneidade nas informações das bulas sobre o odor dos comprimidos. A percepção do paciente quanto ao odor de enxofre, mesmo dentro do limite tolerado de DSCP, pode levar a não aceitação do medicamento e consequente não adesão ao tratamento da hipertensão, além de gerar prejuízos ao SUS.

Introduction: Captopril (CP) is the drug of choice for the treatment of hypertension. Its degradation leads to the formation of captopril disulfide dimer (DSCP), associated with a strong odor in the drug, which can cause the patient abandonment of treatment. Objective: To determine DCSP, associate the olfactory perception of the sulfur odor given off by the product and carry out the evaluation of the package insert for captopril 25 mg tablets distributed in the public and private sectors. Method: The performance of CP and DSCP determination method of the Brazilian Pharmacopoeia 6 ed was verified by HPLC (DAD). Thirteen products of 25 mg captopril tablets were analyzed, 2 of which came from the public sector from different batches and the same manufacturer: the other 11 came from the private sector from different batches and manufacturers. The samples were analyzed regarding appearance, odor perception, identification, weight determination, CP and DSCP content (by HPLC) and package insert content. Results: Among the 13, the expired drug had 4.4% DSCP; the others were in accordance with the specification. Correspondence of perceptible sulfur odor was established for drugs with DSCP content above 0.5%. Considering the texts on sulfur odor in the package inserts, the findings were: none information (3 products), characteristic odor (2), slight sulfur odor (1), slight sulfur odor without decreasing effectiveness (7). Conclusions: The samples showed satisfactory results for the tests performed. There was a lack of homogeneity in the information in the package inserts about odor of the tablets. The patient's perception of sulfur odor, even within the tolerated limit of DSCP, can lead to non-acceptance of the drug and consequent non- adherence to the treatment of hypertension, in addition to causing damage to the SUS.

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Abstract he aim of this work was to develop an oral solution of captopril at 5 mg/mL preservative-free. Two formulations were prepared, one containing sweetener (formulation 1) and the other without this excipient (formulation 2). The results found of validation parameters from analytical method performed by HPLC for captopril were, linearity 0.9998, the limit of detection 15.71 µg/mL, the limit of quantification 47.60 µg/mL, repeatability 1.05%, intermediate precision 2.42%, accuracy intraday 101,53%, accuracy inter-day 99.85%. Moreover, the results found for captopril disulfide were, linearity 0.9999, limit of detection 0.65 µg/mL, limit of quantification 1.96 µg/mL, repeatability 2.28%, intermediate precision 1.51%, accuracy intraday 101.36%, accuracy inter-day 100.29%. The appearance of formulations was clear and colorless, pH measures were 3.12 and 3.04, dosage of captopril and captopril disulfide were 99.45% and 99.82%, 0.24% and 0.12% for formulation 1 and formulation 2, respectively. The stability study demonstrated that the concentration of captopril and captopril disulfide in the formulations was > 90% and below 3%, respectively. The in vivo palatability study in animals and humans showed that Formulation 1 containing the sweetener had better acceptance. Thus, the sweetener was able to improve the unpleasant taste of the formulation

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Abstract Ischemic heart disease is the leading cause of death in postmenopausal women. The activity of heart ACE increases whereas the activity of ACE-2 decreases after menopause. The present study was designed to investigate the role of ACE and ACE-2 in the abrogated cardioprotective effect of IPC in OVX rat heart. The heart was isolated from OVX rat and mounted on Langendorff's apparatus for giving intermittent cycles of IPC. The infarct size was estimated using TTC stain, and coronary effluent was analyzed for LDH, CK-MB, and nitrite release. IPC induced cardioprotection was significantly attenuated in the ovariectomized rat heart as compared to the normal rat heart. However, this attenuated cardioprotection was significantly restored by perfusion of DIZE, an ACE-2 activator, and captopril, an ACE inhibitor, alone or in combination noted in terms of decrease in myocardial infarct size, the release of LDH and CK-MB, and also increase in the release of NO as compared to untreated OVX rat heart. Thus, it is suggested that DIZE and captopril, alone or in combination restore the attenuated cardioprotective effect of IPC in OVX rat heart which is due to an increase in ACE-2 activity and decrease in ACE activity after treatment.

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SUMMARY: Osteoarthritis (OA) is an inflammatory disease that damages the joints and affects millions of people worldwide. The potential inhibitory effects of the antidiabetic drug metformin combined with captopril, the angiotensin-converting enzyme inhibitor, on diabetes-induced damage to the knee joint articular cartilage associated with the inhibition of glycemia, dyslipidemia, and inflammation has not been investigated before. Therefore, we induced diabetes in rats using high carbohydrate and fat diets and a single injection of streptozotocin (50 mg/kg). The protective group of rats was pre-treated with combined daily doses of metformin (Met; 200 mg/kg body weight) and captopril (Cap; 150 mg/kg body weight) for 14 days before diabetic induction and continued on metformin and resveratrol until the end of the experiment at week 12. Harvested tissues obtained from knee joints were prepared for basic histology staining with haematoxylin and eosin (H&E) and examined under light microscopy. Representative H&E images showed that OA was developed in the diabetic rats as demonstrated by a profound damage to the knee joints such as irregular eroded and a sharp decrease in the thickness of the articular cartilage surface and abnormal remodeling of the subchondral bone that were substantially ameliorated by Met+Cap. Met+Cap also significantly (p< 0.05) reduced blood levels of glucose, glycated hemoglobin (HbA1c), dyslipidemia, and the inflammatory biomarkers, high sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-α) induced by diabetes. In addition, a significant (p≤ 0.0014) correlation between the articular cartilage thickness and the blood levels of glucose, HbA1c, triglyceride (TG), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein- cholesterol (HDL-C), and hs-CRP were observed. Thus, we demonstrate that Met+Cap effectively protect the knee joint against injuries induced secondary to diabetes in rats, possibly due to the inhibition of glycemia, dyslipidemia, and biomarkers of inflammation.

RESUMEN: La osteoartritis (OA) es una enfermedad inflamatoria que daña las articulaciones y afecta a millones de per- sonas en todo el mundo. No se han investigado los posibles efectos inhibidores del fármaco antidiabético metformina combinado con captopril, el inhibidor de la enzima convertidora de angiotensina, sobre el daño inducido por la diabetes en el cartílago articular de la articulación de la rodilla asociado con la inhibición de la glucemia, dislipidemia e inflamación. En este estudio fue inducida la diabetes en ratas con dietas altas en carbohidratos y grasas y una sola inyección de estreptozotocina (50 mg / kg). El grupo protector de ratas se pretrató con dosis diarias combinadas de metformina (Met; 200 mg / kg de peso corporal) y captopril (Cap; 150 mg / kg de peso corporal) durante 14 días antes de la inducción diabética. El tratamiento se continuó con metformina y resveratrol hasta el final del experimento en la semana 12. Los tejidos obtenidos de las articulaciones de la rodilla se prepararon para la tinción de histología básica con hematoxilina y eosina (H&E) y se examinaron con microscopía óptica. Imágenes representativas de H&E mostraron que la OA se desarrolló en las ratas diabéticas, como lo evidencia un daño profundo en las articulaciones de la rodilla, como la erosión irregular y una fuerte disminución en el grosor de la superficie del cartílago articular y remodelación anor- mal del hueso subcondral que fueron mejorados sustancialmente por Met + Cap. Met + Cap. También redujo significativamente (p <0.05) los niveles sanguíneos de glucosa, hemoglobina glicosilada (HbA1c), dislipidemia y los biomarcadores inflamatorios, proteína C reactiva de alta sensibilidad (hs-CRP), interleucina-6 (IL-6), y factor de necrosis tumoral alfa (TNF-α) inducido por diabetes. Además, una correlación significativa (p≤ 0,0014) entre el grosor del cartílago articular y los niveles sanguíneos de glucosa, HbA1c, triglicéridos (TG), lipoproteínas-colesterol de baja densidad (LDL- C), lipoproteínas de alta densidad-colesterol (HDL-C) ) y hs-CRP. Así, demostramos que Met + Cap protege eficazmente la articulación de la rodilla contra lesiones inducidas por diabetes en ratas, posiblemente debido a la inhibición de la glicemia, dislipidemia y biomarcadores de inflamación.

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OBJECTIVES: This study aimed to evaluate the involvement of Angiotensin II (Ang II) in joint lesions associated with osteoarthritis (OA) in vitro and in vivo. METHODS: Chondrocyte cultures were obtained from knee joints of neonatal rats and stimulated with Ang II/MIA/ACE inhibitors. In vivo, rats treated or not with the ACE inhibitor captopril, received daily injections of Ang II or sodium monoiodoacetate (MIA) in knee joints for evaluation of cartilage, bone, and synovial lesions. RESULTS: Cultured chondrocytes expressed the mRNA for Ace, Agtr1, Agtr2, and Mas1. Stimulating cells with Ang II reduced chondrocyte viability and metabolism. Accordingly, in vivo Ang II injection into the knees of rats triggered hyperalgesia, joint edema, increased the number of leukocytes in the joint cavity, and induced cartilage lesions associated with OA alterations. In further experiments, Ang II synthesis was prevented with the ACE inhibitor Captopril in the context of MIA-induced OA. Ang II inhibition with captopril improved the OARSI score, induced chondroprotection, and reduced the leukocyte recruitment from synovium after MIA. Additionally, captopril prevented MIA-induced bone resorption, by decreasing the number of osteoclasts and increasing the expression of IL-10 in the bone. In vitro, inhibiting Ang II synthesis decreased MIA-induced chondrocyte death and increased Col2a1 transcription. CONCLUSION: Ang II induces chondrocyte death and joint tissue damages associated with OA and its modulation can be a therapeutic strategy in osteoarthritis.

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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.

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INTRODUCCIÓN: La crisis hipertensiva es considerada una complicación aguda de la Hipertensión Arterial Sistémica, y contribuye a las 9.4 millones de muertes anuales estimadas, asociadas a la misma. La morbilidad que ocasionan es otro problema de importancia. Los datos a nivel local son escasos, por lo que conocer las características clínico-epidemiológicas de las crisis hipertensivas reviste gran importancia. El objetivo de este estudio fue caracterizar las Crisis hipertensivas en adultos de la Emergencia del Hospital José Félix Valdivieso Santa Isabel, periodo enero 2016 a diciembre 2018. METODOLOGÍA: Se trató de un estudio descriptivo, transversal, con un universo de 151 pacientes diagnosticados con crisis hipertensiva en el Hospital José Félix Valdivieso entre enero 2016 y diciembre 2018, realizando un muestreo aleatorio simple se obtuvo 122 pacientes. Se recolectó la información mediante revisión de las historias clínicas. Se procesaron los datos mediante Excel 2016, para posteriormente interpretarlos mediante tablas y gráficos. RESULTADOS: El 57% de los pacientes fue de sexo femenino, el grupo de edad de 40 a 65 años que representa el 49% de la muestra, 67% tuvieron un nivel de instrucción primaria, 65% fueron de una procedencia rural. En cuanto a la presencia de factores de riesgo conocidos para crisis hipertensivas, el 50% de la población tuvo sobrepeso, el 70% hipertensión arterial previa. Según el tipo de crisis hipertensiva, el 93% fueron urgencia hipertensivas, en las emergencias hipertensivas el órgano afecto con mayor frecuencia fue el cerebro con 89%. La manifestación clínica más frecuente fue cefalea con un 59%, seguida de sintomatología neurológica.. En cuanto al manejo la terapéutica inicial fue Captopril en el 61%. CONCLUSIÓN: La mayor parte de pacientes afectados fueron del sexo femenino, adultos de edad media. La mayoría de la muestra tuvo antecedentes de sobrepeso u obesidad. El 70% de la población tenia diagnóstico previo de Hipertensión Arterial, y de ellos solamente el 80% tomaba fármacos antihipertensivos. La mayoría de crisis fueron urgencias hipertensivas, en las emergencias hipertensivas el órgano diana más afectado fue el cerebro. El medicamento que se administró con mayor frecuencia en el manejo inicial de la crisis hipertensiva fue captopril. No se registró mortalidad en ese estudio.(au)

BACKGROUND: Hypertensive crisis is considered an acute complication of Hypertension, causing 9.4 million deaths annually. Another important problem is the resulting morbidity. Locally, data is limited, that is the importance of presenting the clinical and epidemiological characteristics of hypertensive crisis. The aim of this study was characterizing hypertensive crisis in adults, in Hospital José Félix Valdivieso, Santa Isabel, from January 2016 to December 2018. METHODS: Descriptive, cross-sectional study, the study universe were 151 patients diagnosed with hypertensive crisis in Hospital José Félix Valdivieso from January 2016 to December 2018, by simple random sampling we picked 122 patients. The information was obtained from the patient's medical chart. The data was processed using Excel 2016, and later interpreted using tables and charts. RESULTS: 57% of the sample were female, 49% had between 40 to 65 years of age, 67% had primary education, 65% came from rural areas. About risk factors; 50% of the population was overweight, 70% had previous diagnosis of hypertension. About the type of hypertensive crisis; 93% were hypertensive urgencies, the most commonly affected organ in hypertensive emergencies was the brain, in 89% of the cases. Headache, was the most frequent symptom(59%), followed by neurological symptoms. Captopril was used as initial treatment in 61% of the cases. CONCLUSION: The majority of affected patients were female, middle aged adults. Most of the sample had overweight or obesity. 70% of the population had previous diagnosis of hypertension, of this patients only 80% had hypertensive treatment. Most of the crisis were hypertensive urgencies, in hypertensive emergencies the most commonly affect organ was the brain. Captopril was used in most of the cases for initial treatment. This study didn't registered any deaths.(au)

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Multi-wall lipid-core nanocapsule (MLNC) functionalized with captopril and nanoencapsulating furosemide within the core was developed as a liquid formulation for oral administration. The nanocapsules had mean particle size below 200 nm, showing unimodal and narrow size distributions with moderate dispersity (laser diffraction and dynamic light scattering). Zeta potential was inverted from -14.3 mV [LNC-Fur(0,5)] to +18.3 mV after chitosan coating. Transmission electron microscopy and atomic force microscopy showed spherical structures corroborating the nanometric diameter of the nanocapsules. Regarding the systolic pressure, on the first day, the formulations showed antihypertensive effect and a longer effect than the respective drug solutions. When both drugs were associated, the anti-hypertensive effect was prolonged. On the fifth day, a time effect reduction was observed for all treatments, except for the nanocapsule formulation containing both drugs [Capt(0.5)-Zn(25)-MLNC-Fur(0.45)]. For diastolic pressure, only Capt(0.5)-Zn(25)-MLNC-Fur(0.45) presented a significant difference (p < 0.05) on the first day. On the fifth day, both Capt(0.5)-MLNC-Fur(0.45) and Capt(0.5)-Zn(25)-MLNC-Fur(0.45) had an effect lasting up to 24 h. The analysis of early kidney damage marker showed a potential protection in renal function by Capt(0.5)-Zn(25)-MLNC-Fur(0.45). In conclusion, the formulation Capt(0.5)-Zn(25)-MLNC-Fur(0.45) proved to be suitable for hypertension treatment envisaging an important innovation.

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Angiotensin-converting enzyme inhibitors (ACEis) may cause adverse airway events, such as cough and angioedema, due to a reduction in bradykinin breakdown and consequent activation of bradykinin type 2 receptor (B2 receptor). Recent studies have shown that bradykinin can also sensitize pro-inflammatory receptors such as the transient receptor potential ankyrin 1 (TRPA1) and vanilloid 4 (TRPV4), which are implicated in several inflammatory airway diseases. Based on these considerations, the aim of this study was to understand the role of TRPA1 and TRPV4 channels in the bronchoconstrictive response and plasma extravasation in the trachea of rats pretreated with captopril. Using methods to detect alterations in airway resistance and plasma extravasation, we found that intravenous (i.v.) administration of bradykinin (0.03-0.3 µmol/kg, B2 receptor agonist), allyl isothiocyanate (100-1000 µmol/kg, TRPA1 agonist) or GSK1016790A (0.01-0.1 µmol/kg, TRPV4 agonist), but not des-arg9-bradykinin (DABK; 100-300 µmol/kg, B1 receptor agonist), induced bronchoconstriction in anaesthetized rats. In doses that did not cause significant bronchoconstriction, bradykinin (0.03 µmol/kg) or allyl isothiocyanate (100 µmol/kg), but not GSK1016790A (0.01 µmol/kg) or DABK (300 µmol/kg) induced an increased bronchoconstrictive response in rats pretreated with captopril (2.5 mg/kg, i.v.). On the other hand, in rats pretreated with captopril (5 mg/kg, i.v.), an increased bronchoconstrictive response to GSK1016790A (0.01 µmol/kg) was observed. The bronchoconstrictive response induced by bradykinin in captopril-pretreated rats was inhibited by intratracheal treatment (i.t.) with HC030031 (300 µg/50 µl; 36 ± 9%) or HC067047 (300 µg/50 µl; 35.1 ± 16%), for TRPA1 and TRPV4 antagonists, respectively. However, the co-administration of both antagonists did not increase this inhibition. The bronchoconstriction induced by allyl isothiocyanate in captopril-pretreated rats (2.5 mg/kg) was inhibited (58.3 ± 8%) by the B2 receptor antagonist HOE140 (10 nmol/50 µl, i.t.). Similarly, the bronchoconstriction induced by GSK1016790A in captopril-pretreated rats (5 mg/kg) was also inhibited (84.2 ± 4%) by HOE140 (10 nmol/50 µl, i.t.). Furthermore, the plasma extravasation induced by captopril on the trachea of rats was inhibited by pretreatment with HC030031 (47.2 ± 8%) or HC067047 (38.9 ± 8%). Collectively, these findings support the hypothesis that TRPA1 and TRPV4, via a B2 receptor activation-dependent pathway, are involved in the plasma extravasation and bronchoconstriction induced by captopril, making them possible pharmacological targets to prevent or remediate ACEi-induced adverse respiratory reactions.

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BACKGROUND: Malaria represents a worldwide medical emergency affecting mainly poor areas. Plasmodium parasites during blood stages can release kinins to the extracellular space after internalization of host kininogen inside erythrocytes and these released peptides could represent an important mechanism in liver pathophysiology by activation of calcium signaling pathway in endothelial cells of vertebrate host. Receptors (B1 and B2) activated by kinins peptides are important elements for the control of haemodynamics in liver and its physiology. The aim of this study was to identify changes in the liver host responses (i.e. kinin receptors expression and localization) and the effect of ACE inhibition during malaria infection using a murine model. METHODS: Balb/C mice infected by Plasmodium chabaudi were treated with captopril, an angiotensin I-converting enzyme (ACE) inhibitor, used alone or in association with the anti-malarial chloroquine in order to study the effect of ACE inhibition on mice survival and the activation of liver responses involving B1R and B2R signaling pathways. The kinin receptors (B1R and B2R) expression and localization was analysed in liver by western blotting and immunolocalization in different conditions. RESULTS: It was verified that captopril treatment caused host death during the peak of malaria infection (parasitaemia about 45%). B1R expression was stimulated in endothelial cells of sinusoids and other blood vessels of mice liver infected by P. chabaudi. At the same time, it was also demonstrated that B1R knockout mice infected presented a significant reduction of survival. However, the infection did not alter the B2R levels and localization in liver blood vessels. CONCLUSIONS: Thus, it was observed through in vivo studies that the vasodilation induced by plasma ACE inhibition increases mice mortality during P. chabaudi infection. Besides, it was also seen that the anti-malarial chloroquine causes changes in B1R expression in liver, even after days of parasite clearance. The differential expression of B1R and B2R in liver during malaria infection may have an important role in the disease pathophysiology and represents an issue for clinical treatments.

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Este trabalho objetivou analisar a qualidade dos comprimidos e a relação entre os medicamentos de referência, genéricos e similares. Para estudo e coleta de dados, foram realizados testes físicos e físico-químicos de acordo com a farmacopéia brasileira 5º edição 2010. Os produtos analisados apresentaram resultados satisfatórios quanto aos aspectos visuais, teste de vazamento, determinação de peso médio em formas farmacêuticas sólidas, determinação de resistência mecânica através dos testes de dureza e friabilidade e teste de desintegração, demonstraram qualidade conforme com devidas especificações, estando adequados para o consumo.

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Currently, medications used in children are typically modified from pharmaceutical dosage forms designed for adults. Captopril is widely adapted to liquid formulations for use in hospitals. Its stability in the aqueous medium is reduced since it undergoes oxidation producing captopril disulfide (its main metabolite). The aim of this formulation study was to suggest favorable conditions for the development of a stable captopril formulation. The compatibility between the drug and excipients was evaluated by differential scanning calorimetry analysis (DSC). For studies in solution, different formulations were prepared according to a factorial design varying EDTA concentration, water purity and pH. The resultant formulations were stored at 60°C and analyzed over a twelve-day period using HPLC. The DSC curves obtained suggested, although not conclusive to elucidation, interactions of captopril with citric acid and sucralose. The stability study of these solutions revealed that the variables significantly influenced captopril content, which degraded at zero order kinetics and rates differing by a factor of up to 7 times, where pH proved the most influential factor. Interactions between variables were observed. Therefore, development of a stable captopril formulation is feasible provided EDTA and a buffering agent is used at suitable concentrations (0.08% and pH 3.85).

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Abstract Angioedema induced by the use of angiotensin converting enzyme (ACE) inhibitors is an uncommon but life-threatening complication, especially when the airway is affected, creating unexpected difficult airway management. A prompt differential diagnosis with anaphylactic shock is critical, given that adrenaline treatment does not improve angioedema. We report a case of angioedema induced by ACE inhibitor following in-hospital administration of captopril, with almost impossible intubation, and secondary aspiration during airway management. Angioedema was erroneously treated, because it was mistakenly considered to be an anaphylactic reaction, and it could have ended in death.

Resumen El angioedema es una complicación poco frecuente relacionada con el uso de inhibidores de la enzima convertidora de angiotensina, pero potencialmente mortal, especialmente en el caso de afectar a la vía aérea, generando vías aéreas difíciles no previstas. Es de vital importancia realizar un rápido diagnóstico diferencial del cuadro con el shock anafiláctico, dado que el tratamiento con adrenalina, no mejora el angioedema. Presentamos un caso de angioedema tras administración intrahospitalaria de Captopril a un paciente sano, sin vía aérea difícil prevista, generando una intubación casi imposible y broncoaspiración secundaria durante el manejo de la vía aérea. El cuadro clínico se desencadenó por la confusión del angioedema, con una reacción anafiláctica, realizándose un tratamiento inapropiado. Las consecuencias del mismo pudieron ser mortales.

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A simple, accurate, and low-cost analytical procedure for captopril determination through digital imaging is presented. The method relies on the spot test reaction between captopril and palladium (II) chloride, which produces a yellow and water-soluble complex with maximum absorption at 380 nm. A smartphone camera and a portable apparatus built for internal lighting control were put together to acquire digital images of reaction mixtures. Digital image processing through the RGB approach was used to establish a quantitative relationship between color intensity and captopril concentration. Under the most suitable operational and experimental conditions, an analytical curve was built monitoring the Blue channel within the concentration range of 3.12 × 10-5 to 1.21 × 10-3 mol L-1. Limits of detection and quantification were equal to 8.06 × 10-6 and 2.69 × 10-5 mol L-1, respectively. Recovery percentage in synthetic urine samples ranged from 97.1% to 102.9%. Results were compared with a reference method and no significant differences were detected at the 95% confidence level. The developed method presents budgetary and environmental advantages concerning the use of cheap and easy-handled devices and the consumption of very low volumes of reagent (800 µL per determination). It can be a useful analytical tool for laboratories with limited financial resources while abiding by green chemistry principles.

Assuntos

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Hypertension is a global health problem, and angiotensin I (ANG I)-converting enzyme (ACE) inhibitors are largely used to control this pathology. Recently, it has been shown that ACE can also act as a transducer signal molecule when its inhibitors or substrates bind to it. This new role of ACE could contribute to understanding some of the effects not explained by its catalytic activity only. In this study, we investigated signaling pathway activation in Chinese hamster ovary (CHO) cells stably expressing ACE (CHO-ACE) under different conditions. We also investigated gene modulation after 4 h and 24 h of captopril treatment. Our results demonstrated that CHO-ACE cells when stimulated with ANG I, ramipril, or captopril led to JNK and ERK1/2 phosphorylation. To verify any physiological role at the endogenous level, we made use of primary cultures of mesangial cells from spontaneously hypertensive rats (SHR) and Wistar rats. Our results showed that ERK1/2 activation occurred mainly in primary cultures of mesangial cells from SHR rats upon captopril stimulation, suggesting that this signaling pathway could be differentially regulated during hypertension. Our results also showed that captopril treatment leads to a decrease of cyclooxygenase 2, interleukin-1ß, and ß-arrestin2 and a significant increase of AP2 gene expression levels. Our findings strengthen the fact that, in addition to the blockage of enzymatic activity, ACE inhibitors also trigger signaling pathway activation, and this may contribute to their beneficial effects in the treatment of hypertension and other pathologies.

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BACKGROUND: In recent years, it has been demonstrated the inhibitory effect of some plant species on the angiotensin-converting enzyme and rosmarinic acid is a prominent constituent of these species. HYPOTHESIS/PURPOSE: This study was carried out to verify the effect of rosmarinic acid on blood pressure through inhibitory activity on angiotensin-converting enzyme in rats. STUDY DESIGN: The arterial hypertension was promoted using 2-kidneys 1-clip model in rats. The potential inhibitory rosmarinic acid effect on angiotensin-converting enzyme activity was compared with captopril actions by analyzing in vivo blood pressure dose-response curves to angiotensin I and bradykinin. The in vitro plasma angiotensin-converting enzyme activity was measured by fluorimetry using the substrate Abz-FRK(Dnp)P-OH substrate. In addition, dosages of nitrite/nítrate analysis were carried out. RESULTS: (1) rosmarinic acid caused systolic blood pressure dose-dependent decrease in hypertensive rats; (2) The angiotensin I dose-response curves demonstrated that rosmarinic acid promotes minor changes in systolic blood pressure only in the hypertensive group; (3) The bradykinin dose-response curves showed that both rosmarinic acid and captopril promoted a systolic blood pressure reduction, but only the captopril effect was significant; (4) The angiotensin-converting enzyme activity in rat lung tissue was inhibited by the rosmarinic acid in a dose dependent manner; (5) The analysis of nitrite/nítrate plasma concentrations showed no significant difference among the experimental groups. CONCLUSION: The rosmarinic acid is effective in reducing blood pressure, selectively, only in hypertensive animals. The rosmarinic acid (173µM) promoted almost a 98.96% reduction on angiotensin-converting enzyme activity.

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Hypertensive renal damage generally occurs during the middle and late stages of hypertension, which is typically characterized by proteinuria and renal inflammation. Captopril, an angiotensin-converting enzyme (ACE) inhibitor, has been widely used for therapy of arterial hypertension and cardiovascular diseases. However, the protective effects of captopril on hypertension-induced organ damage remain elusive. The present study was designed to explore the renoprotective action of captopril in spontaneously hypertensive rats (SHR). The 6-week-old male SHR and age-matched Wistar-Kyoto rats were randomized into long-term captopril-treated (34 mg/kg) and vehicle-treated groups. The results showed that in SHR there was obvious renal injury characterized by the increased levels of urine albumin, total protein, serum creatinine, blood urea nitrogen, renal inflammation manifested by the increased mRNA and protein expression of inflammatory factors including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and inducible nitric oxide synthase, and enhanced nuclear factor-κB (NF-κB) activation. Captopril treatment could lower blood pressure, improve renal injury, and suppress renal inflammation and NF-κB activation in SHR rats. In conclusion, captopril ameliorates renal injury and inflammation in SHR possibly via inactivation of NF-κB signaling.

Assuntos

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In hypertension, the combination therapy is frequently used to obtain a better therapeutic effect and reduce adverse effects. One effective combination is with inhibitors and ß-blockers of renin-angiotensin system. Although the mechanisms of action of each drug are already known, the antihypertensive mechanism is more complex and therefore the combined treatment mechanism is unclear. Specifically, the effect of the treatments of angiotensin-converting enzyme inhibitor or AT1 receptor antagonist with ß-blocker on the angiotensin II and bradykinin reactivity has not been studied. For this reason, we evaluated the interaction between propranolol and captopril or losartan on vascular reactivity to bradykinin and angiotensin II in spontaneously hypertensive rat. We constructed concentration-response curves to angiotensin II and bradykinin after treatment of SHR with propranolol-captopril or propranolol-losartan by using rat aortic rings. While losartan or captopril with propranolol potentiated bradykinin-induced vasodilation effect, the propranolol-losartan interaction decreased the angiotensin II-induced vasoconstriction. In addition, the combinations did not reduce the heart rate significantly. These results suggest that the combined therapy decreased blood pressure to normotensive values and showed less effect for angiotensin II and greater effect for bradykinin than monotherapy which could contribute in the antihypertensive effect.