Sildenafil (Viagra®) blocks inflammatory injury in LPS-induced mouse abortion: A potential prophylactic treatment against acute pregnancy loss?

INTRODUCTION: Recurrent pregnancy losses (RPL) are common women's health issues. Inflammatory and thrombotic events have been associated with RPL including excessive production of cytokines, in particular TNF-α. However, mechanisms behind gestational losses are not yet fully understood. Sildenafil inhibits phosphodiesterase Type-5 (PDE5). This drug increases intracellular cyclic guanosine monophosphate, having vasodilatory and, more recently described, anti-inflammatory properties. PDE5 is present in murine and human uterus and placenta. Sildenafil is already used clinically for treatment of human fetal growth restriction (FGR). Our objective was to determine if Sildenafil alone or in combination with Heparin had protective effects in pregnant Swiss albino challenged to abort by lipopolysaccharide (LPS). METHODS: Treatments (Sildenafil (50 mg/kg/day), Heparin (500 IU/Kg/day) or Sildenafil + Heparin at the same doses) were initiated the morning of copulation plug detection (gestational day (gd0)). On the 15th day of pregnancy, an intra-peritoneal injection of LPS (100 µg/kg) was administered. Untreated, pregnant mice challenged by LPS served as controls. RESULTS: Assessments at 48 h after LPS revealed that Sildenafil + Heparin prevented fetal loss. Early assessments at 2 h after LPS indicated that the pretreatments prevented induction of inflammatory cytokine production (TNF-α, IL-1ß/NF-κß) and preserved placental histopathology. DISCUSSION: Combined Sildenafil + Heparin therapy was superior to either treatment alone in most analyses. The known safety of Sildenafil and Heparin in human pregnancy suggests that usage of these combined agents may be of value for treatment of patients with impending pregnancy loss or prophylactically in women with a history of recurrent miscarriages.

[Efficacy and tolerance of the bisoprolol/hydrochlorothiazide combination in arterial hypertension]. / Eficácia e tolerabilidade da associação bisoprolol/ hidroclorotiazida na hipertensão arterial.

PURPOSE: Multicenter, open and non-controlled study to evaluated the efficacy and the tolerability of a low-dose combination of two anti-hypertensive agents: a cardioselective beta-blocker, bisoprolol (2.5 and 5.0 mg) with 6.25 mg of hydrochlorothiazide. METHODS: One hundred and six patients in the stage I and stage II of the systemic hypertension (mild to moderate) were given the bisoprolol/hydrochlorothiazide combination once daily and the diastolic and systolic blood pressures were monitored during the 8-week trial. RESULTS: The bisoprolol/hydrochlorothiazide combination reduced the initial mean values of systolic and diastolic blood pressures, respectively, from the 157.4 mmHg and 98.8 mmHg to 137.3 mmHg and 87.4 mmHg. At the end of the treatment period, 61% of the patients normalized blood pressure values (< 90 mmHg) and 22.9% of them had responded to the treatment, resulting in a total response rate (normalized + responsive) of 83.9% of cases. Adverse events were described only in 18.9% of the patients and dizziness and headache were the most common. There were no clinically significant changes on plasma levels of potassium, uric acid, glucose, or in the lipid profile. CONCLUSION: The combination of low dosages of bisoprolol and hydrochlorothiazide may be considered an effective, well tolerated and rational alternative for the initial treatment of the patients with mild to moderate hypertension.

[Diagnostic value of echocardiography with dipyridamole in coronary disease and evaluation of its prognostic potentiality face to ergometry, plane dipyridamole Tc99m-MIBI myocardial perfusion scintigraphy and coronary cineangiography]. / Valor diagnóstico da ecocardiografia com dipiridamol em doença coronária e avaliação de sua potencialidade prognóstica frente à ergometria, cintigrafia de perfusão miocárdica planar com dipiridamol e Tc99m-MIBI e cinecoronariografia.

PURPOSE: To assess in a consecutive series of patients, the diagnostic accuracy of dipyridamole echocardiography and to compare its prognostic power with that from other tests. METHODS: Seventy eight patients prospectively were underwent to dipyridamole echocardiography (DET) and coronary arteriography for diagnostic and post-infarction investigation. The majority was underwent to treadmill stress test and Tc99MIBI-dipyridamole planar myocardial scintigraphy. Eleven variables with possible prognostic importance were analyzed in a stepwise model to identify independent predictors of events. RESULTS: Sensitivity and specificity for the presence of coronary artery disease (in non-M patients) and multivessel disease (in post-MI patients) were, respectively, 44%, 91%, 53% and 88%. Mean follow-up was 21 +/- 9 months, during which there were four deaths, four unstable angina episodes, four nonfatal myocardial infarctions and eight revascularization procedures. By multivariate analysis, the only independent predictor of events was the change in wall motion score index from rest to peak stress. CONCLUSION: DET is a valuable alternative to exercise stress test and myocardial perfusion scintigraphy. Semiquantitative estimation of ischemic area during pharmacological stress is an important prognostic marker.

A perfusäo miocárdica na hipertrofia ventricular esquerda secundária à hipertensäo arterial / Myocardial perfusion in left ventricular hypertrophy secondary to arterial hypertension

A hipertensäo arterial causa frequentemente hipertrofia ventricular esquerda a qual tem sido considerada como um forte fator de risco de mortalidade nestes pacientes. A principal determinante da hipertrofia ventricular é a tensäo sistólica da parede e quanto maior o volume diastólico maior a tensäo miocárdica necessária para desenvolver um determinado nível de pressäo intraventricular. O aumento da tensäo sistólica leva à produçäo de novos miofilamentos, miofibrilas, mitocôndrias e ribosomas. A hirtrofia ventricular é acompanhada de aumento do consumo de oxigênio pelo miocárdio, aumento da massa ventricular, maior compressäo sistólica das artérias intramurais, densidade capilar inadequada e elevaçäo da pressäo de enchimento ventricular. Tem-se observado em pacientes hipertensos e com artérias coronárias epicárdicas angiograficamente normais uma reserva de fluxo sanguíneo inadequada, sugerindo uma alteraçäo da microcirculaçäo. Esta reduzida reserva de fluxo coronariano leva em determinadas circuntncias ao comprometimento da perfusäo miocárdica, com isquemia miocárdica e consequente fibrose. Atuamente, a melhor explicaçäo para esta baixa reserva coronária na hipetensäo arterial seria a disfunçäo endotelial. A supeita de comprometimento da perfusäo miocárdica na hipertensäo arterial seria levantada pela história de dor anginosa, pela presença de alteraçöes da repolarizaçäo ventricular no eletrocardiogrma, existência de arritmias cardíacas e de disfunçäo sistólica e/ou diastólica ventricular. Em mits destes pacientes observa-se obstruçäo coronária aterosclerótica significativa. Contudo, em outros pacientes se observa artéria coronárias angiograficamente normais e a origem do defeito da perfusäo parece estar na microcirculaçäo pela disfunçäo endotelial. A determinaçäo da reduçäo da reserva coronária permitiria identificar pacientes hipertensos de maior risco e, consequentemente, estratificá-los mais apropriadamente.

[Fosinopril in a daily single dose in mild and moderate hypertension. Brazilian multicenter study]. / Fosinopril em dose única diária na hipertensão leve e moderada. Estudo multicêntrico brasileiro.

PURPOSE: To evaluate during 12 weeks the effectiveness and safety of once-a-day fosinopril (10 or 20 mg/day comparative to placebo) in mild to moderate hypertensives according to an open design comparative to placebo. METHODS: One hundred and nineteen patients were studied; 52 +/- 11 years (mean +/- sd) range 18 a 76 years, 86 women and 33 men, 57% whites, 26% blacks and 17% mulattos, 71 mild hypertensives (95 < or = diastolic pressure < or = 104mmHg) e 48 moderate hypertensives (101 < diastolic pressure < or = 115mmHg). RESULTS: There was a significant reduction in systolic/diastolic pressure on the 6th week of treatment (from 161 +/- 16/103 +/- 7 before to 148 +/- 16/94 +/- 9mmHg on the 6th week). On the 12th week of treatment there was an additional significant reduction in systolic/diastolic pressure (from 148 +/- 16/94 +/- 9 on the 6th week to 145 +/- 17/89 +/- 8mmHg on the 12th week). There was a "favorable" response in 71% of the patients on the 12th week; 62% showed diastolic pressure < or = 90mmHg and 9% presented diastolic reduction > or = 10mmHg. There was no difference in the normalization rates between whites and non-whites, mild and moderate hypertensive, obese and non-obese patients, under or above 50 years of age and those patients from no drug-treatment to those on 3 drug before the study. There was no clinically relevant changes in laboratory evaluations before and at the end of the study. The number of adverse reactions was reduced in comparison with previous treatment. CONCLUSION: Fosinopril, according to our and others data, is effective and safe for the treatment of mild to moderate hypertensives, in whites or non-whites, obese or non-obese, younger or older than 50 years and receiving 0 or 3 drugs before the study.

[An open comparative study of captopril + hydrochlorothiazide versus chlorthalidone for the treatment of mild and moderate primary hypertension]. / Estudo aberto comparativo captopril + hidroclorotiazida versus clortalidona para tratamento da hipertensão primária leve e moderada.

PURPOSE: To compare the antihypertensive and metabolic effects of captopril combined with hydrochlorothiazide (C+HCTZ) versus chlorthalidone (CT) in mild and moderate primary hypertensive patients. METHODS: Fifty five patients, without treatment or treated with 15 days placebo were randomized for treatment with the combination of captopril 50mg and hydrochlorothiazide 25mg (n = 29) against chlorthalidone (n = 26). The clinical evaluation was done during placebo and monthly throughout three months, and the laboratory tests were done before and at the end of the study. RESULTS: The blood pressure were similar between groups during placebo period (C + HCTZ: 161 +/- 25/102 +/- 6-CT: 155 +/- 18/101 +/- 6 mmHg); the diastolic blood pressure decreases significantly at first month already in the group C + HCTZ (89 +/- 8 mmHg) compared to group CT (94 +/- 8 mmHg, p < 0.05). The percentile diastolic and mean blood pressure dropped, in average, 12% in C + HCTZ group and in CT varied between 7 (1st and 2nd month) to 11% (3rd month). Without statistical difference, the blood pressure normalization was obtained in 69% of the patients with the association captopril and diuretic and in 50% of the patients in the chlorthalidone group. It was observed a significant reduction of potassium in patients treated with chlorthalidone (4.2 +/- 0.7 to 3.7 +/- 0.4 mEq/L, p < 0.01) that was not observed with the captopril and the thiazide associated. The last treatment also significantly reduced the cholesterol levels (219 +/- 39 mg/dl to 202 +/- 39 mg/dl, p < 0.04). CONCLUSION: Our results indicate that captopril combined with low diuretic dose normalize the blood pressure in 69% mild to moderate primary hypertensive patients, and acts faster than chlorthalidone in this control. In addition has metabolic benefits reducing cholesterol levels with no alteration in potassium levels.

Tratamento da hipertensäo arterial sistêmica com urapidil: estudo multicêntrico comparativo com nifedipina / Treatment of sistematic arterial hypertension with urapradil multicenter studies comparative with nifedipina

Estudo multicêntrico, aberto, comparativo entre o Urapidil e a Nifedipina, alocando os pacientes, aleatoriamente, em dois grupos de tratamento, com 95 pacientes (46 pacientes tratados com Urapidil e 49 pacientes tratados com Nifedipina). Houve um período de washout de duas a quatro semanas e, um período de tratamento ativo de 10 semanas, sendo que, após duas semanas, a dose inicial (Urapidil: 60mg/d e Nifedipina: 40mg/d) foi duplicada nos pacientes näo-responsivos. O critério de normalizaçäo foi o de uma pressäo diastólica igual ou inferior a 90 mmHg ou 10% na reduçäo, se a diastólica fosse inferior a 100mmHg. Nos 95 pacientes estudados a porporçäo de pacientes responsivos foi de 78% paa o Urapidil e de 76% para a Nifedipina; a queda de pressäo levou a 139/88mmHg; no grupo do Urapidil e 131/83mmHg no grupo da Nifedipina. A tolerância foi satisfatória com o Urapidil, sendo as principais queixas a vertigem, o mal-estar e a fraqueza que apareceram em 10 doentes; entre os pacientes tratados com Nifedipina 17 apresentaram queixas de cefaléia e 14 pacientes apresentaram vertigem e flushing

Efficacy of verapamil in patients resistant to other antihypertensive therapy.

A solution of verapamil in sequential intravenous infusion was used in patients with severe arterial hypertension who were resistant to various antihypertensive drug regimens. The infusion--25-mg verapamil diluted in 100-ml glucose and slowly injected over 10 minutes--was given daily until a diastolic pressure less than 100 mm Hg was sustained for more than 24 hours. Then patients were maintained on their conventional oral medication alone. This trial involved 11 patients, 10 of whom had primary hypertension and 1 a renovascular type of secondary hypertension. Normal pressure was maintained in all patients with the conventional medication after the verapamil infusions, which varied from 2 to 10; surprisingly, this situation continued from 30 to 120 days and this result was attributed to resetting of the baroreceptors. To confirm this theory, another group of patients underwent baroreceptor testing with angiotensin before and after the use of verapamil; the baroreceptors were functioning at a lower threshold of excitability after verapamil. We conclude that verapamil is capable of resetting the baroreceptors to a lower level, rendering them responsive to increases in blood pressure.