Bilateral fracture of the shoulders following epileptic seizures: a case report / Fratura bilateral de ombros após convulsões epilépticas: relato de caso

Convulsive seizures caused by hyponatremia occur when this condition is severe and develops quickly, resulting in a brain's adaptive inability to contain brain swelling. Seizures are rarely the cause of shoulder fractures. This is a case report of bilateral humerus fracture following a single epileptic seizure caused by drug hyponatremia, an unconventional event in medical practice. A 69-year-old woman was admitted to the emergency room after a single tonic-clonic seizure with spontaneously ceased sphincter relaxation, showing Glasgow 6. No falls or restraint were reported by observers. When alert, the patient reported pain and difficulty moving both arms. During examination, the movement was li- mited to the right and left. Anteroposterior radiographs revealed bilateral fracture at the neck of humerus. To complement inves- tigation for further lesions, a computed tomography confirmed bilateral fracture-dislocation with impaction of the humeral head with the glenoid. Atraumatic bilateral fracture-dislocation of the humerus after epileptic seizure is a very rare event. It is believed that some of these diagnoses have been neglected due to the difficulty of characterizing the patient's pain in a postictal state. The importance of a detailed physical examination shall be emphasized in risk groups such as the polymedicated elderly.

Convulsive seizures caused by hyponatremia occur when this condition is severe and develops quickly, resulting in a brain's adaptive inability to contain brain swelling. Seizures are rarely the cause of shoulder fractures. This is a case report of bilateral humerus fracture following a single epileptic seizure caused by drug hyponatremia, an unconventional event in medical practice. A 69-year-old woman was admitted to the emergency room after a single tonic-clonic seizure with spontaneously ceased sphincter relaxation, showing Glasgow 6. No falls or restraint were reported by observers. When alert, the patient reported pain and difficulty moving both arms. During examination, the movement was li- mited to the right and left. Anteroposterior radiographs revealed bilateral fracture at the neck of humerus. To complement inves- tigation for further lesions, a computed tomography confirmed bilateral fracture-dislocation with impaction of the humeral head with the glenoid. Atraumatic bilateral fracture-dislocation of the humerus after epileptic seizure is a very rare event. It is believed that some of these diagnoses have been neglected due to the difficulty of characterizing the patient's pain in a postictal state. The importance of a detailed physical examination shall be emphasized in risk groups such as the polymedicated elderly.

Meta-analysis of clinical efficacy and safety of Compound Danshen Dripping Pills combined with conventional antihypertensive drugs in treatment of hypertensive left ventricular hypertrophy / 中国中药杂志

To systematically evaluate the clinical efficacy and safety of Compound Danshen Dripping Pills combined with conventional antihypertensive drugs in the treatment of hypertensive left ventricular hypertrophy. China National Knowledge Infrastructure(CNKI), Wanfang, VIP, PubMed, EMbase, Cochrane Library, Ovid and Web of Science databases were searched by computer to retrieve the randomized controlled trials(RCTs) of Compound Danshen Dripping Pills combined with conventional antihypertensive drugs in the treatment of hypertensive left ventricular hypertrophy from the establishment of databases to July 2020. After two researchers performed data retrieval, data extraction, and risk assessment of bias, they used RevMan 5.3 software for Meta-analysis. A total of 10 RCTs were included, with a total of 979 patients. Meta-analysis results showed that in terms of interventricular septal thickness(MD=-0.70, 95%CI[-1.15,-0.24], P=0.003), left ventricular posterior wall thickness(MD=-0.81, 95%CI[-1.41,-0.21], P=0.008), left ventricular mass index(MD=-8.75, 95%CI[-17.40,-0.10], P=0.05), systolic blood pressure(MD=-8.97, 95%CI[-13.46,-4.48], P<0.000 1), diastolic blood pressure(MD=-5.87, 95%CI[-8.39,-3.34], P<0.000 01) and left ventricular end-diastolic diameter(MD=-1.73, 95%CI[-2.38,-1.08], P<0.000 01), Compound Danshen Dripping Pills combined with conventional antihypertensive drugs was superior to conventional antihypertensive drugs. In terms of left ventricular ejection fraction(MD=0.41, 95%CI[-0.74, 1.55], P=0.49), there was no statistical difference in treatment between the two groups. Because of the small amount of literatures included in the safety aspect, it is impossible to give an accurate conclusion. The GRADE score showed that the level of evidence was low and extremely low. The results show that the Compound Danshen Dripping Pills combined with conventional antihypertensive drugs may effectively improve the clinical efficacy for hypertensive ventricular hypertrophy, and the safety needs to be further explored. Due to the low quality of the included literatures, more high-quality RCTs are needed for verification.

Systematic evaluation and trail sequential analysis of efficacy and safety of Yangxue Qingnao Granules in treatment of essential hypertension and its accompanying symptoms / 中国中药杂志

To systematically evaluate the efficacy and safety of Yangxue Qingnao Granules combined with conventional Western medicine in the treatment of essential hypertension and its accompanying symptoms. PubMed, EMbase, Cochrane Library, VIP, CNKI, Wanfang, and China biomedical database(CBD) were searched to screen out from the establishment of the database to April 2020 about the clinical randomized controlled trials of Yangxue Qingnao Granules combined with conventional Western medicine in the treatment of essential hypertension and accompanying symptoms. The articles were selected according to the inclusion and exclusion criteria. RevMan 5.3 software was used for Meta-analysis. TSA 0.9.5.10 Beta software was used for sequential analysis, and GRADE 3.6 was used for evidence quality evaluation. A total of 4 532 patients were included in 34 randomized controlled trials. Meta-analysis results showed that: Yangxue Qingnao Granules combined with conventional anti-hypertensive agents reduced systolic blood pressure(MD=-10.56, 95%CI[-13.63,-7.50], P<0.000 01) and diastolic blood pressure(MD=-8.21, 95%CI[-10.84,-5.59], P<0.000 01), improved total effective rate(RR=1.21, 95%CI[1.14, 1.29], P<0.000 01), improved patients dizziness(RR=1.29, 95%CI[1.21, 1.37], P<0.000 01), insomnia(RR=1.66, 95%CI[1.44, 1.91], P<0.000 01), headache(RR=1.32, 95%CI[1.21, 1.43], P<0.000 01), chest distress(RR=1.26, 95%CI[1.12, 1.42], P=0.000 1), memory loss(RR=1.24, 95%CI[1.10, 1.40], P=0.000 4), palpitation(RR=1.28, 95%CI[1.17, 1.41], P<0.000 01), and improved traditional Chinese medicine symptom scores(MD=-4.24, 95%CI[-5.25,-3.23], P<0.000 01) and headache symptom improvement scores(MD=-2.02, 95%CI[-2.51,-1.53], P<0.000 01) as compared with Western medicine group alone. Subgroup analysis results showed that Yang-xue Qingnao Granules combined with ACEI drug had more obvious effects in lowering systolic blood pressure and diastolic blood pressure. There was no statistically significant difference in the incidence of adverse reactions, and no abnormal liver and kidney function was observed in each study. Trial sequential analysis showed that the total effective rate was cumulative across the traditional and TSA thresholds, further confirming its clinical efficacy. The evidence level was mostly low or extremely low in GRADE evaluation. The clinical application of Yangxue Qingnao Granules combined with conventional Western medicine in the treatment of essential hypertension and its accompanying symptoms is clear and safe, so it is recommended for clinical application.

Impact of antihypertensive agents on clinical course and in-hospital mortality: analysis of 169 hypertensive patients hospitalized for COVID-19

SUMMARY OBJECTIVE Coronavirus disease 2019 (COVID-19) is an emerging health threat caused by a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). Previous studies have noted hypertension is associated with increased mortality due to COVID-19; however, it is not clear whether the increased risk is due to hypertension itself or antihypertensive agents. We aimed to evaluate the impact of antihypertensive agents on the clinical outcomes of hypertensive patients with COVID-19. METHODS Our study included 169 consecutive hypertensive patients hospitalized due to COVID-19 between March 20 and April 10, 2020. The demographic characteristics, clinical data, and type of antihypertensive agents being used were reviewed. RESULTS The mean age of patients was 65.8±11.7 years.30 patients(17.7%) died during hospitalization. A total of 142 patients(84%) were using angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), 91 (53.8%) were using diuretics, 69 (40.8%) were using calcium channel blockers (CCBs), 66 (39.1%) were using beta-blockers, 12 (7.1%) were using alpha-blockers, and 5 (2.9%) were using mineralocorticoid receptor antagonists (MRAs). There was no significant difference between survivors and non-survivors based on the type of antihypertensive agents being used. Binary logistic regression analysis showed that the type of the antihypertensive agent being used had no effect on mortality [OR=0.527 (0.130-2.138), p=0.370 for ACEIs/ARBs; OR=0.731 (0.296-1.808), p=0.498 for CCBs; OR=0.673 (0.254-1.782), p=0.425 for diuretics; OR=1.846 (0.688-4.950), p=0.223 for beta-blockers; OR=0.389 (0.089-1.695), p=0.208 for alpha-blockers; and OR=1.372 (0.107-17.639), p=0.808 for MRAs]. CONCLUSION The type of antihypertensive agent being used had no effect on the clinical course and mortality in hypertensive patients with COVID-19. The use of these agents should be maintained for the treatment of hypertension during hospitalization.

RESUMO OBJETIVO A doença de coronavírus 2019 (COVID-19) é uma ameaça emergente à saúde causada por um novo coronavírus denominado síndrome respiratória aguda grave coronavírus 2 (Sars-COV-2). Estudos anteriores observaram que a hipertensão está associada a um aumento da mortalidade devido ao COVID-19, no entanto, não está claro se o aumento do risco pertence à própria hipertensão ou a agentes anti-hipertensivos. Nosso objetivo foi avaliar o impacto de agentes anti-hipertensivos nos resultados clínicos em pacientes hipertensos com COVID-19. MÉTODOS Nosso estudo incluiu 169 hipertensos consecutivos internados por COVID-19 entre 20 de março e 10 de abril de 2020. As características demográficas, dados clínicos e o tipo de anti-hipertensivos em uso foram revistos. RESULTADOS A idade média dos pacientes foi de 65,8±11,7 anos. Trinta pacientes (17,7%) faleceram durante a internação. Cento e quarenta e dois pacientes (84%) usavam inibidores da enzima de conversão da angiotensina (ACEIs) ou bloqueadores dos receptores da angiotensina II (ARBs), 91 (53,8%) usavam diuréticos, 69 (40,8%) usavam bloqueadores dos canais de cálcio (CCBs), 66 (39,1%) usavam betabloqueadores, 12 (7,1%) usavam bloqueadores alpha e cinco (2,9%) usavam antagonistas dos receptores de mineralocorticoides (MRAs). Não houve diferença significativa entre sobreviventes e não sobreviventes com base no tipo de agentes anti-hipertensivos em uso. A análise de regressão logística binária mostrou que o tipo de agente anti-hipertensivo utilizado não teve efeito na mortalidade (OR=0,527 (0,130-2,138), p=0,370 para ACEIs/ARB; OR=0,731 (0,296-1,808), p=0,498 para CCBs; OR=0,673 (0,254-1,782), p=0,425 para diuréticos; OR=1,846 (0,688-4,950), p=0,223 para bloqueadores beta; OR=0,389 (0,089-1,695), p=0,208 para bloqueadores alpha e OR=1,372 (0,107-17,639), p=0,808 para MRAs). CONCLUSÃO O tipo de agente anti-hipertensivo utilizado não teve efeito no curso clínico e na mortalidade em pacientes hipertensos com COVID-19. O uso desses agentes deve ser mantido no tratamento da hipertensão durante a hospitalização.

Recomendación rápida sobre el uso de antihipertensivos IECA/ARA II en pacientes con riesgo o documentación de COVID-19 / Rapid recommendation on the use of ACEI/ARA antihypertensives in patients at risk or with documented COVID-19

Ciertos hallazgos preclínicos generaron preocupación en la comunidad científica y en la población general sobre el uso de inhibidores de la enzima convertidora de angiotensina (IECA) y los antagonistas del receptor de la angiotensina II (ARAII), y los posibles desenlaces adversos asociados con relación a la infección por el nuevo Coronavirus (SARS-Cov-2).Por este motivo, nos planteamos como objetivo proveer de recomendaciones dinámicas (living recommendations) para el tratamiento con fármacos IECA o ARA II en pacientes con riesgo o documentación de infección por SARS-CoV-2 (en todo su espectro de gravedad). Se utilizó como metodología la adaptación/adopción de guías de práctica clínica bajo el enfoque GRADE, actualizando la evidencia al 7 de abril de 2020 mediante búsquedas en múltiples bases de datos y consultando a un panel multidisciplinario libre de conflictos de interés. Como resultado de este proceso se arribó a la siguiente afirmación: se recomienda, en contexto de la pandemia de COVID-19, en personas que se encuentran en tratamiento con IECA/ARAII, mantener el tratamiento sin cambios por sobre suspenderlo o reemplazarlo por otros fármacos (Recomendación fuerte a favor - calidad de evidencia baja). (AU)

Certain preclinical findings raised concerns in the scientific community and in the general population about the use ofangiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor antagonists (ARA) and the possible adverse outcomes associated with the infection with the new Coronavirus (SARS-Cov-2). For this reason, our objective is to provide living recommendations for treatment with ACEI or ARA in patients with risk or documentation of SARS-CoV-2 infection (inall its severity spectrum). The adaptation/adoption of clinical practice guidelines under the GRADE approach was used as a methodology, updating the evidence as of April 7, 2020, by searching multiple databases and consulting a multidisciplinary panel free of conflicts of interest. As a result of this process, the following statement was reached: it is recommended, in the context of the COVID-19 pandemic, in people who are undergoing treatment with ACEI/ARA, to maintain the treatment unchanged instead of its suspension or replacement with other drugs (Strong recommendation in favor - low quality ofevidence). (AU)

Comparative evaluation of Latanoprostene Bunod, Timolol Maleate, and latanoprost Ophthalmic Solutions to assess their safety and efficacy in lowering intraocular pressure for the management of Open-Angle Glaucoma

OBJECTIVES: Timolol maleate has been reported to be a safer intraocular pressure (IOP) lowering treatment than latanoprost. The United States Food and Drug Administration approved latanoprostene bunod, a nitric oxide-donating prodrug of latanoprost, for lowering IOP. This study compared the safety and efficacy of latanoprost, latanoprostene bunod, and timolol maleate in patients with open-angle glaucoma. METHODS: Patients who received latanoprost eye drops once daily in the evening were included in the latanoprost Ophthalmic Solutions (LP) cohort (n=104). Those who received latanoprostene bunod eye drops once daily in the evening were included in the Latanoprostene Bunod (LB) cohort (n=94). Those who received timolol eye drops twice daily were included in the Timolol Maleate (TM) cohort (n=115). All treatments were administered to the affected eye(s) for 3 months. Informed Consent has been taken from each participant before the trial. RESULTS: At the end of 3 months of treatment, latanoprost, latanoprostene bunod, and timolol were all successful in reducing IOP. The LB cohort had the highest reduction in IOP, compared to the LP and TM cohorts. All treatments had some common adverse ocular effects. CONCLUSION: Latanoprostene bunod was superior to latanoprost and timolol for the treatment of open-angle glaucoma.

Brimonidine-induced unilateral ocular lichen planus: a case report / Líquen plano ocular unilateral induzido por brimonidina: relato de caso

ABSTRACT This report was written to describe a case of unilateral brimonidine-induced conjunctival lichen planus. Because the ophthalmic examination indicated chronic conjunctivitis or drug-induced pseudopemphigoid, the patient underwent thorough ophthalmic and systemic examinations, as well as conjunctival biopsy and direct immunofluorescence studies. A 71-year-old woman with unilateral left eye findings of chronic conjunctivitis was referred to our Ophthalmology Department. The patient reported that chronic conjunctivitis began shortly after she initiated use of topical brimonidine. Ophthalmic examination revealed foreshortening of the inferior fornix and symblepharon. Conjunctival biopsy revealed submucous lymphocytes and shaggy distribution of fibrinogen on direct immunofluorescence; this was suggestive of ocular lichen planus. No other systemic lesions were found that were consistent with the presentation of lichen planus. A good response was observed to topical cyclosporine treatment. To our knowledge, this may be the first report of unilateral ocular lichen planus without systemic findings. The correlation with the initiation of topical brimonidine suggests that this might be the first case of biopsy-confirmed brimonidine-induced ocular lichen planus.

RESUMO Este relato é para descrever um caso de líquen plano conjuntival unilateral induzido por brimonidina. Como o exame oftalmológico indicava conjuntivite crônica ou pseudopenfigóide induzido por medicamento, o paciente foi submetido a exames oftalmológicos e sistémicos completos, além de biópsia conjuntival e estudos de imunofluorescência direta. Uma mulher de 71 anos de idade com achados unilaterais do olho esquerdo de conjuntivite crônica foi encaminhada ao nosso departamento de Oftalmologia. A paciente relatou que a conjuntivite crônica começou logo após o início do uso da brimonidina tópica. O exame oftalmológico revelou encurtamento do fórnice inferior e do symblepharon. A biópsia conjuntival revelou linfócitos submucosos e distribuição felpuda de fibrinogênio na imunofluorescência direta; isso era sugestivo de líquen plano ocular. Não foram encontradas outras lesões sistêmicas compatíveis com a apresentação do líquen plano. Uma boa resposta foi observada no tratamento tópico com ciclosporina. Pelo nosso conhecimento, este pode ser o primeiro relato de líquen plano ocular unilateral sem achados sistêmicos. A correlação com o início da brimonidina tópica sugere que este pode ser o primeiro caso de líquen plano ocular induzido por brimonidina confirmado por biópsia.

Adherencia terapéutica antihipertensiva en adultos mayores / Adesão à terapia anti-hipertensiva em idosos / Adherence to antihypertensive therapy in elderly patients

Introducción: la hipertensión es el principal factor de riesgo de enfermedades cardiovasculares, por tanto, la adopción responsable del tratamiento antihipertensivo es fundamental para el control adecuado de las cifras tensionales. Objetivo: caracterizar la adherencia al tratamiento antihipertensivo en los pacientes adultos mayores del consultorio de Arroyo Bueno del policlínico Fausto Favier Favier del área de salud de Palenque de Yateras en la provincia Guantánamo de junio a diciembre del 2017. Método: se realizó un estudio descriptivo, de corte transversal en los 21 pacientes adultos mayores hipertensos del consultorio. La información se obtuvo a través de una entrevista a pacientes y familiares apoyados en una guía en correspondencia con las variables a investigar (edad, sexo, medicamento prescrito, enfermedades asociadas, efectos indeseables) y de las historias clínicas. La adherencia se evaluó según el Test de Cumplimiento Autocomunicado de Morisky-Green. Resultados: el 57,1 por ciento de los pacientes correspondieron al sexo femenino y el 52,4 por ciento tenían entre 60 y 60 años de edad; la mayoría de los adultos mayores no tenían controlada su presión arterial 66,7 por ciento y en el 80,9 por ciento de ellos se identificó inadecuada adherencia al tratamiento antihipertensivo por diversos motivos pero el incumplimiento por las reacciones adversas de los medicamentos fue el más frecuente para un 28,6 por ciento; entre éstas se reportaron el decaimiento en un 52,4 por ciento, la tos nocturna en un 47,6 por ciento y los calambres musculares en el 33,3 por ciento. Conclusiones: la mayoría de los pacientes no se adherían al tratamiento antihipertensivo por diversas causas, más prevaleció el temor a las reacciones adversas, situación que condicionó el pobre control de la presión arterial de los mismos(AU)

Introduction: hypertension is the main risk factor of cardiovascular diseases, therefore, the responsible adoption of antihypertensive treatment is fundamental for the adequate control of the blood pressure figures. Objective: to characterize adherence to antihypertensive treatment in elderly patients in the Arroyo Bueno clinic of the Fausto Favier Favier polyclinic in the health area of Palenque de Yateras in Guantánamo province from June to December 2017. Method: a study was conducted descriptive, cross-sectional in the 21 hypertensive elderly patients of the office. The information was obtained through an interview with patients and relatives supported by a guide in correspondence with the variables to be investigated (age, sex, prescribed medication, associated diseases, undesirable effects) and the medical records. Adherence was assessed according to the MoriskyGreen Self-Reported Compliance Test. Results: 57.1 percent of the patients corresponded to the female sex and 52.4 percent were between 60 and 60 years of age; Most of the older adults did not have their blood pressure under control, 66.7 percent and in 80.9 percent of them inadequate adherence to antihypertensive treatment was identified for various reasons, but noncompliance due to adverse drug reactions was the most frequent. 28.6 percent; among these, the decline was reported in 52.4 percent, night cough in 47.6 percent and muscle cramps in 33.3 percent. Conclusions: the majority of patients did not adhere to antihypertensive treatment for various reasons, but the fear of adverse reactions prevailed, a situation that conditioned the poor control of their blood pressure(AU)

Introdução: a hipertensão é o principal fator de risco das doenças cardiovasculares, portanto, a adoção responsável do tratamento antihipertensivo é fundamental para o controle adequado dos valores da pressão arterial. Objetivo: Caracterizar a adesão ao tratamento antihipertensivo em pacientes idosos escritório Boa policlínica do Arroyo Fausto Favier Favier área de saúde de Palenque de Yateras na província de Guantánamo de junho a dezembro de 2017. Método: Foi realizado um estudo descritivo, transversal nos 21 pacientes idosos hipertensos do consultório. As informações foram obtidas por meio de entrevista com pacientes e familiares apoiados por um guia em correspondência às variáveis a serem investigadas (idade, sexo, medicação prescrita, doenças associadas, efeitos indesejáveis) e prontuários. A adesão foi avaliada de acordo com o Teste de Conformidade Auto-Relatado de Morisky-Green. Resultados: 57,1 por cento dos pacientes correspondiam ao sexo feminino e 52,4 por cento tinham entre 60 e 60 anos de idade; A maioria dos idosos não tinha a pressão arterial controlada, 66,7 por cento e em 80,9 por cento deles a adesão inadequada ao tratamento anti-hipertensivo foi identificada por vários motivos, mas a não adesão devido a reações adversas a medicamentos foi a mais frequente. 28,6 por cento; dentre estes, o declínio foi relatado em 52,4 por cento, tosse noturna em 47,6 por cento e cãibras musculares em 33,3 por cento. Conclusões: a maioria dos pacientes não aderiu ao tratamento anti-hipertensivo por várias razões, mas prevaleceu o medo de reações adversas, situação que condicionou o mau controle da pressão arterial(AU)

Insulin autoimmune syndrome in an occidental woman: a case report and literature review

SUMMARY Insulin autoimmune syndrome (IAS, Hirata's disease) is a rare hypoglycemic disorder characterized by spontaneous hypoglycemia associated with extremely high circulating insulin levels and positive anti-insulin antibody results. Thus far, most cases have been reported in Asian countries, notably Japan, with few cases reported in western countries. As a possible cause, it is associated with the use of drugs containing sulfhydryl radicals, such as captopril. This report refers to a 63-year-old female Brazilian patient with a history of postprandial hypoglycemia. After extensive investigation and exclusion of other causes, her hyperinsulinemic hypoglycemia was considered to have likely been induced by captopril. Most cases of IAS are self-limiting. However, dietary management, corticosteroids, plasmapheresis, and rituximab have already been used to treat patients with IAS. In our case, after discontinuation of captopril, an initial decrease in insulin autoantibody levels was observed followed by improvement in episodes of hypoglycemia. Although it is a rare disease, IAS should be considered in the differential diagnosis of endogenous hyperinsulinemic hypoglycemia. Patients with suspected IAS must be screened for autoimmunity-related drugs for insulin. Initial clinical suspicion of IAS can avoid unnecessary costs associated with imaging examinations and/or invasive surgical procedures.

Hydralazine-associated adverse events: a report of two cases of hydralazine-induced ANCA vasculitis / Eventos adversos associados à hidralazina: um relatório de dois casos de vasculite associada ao ANCA induzida por hidralazina

Abstract Hydralazine is a direct-acting vasodilator, which has been used in treatment for hypertension (HTN) since the 1950s. While it is well known to cause drug-induced lupus (DIL), recent reports are indicating the emergence of the drug-induced anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (DIV). Herein, we describe two patients (aged 57 and 87 years) who presented with severe acute kidney injury (AKI), proteinuria, and hematuria. Both were receiving hydralazine for the treatment of hypertension. ANCA serology was positive in both patients along with anti-histone antibodies (commonly seen in drug-induced vasculitis). Renal biopsy revealed classic crescentic (pauci-immune) glomerulonephritis in these patients and hydralazine was discontinued. During the hospital course, the 57-year-old patient required dialysis therapy and was treated with steroids and rituximab for the ANCA disease. Renal function improved and the patient was discharged (off dialysis) with a serum creatinine of 3.6 mg/dL (baseline = 0.9 mg/dL). At a follow-up of 2 years, the patient remained off dialysis with advanced chronic kidney disease (CKD) (stage IIIb). The 87-year-old patient had severe AKI with serum creatinine at 10.41 mg/dL (baseline = 2.27 mg/dL). The patient required hemodialysis and was treated with steroids, rituximab, and plasmapheresis. Unfortunately, the patient developed catheter-induced bacteremia and subsequently died of sepsis. Hydralazine can cause severe AKI resulting in CKD or death. Given this extremely unfavorable adverse-event profile and the widespread availability of alternative anti-hypertensive agents, the use of hydralazine should be carefully considered.

Resumo A hidralazina é um vasodilatador de ação direta, que vem sendo utilizado no tratamento da hipertensão arterial (HA) desde a década de 1950. Embora seja bem conhecido por causar lúpus induzido por drogas (LID), relatórios recentes estão indicando o surgimento da vasculite associada ao anticorpo citoplasmático anti-neutrófilo (ANCA), induzida por drogas (VID). Aqui, descrevemos dois pacientes (com idade entre 57 e 87 anos) que apresentaram lesão renal aguda grave (LRA), proteinúria e hematúria. Ambos estavam usando hidralazina para o tratamento da hipertensão. A sorologia para ANCA foi positiva em ambos os pacientes, juntamente com anticorpos anti-histona (comumente vistos na vasculite induzida por drogas). A biópsia renal revelou glomerulonefrite rapidamente progressiva clássica (pauci-imune) nestes pacientes e a hidralazina foi interrompida. Durante a internação hospitalar, o paciente de 57 anos necessitou de diálise e foi tratado com esteroides e rituximab para a doença do ANCA. A função renal melhorou e o paciente recebeu alta (fora da diálise) com creatinina sérica de 3,6 mg/dL (basal = 0,9 mg/dL). Em um seguimento de 2 anos, o paciente permaneceu fora da diálise com doença renal crônica avançada (DRC) (estágio IIIb). O paciente de 87 anos apresentava IRA grave com creatinina sérica em 10,41 mg/dL (valor basal de = 2,27 mg/dL). O paciente necessitou de hemodiálise e foi tratado com esteroides, rituximabe e plasmaferese. Infelizmente, o paciente desenvolveu bacteremia induzida por cateter e, posteriormente, evoluiu a óbito por sepse. A hidralazina pode causar IRA grave, resultando em DRC ou óbito. Dado este perfil de eventos adversos extremamente desfavorável e a disponibilidade generalizada de agentes anti-hipertensivos alternativos, o uso de hidralazina deve ser considerado com muita parcimônia.

Angioedema intestinal aislado inducido por enalapril / Isolated intestinal angioedema induced by enalapril

El angioedema inducido por inhibidores de la enzima convertidora de angiotensina es una entidad poco frecuente caracterizada por edema en piel y mucosas, debido al aumento de la permeabilidad vascular provocada por la inhibición de la enzima convertidora y el subsiguiente aumento de la bradiquinina. De manera frecuente cursa con compromiso facial y de mucosas, siendo infrecuente el compromiso intestinal o de vía aérea. El angioedema intestinal puede presentarse asociado a angioedema facial o aislado, siendo este último excepcional. Cursa con episodios recurrentes de dolor, distensión abdominal y diarrea acuosa con recuperación completa en dos o tres días. Si bien es una entidad poco frecuente, el hecho de que esté asociada a fármacos utilizados con frecuencia nos hace incluirla en el diagnóstico diferencial del dolor abdominal recurrente. Presentamos un caso de angioedema intestinal aislado, asociado al uso de enalapril.

Angioedema induced by angiotensin converting enzyme inhibitors is a rare entity characterized by skin and mucosal edema, due to increased vascular permeability caused by inhibition of the converting enzyme and subsequent increase in bradykinin. It frequently presents with facial and mucosal involvement, being uncommon the intestinal or airway compromise. Intestinal angioedema may be associated with facial or isolated angioedema, the latter being exceptional. It is associated with recurrent episodes of pain, abdominal distention and watery diarrhea which complete recovery in two or three days. Although it is a rare entity, the fact that it is associated with frequently used drugs makes us include it in the differential diagnosis of recurrent abdominal pain. We report a case of isolated intestinal angioedema associated with the use of enalapril.

Augmented cytotoxic, mutagenic and genotoxic response triggered by carvedilol and celecoxib combinations

It is understood that drugs regardless of their order of administration can exhibit drug interactions. Established on the fact that treatment of hypertension may last for decades and prolong usage of multiple drug regimen may induce substantial pathophysiological changes. Hence, This study was designed to evaluate the possible synergistic toxic effects of anti-hypertensive (carvedilol), and anti-inflammatory drug (celecoxib) alone and in combinations. Well-established MTT assay, Single Cell Gel Electrophoresis (SCGE) and Ames assay were employed to evaluate the toxicity at cellular level. Results from MTT assay on Vero cell line revealed that drug combinations have more pronounced anti-proliferative activity with combine IC50 value of 13.7:47.8 µg/mL. Likewise, exposure of peripheral blood mononuclear cells with drug combinations revealed significant (P<0.05) DNA damage (Class 3) in a dose dependent manner at concentrations ≥ 0.78: 2.34 µg/mL. However, carvedilol and celecoxib were non mutagenic against either mutant strain (TA 100 and TA 98) and combinations have also shown mild to moderate mutagenic potential. Nevertheless, upon addition of metabolic activation enzyme, concentration <12.5:37.5 µg/plate exhibited significant (P<0.05) mutagenicity against both tester strains. In conclusion, this study provides additional genotoxicity and mutagenicity data that could be used in considering options for formulating regimens with reduced mutagenic potential

Edema pulmonar agudo no cardiogénico secundario a hidroclorotiazida: reporte de un caso y revisión de la literatura / Hydrochlorothiazide induced non-cardiogenic acute pulmonary edema: a case report

Las tiazidas son fármacos frecuentemente usados en la terapia de la hipertensión arterial. Las reacciones adversas de riesgo vital como shock y edema pulmonar agudo son raros. Comunicamos el caso de una mujer de 55 años de edad atendida en Hospital de Puerto Montt, quien tras dos horas de ingerir hidroclorotiazida presentó disnea. Los exámenes de laboratorio generales e imágenes muestran cuadro concordante con edema pulmonar agudo no cardiogénico. Además de la suspensión del fármaco, se realizó soporte hemodinámico y ventilatorio no invasivo, evidenciándose resolución del cuadro a las 48 h. La paciente fue dada de alta 3 días después de su ingreso sin sintomatología.

Thiazides are drugs often used in management of high arterial blood pressure. Shock and acute pulmonary edema are rarely described as adverse reactions related to this drug. We report the case of a 55 years-old woman admitted at Hospital de Puerto Montt, Chile. Two hours after having her first dose of hydrochlorothiazide she presented dyspnea. Laboratory tests and images support the diagnosis of non-cardiogenic pulmonary edema. Resolution of her clinical picture was observed 48 hours after hydrochlorothiazide administration was discontinued and hemodynamic and non invasive ventilation support were supplied. The patient was discharged without symptoms, 3 days after entering to hospital.

Safety and efficacy of fimasartan in Mexican patients with grade 1-2 essential hypertension / Seguridad y eficacia de fimasartán en pacientes mexicanos con hipertensión esencial de grados 1-2

Abstract: Objective: To evaluate efficacy and safety of 60 mg and 120 mg Fimasartan (FMS) alone or combined with 12.5 mg hydrochlorothiazide (HCTZ) in a Mexican population. Methods: A six month, treat-to-target, open study was conducted on subjects with grade 1-2 hypertension. The subjects were initially treated with 60 mg FMS once daily. In week 8, those with Diastolic Blood Pressure (DBP) <90 mmHg continued on the same FMS dose during the rest of the study, while those with DBP ≥90 mmHg were randomised to either 120 mg FMS or 60 mg FMS + 12.5 mg HCTZ once daily. In week 12, randomised subjects with DBP ≥90 mmHg received 120 mg FMS + 12.5 mg HCTZ, while those achieving target continued with their assigned treatment until the end of the study. Results: FMS 60 mg (n = 272) decreased both DBP and Systolic Blood Pressure (SBP) by 11.3 ± 8.9 (p<.0001) and 16.0 ± 14.1 (p<.0001) mmHg, respectively, with 75.4% of subjects reaching the treatment target. Subjects assigned to FMS 120 mg, FMS 60 mg + HCTZ 12.5 mg, or FMS 120 mg + HCTZ 12.5 mg once daily, showed significant reductions in DBP and SBP with their assigned treatment. At the end of the study, 237/272 subjects (87.1%) achieved a DBP < 90 mmHg and an SBP<140 mmHg. The most frequently reported adverse reactions included headache (3.7%), dry mouth (1.1%), transient liver enzyme increase (1.1%), and dizziness (0.7%). Conclusion: Fimasartan is safe and effective in Mexican subjects with grade 1-2 essential hypertension.

Resumen: Objetivo: Evaluar la eficacia y la seguridad de 60 y 120 mg de fimasartán (FMS) solo o combinado con 12.5 mg de hidroclorotiazida (HCTZ) en población mexicana. Métodos: Estudio abierto, de 24 semanas, con tratamiento escalado hasta el objetivo terapéutico en sujetos hipertensos grados 1-2. Tratamiento inicial: FMS 60 mg una vez al día; en la semana 8, los sujetos con presión arterial diastólica (PAD) <90 mmHg mantuvieron su tratamiento inicial durante el estudio, mientras que los sujetos con PAD ≥90 mmHg fueron aleatorizados a 120 mg de FMS o a 60 mg de FMS + 12.5 mg de HCTZ. En la semana 12, los sujetos aleatorizados con PAD ≥90 mmHg recibieron 120 mg de FMS + 12.5 mg de HCTZ; quienes alcanzaron el objetivo terapéutico mantuvieron su tratamiento asignado hasta finalizar el estudio. Resultados: FMS 60 mg (n = 272) disminuyó la PAD y la presión arterial sistólica (PAS) en 11.3 ± 8.9 (p < 0.0001) y 16.0 ± 14.1 (p < 0.0001) mmHg, respectivamente, con logro del objetivo de tratamiento en el 75.4% de los sujetos. Los sujetos asignados a 120 mg de FMS, a 60 mg de FMS + 12.5 mg de HCTZ 12.5 y a 120 mg de FMS + 12.5 mg de HCTZ mostraron reducciones significativas de PAD y PAS; al final del estudio, 237/272 sujetos (87.1%) lograron PAD <90 y PAS <140 mmHg. Las reacciones adversas más frecuentemente reportadas fueron: cefalea (3.7%), boca seca (1.1%), incremento de enzimas hepáticas (1.1%) y mareo (0.7%). Conclusión: FMS es seguro y eficaz en sujetos mexicanos con hipertensión esencial de grados 1-2.

Desenvolvimento de sistemas multiparticulados de liberação imediata e modificada para associação de fármacos anti-hipertensivos / Development of immediate and modified release multiparticulate systems for antihypertensive drugs association

Os sistemas multiparticulados são aqueles nos quais a dose do fármaco está dividida em pequenas unidades funcionais, tendo assim, uma série de vantagens sobre os sistemas monolíticos convencionais. Este trabalho teve por objetivo desenvolver formulações multiparticuladas de uso oral para fármacos anti-hipertensivos que serão utilizados na composição de associações. O material está dividido em seis capítulos, sendo inicialmente apresentada uma revisão da literatura a respeito da caracterização física destas pequenas unidades. Ensaios como análise granulométrica, morfologia, densidade, porosidade, avaliação de resistência mecânica e desintegração são os mais empregados para esta finalidade, possibilitando ao formulador conhecer os fatores de maior impacto relacionados às matérias primas e ao processo de fabricação no comportamento das formulações produzidas. Os demais capítulos seguem com o desenvolvimento dos sistemas multiparticulados, que foram embasados em diferentes delineamentos experimentais, seja pela utilização de planejamento fatorial fracionado ou projeto de mistura. Para o metoprolol, fármaco de alta solubilidade, foram produzidas formulações de liberação controlada, sendo a estratégia dividida em três etapas: (I) Produção de minicomprimidos revestidos, nos quais foram avaliadas diferentes combinações do polímero modulador de liberação; (II) otimização do perfil de liberação do fármaco, com avaliação de misturas das formulações produzidas na primeira etapa; (III) Processo de extrusão a quente, no qual diferentes proporções de fármaco e polímero hidrofóbico foram avaliadas. Para os fármacos hidroclorotiazida e olmesartana medoxomila, ambos de baixa solubilidade, a estratégia adotada foi a incorporação de uma dispersão dos fármacos e agentes solubilizantes em grânulos inertes obtidos por extrusão/revestimento. Adicionalmente, também foram produzidas formulações por extrusão a quente de diferentes proporções destes fármacos em polímero hidrofílico. De acordo com os resultados obtidos, foi possível obter formulações de minicomprimidos e grânulos com perfil de dissolução satisfatório, semelhantes aos apresentados pelos medicamentos adotados como referência. Em relação à extrusão a quente foi possível avaliar a influência do processo e polímeros empregados no perfil de dissolução dos grânulos produzidos

Multiparticulate systems are dosage forms in which dose is divided into small functional units presenting some advantages over monolithic conventional systems. The objective of this work was developing multiparticulate formulations for oral use containing antihypertensive drugs to be used in association. The thesis is divided into six issues, been first presented a literature review about physical characterization of multiparticulate systems. Granulometric analysis, morphology, density, porosity, mechanical strength and disintegration are the most used physical characterization tests, enabling formulator knowing the major impact factors related to raw materials and manufacturing process in the performance of the produced formulations. The other issues present the development of the multiparticulate systems based on different statistical experimental design, as fractional factorial design or mixture project. For metoprolol, a highly soluble drug, controlled release formulations were obtained, and the strategy was divided into three steps: (I) coated minitablets production, where different combinations of the controlled release polymer were analyzed; (II) drug release profile optimization, evaluating formulations mixtures produced in the first step; (III) hot melt extrusion process, where different drug: hydrophobic polymer ratios were evaluated. For hydrochlorothiazide and olmesartan medoxomil, both low soluble drugs, the strategy was incorporating a dispersion containing the drugs and solubilizing agents in inert granules obtained by extrusion/coating processes. Additionally, formulations containing different ratios of these drugs and hydrophilic polymers were produced by hot melt extrusion. According to the results, it was possible to obtain minitablets and granules with good dissolution profile, similar to the reference products. Regarding to hot melt extrusion, it was possible to evaluate the influence of process and polymers used in the dissolution profile of the produced granules