Human fetal malformations associated with the use of an angiotensin II receptor antagonist: Case Report / Malformações fetais associadas ao uso de antagonista dos receptores de angiotensina II: Relato de Caso

Introduction: The potential risks related to drug exposure during pregnancy represent a vast chapter in modern obstetrics and data regarding the safety of antihypertensive drugs during pregnancy are relatively scarce. Case report: A 37-year-old patient discovered her fifth pregnancy at our hospital after 26 weeks and 4 days of gestation. She reported a history of hypertension and was currently being treated with Losartan. Hospitalization was recommended for the patient and further evaluation of fetal vitality was performed. On the fourth day an ultrasound was performed, resulting in a severe oligohydramnios, fetal centralization and abnormal ductus venosus. After 36 hours, the newborn died. Pathologic evaluation: At autopsy, the skullcap had large fontanels and deficient ossification. The kidneys were slightly enlarged. A microscopic examination detected underdevelopment of the tubules and the presence of some dilated lumens. Immunohistochemical detection of epithelial membrane antigen was positive. Immunoreactivity of CD 15 was also assayed to characterize the proximal tubules, and lumen collapse was observed in some regions. Discussion: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor antagonists (ARAs) are among the most widely prescribed drugs for hypertension. They are often used by hypertensive women who are considering become pregnant. While their fetal toxicity in the second or third trimesters has been documented, their teratogenic effect during the first trimester has only recently been demonstrated. Conclusion: Constant awareness by physicians and patients should be encouraged, particularly in regard to the prescription of antihypertensive drugs in women of childbearing age who are or intend to become pregnant. .

Introdução: Os riscos relacionados à exposição de drogas durante a gestação representam um vasto capítulo na obstetrícia moderna e dados sobre a segurança de drogas anti-hipertensivas são relativamente escassos. Relato do caso: Paciente de 37 anos, hipertensa crônica, descobriu a gravidez com 26 semanas e 4 dias de gestação. Estava em uso regular de Losartana. Durante avaliação fetal ultrassonográfica, foi relatada a presença de grave oligoâmnio associado ao quadro de centralização fetal com alteração de ducto venoso, e, após 36 horas, verificou-se óbito neonatal. Necrópsia: Observou-se calota craniana com fontanelas amplas e ossificação deficiente. Rins levemente aumentados de volume e, à microscopia, hipodesenvolvimento de túbulos com presença de lúmen dilatado. Imunohistoquímica com expressão em túbulos distais de antígeno epitelial de membrana. Imunoperoxidade com expressão em túbulos proximais de CD 15 em células epiteliais e colapso de alguns lúmens fora observado. Discussão: Inibidores da conversão de angiotensina e antagonistas de receptor de angiotensina estão entre as drogas mais prescritas para hipertensão. Estas drogas são frequentemente prescritas para mulheres em idade fértil e que pretendem engravidar. Enquanto a toxicidade fetal destas, nos segundo e terceiro trimestres, já é conhecida, seus efeitos durante o primeiro trimestre foi apenas recentemente demostrado. Conclusão: A conscientização por parte de médicos e pacientes deve ser realizada de rotina, principalmente no que diz respeito à prescrição e utilização de drogas potencialmente teratogênicas ou fetotóxicas. Este cuidado deve ser redobrado para pacientes que estão ...

An economic evaluation of antihypertensive therapies based on clinical trials

OBJECTIVE: Hypertension is a major issue in public health, and the financial costs associated with hypertension continue to increase. Cost-effectiveness studies focusing on antihypertensive drug combinations, however, have been scarce. The cost-effectiveness ratios of the traditional treatment (hydrochlorothiazide and atenolol) and the current treatment (losartan and amlodipine) were evaluated in patients with grade 1 or 2 hypertension (HT1-2). For patients with grade 3 hypertension (HT3), a third drug was added to the treatment combinations: enalapril was added to the traditional treatment, and hydrochlorothiazide was added to the current treatment. METHODS: Hypertension treatment costs were estimated on the basis of the purchase prices of the antihypertensive medications, and effectiveness was measured as the reduction in systolic blood pressure and diastolic blood pressure (in mm Hg) at the end of a 12-month study period. RESULTS: When the purchase price of the brand-name medication was used to calculate the cost, the traditional treatment presented a lower cost-effectiveness ratio [US$/mm Hg] than the current treatment in the HT1-2 group. In the HT3 group, however, there was no difference in cost-effectiveness ratio between the traditional treatment and the current treatment. The cost-effectiveness ratio differences between the treatment regimens maintained the same pattern when the purchase price of the lower-cost medication was used. CONCLUSIONS: We conclude that the traditional treatment is more cost-effective (US$/mm Hg) than the current treatment in the HT1-2 group. There was no difference in cost-effectiveness between the traditional treatment and the current treatment for the HT3 group.

Farmacovigilancia activa en pacientes afiliados al sistema general de seguridad social en salud / Active pharmacosurveillance of patients affiliated to the Colombian general social security/health system

Objetivos Determinar los posibles resultados negativos asociados a la medicación mediante la metodología de búsqueda activa de posibles interacciones medicamentosas en bases de datos de pacientes afiliados al Sistema General de Seguridad Social en Salud. Métodos A partir de las bases de datos de dispensación de medicamentos de Audifarma S.A a unos 4 millones de usuarios del país, se hizo una revisión sistemática de estadísticas de una serie de medicamentos identificados por presentar interacciones de riesgo, dosis diferentes a las recomendadas o dispensación irregular. Los casos son socializados con las EPS responsables. Resultados Se encontró un caso de nefrotoxicidad por ácido zoledrónico; el 37,0 por ciento de los usuarios de clopidogrel recibían concomitantemente omeprazol, que reduce la efectividad del primero; el 29,9 por ciento de los pacientes que toman losartan están recibiendo dosis superiores a las recomendadas para su indicación; el 2,0 por ciento de los pacientes que toman metoprolol o verapamilo, los recibe simultáneamente, con riesgo de generar bradicardia sinusal, bloqueos auriculoventriculares o disfunción sistólica. Todos los casos fueron notificados a los responsables en la EPS que atienden estos pacientes. Discusión La farmacovigilancia activa permite optimizar recursos, prevenir eventos adversos que puedan potencialmente causar morbilidad importante o incluso letalidad o determinar problemas que podrían ser responsables del fracaso terapéutico. Este tipo de estrategia se anticipa a la aparición de posibles riesgos para el paciente por lo que se recomienda considerarla para reforzar los programas de vigilancia de uso de medicamentos en el país.

Objectives Determining negative results associated with medication through an active search of possible drug interactions in databases for patients affiliated to the Colombian general social security/health system. Methods Statistics related to Audifarma S.A. dispensation drug databases for about 4 million Colombian users were systematically reviewed for identifying drugs having known interactions involving risk, doses different from recommended ones or irregular dispensation. The pertinent health-care providing services were made aware of the above. Results There was one case of nephrotoxicity being caused by zoledronic acid. 37 percent of clopidogrel users concomitantly received omeprazole which reduces the former's effectiveness. 29.9 percent of patients who were taking losartan were receiving doses higher than the recommended ones. 2.0 percent of patients who were taking metoprolol or verapamil were simultaneously receiving them, at the risk of generating first-degree heart block, bradycardia, or systolic dysfunction. All these cases were notified to the pertinent health-care services. Conclusions Active pharmacosurveillance leads to resources being optimised, adverse events which can potentially cause morbidity or lethality being prevented or even determining problems which could be responsible for therapeutic failure. This type of strategy anticipates the appearance of possible risks for patients, meaning that drug use monitoring programmes in Colombia should be reinforced.

A case of losartan induced angioedema.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) target the renin-angiotensin system and are used in the management of hypertension. Both classes of drugs have similar side effects. ARBs are considered to be much better tolerated than ACE inhibitors with lesser incidence of side effects. Angioedema is a very rare side effect associated with ACE inhibitors (ACEI) and even rarer so with ARBs. The cause for angioedema in ACE inhibitors is said to be the rise in bradykinin levels. It has been postulated that angiotensin II receptor activates the bradykinin-prostaglandin-nitric oxide cascade, resulting in bradykinin-mediated side effects of ARBs such as angioedema, but the true mechanism remains largely unknown. We present here a rare case of late onset angioedema associated with losartan (an ARB) in a female patient. She had been started on an ARB as a first line treatment for uncomplicated mild to moderate hypertension. She had no prior exposure to ACE inhibitors and did not have any other significant medical history. Though rare angioedema is a serious recognized side effect of ARB therapy and the patients started on them should be warned to look for the early signs so as to take corrective action.

Ação do lisinopril e do losartan na função endotelial após infarto agudo do miocárdio. Estudo experimental em ratos / Action of lisinopril and losartan in endothelial function after acute myocardialinfarction. Experimental study in rats.

JUSTIFICATIVA E OBJETIVOS: O presente estudo teve como objetivo estudar a influência do lisinopril e do losartan na função endotelial em ratos com infarto experimental do miocárdio. MÉTODO: Ratos Wistar machos, peso entre 350 e 400 g, divididos em quatro grupos (n igual 10): G1 igual ratos controle sem infarto, G2 igual ratos com infarto, G3 igual ratos com infarto e tratados com lisinopril (20 mg/kg/dia) e G4 igual ratos com infarto e tratados com losartan (30 mg/kg/dia). Os fármacos foram administrados via gavagem dois dias antes do infarto e continuado por mais sete dias. Os ratos foram anestesiados com éter para a ligadura da coronária descendente anterior. Após nove dias os animais foram anestesiados, o coração excisado e verificado a extensão do infarto. Utilizou-se para este fim a coloração pelo método do cloreto de trifeniltetrazólio a 1%, se considerando infarto grande quando excedia 40% da área do ventrículo esquerdo. A função endotelial foi verificada através de curva de concen­tração efeito com acetilcolina em segmento proximal da aorta torácica. Foram utilizados os testes estatísticos de ANOVA e de Duncan, sendo considerado significativo o valor de p menor que 0,05. RESULTADOS: Os resultados obtidos para a função en­dotelial para o relaxamento máximo foram: G 1 igual 78,24% mais ou menos 3,57%; G2 igual 14,04% mais ou menos 5,20%, G3 igual 48,94% mais ou menos 9,29% e G4 igual 26,98% mais ou menos 7,80%. Houve diferença estatístíca significatíva para entre os G3 e G4. CONCLUSÃO: Ocorreu disfunção endotelial em ratos na fase recente do infarto do miocárdio e o tratamento com lisinopril e losartan melhoraram esta disfunção endotelial.

Efectos sobre la función renal fetal y neonatal del tratamiento con antagonista del receptor de angiotensina II en el embarazo: Caso clínico / Transient renal failure in a newborn due angiotensin receptor II antagonist use during pregnancy: Report of one case

Fetal renal structure and function can be altered by medications prescribed to pregnant women. We report a chronic hypertensive pregnant woman treated with ¡osarían before and throughout pregnancy. At 30 weeks the patient was referred to our Fetal Medicine Unit due to absent amniotic fluid with normal uterine artery Doppler and fetal growth. During her hospitalization a new scan was performed showing that both fetal kidneys were enlarged and slightly hyperechogenic and placental and fetal artery Doppler showed signs of hypovolemia or increased resistance to feto-placental blood flow. Ductus venosous was normal. The fetus was delivered after three days by caesarean section at 30+4 weeks of gestation due to abnormal fetal heart rate tracing. Following delivery, the preterm newborn was treated for a transient renal failure characterized by anuria-oliguria and high plasma creatinine levels (from 3.8 mg/dL at day 5 to 0.8 mg/dL at 16 days). At 30 days of age, ultrasound showed kidneys of normal form and size. The adverse effects of Angiotensin II receptor antagonists in fetal nephrogenesis and function are discussed

Efeito a curto prazo do losartan comparado ao enalapril na função ventricular esquerda e na capacidade de pacientes com insuficiência aórtica crônica grave oligo grave ou assintomáticos / Effect in short term of losartan compared with the enalapril in the left ventricular function and the physical capacity of patients with asymptomatic or minimally symptomatic chronic severe aortic regurgitation

Objetivo: analisar o efeito a curto prazo do lasartan comparado ao enalapril sobre a função ventricular esquerda em pacientes com insuficiência valvar aórtica grave, oligo ou assintomáticos, testar a segurança do lasartan nessas condições e estudar o impacto destas drogas sobre a capacidade física. Métodos: Dez pacientes com insuficiência valvar aórtica (IAo)crônica grave e com função ventricular esquerda preservada (fração de ejeção menor ou igual 0,55), foram estudados de forma prospectiva em um estudo de intervenção medicamentosa cross-over, comparando-se duas drogas: losartan e o enalapril, através de avaliação clínico-laboratorial, ecocardiograma de repouso e teste cardiopulmonar em três momentos diferentes: sem medicação, em uso de losartan, em uso de enalapril. Resultados: Foram estudados 7 (70 por cento homens e 3 (30 por cento) mulheres com idade entre 15 e 41 anos (média de 26 anos). A dose média diária de enalapril foi de 38mg com tempo médio de 3,9 meses e a de losartan foi de 90mg com tempo médio de três meses. Não houve efeitos adversos graves....

Estudo `LOTHAR`: avaliação de eficácia e tolerabilidade da combinação fixa de anlodipino e losartana no tratamento da hipertensão arterial primária / The `LOTHAR` study: evaluation of efficacy and tolerability of the fixed combination of amlodipine and losartan in the treatment of essential hypertension

OBJETIVO: O estudo LOTHAR avaliou a eficácia, tolerabilidade e os efeitos metabólicos em médio e longo prazo (um ano) da combinação fixa de anlodipino e losartana versus anlodipino e losartana isoladamente. MÉTODOS: Estudo multicêntrico brasileiro, randomizado, duplo-cego e comparativo realizado com 198 pacientes com hipertensão arterial primária em estágios 1 e 2. RESULTADOS: A combinação fixa apresenta alta eficácia anti-hipertensiva que se mantém em longo prazo com percentual reduzido de escape do controle pressórico, inferior a dos dois regimes monoterápicos de comparação. Em longo prazo, mais de 60 por cento dos pacientes tratados com a combinação fixa permaneceram com níveis da PAD < 85 mmHg e o efeito anti-hipertensivo quando avaliado pela MAPA persistiu nas 24 horas com relação vale-pico de 76,7 por cento. A freqüência de eventos adversos foi bastante reduzida neste grupo sendo a incidência em longo prazo de edema de membros inferiores cerca de quatro vezes menor que a observada com o anlodipino isolado. A combinação fixa não alterou os metabolismos da glicose e dos lípides tanto em médio quanto em longo prazos. CONCLUSAO: Estes resultados nos permitem afirmar que a combinação de anlodipino e losartana, a primeira combinação fixa de um antagonista dos canais de cálcio e um bloqueador do receptor da angiotensina II disponível no mercado farmacêutico constitui-se em excelente opção para o tratamento da hipertensão arterial em larga gama de pacientes hipertensos.

Hiperkalemia grave asociada a drogas que actúan sobre el sistema renina, angiotensina, aldosterona: Un problema que requiere atención: Caso clínico / Severe hyperkalemia associated to the use of losartan and spironolactone: Case report

Hyperkalemia is a complications of the use of angiotensin converting enzyme inhibitors, angiotensin receptor antagonists and aldosterone antagonists. These drugs are commonly used for the treatment of hypertension and cardiac failure. We report a 84 year-old female treated with losartan 50 mg/day and spironolactone 25 mg/day that presented with a hyperkalemia of 8.4 mEq/l and bradicardia, drowsiness and respiratory depression. She required hemodialysis and ventilatory assistance. She was discharged in good conditions five days after admission.

Efectos de la administración temprana de losartan sobre el remodelamiento ventricular en conejos con infarto de miocardio experimental / Effects of the early administration of losartan on ventricular remodeling in rabbits with experimental myocardial infarction

En el presente trabajo se evaluaron los efectos de la administración temprana de losartán (Los) sobre el remodelamiento ventricular (RV) en conejos con infarto de miocardio experimental (IM). Conejos Neozelandeses fueron sometidos a ligadura de la arteria coronaria izquierda. Se analizaron 4 grupos: operación simulada o sham (G1, n=13), IM (G2, n=13), sham+Los (G3, n=13), IM+Los (G4, n=13). Los (12.5 mg/ kg/día) comenzó a administrarse a las 3 horas post-cirugía. Los animales fueron sacrificados a los 35 días y los corazones fueron perfundidos según la técnica de Langendorff. Se determinaron curvas presión-volumen (P/V) sistólicas y diastólicas. Cuatro animales por grupo se utilizaron para análisis histológico. Los corazones fueron fijados en formol, se calculó la relación entre el peso del corazón y del animal (Pc/Pa), seguidamente fueron cortados y teñidos con tricrómico de Masson y picrosirius red. Se midió el tamaño de infarto (TIM%), el espesor del septum (ES) y de la cicatriz, mediante análisis morfométrico. Los valores se expresaron como X ±SEM. Resultados: El TIM% fue en G2=25.38±5.31% y en G4=21.85±4.13%. El Pc/Pa fue: 3.45±0.16; 3.52±0.25; 2.87±0.16 (p<0.05 vs grupos no tratados) y 3.23±0.18 en G1, G2, G3 y G4 respectivamente. El Los desplazó la relación P/V diastólica a la derecha tanto en G3 y G4 (p<0.05 vs G1 y G2) y no modificó la función sistólica. El ES fue menor en G3 y G4 (P<0.05 vs G2), y G4 presentó menor cantidad de colágeno en la cicatriz (p<0.05 vs G2). En conclusión: la administración temprana de losartán modificó desfavorablemete el RV, incrementando la dilatación y disminuyendo el colágeno y el espesor de la cicatriz.

Comparison of the efficacy, safety and tolerability of telmisartan with losartan in Indian patients with mild to moderate hypertension: a pilot study.

A prospective, randomised, double-blind, parallel group study was carried out to compare the efficacy, safety and tolerability of telmisartan 40 mg once daily with losartan 50 mg once daily in Indian patients with mild to moderate hypertension. It had a placebo run-in period of 2 weeks followed by drug treatment (telmisartan 40 mg, once daily or losartan 50 mg once daily) for 8 weeks. Supine BP was assessed at the end of every 2 weeks. Tolerability and safety was assessed by physical examination, laboratory parameters and evaluation of adverse events. Treatment with telmisartan resulted in a significant reduction of SBP of 10.3% and 13.7% as compared to 6.6% and 10.6% in losartan group at the end of 6th and 8th weeks respectively. At the end of 6th and 8th weeks, the reduction was 14.3% and 18.1% among telmisartan which was significantly more as compared to 8.8% and 14.3% in losartan group respectively. The laboratory values were within normal limits. Both drugs were well tolerated. Telmisartan monotherapy in a dose of 40 mg once daily has a clinically better therapeutic effect as compared to losartan 50 mg and a good tolerability profile in patients with mild to moderate hypertension.

Role of losartan therapy in the management of diabetic hypertension.

The management of diabetic hypertension requires meticulous selection of agents in the antihypertension armamentorium. There may be several associated factors to be considered while treating a hypertensive diabetic. These include hyperglycemia, dyslipidemia, proteinuria, left ventricular hypertrophy and heart failure to name a few. Losartan is the first of a new class of agents in the list of antihypertensive drugs. By its selective angiotension II receptor (subtype AT1) blocking action it is postulated to bring about a more complete inhibition of the renin-angiotensin system. Thus, it might produce all the benefits of angiotensin converting enzyme (ACE) inhibitor therapy with the freedom from cough so commonly seen with the use of ACE inhibitors. This review attempts to analyze the possible benefits of losartan therapy in diabetes.

Evaluation of efficacy and safety of losartan potassium in the treatment of mild to moderate hypertension as compared to enalapril maleate.

AIM: To study the effect of losartan potassium in the treatment of mild to moderate hypertension and to compare its efficacy and adverse effect profile with enalaparil maleate. MATERIAL AND METHODS: One hundred and forty five patients with mild to moderate essential hypertension were enrolled in this randomized, double blind, controlled, parallel and multicentric study. Seventy two patients received losartan potassium 50 mg and seventy three received enalapril maleate 5 mg. RESULTS: Losartan potassium reduced the DBP to < 90 mm Hg in 59% of the patients at the end of 8 weeks compared to 45% in the enalapril maleate group. DBP was reduced by 10 or > than 10 mm Hg in 89% of the patients with losartan as compared to the baseline whereas it was 80% in the enalapril group. Percentage of side effects seen in losartan and enalapril groups were 12 and 22 respectively. CONCLUSION: Losartan potassium is an efficacious antihypertensive agent in mild to moderate hypertension. It also has fewer side effects when compared to enalapril maleate.

Efeito de agentes anti-hipertensivos sobre as células estreladas durante a regeneraçäo hepática em ratos / Effect of antihypertensive agents on the starry cells during hepatic regeneration in rats

O efeito de um inibidor da enzima conversora da angiotensina (lisinopril), de um antagonista do receptor da angiotensina II (losartan) e da bradicinina na população de células estreladas (CE) durante o fenômeno regenerativo hepático foi estudado. Ratos machos Wistar receberam lisinopril, losartan, bradicinina ou solução salina em volumes proporcionais, intraperitonealmente, antes e após hepatectomia parcial a 70 por cento (HP). Cinco animais de cada grupo experimental e controle foram sacrificados sob anestesia com éter em 36 horas após a HP. A população de CE marcadas para alfa-actina de músculo liso foi estimada nas zonas periportal e pericentral das amostras hepáticas. A população de CE foi menor no grupo tratado com losartan, e maior nos grupos tratados com bradicinina e lisinopril que no grupo controle. Estes resultados sugerem que o losartan pode inibir, e a bradicinina e o lisinopril podem estimular a população de CE durante a regeneração hepática em ratos.

The hyperglycemia induced by angiotensin II in rats is mediated by AT1 receptors

We have shown that the renin-angiotensin system (RAS) is involved in glucose homeostasis during acute hemorrhage. Since almost all of the physiological actions described for angiotensin II were mediated by AT1 receptors, the present experiments were designed to determine the participation of AT1 receptors in the hyperglycemic action of angiotensin II in freely moving rats. The animals were divided into two experimental groups: 1) animals submitted to intravenous administration of angiotensin II (0.96 nmol/100 g body weight) which caused a rapid increase in plasma glucose reaching the highest values at 5 min after the injection (33 per cent of the initial values, P<0.01), and 2) animals submitted to intravenous administration of DuP-753 (losartan), a non-peptide antagonist of angiotensin II with AT1-receptor type specificity (1.63 µmol/100 g body weight as a bolus, iv, plus a 30-min infusion of 0.018 µmol 100 g body weight-1 min-1 before the injection of angiotensin II), which completely blocked the hyperglycemic response to angiotensin II (P<0.01). This inhibitory effect on glycemia was already demonstrable 5 min (8.9 ñ 0.28 mM, angiotensin II, N = 9 vs 6.4 ñ 0.22 mM, losartan plus angiotensin II, N = 11) after angiotensin II injection and persisted throughout the 30-min experiment. Controls were treated with the same volume of saline solution (0.15 M NaCl). These data demonstrate that the angiotensin II receptors involved in the direct and indirect hyperglycemic actions of angiotensin II are mainly of the AT1-type.