Análisis crítico de un artículo: La suspensión de inhibidores de la bomba de protones induciría síntomas de reflujo / Critically appraised article

Background & Aims: Rebound acid hypersecretion (RAHS) has been demonstrated after 8 weeks of treatment with a proton-pump inhibitor (PPI). IfRAHS induces acid-related symptoms, this might lead to PPI dependency and thus have important implications. Methods: A randomized, double-blind, placebo-controlled trial with 120 healthy volunteers was conducted. Participants were randomized to 12 weeks of placebo or 8 weeks of esomeprazole 40 mg/d followed by 4 weeks with placebo. The Gastrointestinal Symptom Rating Scale (GSRS) was filled out weekly. A score of >2 on 1 of the questions regarding heartburn, acid regurgitation, or dyspepsia was defined as a clinically relevant acid-related symptom. Results: There were no significant differences between groups in GSRS scores at baseline. GSRS scores for acid-related symptoms were significantly higher in the PPIgroup at week 10 (1.4 ± 1.4 vs 1.2 ± 0.9; P = .023), week 11 (1.4 ± 1.4 vs 1.2 ± 0.9; P = .009), and week 12 (1.3 ± 1.2 vs 1.0 ± 0.3; P = .001). Forty-four percent (26/59) of those randomized to PPI reported >1 relevant, acid-related symptom in weeks 9-12 compared with 15% (9/59; P < .001) in the placebo group. The proportion reporting dyspepsia, heartburn, or acid regurgitation in the PPIgroup was 13 of 59 (22%) at week 10,13 of59 (22%) at week 11, and 12 of 58 (21%) at week 12. Corresponding figures in the placebo group were 7% at week 10 (P = .034), 5% at week 11 (P = .013), and 2% at week 12 (P = .001). Conclusions: PPI therapy for 8 weeks induces acid-related symptoms in healthy volunteers after withdrawal. This study indicates unrecognized aspects of PPI withdrawal and supports the hypothesis that RAHS has clinical implications.

A pilot study on the effect of telmisartan & ramipril on 24 h blood pressure profile & dipping pattern in type 1 diabetes patients with nephropathy.

Background & objectives: Angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) have been used to normalize the blood pressure and the dipping pattern in patients with type 1 diabetes mellitus (T1DM) and nephropathy. However, there are no data on the effect of the dual blockade on the dipping pattern in these subjects. We therefore, carried out this study to evaluate the effect of administrating an ACEI followed by ARB in the optimum doses in T1DM patients with nephropathy on 24 h blood pressure (BP) profile and nocturnal dipping pattern. Methods: An open label interventional pilot study was done during a one year period involving 30 consecutive patients who were treated with telmisartan 80 mg (0800-1000 h) for eight weeks followed by addition of ramipril 10 mg (1200-1400 h) for the next eight weeks. Ambulatory BP, dipping pattern and albumin excretion rate were studied after each phase. Twenty patients were hypertensive and 10 patients had macro- and 20 patients had microalbuminuria. Results: Telmisartan produced a fall in the clinic BP by 4/1.3 mm Hg (P<0.05 and P<0.362, respectively), 2/1.9 mm Hg in the mean 24 h BP, 1.4/1.1 mm Hg in the day BP and 3.7/3 mm Hg in the trough BP. Addition of ramipril to telmisartan produced a further reduction of 6.3/5.9 mm Hg in the clinic BP (P<0.001 for both), 4.3/4.2 mm Hg in the mean 24 h BP (P<0.01 and P<0.0001, respectively), 5.8/3.9 mm Hg in the day BP (P<0.01 for both), 4.2/2.5 mm Hg in the trough BP, with a reduction of clinic SBP and DBP of 10.3/7.2 mm Hg from the baseline. Telmisartan restored normal systolic dipping pattern in 33.3 per cent of the nondippers (P<0.01) but addition of ramipril was not complimentary. Hyperkalamia (>5.5 mmol/l) was observed only in 2 patients towards the end of the study. Interpretation & conclusions: The dual blockade with telmisartan and ramipril had complimentary effect on lowering of the BP, however, similar beneficial effect on the nocturnal dipping was not observed. Further studies with large number of subjects with longer duration of follow-up are required to validate these observations.

Efeito do ramipril e da sinvastatina sobre o estresse oxidativo de ratos diabéticos / Effects of ramipril and simvastatin on the oxidative stress of diabetic rats

OBJETIVO: Avaliar se o ramipril, isoladamente ou em combinação com a sinvastatina, seria capaz de reduzir o estresse oxidativo de ratos diabéticos pela estreptozotocina (STZ). MÉTODOS: As drogas foram administradas a ratos diabéticos por duas semanas; o estresse oxidativo foi medido por dosagem de capacidade antioxidante total plasmática (TRAP) e malonaldeído (MDA). RESULTADOS: O ramipril usado isoladamente foi capaz de aumentar significativamente as defesas antioxidantes do rato diabético; a sinvastatina isoladamente ou combinada ao ramipril em tomadas separadas não produziu efeito significativo sobre o estresse oxidativo; a administração simultânea de ramipril e sinvastatina reduziu as defesas antioxidantes plasmáticas de ratos com diabetes melito químico. CONCLUSÕES: Os dados do presente estudo corroboram o efeito positivo do ramipril sobre a defesa antioxidante do plasma, mas não confirmam um possível efeito benéfico da sinvastatina no modelo. Pesquisas adicionais são necessárias para clarificar a paradoxal redução da TRAP verificada pela administração simultânea das drogas.

OBJECTIVE: To evaluate if ramipril, with or without simultaneous use of simvastatin, would be capable of reducing oxidative stress of streptozotocin (STZ) induced diabetic rats. METHODS: The drugs were given to the diabetic rats for 2 weeks; oxidative stress was measured by dosage of total plasma antioxidant capacity (TRAP) and malondialdehyde (MDA). RESULTS: Ramipril, used alone, was capable of significantly increasing the antioxidative defenses of the diabetic rat; simvastatin, given alone or combined with ramipril in separate administrations, did not produce any significant effect on the oxidative stress; concomitant administration of ramipril and simvastatin significantly reduced the antioxidative plasmatic defenses of rats with chemically induced diabetes mellitus CONCLUSIONS: Our data corroborate the positive effect of ramipril upon plasma antioxidative defenses but did not confirm a possible beneficial effect of simvastatin in the model. More research is needed to clarify the paradoxal TRAP reduction verified with simultaneous administration of the drugs.

Evaluation of fixed dose combination (FDC) of telmisartan+ramipril usage in patients with micro-albuminuria and persistent hypertension: A TRIUMPH study.

Micro-albuminuria is a marker for declining kidney function and predicts increasing cardiovascular risk especially in diabetic hypertensives. Angiotensin receptor blockers and angiotensin-converting enzyme inhibitors may slow the progression of proteinuric kidney disease and thus would be valuable in these high risk patients. The present study was undertaken to assess the efficacy and tolerability of a fixed dose combination (FDC) of telmisartan and ramipril in adult Indian patients with sustained stage 2 hypertension, comorbidities and micro-albuminuria. A total 382 patients were enrolled in this multicentric, prospective open, non-comparative phase IV postmarketing surveillance study by 40 physicians in India and treated with FDC of telmisartan 40 mg+ ramipril 5 mg once daily for 12 weeks. A total 370 patients completed the study but 12 patients were lost to follow-up and considered as drop-outs. There was a significant (p<0.05) reduction in the systolic blood pressure (SBP) from 170.89 at baseline to 132. 77 mm Hg at week 12 and diastolic blood pressure (DBP) from 104.47 to 83.30 mm Hg at the end of 12 weeks therapy as well as urine albumin levels from 186.25 mg/24-hour to 62.42 mg/24-hour (66.49%) at the end of 12 weeks. Overall assessment of treatment was rated as good to excellent in 87.3% and fair in 11.4% patients. The most common adverse event reported was cough (5.2%). Results of the present study indicate that the FDC of telmisartan+ramipril brings about significant reductions in the systolic and diastolic blood pressure as well as urine albumin excretion.

The Therapeutic Effects of Angiotensin-Converting Enzyme Inhibitors in Severe Non-proliferative Diabetic Retinopathy

PURPOSE: To evaluate the effects of angiotensin-converting enzyme inhibitors (ACE-I) in retarding progression of severe non-proliferative diabetic retinopathy (NPDR) in normotensive type 2 diabetic patients. METHODS: This was a retrospective case control study of 128 patients with normotensive type 2 diabetes with lower than +1 dipstick proteinuria and severe NPDR who were classified into either an ACE-I treated group (Enalapril maleate 10 mg, n=12 , Ramipril 5 mg, n=17) or an ACE-I untreated group (n=99). Medical records were reviewed for endpoints of (a) occurrence of proliferative diabetic retinopathy (PDR) or macular edema (ME) for which laser phototherapy was necessary or (b) development of proteinuria of higher than +1 level requiring medication of ACE-I. RESULTS: From the total of 128 patients, there were 29 ACE-I treated patients and 99 ACE-I untreated patients. There were no differences in the average age, duration of diabetes, body mass indices, blood pressure and levels of hyperglycemia or HbA1C between the two groups. Blood pressure and HbA1C levels in both groups remained unchanged during the study. The mean follow-up period was 41.6 months. In the ACE-I group, 6 patients progressed to PDR, 5 to ME and 6 developed proteinuria of greater than +1 over the follow-up period. In the control group, 30 patients progressed to PDR, 6 to ME and 9 developed proteinuria of greater than +1 over the follow-up period. CONCLUSIONS: Small doses of ACE-I did not yield any beneficial effects in retarding the progression of severe NPDR.

Evaluation of efficacy and tolerability of Losartan and Ramipril combination in the management of hypertensive patients with associated diabetes mellitus in India (LORD Trial).

AIM: The study was conducted to evaluate efficacy and tolerability of fixed dose combination (FDC) of Losartan and Ramipril in the management of mild to moderate hypertensive Native Asian Indian patients with associated diabetes mellitus. The secondary objective was to evaluate the efficacy of the combination in reducing microalbuminuria. MATERIAL AND METHODS: The study was an open, non-comparative, multicentric clinical trial conducted in seven Indian centres in 315 eligible patients. All the patients were treated with Losartan 50 mg + Ramipril 2.5 mg or Losartan 50 mg + Ramipril 5 mg once a day in 12 weeks and consisted of a total of eight visits. RESULTS: The mean age of patients was 52.93 years (range 45 - 60 years). Of the total patients, 62.86% were males and 37.14% were females. The mean prestudy systolic blood pressure was 160.56 +/- 14.44 which was significantly reduced to 126.85 +/- 9.78 at the end of 12 weeks (P < 0.001). Similarly the mean diastolic blood pressure was 98.91 +/- 8.33 at baseline (stage I) which was significantly reduced to 79.82 +/- 5.42 at the end of 12 weeks (P < 0.001). A mean fall of 33.72 mmHg in systolic blood pressure and the mean fall of 19.10 mmHg was observed in systolic and diastolic blood pressure respectively at the end of the treatment which was statistically highly significant (P < 0.001). The JNC-VII goal of blood pressure < 130/80 was achieved in 79.05% patients after the treatment which losartan and ramipril combination only. Microalbuminuria (urinary albumin excretion > 30 but < 300 mg/day) was seen in 83/250 (33.2%) patients and 135 (54%) patients had clinical proteinuria (albuminuria) at baseline. At the end of the therapy 20.8% patients achieved normoalbuminuria. Good to excellent efficacy response was reported in 98.09% patients and 98.41% patients reported good to excellent tolerability to the treatment. CONCLUSION: The fixed dose combination of Losartan and Ramipril showed good to excellent efficacy response in 98.10% patients and achieved a target blood pressure of 130/80 mmHg in 79.05% patients in 12 weeks. The combination reduced the urinary albumin excretion in majority of the patients with microalbuminuria and proteinuria (the major marker of nephropathy).

Antihypertensive efficacy and tolerability of once-daily sustained-release diltiazem alone and in combination with ramipril in hypertension.

This study assessed once-daily (OD), sustained-release (SR) diltiazem alone and in combination with ramipril in essential hypertension. Fifty patients with supine diastolic blood pressure (DBP) > or = 95-< or = 114 mm Hg were entered into the active treatment phase of the study after 2 weeks of placebo run-in. Sustained-release diltiazem 180 mg OD was administered for 2 weeks, then optimally titrated, at 2 week intervals, to SR diltiazem 240 mg OD and then SR diltiazem 180 mg + ramipril 2.5 mg OD to achieve supine DBP < or = 90 mm Hg. After 4 weeks of diltiazem monotherapy (SR diltiazem 180 mg or 240 mg OD) mean supine DBP was reduced from 102.84 +/- 3.81 mm Hg to 90.15 +/- 5.02 mm Hg (P < 0.01) and mean supine heart rate was reduced from 85.15 +/- 11.02 bpm to 77.62 +/- 11.45 bpm (p < 0.01). Diltiazem monotherapy reduced supine DBP to < or = 90 mm Hg in 35/45 (77.77%) patients. Combination therapy (SR diltiazem 180 mg + ramipril 2.5 mg OD), received by non-responders to diltiazem monotherapy, reduced supine DBP to < or = 90 mm Hg in 3/10 (30%) patients. Sinus bradycardia was observed in one patient. Sustained-release diltiazem alone and in combination with ramipril reduce blood pressure in a dose related manner and is well tolerated.

Impediment of the progressions of microalbuminuria and hyperlipidemia in normotensive type 2 diabetes by low-dose ramipril.

In a randomized, double-blind, placebo-controlled study, we investigated in normotensive type 2 diabetics with microalbuminuria the effect of ramipril, an ACE inhibitor, on urine albumin excretion and serum lipids. A total of 1,882 patients were screened for urine microalbumin consecutively by dipstick test, Rapi Tex-Albumin test and RIA. The final 28 normotensive and microalbuminuric patients were assigned to receive either ramipril (1.25 mg/d, n = 16) or placebo (n = 12) for 12 weeks. Throughout the study, both groups had no changes in blood pressure, fasting plasma glucose, HbA1C, serum creatinine and electrolytes and no difference in creatinine clearance. At week 12 only the placebo group showed the significant increment of urine albumin excretion and triacylglycerol (30.6 +/- 38.3 to 39.0 +/- 19.7 and 167 +/- 64 to 208 +/- 77 mg/dl, respectively) but the decrement of HDL-cholesterol (46 +/- 16 to 35 +/- 6 mg/dl). During a 3 month period, increased urine albumin excretion was observed in normotensive type 2 diabetes with microalbuminuria who received only placebo. We conclude that ramipril may arrest the progression of albumin excretion and had favorable effects on serum lipids. Ramipril was safe and well-tolerated without untoward side effects during the study period.

Cardiomiopatias näo-inflamatórias / Non-inflammatory cardiomyopathies

Cardiomiopatias, conforme definiçäo de 1995, säo doenças do miocárdio associadas à disfunçäo cardíaca. Neste artigo discutiremos as cardiomiopatias primárias, hoje simplesmente denominadas cardiomiopatias. Säo quatro as formas de apresentaçäo das cardiomiopatias: jipertrófica, dilatada, restritiva e displasia arritmogênica do ventrículo direito. Cada uma apresenta suas próprias peculiaridades, com diferentes manifestaçöes clínicas e conduta diversa. A cardiomiopatia dilatada é a mais frequente delas, e seus portadopres evoluem com insuficiência cardíaca congestiva. No artigo destacamos a importância do diagnóstico precoce e do emprego de doses corretas dos inibidores da enzima conversora. A cardiomipatia hipertrófica é doença geneticamente transmitida, com peculiaridades diferentes conforme a mutaçäo que a provocou. A terapêutica é diferente, conforme a forma de manifestaçäo. Betabloqueadores ou bloqueadores de canais de cálcio säo empregados quando predominam as manifestaçöes da disfunçäo diastólica. Amiodarona é a droga mais utilzada para controlar a frequente arritmia observada nos portadores da doença. marcapasso bicameral ou cirurgia säo indicados nos pacientes em que os sintomas näo säo controlados com a terapêutica clínica. A cardiomiopatia restritiva é a forma mais rara. Endomiocardiofibrose, amiloidose e cardiomiopatia restritiva idiopática säo três formas de apresentaçäo da doença, com condutas e prognóstico diversos. Aspectos dessas formas de apresentaçäo säo discutidos no artigo. Displasia arrtimogênica do ventrículo direito é a mais recente cardiomiopatia descrita. Atinge jovens e é controlada com betabloqueadores, na maioria dos casos em sua forma inicial.

Injection of ramipril into the lateral ventricle interferes with the drinking response induced by pharmacological and natural thirst stimuli

We investigated the effects of ramipril, an angiotensin I-converting enzyme (ACE) inhibitor, on water intake by male Holtzman rats (250-300 g) with cannulae implanted into the lateral ventricle. Intracerebroventricular (icv) injection of ramipril (1 µg/µl) significantly reduced drinking in response to subcutaneous (sc) injection of isoprenaline (100 µg/kg) from 8.49 + or - 0.69 to 2.96 + or - 0.36 ml/2 h, polyenthyleneglycol (PEG) (30 percent w/v, 10 ml/kg) from 9.51 + or - 2.20 to 1.6 + - 0.34 ml/2 h or water deprivation for 24 h from 12.61 + or - 0.83 to 5.10 + or - 1.37 ml/2 h. Ramipril had no effect on water intake induced by cellular dehydration produced by sc injection of hypertonic saline (2 M NaCl). These results are consistent with the hypothesis that ramipril acts as an ACE-blocking agent in the brain. The possibility that ramipril is transformed to ramiprilat, the active drug, by the brain is suggested