Renal function and effectiveness of angiotensin-converting enzyme inhibitor therapy in patients with chronic stable coronary disease in the Prevention of Events with ACE inhibition (PEACE) trial. [The effects of angiotensin-converting enzyme inhibitor on IgA nephropathy and the influencing factors]. N-acetylcysteine for preventing acute kidney injury in cardiac surgery patients with pre-existing moderate renal insufficiency. ACE inhibitor mediated reductions in renal size and microalbuminuria in normotensive, diabetic subjects. ACE inhibitor versus beta-blocker for the treatment of hypertension in renal allograft recipients. ACE inhibitors and persistent left ventricular hypertrophy after renal transplantation: a randomized clinical trial. Successful implementation of the randomized discontinuation trial design: an application to the study of the putative antiangiogenic agent carboxyaminoimidazole in renal cell carcinoma--CALGB 69901. Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy. Enalapril to prevent cardiac function decline in long-term survivors of pediatric cancer exposed to anthracyclines. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. Donepezil treatment of patients with MCI: a 48-week randomized, placebo-controlled trial. A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis. Prospective randomized controlled trial of hepatic arterial embolization or infusion chemotherapy with 5-fluorouracil and degradable starch microspheres for colorectal liver metastases. A combination of galantamine and memantine modifies cognitive function in subjects with amnestic MCI. Hepatic arterial infusion of floxuridine in patients with liver metastases from colorectal carcinoma: long-term results of a prospective randomized trial. Randomized trial of candesartan cilexetil in the treatment of patients with congestive heart failure and a history of intolerance to angiotensin-converting enzyme inhibitors. Additive antiproteinuric effect of pentoxifylline in patients with type 2 diabetes under angiotensin II receptor blockade: a short-term, randomized, controlled trial. Efficacy of donepezil in mild cognitive impairment: a randomized placebo-controlled trial. Docetaxel and continuous-infusion fluorouracil versus epirubicin, cisplatin, and fluorouracil for advanced gastric adenocarcinoma: a randomized phase II study. ADEPT: Addition of the AT1 receptor antagonist eprosartan to ACE inhibitor therapy in chronic heart failure trial: hemodynamic and neurohormonal effects. Effective postponement of diabetic nephropathy with enalapril in normotensive type 2 diabetic patients with microalbuminuria. Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. The EUCLID Study Group. Meta-analysis of observed mortality data from all-controlled, double-blind, multiple-dose studies of losartan in heart failure. Losartan Heart Failure Mortality Meta-analysis Study Group. Addition of angiotensin II receptor blockade to maximal angiotensin-converting enzyme inhibition improves exercise capacity in patients with severe congestive heart failure. A comparison between oral antiarrhythmic drugs in the prevention of atrial fibrillation after cardiac surgery: the pilot study of prevention of postoperative atrial fibrillation (SPPAF), a randomized, placebo-controlled trial. Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients. Multicycle dose-intensive chemotherapy for women with high-risk primary breast cancer: results of International Breast Cancer Study Group Trial 15-95. Prophylactic actinomycin D for high-risk complete hydatidiform mole. The antiproteinuric effect of angiotensin antagonism in human IgA nephropathy is potentiated by indomethacin. Enalapril/amlodipine combination in cyclosporine-treated renal transplant recipients: a prospective randomized trial. The efficacy and safety of short- and long-term dual antiplatelet therapy in patients with mild or moderate chronic kidney disease: results from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. Efficacy of ACE inhibitors and ATII receptor blockers in patients with microalbuminuria: a prospective study. Effects of angiotensin-converting enzyme inhibitor, angiotensin II receptor antagonist and calcium antagonist on urinary podocytes in patients with IgA nephropathy. Converting-enzyme inhibitor versus calcium antagonist in cyclosporine-treated renal transplants. Reduction of ACE activity is insufficient to decrease microalbuminuria in normotensive patients with type 1 diabetes. Treatment of arterial hypertension in diabetic humans: importance of therapeutic selection. Treatment of IgA nephropathy with ACE inhibitors: a randomized and controlled trial. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. The effect of ACE inhibitor and angiotensin II receptor antagonist therapy on serum uric acid levels and potassium homeostasis in hypertensive renal transplant recipients treated with CsA. Randomized study of initial versus late chest irradiation combined with chemotherapy in limited-stage small-cell lung cancer. Aarhus Lung Cancer Group. Randomized pilot trial of postoperative aspirin in subarachnoid hemorrhage. Randomised study using IFN-alpha versus IFN-alpha plus coumarin and cimetidine for treatment of advanced renal cell cancer. Short-term effects of early intravenous treatment with a beta-adrenergic blocking agent or a specific bradycardiac agent in patients with acute myocardial infarction receiving thrombolytic therapy. ACEI/ATRA therapy decreases proteinuria by improving glomerular permselectivity in IgA nephritis. Haemodynamic and renal effects of intravenous enalaprilat during coronary artery bypass graft surgery in patients with ischaemic heart dysfunction.
Patients with reduced renal function are at increased risk for adverse cardiovascular outcomes. In the post-myocardial infarction setting, angiotensin-converting enzyme (ACE) inhibitors have been shown to be as effective in patients with impaired renal function as in those with preserved renal function.
                We assessed the relation between renal function and outcomes, the influence of ACE inhibition on this relation, and whether renal function modifies the effectiveness of ACE inhibition in patients with stable coronary artery disease and preserved systolic function enrolled in the Prevention of Events with ACE inhibition trial (PEACE). Patients (n=8290) were randomly assigned to receive trandolapril (target, 4 mg/d) or placebo. Clinical creatinine measures were available for 8280 patients before randomization. The estimated glomerular filtration rate (eGFR) was calculated with the 4-point Modification of Diet in Renal Disease equation. Renal function was related to outcomes, and the influence of ACE-inhibitor therapy was assessed with formal interaction modeling. The mean eGFR in PEACE was 77.6+/-19.4, and 1355 (16.3%) patients had reduced renal function (eGFR <60 mg.mL(-1).1.73 m(-2)). We observed a significant interaction between eGFR and treatment group with respect to cardiovascular and all-cause mortality (P=0.02). Trandolapril was associated with a reduction in total mortality in patients with reduced renal function (adjusted HR, 0.73; 95% CI, 0.54 to 1.00) but not in patients with preserved renal function (adjusted HR, 0.94; 95% CI, 0.78 to 1.13).
                Although trandolapril did not improve survival in the overall PEACE cohort, in which mean eGFR was relatively high, trandolapril reduced mortality in patients with reduced eGFR. These data suggest that reduced renal function may define a subset of patients most likely to benefit from ACE-inhibitor therapy for cardiovascular protection. OBJECTIVE To investigate the effects of angiotensin-converting enzyme inhibitor (ACEI) on IgA nephropathy(IgAN) and the factors influencing the therapeutic effects. METHODS 131 cases with IgAN diagnosed by renal biopsy were randomly divided into two groups: ACEI group (benazepril 10 mg/d) and non-ACEI group as control. The pathological changes in the kidney were analyzed using Lee SMK. RESULTS After 1 month treatment of ACEI, the levels of proteinuria and serum cholesterol decreased significantly, meanwhile those of serum albumin and total protein increased obviously in patients with IgAN(P < 0.05). The proteinuria level at the 3rd month after treatment was lower than that at the 1st month, but was same as that at the 18th month. While in the control group the proteinuria level increased and the clearance of creatinine decreased continuously during the observation (P < 0.05). The effects correlated positively with mesangial proliferation and negatively with course of the disease glomerular sclerosis in glomerulus and changes of small arterioles in the kidney. Normal blood pressare normal renal function I approximately II degree of Lee SMK I degee of interstitial changes minimal changes of small arterioles and mild glomerular sclerosis predicted better response to ACEI treatment than hypertension renal insufficiency V degree of Lee SMK IV degee of interstitial changes severe changes of small arterioles and massive glomerular sclerosis. CONCLUSIONS It is suggested that benezepril could definitely reduce the excretion of urinary protein and protect renal function of patients with IgAN and should be used as earlier as possible. Mesangial prolife ration glomerular sclerosis in glomerulus changes of small arterioles in kidney and course of the disease are the major influencing factors of ACEI treatment on IgAN. N-acetylcysteine may prevent acute kidney injury after cardiac surgery. To determine if N-acetylcysteine warrants definitive evaluation in a large multicentre trial, we evaluated its effects on a surrogate outcome, estimated glomerular filtration rate (eGFR), in a randomized trial.
                One-hundred-seventy-seven cardiac surgery patients with moderate pre-existing renal insufficiency (eGFR <or= 60 mLxmin(-1)) were recruited in a blinded (patients, clinicians, data-collectors) placebo-controlled randomized trial. Eighty-nine were randomized to N-acetylcysteine (100 mgxkg(-1) i.v. bolus, 20 mgxkg(-1)xhr(-1) infusion until four hours after cardiopulmonary bypass), and 88 to placebo. The primary outcome was the percent change in eGFR during the first 72 postoperative hours. Secondary outcomes included renal replacement therapy, mortality, atrial fibrillation, vasoactive medications, and adverse effects. A future multicentre trial was deemed to be warranted if N-acetylcysteine was associated with a percent change in eGFR that was 3.8 better (small benefit), and with an upper 95% confidence interval including 9.5 (moderate benefit).
                The median percent change in eGFR was 5.2% better (absolute difference) in the N-acetylcysteine arm (95% confidence interval 2.4% worse to 12.1% better; P=0.22). With regard to secondary outcomes, all-cause mortality was lower in the N-acetylcysteine arm (0% vs 8%; P=0.007).
                N-acetylcysteine did not cause a statistically significant improvement in postoperative eGFR in this single-centre study. Nonetheless, its treatment effect was consistent with a plausible small-to-moderate benefit. Given this finding, N-acetylcysteine should be definitively evaluated in a large randomized trial. Recent studies utilizing converting enzyme inhibitors (CEI) in diabetic rats document reductions in both renal hypertrophy and albuminuria. Four separate clinical studies in normotensive patients with diabetes demonstrate reduction of microalbuminuria with CEIs independent of blood pressure reduction. The present pilot study examines the results of reducing an elevated glomerular filtration rate on changes in renal size and microalbuminuria in normotensive, hyperfiltering insulin-dependent diabetic (IDDM) patients. Fifteen IDDM patients were randomized to either placebo or the CEI, lisinopril. Dosage of lisinopril was titrated over 3 months to reduce glomerular filtration rate (GFR) to < or = 2.33 mL/sec. Evaluation at 18 months demonstrated the lisinopril group had a marked reduction in renal size (16.9 +/- 1.1, baseline versus 12.8 +/- 0.9 cm, 18 months; p < 0.05) and microalbuminuria (92 +/- 11 micrograms/min, baseline versus 23 +/- 26 micrograms/min, 18 months; p < 0.05). No change in renal size was noted in the placebo group (15.4 +/- 0.8, baseline versus 14.9 +/- 0.7 cm, 18 months; NS) and albuminuria increased (118 +/- 15 micrograms/min, baseline versus 293 +/- 32 micrograms/min, 18 months; p < 0.05). Mean arterial pressure at 18 months was significantly lower in the lisinopril group compared to placebo (102 +/- 4, placebo versus 87 +/- 6 mm Hg, CEI, p < 0.05). This study supports previous animal studies that document reductions in both microalbuminuria and renal size by a CEI. The overall impact of these findings on preservation of renal function cannot be assessed, however, in this short-term study. Angiotensin-converting enzyme (ACE) inhibitors have been shown to slow the progression of chronic renal failure. However, the value of ACE inhibitors for the treatment of hypertension in renal allograft recipients has not been established. ACE inhibitors dilate the efferent glomerular arteriole, an effect that may aggravate the decrease in glomerular filtration rate resulting from cyclosporine-induced vasoconstriction at the afferent glomerular arteriole. Therefore, the goal of this double-blind, randomized study was to compare the antihypertensive and renal effects of the ACE inhibitor quinapril with those of the beta-blocker atenolol in renal allograft recipients in whom hypertension developed 6 to 12 weeks after transplantation. All patients received cyclosporine as an immunosuppressant and had stable graft function (serum creatinine concentration, <220 micromol/L) at entry into the study. Twenty-nine patients who received quinapril (daily dose titrated between 2.5 and 20 mg) and 30 patients who received atenolol (daily dose titrated between 12.5 and 100 mg) completed the 24-month study. The two groups did not differ in age, sex ratio, height, and weight before entry into the study. Quinapril decreased diastolic blood pressure from 96+/-1 to 84+/-1 mm Hg (average throughout treatment period), and atenolol decreased diastolic blood pressure from 96+/-1 to 83+/-1 mm Hg. The serum creatinine concentration did not change significantly in either group after 24 months (129+/-8 micromol/L at entry and 148+/-19 micromol/L after 24 months in the quinapril group and 131+/-6 micromol/L at entry and 152+/-15 micromol/L after 24 months in the atenolol group; P=NS for both groups). After 24 months, the change in urinary albumin excretion from baseline was -10+/-15 mg/d in the quinapril group and 52+/-32 mg/d in the atenolol group (P=0.03). These results show that quinapril and atenolol are effective antihypertensive drugs when used after renal transplantation. Moreover, compared with atenolol, quinapril has no adverse effects on graft function. The relative reduction in albuminuria observed with quinapril as compared with atenolol could indicate a beneficial effect of quinapril on long-term graft function. Interventional studies of left ventricular hypertrophy (LVH) in renal transplant recipients are scarce and to date evaluated only patients immediately after renal transplantation.
                Randomized controlled trial that assessed the effectiveness of angiotensin-converting enzyme (ACE) inhibitors in regressing persistent LVH after successful transplantation.
                70 renal transplant recipients (47 men; age, 30 to 68 years) without diabetes previously randomly assigned to either cyclosporine or tacrolimus therapy, with LVH persisting 3 to 6 months after transplantation.
                Subjects were randomly assigned to either lisinopril (ACE-inhibitor group; 36 patients) or no therapy (control group; 34 subjects).
                Main outcome was change in left ventricular mass index (LVMi) at month 18.
                A consistent decrease in both systolic (SBP) and diastolic blood pressure (DBP) was observed in both groups (between-group differences, -1.7 +/- 3.3 mm Hg; 95% confidence interval [CI], -4.8 to 8.2; P = 0.6 for SBP; 0.3 +/- 2.2 mm Hg; 95% CI, -4.8 to 4.1; P = 0.9 for DBP), whereas LVMi regressed more in the ACE-inhibitor group (between-group difference, 10.1 +/- 16.3 g/m(2.7); 95% CI, 4.2 to 16.1; P < 0.01). A significant interaction of ACE inhibitors with cyclosporine in affecting LVMi change was shown by means of post hoc multiple regression analysis (P < 0.01; differences between cyclosporine and tacrolimus group, 13.3 +/- 3.9 g/m(2.7); 95% CI, 5.3 to 21.2; P < 0.01 in the ACE-inhibitor group; 3.7 +/- 4.2 g/m(2.7); 95% CI, -4.7 to 12.2; P = 0.4 in the control group).
                Single-center study with small sample size. Interaction of ACE inhibitors with cyclosporine treatment emerged from post hoc analysis.
                A prolonged course of ACE-inhibitor therapy is effective in regressing the persistent LVH of renal transplant recipients by mechanisms independent of effects on BP. This regression seems to be at least in part the effect of an interaction between ACE inhibitors and cyclosporine. To assess the disease-stabilizing activity of carboxyaminoimidazole (CAI) in patients with metastatic renal cell cancer (RCC) using a randomized discontinuation trial (RDT) design.
                Recruited patients had a performance status of 0 to 2, minimal neuropathy or cerebellar dysfunction, measurable disease, and normal organ function. Treatment with 250 mg/d CAI was initiated in all patients and continued until disease progression in those with an objective response. Protocol treatment was discontinued for unacceptable toxicity or progressive disease; patients with stable disease at the 16-week evaluation point were randomly assigned in a double-blind manner to continued CAI or placebo. The primary end point was the stable disease rate in the randomized groups.
                A total of 368 patients were accrued and received therapy. Ninety percent had a performance status of 0 or 1, 80% underwent a prior nephrectomy, and 41% had received no prior systemic therapy. Serious or life-threatening toxicity was experienced by 34%, with asthenia (15%) and neuropsychiatric difficulties (7%) being most common. At the randomization point, 51% of patients had progressed, 30% withdrew, 1% experienced a partial response, and 17% had stable disease and were randomly assigned. A Bayesian futility analysis utilizing the first 49 randomly assigned patients suggested that the probability of demonstrating a higher stable disease rate in the experimental group was less than 9% even under the most optimistic a priori assumptions, and further trial accrual was halted.
                CAI is inactive in RCC. The RDT design should be further explored for evaluating activity of putative disease stabilizing agents. Angiotensin-converting enzyme (ACE) inhibitors and AT1-receptor antagonists (ARAs) are widely administered to reduce urinary protein loss and slow the progression of proteinuric nephropathy to end-stage renal failure. Our group recently observed that the combination of ACE inhibitors and ARAs may have an additive antiproteinuric effect, which may occur because ACE inhibitors do not completely reduce angiotensin II (Ang II) production. Ang II is also produced by chymase. Thus, combination therapy better antagonizes the effects of Ang II. The purpose of this study is to ascertain whether the additive antiproteinuric effect of ACE inhibitors plus ARAs is dose dependent and related to the drug-induced reduction in systemic blood pressure. Therefore, enalapril (E; 10 mg/d) and losartan (LOS; 50 mg/d) were randomly administered alone and then in association; initial dosages were doubled when drugs were administered alone and in association. To determine the influence of the drug-dependent effect on reducing blood pressure and the reduction in urinary proteinuria, both ambulatory and office blood pressures were recorded. E and LOS administered alone reduced proteinuria by the same extent; no further reduction was observed when E and LOS alone were administered at a doubled dose. When E and LOS were coadministered, proteinuria decreased by a greater extent compared with E and LOS alone; an additional reduction in proteinuria was observed when combined therapy doses were doubled. The reduction in proteinuria was not correlated with clinical through blood pressure; however, reductions in diastolic and mean ambulatory blood pressures significantly correlated with the decrease in proteinuria, as well as with creatinine clearance. In conclusion, this study shows that combination therapy with E and LOS has an additive dose-dependent antiproteinuric effect that is likely induced by the drug-related reduction in systemic blood pressure. In normotensive proteinuric patients, it is likely that even a small reduction in systemic blood pressure may affect intraglomerular hemodynamics by a great extent because efferent arteriole regulation is hampered more completely by the coadministration of ACE inhibitors and ARAs. To determine whether an angiotensin-converting enzyme (ACE) inhibitor, enalapril, prevents cardiac function deterioration (defined using maximal cardiac index [MCI] on exercise testing or increase in left ventricular end-systolic wall stress [LVESWS]) in long-term survivors of pediatric cancer.
                This was a randomized, double-blind, controlled clinical trial comparing enalapril to placebo in 135 long-term survivors of pediatric cancer who had at least one cardiac abnormality identified at any time after anthracycline exposure.
                There was no difference in the rate of change in MCI per year between enalapril and placebo groups (0.30 v 0.18 L/min/m(2); P =.55). However, during the first year of treatment, the rate of change in LVESWS was greater in the enalapril group than in the placebo group (-8.59 v 1.85 g/cm(2); P =.033) and this difference was maintained over the study period, resulting in a 9% reduction in estimated LVESWS by year 5 in the enalapril group. Six of seven patients removed from random assignment to treatment because of cardiac deterioration were initially treated with placebo (P =.11), and one has died as a result of heart failure. Side effects from enalapril included dizziness or hypotension (22% v 3% in the placebo group; P =.0003) and fatigue (10% v 0%; P =.013).
                Enalapril treatment did not influence exercise performance, but did reduce LVESWS in the first year; this reduction was maintained over the study period. Any theoretical benefits of LVESWS reduction in this anthracycline-exposed population must be weighed against potential side effects from ACE inhibitors when making treatment decisions. Angiotensin-converting-enzyme (ACE) inhibitors improve outcome of patients with chronic heart failure (CHF). A substantial proportion of patients, however, experience no benefit from ACE inhibitors because of previous intolerance. We aimed to find out whether candesartan, an angiotensin-receptor blocker, could improve outcome in such patients not taking an ACE inhibitor.
                Between March, 1999, and March, 2001, we enrolled 2028 patients with symptomatic heart failure and left-ventricular ejection fraction 40% or less who were not receiving ACE inhibitors because of previous intolerance. Patients were randomly assigned candesartan (target dose 32 mg once daily) or matching placebo. The primary outcome of the study was the composite of cardiovascular death or hospital admission for CHF. Analysis was by intention to treat.
                The most common manifestation of ACE-inhibitor intolerance was cough (72%), followed by symptomatic hypotension (13%) and renal dysfunction (12%). During a median follow-up of 33.7 months, 334 (33%) of 1013 patients in the candesartan group and 406 (40%) of 1015 in the placebo group had cardiovascular death or hospital admission for CHF (unadjusted hazard ratio 0.77 [95% CI 0.67-0.89], p=0.0004; covariate adjusted 0.70 [0.60-0.81], p<0.0001). Each component of the primary outcome was reduced, as was the total number of hospital admissions for CHF. Study-drug discontinuation rates were similar in the candesartan (30%) and placebo (29%) groups.
                Candesartan was generally well tolerated and reduced cardiovascular mortality and morbidity in patients with symptomatic chronic heart failure and intolerance to ACE inhibitors. We report the results of a prospectively randomized study that compared the combination of epirubicin, cisplatin, and protracted venous infusion fluorouracil (5-FU) (ECF regimen) with the standard combination of 5-FU, doxorubicin, and methotrexate (FAMTX) in previously untreated patients with advanced esophagogastric cancer.
                Two hundred seventy-four patients with adenocarcinoma or undifferentiated carcinoma were randomized and analyzed for survival, tumor response, toxicity, and quality of life (QL).
                The overall response rate was 45% (95% confidence interval [CI], 36% to 54%) with ECF and 21% (95% CI, 13% to 29%) with FAMTX (P = .0002). Toxicity was tolerable and there were only three toxic deaths. The FAMTX regimen caused more hematologic toxicity and serious infections, but ECF caused more emesis and alopecia. The median survival duration was 8.9 months with ECF and 5.7 months with FAMTX (P = .0009); at 1 year, 36% (95% CI, 27% to 45%) of ECF and 21% (95% CI, 14% to 29%) of FAMTX patients were alive. The median failure-free survival duration was 7.4 months with ECF and 3.4 months with FAMTX (P = .00006). The global QL scores were better for ECF at 24 weeks, but the remaining QL data showed no differences between either arm of the study. Hospital-based cost analysis on a subset of patients was similar for each arm and translated into an increment cost of $975 per life-year gained.
                The ECF regimen results in a survival and response advantage, tolerable toxicity, better QL and cost-effectiveness compared with FAMTX chemotherapy. This regimen should now be considered the standard treatment for advanced esophagogastric cancer. Treatment of mild cognitive impairment (MCI) with cholinesterase inhibitors may improve symptoms.
                In this multicenter, randomized, placebo-controlled trial, subjects with MCI entered a 3-week placebo run-in period followed by 48 weeks of double-blind donepezil (5 mg/day for 6 weeks, then 10 mg/day for 42 weeks) or placebo treatment. Primary efficacy variables included change from baseline in the modified Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-Cog) and Clinical Dementia Rating Scale-sum of boxes (CDR-SB) after 48 weeks of treatment (modified intention-to-treat analysis). Secondary efficacy measures evaluated cognition, behavior, and function.
                The dual primary efficacy endpoint was not reached. We noted a small, but significant, decrease in modified ADAS-Cog scores in favor of donepezil at study endpoint. Little change from baseline in CDR-SB and secondary variables was observed for either group. Patient Global Assessment scores favored donepezil at all time points except week 12 (p < or = 0.05). Perceived Deficits Questionnaire scores favored donepezil at week 24 (p = 0.05). Clinical Global Impression of Change-MCI scores favored donepezil only at week 6 (p = 0.04). Adverse events were generally mild or moderate. More donepezil-treated subjects (18.4%) discontinued treatment due to adverse events than placebo-treated subjects (8.3%).
                Donepezil demonstrated small but significant improvement on the primary measure of cognition but there was no change on the primary measure of global function. Most other measures of global impairment, cognition, and function were not improved, possibly because these measures are insensitive to change in MCI. Responses on subjective measures suggest subjects perceived benefits with donepezil treatment. To determine if long-term topiramate therapy is safe and slows disease progression in patients with ALS.
                A double-blind, placebo-controlled, multicenter randomized clinical trial was conducted. Participants with ALS (n = 296) were randomized (2:1) to receive topiramate (maximum tolerated dose up to 800 mg/day) or placebo for 12 months. The primary outcome measure was the rate of change in upper extremity motor function as measured by the maximum voluntary isometric contraction (MVIC) strength of eight arm muscle groups. Secondary endpoints included safety and the rate of decline of forced vital capacity (FVC), grip strength, ALS functional rating scale (ALSFRS), and survival.
                Patients treated with topiramate showed a faster decrease in arm strength (33.3%) during 12 months (0.0997 vs 0.0748 unit decline/month, p = 0.012). Topiramate did not significantly alter the decline in FVC and ALSFRS or affect survival. Topiramate was associated with an increased frequency of anorexia, depression, diarrhea, ecchymosis, nausea, kidney calculus, paresthesia, taste perversion, thinking abnormalities, weight loss, and abnormal blood clotting (pulmonary embolism and deep venous thrombosis).
                At the dose studied, topiramate did not have a beneficial effect for patients with ALS. High-dose topiramate treatment was associated with a faster rate of decline in muscle strength as measured by MVIC and with an increased risk for several adverse events in patients with ALS. Given the lack of efficacy and large number of adverse effects, further studies of topiramate at a dose of 800 mg or maximum tolerated dose up to 800 mg/day are not warranted. Survival benefit from hepatic artery embolization (HAE) or hepatic arterial infusion chemotherapy (HAI) in patients with unresectable colorectal liver metastases has not previously been assessed in a randomized controlled trial. Sixty-one patients were randomized, 20 to receive no treatment, 22 to receive HAE, and 19 to receive HAI with 5-fluorouracil and degradable starch microspheres. Both treatments were acceptable to the patients in terms of low treatment morbidity rate. Median survival from diagnosis of metastases was 9.6 months for controls, 8.7 months for the HAE group and 13.0 months in the HAI group. There was no apparent survival benefit for the HAE group. The increased survival in the HAI group was observed in all the subgroups analysed but failed to reach statistical significance. The greatest observed benefit was achieved in the subgroup with less than 50 per cent hepatic replacement with tumour at presentation (median survival from diagnosis 10.0 months for controls, 10.2 months for HAE and 23.6 months for HAI); 36 per cent of patients developed extrahepatic disease recurrence. No significant benefit has been shown from either HAE or HAI, but a more carefully selected group of patients with only low volume hepatic disease may benefit from HAI therapy. Mild cognitive impairment (MCI) is etiologically heterogeneous, and a substantial proportion of MCI subjects will develop different dementia disorders. One subtype of this syndrome, amnestic MCI, occurs preferentially but not exclusively in prodromal AD and is characterized by defined deficits of episodic memory.
                For a 2-year, double-blinded, placebo-controlled study MCI patients, presenting with an amnestic syndrome but not necessarily based on presumed prodromal AD were randomized.
                Patients received (a) a combination of 16 mg galantamine plus 20 mg memantine, or (b) 16 mg galantamine alone or (c) placebo.
                The primary objective was to explore the differential impact of these interventions on the progression to dementia and on cognitive changes as measured by the ADAScog.
                After recruitment of 232 subjects, the trial was halted before reaching the planned sample size, because safety concerns arose in other studies with galantamine in MCI. This resulted in a variable treatment duration of 2-52 weeks. The statistical analysis plan was amended for studying cognitive effects of discontinuing the study medication, which was done separately for galantamine and memantine, and under double-blind conditions. There was one death, no unexpected severe adverse events, and no differences of severe adverse events between the treatment arms. The cognitive changes on the ADAScog were not different among the groups. Only for the subgroup of amnestic MCI with presumed AD etiology, a significant improvement of ADAScog score over placebo before the discontinuation of medication was observed, while amnestic MCI presumably due to other etiologies showed no cognitive changes with broad variation. Cognitive improvement was numerically larger in the combination treatment group than under galantamine alone. Patients who received placebo declined as expected. Discontinuation of galantamine, either as part of the combination regimen or as mono treatment, resulted in a transient decline of the ADAScog score in amnestic MCI of presumed AD etiology, while discontinuation of Memantine did not change the cognitive status.
                In an interrupted trial with amnestic MCI subjects the combination of galantamine plus memantine were generally well tolerated. In the subgroup of MCI subjects with presumed AD etiology, a cognitive benefit of a short-term combination treatment of galantamine plus memantine was observed, and cognitive decline occurred after discontinuation of galantamine. A multicentric randomized study that compared patients who received intrahepatic arterial infusion (HAI) to a group of patients who did not receive HAI (control group) was performed for unresectable hepatic metastases from primary colorectal carcinoma.
                One hundred sixty-six patients were assigned randomly to HAI of floxuridine (5 fluoro-2'deoxyuridine [FUDR]) 0.3 mg/kg/d for 14 days every 4 weeks or to the control group; this latter group, depending on the investigator's choice, was either under observation or received systemic fluorouracil (5-FU). The same regimen of systemic 5-FU also was administered to the HAI group in the event of extrahepatic progression. No crossover from the control group to the HAI group was permitted. The mean duration of follow-up was 54 months (range, 31 to 72), and 163 patients were analyzed.
                A significant improvement was observed in the survival rate for the 81 patients assigned to HAI group (P less than .02) with a 1-year survival rate of 64% versus 44% in the control group (82 patients). The 2-year survival rate was 23% versus 13%. The median survival was 15 months versus 11 months for the HAI group and the control group, respectively. Survival was better for patients with a less than 30% liver involvement, and for those treated in more specialized centers. The hepatotoxic effects of HAI were observed in 47 patients (chemical hepatitis [n = 28], and biliary sclerosis [n = 19]). The 1-year rate of sclerosing cholangitis was equal to 25%. Gastrointestinal toxicity was infrequent and consisted of gastritis or diarrhea.
                Therapy with HAI of FUDR improves the survival of patients with liver metastases over colorectal carcinoma. However, the methods that are used to diminish the toxicity of HAI and efficient systemic chemotherapy, such as a combination of 5-FU and leucovorin, are required to prevent extrahepatic metastases. Many patients with congestive heart failure do not receive the benefits of angiotensin-converting enzyme (ACE) inhibitors because of intolerance. We sought to determine the tolerability of an angiotensin II receptor blocker, candesartan cilexetil, among patients considered intolerant of ACE inhibitors.
                Patients with CHF, left ventricular ejection fraction less than 35%, and history of discontinuing an ACE inhibitor because of intolerance underwent double-blind randomization in a 2:1 ratio to receive candesartan (n = 179) or a placebo (n = 91). The initial dosage of candesartan was 4 mg/d; the dosage was increased to 16 mg/d if the drug was tolerated. A history of intolerance of ACE inhibitor was attributed to cough (67% of patients), hypotension (15%), or renal dysfunction (11%).
                The study drug was continued for 12 weeks by 82.7% of patients who received candesartan versus 86.8% of patients who received the placebo. This 4.1% greater discontinuation rate with active therapy was not significant; the 95% confidence interval ranged from 4.8% more discontinuation with placebo to 13% more with candesartan. Titration to the 16-mg target dose was possible for 69% of patients who received candesartan versus 84% of those who received the placebo. Frequencies of death and morbidity were not significantly different between the candesartan and placebo groups (death 3.4% and 3.3%, worsening heart failure 8.4% and 13.2%, myocardial infarction 2.8% and 5.5%, all-cause hospitalization 12.8% and 18.7%, and death or hospitalization for heart failure 11.7% and 14.3%).
                Candesartan was well tolerated by this population. The effect of candesartan on major clinical end points, including death, remains to be determined. Despite the beneficial effects of blockade of the renin-angiotensin system in diabetic nephropathy (DN), albuminuria and progression of renal disease are not completely halted by these agents. Therefore, it is necessary to explore potential antiproteinuric and renoprotective effects of innovative therapeutic approaches. This study tested the hypothesis that the combination of pentoxifylline (PTF) with angiotensin II receptor blockers in normotensive patients with type 2 diabetes produces an additive antiproteinuric effect. Sixty-one patients with DN and residual albuminuria despite treatment with the recommended doses of ARB for >1 yr were randomly assigned to receive the addition of 1200 mg of PTF daily (n = 30) or to a control group (n = 31). Baseline characteristics were similar between groups, and correlation analysis showed a significant association between urinary albumin excretion (UAE) and urinary TNF-alpha (R = 0.53, P < 0.001). After 4 mo, albuminuria showed a significant decrease in patients who received PTF, from 900 mg/24 h (466 to 1542 mg/d) to 791 mg/24 h (309 to 1400 mg/d; P < 0.001), whereas no significant changes were observed in the control group: 920 mg/24 h (450 to 1489 mg/d) at baseline, and 900 mg/24 h (428 to 1800 mg/d) at the end of the study. The mean percentage variation of UAE in the treatment and control groups was -16.7 and 5.5%, respectively (between-group comparison, P < 0.001). This additive antiproteinuric effect was not dependent on changes in BP or metabolic control. However, both serum and urinary levels of TNF-alpha also decreased in patients who received PTF, from 6.4 pg/ml (2.1 to 9.7) and 16 pg/mg (8 to 29) at baseline to 4.6 pg/ml (0.4 to 9) and 14.2 pg/mg (3 to 26) at the end of the study, respectively (P < 0.01), without significant variations in control patients. Moreover, regression analysis at the end of the study showed a correlation between the change in UAE and the change in urinary TNF-alpha in patients who were treated with PTF (R = 0.49, P < 0.001). In conclusion, administration of PTF to patients who have type 2 diabetes and are under long-term treatment with an ARB produces a significant additive antiproteinuric effect associated with a reduction of urinary TNF-alpha excretion. To evaluate the efficacy and safety of the acetylcholinesterase inhibitor donepezil in a placebo-controlled trial in patients with mild cognitive impairment (MCI).
                A total of 270 patients with MCI were enrolled in a 24-week, multicenter, randomized, double-blind, placebo-controlled study. Patients were randomized to receive donepezil (n = 133; 5 mg/day for 42 days, followed by forced dose escalation to 10 mg/day) or placebo (n = 137). Primary efficacy measures were the New York University (NYU) Paragraph Delayed Recall test and the Alzheimer disease (AD) Cooperative Study Clinician's Global Impression of Change for MCI (ADCS CGIC-MCI). Secondary efficacy measures included the modified AD Assessment Scale-cognitive subscale (ADAS-cog), the Patient Global Assessment (PGA), and additional neuropsychologic measures. Efficacy analyses were performed on intent-to-treat (ITT) and fully evaluable (FE) populations.
                Primary efficacy measures of the NYU Paragraph Recall test and the ADCS CGIC-MCI did not show significant treatment effects in the ITT population. Some secondary measures showed effects favoring donepezil. More donepezil-treated patients showed improvements in ADAS-cog total scores, in tests of attention and psychomotor speed, and in PGA scores. More donepezil-treated than placebo-treated patients experienced adverse events, most of which were mild to moderate and transient.
                Although significant treatment effects were not seen in the primary efficacy measures, outcomes on secondary measures suggest promising directions for further evaluation of donepezil treatment in patients with MCI. A combination of docetaxel and fluorouracil (DF) was evaluated in an outpatient setting and compared with epirubicin, cisplatin, and fluorouracil (ECF), which served as an internal control arm to avoid selection bias.
                Patients with metastatic or locally advanced gastric adenocarcinoma without prior chemotherapy were randomly assigned to receive either ECF (epirubicin 50 mg/m(2) day 1, cisplatin 60 mg/m(2) day 1, and fluorouracil 200 mg/m(2) days 1 through 21, every 3 weeks) or DF (docetaxel 75 mg/m(2) day 1, and fluorouracil 200 mg/m(2) days 1 through 21, every 3 weeks).
                Ninety patients were randomly assigned. Toxicity was rarely severe. Major toxic effects included diarrhea, stomatitis, and leukopenia in the DF arm and nausea, vomiting, and leukopenia in the ECF arm. Forty-three of 45 patients in each arm were assessable. In the DF arm, two patients (4.4%, intent to treat) experienced a confirmed complete tumor remission as best response, and 15 patients (33.3%) experienced a confirmed partial remission (overall response rate [ORR], 37.8%; 95% CI, 25.9% to 51.9%). Two patients (4.4%) in the ECF arm showed confirmed complete remission, and 14 (31.1%) showed confirmed partial remission (ORR, 35.6%; 95% CI, 24.8% to 48.7%). For the DF and ECF arms, the median survival was 9.5 and 9.7 months, and the median time to tumor progression 5.5 and 5.3 months, respectively.
                DF can be safely given in an ambulant setting. Compared with ECF, the dual combination of DF shows promising efficacy and may be an alternative treatment option that avoids cisplatin. Persistent activation of the renin-angiotensin-aldosterone-system (RAAS) is known to occur in patients with chronic heart failure (CHF) despite treatment with angiotensin-converting enzyme inhibitor (ACE) therapy. When added to ACE inhibitors, angiotensin II type 1 (AT1) antagonists may allow more complete blockade of the RAAS and preserve the beneficial effects of bradykinin accumulation not seen with AT1 receptor blockade alone.
                Thirty-six patients with stable New York Heart Association class II-IV CHF receiving ACE inhibitor therapy were randomly assigned in a double-blind manner to receive either eprosartan, a specific competitive AT1 receptor antagonist (400 to 800 mg daily, n = 18) or placebo (n = 18) for 8 weeks. The primary outcome measure was left ventricular ejection fraction (LVEF) as measured by radionuclide ventriculography, and secondary measures were central hemodynamics assessed by Swan-Ganz catheterization and neurohormonal effects.
                There was no change in LVEF with eprosartan therapy (mean relative LVEF percentage change [SEM] +10.5% [9.3] vs +10.1% [5.0], respectively; difference, 0.4; 95% confidence interval [CI], -20.8 to 21.7; P =.97). Eprosartan was associated with a significant reduction in diastolic blood pressure and a trend toward a reduction in systolic blood pressure compared with placebo (-7.3 mm Hg [95% CI, -14.2 to -0.4] diastolic; -8.9 mm Hg [95% CI, -18.6 to 0.8] systolic). No significant change in heart rate or central hemodynamics occurred during treatment with eprosartan compared with placebo. A trend toward an increase in plasma renin activity was noted with eprosartan therapy. Eprosartan was well tolerated, with an adverse event profile similar to placebo, whereas kidney function remained unchanged.
                When added to an ACE inhibitor, eprosartan reduced arterial pressure without increasing heart rate. There was no change in LVEF after 2 months of therapy with eprosartan. This study determines the long-term efficacy of the ACE inhibitor, enalapril, in reducing the progression of microalbuminuria to clinical albuminuria in normotensive patients with type 2 diabetes.
                There were 103 normotensive type 2 diabetic patients with persistent albumin excretion rate (AER) 20-200 micrograms/min and normal renal function followed for 5 years in a prospective randomized single-blind placebo-controlled trial. AER, blood pressure, fasting plasma glucose, and HbA1 were measured very 3-4 months and glomerular filtration rate (GFR), renal plasma flow (RPF), and urinary urea every 12 months.
                In the patients treated with enalapril, AER decreased from 55 +/- 33 to 20 +/- 59 micrograms/min (geometric mean +/- SD), whereas in the placebo group, AER increased from 53 +/- 31 to 85 +/- 90 micrograms/min after 5 years. Within 5 years, 7.7% (4/52) of enalapril-treated subjects and 23.5% (12/51) of placebo-treated subjects progressed to clinical albuminuria defined as AER > 200 micrograms/min and at least 34% above baseline (risk reduction = 66.7%, P < 0.001). AER increased at an annual rate of 12.3% (95% CI 9.8-14.9) in the placebo group, while it declined by 16.7% (95% CI -18.3 to -15.2) in the enalapril group (P < 0.001). In addition, 8 of the 12 placebo-treated patients had evidence of coronary artery disease. The rest of the parameters remained practically unchanged in the two groups.
                After 5 years of therapy with enalapril, compared with placebo, normotensive subjects with type 2 diabetes experienced significantly less progression of microalbuminuria to clinical albuminuria, reduced AER, and preserved GFR. Renal disease in people with insulin-dependent diabetes (IDDM) continues to pose a major health threat. Inhibitors of angiotensin-converting enzyme (ACE) slow the decline of renal function in advanced renal disease, but their effects at earlier stages are unclear, and the degree of albuminuria at which treatment should start is not known.
                We carried out a randomised, double-blind, placebo-controlled trial of the ACE inhibitor lisinopril in 530 men and women with IDDM aged 20-59 years with normoalbuminuria or microalbuminuria. Patients were recruited from 18 European centres, and were not on medication for hypertension. Resting blood pressure at entry was at least 75 and no more than 90 mm Hg diastolic, and no more than 155 mm Hg systolic. Urinary albumin excretion rate (AER) was centrally assessed by means of two overnight urine collections at baseline, 6, 12, 18, and 24 months.
                There were no difference in baseline characteristics by treatment group; mean AER was 8.0 micrograms/min in both groups; and prevalence of microalbuminuria was 13% and 17% in the placebo and lisinopril groups, respectively. On intention-to-treat analysis at 2 years, AER was 2.2 micrograms/min lower in the lisinopril than in the placebo group, a percentage difference of 18.8% (95% CI 2.0-32.7, p = 0.03), adjusted for baseline AER and centre, absolute difference 2.2 micrograms/min. In people with normoalbuminuria, the treatment difference was 1.0 microgram/min (12.7% [-2.9 to 26.0], p = 0.1). In those with microalbuminuria, however, the treatment difference was 34.2 micrograms/min (49.7% [-14.5 to 77.9], p = 0.1; for interaction, p = 0.04). For patients who completed 24 months on the trial, the final treatment difference in AER was 38.5 micrograms/min in those with microalbuminuria at baseline (p = 0.001), and 0.23 microgram/min in those with normoalbuminuria at baseline (p = 0.6). There was no treatment difference in hypoglycaemic events or in metabolic control as assessed by glycated haemoglobin.
                Lisinopril slows the progression of renal disease in normotensive IDDM patients with little or no albuminuria, though greatest effect was in those with microalbuminuria (AER > or = 20 micrograms/min). Our results show that lisinopril does not increase the risk of hypoglycaemic events in IDDM. Clinical studies of heart failure utilizing losartan, an angiotensin-II receptor antagonist, found that this drug is well tolerated and demonstrates hemodynamic, neurohormonal, and symptomatic improvement. To assess all-cause mortality in heart failure patients treated with losartan, a meta-analysis including 1,896 patients was performed on 6 controlled, double-blind, multiple-dose studies, regardless of sample size or duration of follow-up. A combination of logarithmic (log) odds ratios with a continuity correction was utilized for the meta-analysis. Treatment groups were comparable with regard to demographic characteristics, heart failure characteristics, and concomitant cardiovascular therapies. Concomitant use of open-label angiotensin-converting enzyme (ACE) inhibitors was not allowed in any study. The mean left ventricular ejection fraction obtained in individual studies ranged from 23% to 31%. Seven hundred forty patients were randomized to control therapy and 1,154 patients were randomized to losartan therapy. There were 36 deaths (3.12%) in the losartan groups compared with 47 in the control groups (6.35%) during the double-blind periods. The odds of dying in the losartan groups were 0.51 times (0.31 to 0.81) that of dying in the control groups (p = 0.004). In this analysis, treatment with losartan provided a beneficial effect upon survival. However, because the number of deaths in these studies is relatively small and the follow-up relatively short, a large confirmatory study is needed to assess the mortality benefit of losartan compared with an ACE inhibitor. Incomplete suppression of the renin-angiotensin system during long-term ACE inhibition may contribute to symptomatic deterioration in patients with severe congestive heart failure (CHF). Combined angiotensin II type I (AT1) receptor blockade and ACE inhibition more completely suppresses the activated renin-angiotensin system than either intervention alone in sodium-depleted normal individuals. Whether AT1 receptor blockade with losartan improves exercise capacity in patients with severe CHF already treated with ACE inhibitors is unknown.
                Thirty-three patients with severe CHF despite treatment with maximally recommended or tolerated doses of ACE inhibitors were randomized 1:1 to receive 50 mg/d losartan or placebo for 6 months in addition to standard therapy in a multicenter, double-blind trial. Peak aerobic capacity (V(O2)) during symptom-limited treadmill exercise and NYHA functional class were determined at baseline and after 3 and 6 months of double-blind therapy. Peak V(O2) at baseline and after 3 and 6 months were 13.5+/-0.6, 15.1+/-1.0, and 15.7+/-1.1 mL. kg-1. min-1, respectively, in patients receiving losartan and 14.1+/-0.6, 14.3+/-0.9, and 13.6+/-1.1 mL. kg-1. min-1, respectively, in patients receiving placebo (P<0.02 for treatment group-by-time interaction). Functional class improved by at least one NYHA class in 9 of 16 patients receiving losartan and 1 of 17 patients receiving placebo.
                Losartan enhances peak exercise capacity and alleviates symptoms in patients with CHF who are severely symptomatic despite treatment with maximally recommended or tolerated doses of ACE inhibitors. Atrial fibrillation (AF) frequently occurs after cardiac surgical procedures, and beta-blockers, sotalol, and amiodarone may reduce the frequency of AF after open heart surgery. This pilot trial was designed to test whether each of the active oral drug regimens is superior to placebo for prevention of postoperative AF and whether there are differences in favor of 1 of the preventive strategies.
                We conducted a randomized, double-blinded, placebo-controlled trial in which patients undergoing cardiac surgery in the absence of heart failure and without significant left ventricular dysfunction (n = 253; average age, 65 +/- 11 years) received oral amiodarone plus metoprolol (n = 63), metoprolol alone (n = 62), sotalol (n = 63), or placebo (n = 65). Patients receiving combination therapy (amiodarone plus metoprolol) and those receiving sotalol had a significantly lower frequency of AF (30.2% and 31.7%; absolute difference, 23.6% and 22.1%; odds ratios [OR], 0.37 [95% CI, 0.18 to 0.77, P <.01 vs placebo] and 0.40 [0.19 to 0.82, P =.01 vs placebo]) compared with patients receiving placebo (53.8%). Treatment with metoprolol was associated with a 13.5% absolute reduction of AF (P =.16; OR, 0.58 [0.29 to 1.17]. Treatment effects did not differ significantly between active drug groups. Adverse events including cerebrovascular accident, postoperative ventricular tachycardia, nausea, and dyspepsia, in hospital death, postoperative infections, and hypotension, were similar among the groups. Bradycardia necessitating dose reduction or drug withdrawal occurred in 3.1% (placebo), 3.2% (combined amiodarone and metoprolol; P =.65 vs placebo), 12.7% (sotalol; P <.05 vs placebo), and 16.1% (metoprolol; P <.05 vs placebo). Patients in the placebo group had a nonsignificantly longer length of hospital stay as compared with the active treatment groups (13.1 +/- 8.9 days vs 11.3 +/- 7; P =.10), with no significant difference between the active treatment groups.
                Oral active prophylaxis with either sotalol or amiodarone plus metoprolol may reduce the rate of AF after cardiac surgery in a population at high risk for postoperative AF. Treatment with metoprolol alone resulted in a trend to a lower risk for postoperative AF. Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients.
                In hypertensive type 2 diabetic patients, treatment with angiotensin-converting enzyme (ACE) inhibitors is associated with a lower incidence of cardiovascular events than those treated with calcium channel-blocking agents. However, the long-term renal effects of ACE inhibitors in these patients remain inconclusive. In 1989, we commenced a placebo-controlled, double-blind, randomized study to examine the anti-albuminuric effects of enalapril versus nifedipine (slow release) in 102 hypertensive, type 2 diabetic patients. These patients have been followed up for a mean trial duration of 5.5 +/- 2.2 years. We examined the determinants, including the effect of ACE inhibition on clinical outcomes in these patients.
                After a six-week placebo-controlled, run-in period, 52 patients were randomized double-blind to receive nifedipine (slow release) and 50 patients to receive enalapril. After the one-year analysis, which confirmed the superior anti-albuminuric effects of enalapril (-54%) over nifedipine (+11%), all patients were continued on their previously assigned treatment with informed consent. They were subdivided into normoalbuminuric (N = 43), microalbuminuric (N = 34), and macroalbuminuric (N = 25) groups based on two of three 24-hour urinary albumin excretion (UAE) measurements during the run-in period. Renal function was shown by the 24-hour UAE, creatinine clearance (CCr), and the regression coefficient of the yearly plasma creatinine reciprocal (beta-1/Cr). Clinical endpoints were defined as death, cardiovascular events, and/or renal events (need for renal replacement therapy or doubling of baseline plasma creatinine).
                In the whole group, patients treated with enalapril were more likely to revert to being normoalbuminuric (23.8 vs. 15.4%), and fewer of them developed macroalbuminuria (19.1 vs. 30.8%) compared with the nifedipine-treated patients (P < 0.05). In the microalbuminuric group, treatment with enalapril (N = 21) was associated with a 13.0% (P < 0.01) reduction in 24-hour UAE compared with a 17.3% increase in the nifedipine group (N = 13). In the macroalbuminuric patients, enalapril treatment (N = 11) was associated with stabilization compared with a decline in renal function in the nifedipine group, as shown by the beta-1/Cr (0.65 +/- 4.29 vs. -1.93 +/- 2.35 1/micromol x 10-3, P < 0.05) after adjustment for baseline values. Compared with the normoalbuminuric and microalbuminuric patients, those with macroalbuminuria had the lowest mean CCr (75.5 +/- 24.1 vs. 63.5 +/- 21.3 vs. 41.9 +/- 18.5 mL/min, P < 0.001) and the highest frequency of clinical events (4.7 vs. 5.9 vs. 52%, P < 0. 001). On multivariate analysis, beta-1/Cr (R2 = 0.195, P < 0.001) was independently associated with baseline HbA1c (beta = -0.285, P = 0.004), whereas clinical outcomes (R2 = 0.176, P < 0.001) were independently related to the mean low-density lipoprotein cholesterol (beta = 2.426, P = 0.018), high-density lipoprotein cholesterol (beta = -8.797, P = 0.03), baseline UAE (beta = 0.002, P = 0.04), and mean CCr during treatment (beta = -0.211, P = 0.006).
                In this prospective cohort analysis involving 102 hypertensive, type 2 diabetic patients with varying degrees of albuminuria followed up for a mean duration of five years, we observed the importance of good metabolic and blood pressure control on the progression of albuminuria and renal function. Treatment with enalapril was associated with a greater reduction in albuminuria than with nifedipine in the entire patient group, and especially in those with microalbuminuria. In the macroalbuminuric patients, the rate of deterioration in renal function was also attenuated by treatment with enalapril. To compare adjuvant dose-intensive epirubicin and cyclophosphamide chemotherapy administered with filgrastim and progenitor cell support (DI-EC) with standard-dose anthracycline-based chemotherapy (SD-CT) for patients with early-stage breast cancer and a high risk of relapse, defined as stage II disease with 10 or more positive axillary nodes; or an estrogen receptor-negative or stage III tumor with five or more positive axillary nodes.
                Three hundred forty-four patients were randomized after surgery to receive seven cycles of SD-CT over 22 weeks, or three cycles of DI-EC (epirubicin 200 mg/m2 plus cyclophosphamide 4 gm/m2 with filgrastim and progenitor cell support) over 6 weeks. All patients were assigned tamoxifen at the completion of chemotherapy. The primary end point was disease-free survival (DFS).
                After a median follow-up of 5.8 years (range, 3 to 8.4 years), 188 DFS events had occurred (DI-EC, 86 events; SD-CT, 102 events). The 5-year DFS was 52% for DI-EC and 43% for SD-CT, with hazard ratio of DI-EC compared with SD-CT of 0.77 (95% CI, 0.58 to 1.02; P = .07). The 5-year overall survival was 70% for DI-EC and 61% for SD-CT, with a hazard ratio of 0.79 (95% CI, 0.56 to 1.11; P = .17). There were eight cases (5%) of anthracycline-induced cardiomyopathy (two fatal) among those who received DI-EC. Women with hormone receptor-positive tumors benefited significantly from DI-EC.
                There was a trend in favor of DI-EC with respect to disease-free survival. A larger trial or meta-analysis will be required to reveal the true effect of dose-intensive therapy. To evaluate the effectiveness of one course of prophylactic actinomycin D in reducing the malignant sequelae requiring chemotherapy in high-risk complete hydatidiform mole (CHM).
                A double-blind, randomized, controlled clinical trial was carried out at King Chulalongkorn Memorial Hospital. Sixty cases of CHM classified as high risk were recruited and randomly allocated to a chemoprophylactic or control group. Within one week after evacuation of molar tissues, actinomycin D was administered in the chemoprophylactic group. Patients in the control group were given only intravenous fluid and analgesic drugs. The number of patients with malignant sequelae who required therapeutic chemotherapy after evacuation of hydatidiform mole in each group was recorded.
                The incidence of malignant sequelae was 13.8% (95% confidence interval [CI] = 3.9-31.7%) in the chemoprophylactic group and 50.0% (95% CI = 31.3-68.7%) in the control group. The risk reduction of malignant sequelae with one course of actinomycin D chemoprophylaxis in high-risk CHM was 72.4% (95% CI = 26.7-89.6%) (P = .005). The side effects of prophylactic chemotherapy were stomatitis, nausea/vomiting, sore throat with oral ulcer and hair loss.
                One course of actinomycin D given as chemoprophylaxis decreased by 72.4% malignant sequelae after evacuation of molar tissue in patients with high-risk CHM. This may be particularly beneficial in patients with high-risk CHM who cannot be followed closely, whose compliance is in question and for whom hormonal follow-up is not available or unreliable. Evidence is available from animal and human studies that protein traffic through the glomerular capillary has a pathogenetic role in subsequent renal damage and that angiotensin-converting enzyme (ACE) inhibitors appear superior to other drugs in lowering proteinuria and the rate of renal function decline. This study compares the effect of ACE inhibition or angiotensin II (AngII) receptor blockade on urinary protein excretion and renal hemodynamics in 20 patients with IgA glomerulonephritis randomized to receive enalapril (20 mg/d) or irbesartan (100 mg/d) for 28 d in a double-blind study with two parallel groups. This study also evaluated whether addition of indomethacin (75 mg twice a day) to each of the two treatments resulted in a more potent antiproteinuric effect. Enalapril alone reduced total protein excretion (61% change from baseline) and fractional clearance of albumin without changes in GFR and minor elevation in renal plasma flow. Also, patients randomized to receive the AngII receptor antagonist irbesartan for 28 d had lower proteinuria (55% change from baseline) and fractional clearance of albumin at the end of the treatment period with similar renal hemodynamic changes. When indomethacin was added to enalapril treatment, a further significant reduction in urinary proteins and fractional albumin clearance was observed. In patients given irbesartan, the addition of indomethacin further reduced proteinuria and fractional clearance of albumin. The combined therapy with enalapril or irbesartan and indomethacin did not significantly affect GFR and renal plasma flow compared with baseline. These findings indicate that in patients with IgA glomerulonephritis the antiproteinuric effect of blocking AngII activity by either ACE inhibitors or AngII receptor antagonists is potentiated by indomethacin, an effect that occurred without impairment of renal function. Most hypertensive renal transplant recipients require two or more antihypertensive medications to achieve blood pressure control. However, which medications must be combined is still a matter of debate.
                A prospective randomized open-label blinded evaluation trial comparing the six-month effects of the amlodipine-enalapril combination (n = 32) vs. enalapril alone (n = 33) and vs. amlodipine alone (n = 34) on arterial pressure, renal function, albuminuria and tolerability.
                At six months, diastolic arterial pressure was more adequately controlled (i.e., <90 mmHg) in the combination group than in the amlodipine and enalapril groups (100% vs. 82.4% and 84.8%, respectively, p = 0.038). The same trend was observed for systolic arterial pressure (65.6% vs. 58.8% and 51.5%, NS). The six-month change in albuminuria was similar in the combination group and in the enalapril group (-64.7% vs. -59.5%); however, patients in the combination group exhibited a greater reduction in albuminuria than in the amlodipine group (-64.7% vs. -29.0%, p = 0.002). As compared with baseline values, serum creatinine and potassium remained unchanged in the combination group, whereas they increased by 9 +/- 12 micromol/L (p = 0.01) and by 0.2 +/- 0.4 mmol/L (p < 0.01), respectively, in the enalapril group. The cyclosporine trough levels remained unchanged in the combination group, but increased in the amlodipine group.
                Angiotensin-converting enzyme inhibitor (ACEI)-calcium-channel blocker (CCB) combination controls arterial pressure more adequately than ACEI alone or CCB alone, reduces albuminuria and may prevent the ACEI-induced initial rise in serum creatinine. Mild and moderate chronic kidney disease (CKD) is associated with decreased survival and increased adverse events after a percutaneous coronary intervention (PCI). Therapy with clopidogrel decreases adverse events in large patient populations. Therefore, we sought to determine the efficacy and safety of long-term clopidogrel therapy in patients with CKD.
                Two thousand two patients from the CREDO trial in whom an elective PCI of a single or multiple vessels was planned were analyzed. Patients were randomly assigned to a 300-mg loading dose of clopidogrel before PCI followed by clopidogrel 75 mg/d for a year versus a placebo loading dose at the time of the PCI procedure and clopidogrel 75 mg/d for 28 days and placebo for the remainder of a year. Patients were categorized by their estimated creatinine clearance (>90 [normal, n = 999], 60-89 [mild CKD, n = 672], <60 mL/min [moderate CKD, n = 331]).
                Diminished renal function was associated with worse outcomes. Patients with normal renal function who received 1 year of clopidogrel had a marked reduction in death, myocardial infarction, or stroke compared with those who received placebo (10.4% vs 4.4%, P < .001), whereas patients with mild and moderate CKD did not have a significant difference in outcomes with clopidogrel therapy versus placebo (mild: 12.8% vs 10.3%, P = .30; moderate: 13.1% vs 17.8%, P = .24). Clopidogrel use was associated with an increased relative risk of major or minor bleeding, but this increased risk was not different based on renal function (relative risk 1.2, 1.3, 1.1).
                Clopidogrel in mild or moderate CKD patients may not have the same beneficial effect as it does in patients with normal renal function, but was not associated with a greater relative risk of bleeding based on renal function. Further studies are needed to define the role of clopidogrel therapy in patients with CKD. We compared the efficacy of treatment protocols with an angiotensin converting enzyme (ACE) inhibitor alone (enalapril, 5 mg) or angiotensin II (ATII) receptor blocker (losartan, 50 mg) or both enalapril plus losartan in patients with microalbuminuria in a prospective, randomized clinical trial. Normotensive type 2 diabetic patients with microalbuminuria documented by at least 3 consecutive urinary albumin excretion analyses were recruited for the study. Patients were grouped randomly into one of the protocols which consisted of treatment with 5 mg enalapril daily (group 1; n=12), 50 mg losartan daily (group 2; n=12) or both drugs (group 3; n=10). They were reevaluated with regard to HbA1c levels, lipid profiles, blood pressure and urinary albumin excretion rates (UAER) at 3-month intervals for 12 months. Mean age, duration of diabetes, body mass index, plasma lipid profiles and blood pressure levels were similar at the initial visit. In group 1, UAER returned to normal levels in 10 patients. Normalization of UAER occurred in 8 and 7 patients in groups 2 and 3, respectively. Percentage of reduction in UAERs at the end of 12 months were 58%, 59% and 60% (p=0.0001; p=0.0002; p=0.0003, respectively). The amount of reduction in UAER did not differ significantly among the three groups (p=0.346). ACE inhibitors and angiotensin II receptor blockers have similar efficacy in treating diabetic microalbuminuria, and the combination of the two drugs does not add any further benefit. The urinary podocyte is postulated to be a marker for estimation of the severity of active glomerular injury and a predictor of disease progression in children with glomerulonephritis. Non-dihydropyridine calcium antagonist, including verapamil, reduce proteinuria to an extent similar to that of the angiotensin-converting enzyme inhibitor (ACEI), including trandolapril, but to a greater extent than other antihypertensives. Angiotensin (Ang) II receptor antagonists, including candesartan cilexetil, show potent and long-term preventive effects against the progression of renal injury. The aim of the present study is to assess whether verapamil, trandolapril and candesartan cilexetil affect proteinuria and urinary podocytes in patients with IgA nephropathy. Thirty-two normotensive patients aged 18-54 years with biopsy-proven IgA nephropathy, nonnephrotic proteinuria (1-3 g/day), and normal renal function (creatinine clearance >80 ml/min) were studied. Twenty patients with diffuse mesangial proliferative glomerulonephritis (non-IgA PGN) and 20 healthy controls were also included in this study. The number of urinary podocytes in patients with advanced IgA nephropathy (n = 16) was significantly higher than that in patients with the disease in the mild stage (n = 16) (p < 0.01) or in patients with non-IgA PGN (p < 0.01). Urinary podocytes were not detected in healthy controls. The 32 patients with IgA nephropathy were randomly divided into four treatment groups: those treated with verapamil (120 mg/day, n = 8); those treated with trandolapril (2 mg/day, n = 8); those treated with candesartan cilexetil (8 mg/day, n = 8), and those given a placebo (n = 8). Treatment continued for 3 months. Antiproteinuric response in the trandolapril group was similar to that in the candesartan cilexetil group (-38 vs. -40%). The action of trandolapril or candesartan cilexetil was greater than that of verapamil (p < 0.01). Reduction in the number of urinary podocytes from baseline was significantly greater in patients treated with trandolapril or candesartan cilexetil than in patients treated with verapamil (p < 0.01). However, there was no difference between patients treated with trandolapril and those treated with candesartan cilexetil. Proteinuria and urinary podocytes were unaffected in the placebo group. These data suggest that urinary podocytes may be a marker of disease activity in adult patients with IgA nephropathy and that trandolapril and candesartan cilexetil are more effective than verapamil in reducing the number of podocytes.
                Copyright 2000 S. Karger AG, Basel The influence of antihypertensive treatment on the long-term evolution of arterial pressure and renal function was studied in a prospective controlled trial conducted in renal transplant recipients treated by cyclosporine. Within six months after transplantation, patients were randomly allocated to treatment by the angiotensin-converting enzyme inhibitor, lisinopril (ACEI, alone or associated with frusemide; N = 14), or the calcium antagonist, nifedipine (CA, alone or associated with atenolol; N = 11). Glomerular filtration rate (TcDTPA clearance) and effective renal plasma flow (hippuran clearance) as well as 24-hour urinary excretion of electrolytes and albumin were estimated at about 1 and 2.5 years of follow-up. Before initiation of antihypertensive therapy, the two groups were similar with regards to mean arterial pressure (119 +/- 2 vs. 120 +/- 4 mm Hg), effective renal plasma flow (285 +/- 26 vs. 248 +/- 33 ml/min/1.73 m2) and glomerular filtration rate (59 +/- 4 vs. 61 +/- 8 ml/min/1.73 m2 in the ACEI and CA groups, respectively). Both ACEI and CA treatments were associated with no change in renal function, a similar change in mean arterial pressure (ACEI -18 +/- 3; CA -13 +/- 5 mm Hg) and identical trough blood levels of cyclosporine. Urinary albumin excretion did not change significantly in any groups. Of interest, only in the ACEI group did filtration fraction significantly decrease (from 0.22 +/- 0.01% to 0.19 +/- 0.01% at final studies). These results indicate that in cyclosporine-treated transplant recipients, a satisfactory control of hypertension is obtained by chronic ACEI, which is as effective on arterial pressure as a combination of CA and atenolol.(ABSTRACT TRUNCATED AT 250 WORDS) To study whether administration of 1.25 and 5.0 mg ramipril daily, compared with placebo treatment, reduces the urinary albumin excretion rate (UAER) in normotensive patients with type 1 diabetes.
                Ramipril was administered double blind at two different doses (1.25 [n = 19] and 5.0 mg [n = 18]), and compared with placebo (n = 18) after a single-blind placebo period of 1-4 weeks. The patients (total, n = 55; women, n = 14) were followed for 2 years. To document an effect on the renin-angiotensin system, ACE activity and plasma-renin activity (PRA) were measured. In addition, 24-h ambulatory blood pressure (BP) was recorded at baseline and repeated after 1 and 2 years using a Spacelab 90207 ambulatory BP recording device (Spacelab, Redmont, CA).
                Both doses of ramipril were sufficient to reduce ACE activity and to increase PRA significantly as compared with placebo (P < 0.05 for both). On the other hand, neither ambulatory nor clinic BP was affected by either dose of ramipril compared with the placebo group. There was no progression of UAER in the placebo group during the 2 years of the study. Analysis of covariance showed no differences in UAER between the three treatment groups at year 1 (P = 0.94) or year 2 (P = 0.97), after adjusting for baseline. Furthermore, there were no statistically significant changes from baseline UAER within any of the three treatment groups.
                Treatment with ramipril did not affect microalbuminuria or clinic or ambulatory BP in this study. On the basis of the present study, we question the clinical use of ACE inhibitors in stably normotensive patients with type 1 diabetes and microalbuminuria in whom a concomitant reduction in BP is not demonstrated. This study was undertaken to test the hypothesis that, given equal arterial pressure reductions, the combination of an angiotensin converting enzyme (ACE) inhibitor and calcium antagonist slows declines in renal function and yields greater reductions in albuminuria over either agent alone. This hypothesis was evaluated in four groups of hypertensive, non-insulin dependent, diabetic subjects with renal insufficiency (N = 30). Renal hemodynamics, albuminuria and metabolic parameters were evaluated for a period of one year. Subjects were all placed on a 90 mEq sodium, 0.8 g/kg protein, 1500 calorie American Diabetes Association diet for the entire length of the study. Subjects were followed for two weeks off antihypertensive medications and were subsequently randomized to either lisinopril, alone (group I), sustained release verapamil, alone (group II), reduced doses of both lisinopril and sustained release verapamil (group III), and hydrochlorothiazide with guanfacine (group IV). At the end of one year group III had the greatest reduction in albuminuria (78 +/- 7%, group III vs. 59% +/- 4, group I: P less than 0.05). In addition, the decline in glomerular filtration rate (GFR) was the lowest in this group (0.28 +/- 0.07, group III vs. 0.69 +/- 0.12, group I; P less than 0.05) although there was no significant difference between groups II and IV. The highest side effect profiles were noted in group IV, the least in group III. The greatest reductions in renal hemodynamics occurred in all groups within the first month; however, striking differences between groups were noted (7.4 +/- 2%, group I vs. 1.4 +/- 2%, group III; P less than 0.05). We conclude that the combination of reduced doses of an ACE inhibitor and calcium antagonist attenuate both albuminuria and the rate of decline in glomerular filtration rate. Furthermore, the combination of these classes of agents appear to yield the lowest side effect profile over either agent alone. Lastly, high doses of ACE inhibition alone may be detrimental to renal function in late stage diabetics with renal insufficiency. Some retrospective studies have suggested a beneficial influence of angiotensin-converting enzyme (ACE) inhibitors on the progression of IgA nephropathy (IgAN), but prospective and controlled studies demonstrating this effect are lacking. Forty-four patients with biopsy-proven IgAN, proteinuria > or = 0.5 g/d, and serum creatinine (SCr) < or = 1.5 mg/dl were randomly assigned either to receive enalapril (n = 23) or to a control group (n = 21) in whom BP was controlled with antihypertensives other than ACE inhibitors. Primary outcome was renal survival estimated by a 50% increase in baseline SCr. Secondary outcomes were the presence of a SCr > 1.5 mg/dl at the last visit and the evolution of proteinuria. Baseline clinical findings were similar at baseline between enalapril-treated and control group, and there were no differences in BP control during follow-up. Mean follow-up was 78 +/- 37 mo in the enalapril group and 74 +/- 36 mo in the control group. Three patients (13%) in the enalapril group and 12 (57%) in the control group reached the primary end point (P < 0.05). Kaplan-Meier renal survival was significantly better in enalapril group than in control group: 100% versus 70% after 4 yr and 92% versus 55% after 7 yr (P < 0.05). Three patients in the enalapril group (13%) and 11 (52%) in the control group showed SCr > 1.5 mg/dl at the last visit (P < 0.05). Proteinuria significantly decreased in the enalapril group, whereas it tended to increase in the control group (P < 0.001 between groups). In conclusion, ACE inhibitors significantly improve renal survival in proteinuric IgAN with normal or moderately reduced renal function. Diabetic nephropathy is the leading cause of end-stage renal disease. Interruption of the renin-angiotensin system slows the progression of renal disease in patients with type 1 diabetes, but similar data are not available for patients with type 2, the most common form of diabetes. We assessed the role of the angiotensin-II-receptor antagonist losartan in patients with type 2 diabetes and nephropathy.
                A total of 1513 patients were enrolled in this randomized, double-blind study comparing losartan (50 to 100 mg once daily) with placebo, both taken in addition to conventional antihypertensive treatment (calcium-channel antagonists, diuretics, alpha-blockers, beta-blockers, and centrally acting agents), for a mean of 3.4 years. The primary outcome was the composite of a doubling of the base-line serum creatinine concentration, end-stage renal disease, or death. Secondary end points included a composite of morbidity and mortality from cardiovascular causes, proteinuria, and the rate of progression of renal disease.
                A total of 327 patients in the losartan group reached the primary end point, as compared with 359 in the placebo group (risk reduction, 16 percent; P=0.02). Losartan reduced the incidence of a doubling of the serum creatinine concentration (risk reduction, 25 percent; P=0.006) and end-stage renal disease (risk reduction, 28 percent; P=0.002) but had no effect on the rate of death. The benefit exceeded that attributable to changes in blood pressure. The composite of morbidity and mortality from cardiovascular causes was similar in the two groups, although the rate of first hospitalization for heart failure was significantly lower with losartan (risk reduction, 32 percent; P=0.005). The level of proteinuria declined by 35 percent with losartan (P<0.001 for the comparison with placebo).
                Losartan conferred significant renal benefits in patients with type 2 diabetes and nephropathy, and it was generally well tolerated. The angiotensin II (AT II) type I receptor antagonist losartan has been reported to increase urinary uric acid and potassium excretion. These effects might be beneficial in cyclosporin (CsA)-treated renal transplant recipients, who frequently suffer from hyperuricaemia and hyperkalaemia.
                In this prospective, open, randomized, two-way cross-over study we included 13 hypertensive CsA-treated patients after renal transplantation and administered either the angiotensin-converting enzyme (ACE) inhibitors enalapril or losartan. Laboratory parameters, 24-h urinary protein excretion, and mean 24-h arterial blood pressure (MAP) were checked after 3 weeks treatment with enalapril, after a wash-out period of 2 weeks, and before and after a 3-week treatment course with losartan.
                Both drugs slightly reduced MAP (losartan from 97+/-6 to 94+/-9 and enalapril to 93+/-8 mmHg). Serum potassium levels significantly increased during enalapril therapy (from 4.3+/-0.5 to 4.8+/-0.4 mmol/l, P<0.05), as did, although not significantly, uric acid concentrations (from 7.8+/-1.9 to 8.2+/-1.8 mg/dl, P=0.5). Losartan, on the contrary, only mildly affected serum potassium (4.3+/-0.5 vs 4.5+/-0.5 mmol/l, P=0.25) and serum uric acid decreased (from 7.8+/-2.4 to 7.3+/-1.8 mg/dl, P=0.6). Serum aldosterone and urinary aldosterone excretion were significantly reduced only during ACE inhibitor treatment, which might explain the variable effects on potassium homeostasis.
                Losartan may be a useful agent to reduce blood pressure and serum uric acid levels in renal transplant recipients treated with CSA: Furthermore, in this high-risk population, the effects on serum potassium levels are less marked with losartan than with enalapril. To evaluate if the timing of chest irradiation with respect to chemotherapy would influence survival and local and distant control in patients with limited-stage small-cell lung cancer (LSCLC).
                From 1981 to 1989, 199 consecutive patients with LSCLC were randomly allocated to receive initial chest irradiation (ICI; n = 99) or late chest irradiation (LCI; n = 100) given 18 weeks delayed. Both groups received the same nine cycles of combination chemotherapy: three cycles of cisplatin and etoposide and six cycles of cyclophosphamide, doxorubicin, and vincristine. In the first part of the study, prophylactic cranial irradiation (PCI) was only given to patients randomized to ICI, but after inclusion of 42 patients in the LCI arm, the protocol was changed, so that all patients received PCI independent of the timing of the chest irradiation (CI). A total of 157 patients received PCI with a radiation dose of 25 Gy in 11 fractions.
                The timing of radiotherapy had no significant effect on the 2-year overall survival rate (20% after ICI v 19% after LCI, P = .4) or the 2-year in-field recurrence rate (72% after ICI v 68% after LCI, P = .2). Median survival durations were 10.5 (ICI) and 12.0 (LCI) months. Similarly, no difference in the 2-year incidence of CNS recurrences was found between the 2 arms in patients who received PCI (19% after ICI v 13% after LCI, P = .24). Bone marrow toxicity was acceptable, as 15% developed World Health Organization (WHO) grade 4 leukocytopenia and 4% grade 4 thrombocytopenia. Grade 4 leukocytopenia was more pronounced in the ICI group. There was no difference in the frequency and severity of other toxicities between the 2 groups.
                Timing of CI did not significantly influence the incidence of in-field recurrences, CNS recurrences, or overall survival. To assess the safety and feasibility of a clinical trial on the effectiveness of acetylsalicylic acid (ASA) in subarachnoid hemorrhage (SAH).
                Several studies have indicated that increased platelet activity might be involved in the pathogenesis of delayed cerebral ischemia (DCI) after SAH.
                Fifty patients who had early surgery (< or =4 days) for a ruptured aneurysm were enrolled in this randomized, double-blind, placebo-controlled trial. Trial medication, consisting of suppositories with 100 mg ASA versus placebo, was started immediately after surgical clipping of the aneurysm and continued for 21 days. End points were functional outcome and quality of life at 4 months, clinical deterioration after operation, development of DCI, hypodense lesion on postoperative CT, and hemorrhagic complications.
                One-third of all patients with aneurysmal SAH were eligible for the trial. Fifteen of 26 patients receiving placebo deteriorated clinically versus 10 of 24 patients receiving ASA; 4 patients in each group deteriorated from DCI. Postoperative hypodensities on CT were observed in 27 patients, distributed equally in both groups. Functional outcome and quality-of-life scores were slightly in favor of patients who had received ASA, but not to a significant degree (p = 0.22). Two patients in the ASA group had an asymptomatic hemorrhagic complication, and one patient in the placebo group had a fatal and another a symptomatic hemorrhagic complication.
                This pilot study shows that a clinical trial of acetylsalicylic acid (ASA) in subarachnoid hemorrhage (SAH) is feasible and probably safe. The effectiveness of ASA on functional outcome and delayed cerebral ischemia has to be studied in a larger trial. Treatment results in patients with metastatic renal cell cancer (RCC) are still extremely unsatisfactory. Rates of response to IFN-alpha monotherapy and/or IL-2 mono/combination therapy vary between 10% and 20%. Coumarin (Cum) together with cimetidine (Cim) has yielded objective responses in 20%-33% of patients with RCC, according to two recent phase II studies.
                In the present study 148 patients with metastatic RCC were randomised to receive either IFN-alpha (5 MU 5 x weekly s.c.) + coumarin (100 mg/d p.o.) + cimetidine (3 x 400 mg/d p.o.), or IFN-alpha-monotherapy (5 MU 5 x weekly s.c.).
                Of the 148 patients in the study 137 were evaluable for response. No differences in remission rates (RR IFN-alpha + Cum + Cim 17.1% and IFN-alpha 20.8%) or survival times (median survival 9 months and 8 months, respectively) were found between these two treatment arms.
                This study confirms that INFN-alpha has antitumoral activity in RCC. Adding coumarin + cimetidine to IFN-alpha in the dose and regimen prescribed in this study did not increase response rates or survival. This study was conducted to explore mechanisms that could explain the possible clinical benefit of early administration of a beta 1-selective adrenoreceptor blocking agent or a bradycardiac drug as adjunct to thrombolysis in acute myocardial infarction.
                The effects of beta-blockers given concomitantly with thrombolytic therapy in patients with acute myocardial infarction have not been fully examined. The potential role of specific bradycardiac agents lacking negative inotropism as an alternative to beta-blockers in this setting has never been studied in humans.
                In a double-blind study, we examined the effects of early intravenous and continued oral administration of a beta-blocker (atenolol), a specific bradycardiac agent (alinidine) or placebo on left ventricular function, late coronary artery patency, infarct size, exercise capacity and incidence of arrhythmias.
                A total of 292 patients with acute myocardial infarction of < or = 5 h duration and without contraindications to thrombolytic or beta-blocker therapy were studied. Of these, 100 were allocated to treatment with atenolol (5 to 10 mg intravenously followed by 25 to 50 mg orally every 12 h), 98 to alinidine (20 to 40 mg intravenously followed by 20 to 40 mg orally every 8 h) and 94 to placebo. All patients received 100 mg of alteplase over 3 h and full intravenous heparinization. No significant differences in coronary artery patency, global ejection fraction or regional wall motion were observed at 10 to 14 days among the three groups. Likewise, enzymatic and scintigraphic infarct size were also very similar. Neither atenolol nor alinidine was associated with a significant reduction in the incidence of arrhythmias during the 1st 24 h. No significant differences in clinical events were observed, with the exception of a greater incidence of nonfatal pulmonary edema in the atenolol group (6% vs. 1% in the alinidine group and 0% in the placebo group, p = 0.021).
                In the absence of contraindications, the administration of a beta-blocker or a specific bradycardiac agent together with thrombolytic therapy was safe. In this limited number of patients, these agents did not appear to enhance myocardial salvage or preservation of left ventricular function or to reduce the incidence of major arrhythmias in the early phase of infarction. It has been postulated that angiotensin-converting enzyme inhibitor/angiotensin receptor antagonist (ACEI/ATRA) may decrease proteinuria in patients with glomerulonephritis by its action on the glomerular basement membrane. We therefore studied the relationship between the response of patients with IgA nephritis (IgAN) to ACEI/ATRA therapy by decreasing proteinuria and its effect on the selectivity index (SI) in these patients.
                Forty-one patients with biopsy-proven IgAN entered a control trial, with 21 in the treatment group and 20 in the control group. The entry criteria included proteinuria of 1 g or more and/or renal impairment. Patients in the treatment group received ACEI/ATRA or both with three monthly increases in dosage. In the control group, hypertension was treated with atenolol, hydrallazine, or methyldopa. The following tests were performed at three monthly intervals: serum creatinine, total urinary protein, SI, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and low molecular weight (LMW) proteinuria.
                After a mean duration of therapy of 13 +/- 5 months, in the treatment group, there was no significant change in serum creatinine, proteinuria, or SI, but in the control group, serum creatinine deteriorated from 1.8 +/- 0.8 to 2.3 +/- 1.1 mg/dL (P < 0.05). Among the 21 patients in the treatment group, 10 responded to ACEI/ATRA therapy determined as a decrease in proteinuria by 30% (responders), and the other 11 did not respond (nonresponders). Among the responders, SI improved from a mean of 0.26 +/- 0.07 to 0.18 +/- 0. 07 (P < 0.001), indicating a tendency toward selective proteinuria. This was associated with an improvement in serum creatinine from mean 1.7 +/- 0.6 to 1.5 +/- 0.6 mg/dL (P < 0.02) and a decrease in proteinuria from a mean of 2.3 +/- 1.1 to 0.7 +/- 0.5 g/day (P < 0. 001). After treatment, proteinuria in the treatment group (1.8 +/- 1. 6 g/day) was significantly less than in the control group (2.9 +/- 1. 8 g/day, P < 0.05). The post-treatment SI in the responder group (0. 18 +/- 0.07) was better than that of the nonresponder group (0.33 +/- 0.11, P < 0.002). Eight out of 21 patients in the treatment group who had documented renal impairment had improved renal function compared with two in the control group (chi2 = 4.4, P < 0. 05). Of the eight patients in the treatment group who improved their renal function, three normalized their renal function compared with one from the control group.
                Our data suggest that ACEI/ATRA therapy may be beneficial in patients with IgAN with renal impairment and nonselective proteinuria, as such patients may respond to therapy with improvement in protein selectivity, decrease in proteinuria, and improvement in renal function. ACEI/ATRA therapy probably modifies pore size distribution by reducing the radius of large unselective pores, causing the shunt pathway to become less pronounced, resulting in less leakage of protein into the urine. Renal dysfunction occurring after open heart surgery is multifactorial in origin but activation of the renin-angiotensin system may have a prominent role. Fourteen patients with ischaemic heart dysfunction scheduled for elective coronary artery bypass graft (CABG) surgery were allocated to a treatment group [enalaprilat for 2 days; ACEI (angiotensin-converting enzyme inhibitor) group, n=7] or a control group (n=7). The cardiac index was significantly higher in ACEI-treated patients than in the controls before and after cardiopulmonary bypass (CPB) (P<0.05) and on postoperative day 2 (P<0.05). The systemic vascular resistance was significantly lower in the ACEI-treated patients than in the controls before and after CPB (P<0.05). Renal plasma flow, measured as [131I]orthoiodohippuran clearance (ClH), was higher in the ACEI group than in the control group before CPB, as was endogenous creatinine clearance after CPB (P<0.05). On post-operative day 7, ClH was significantly higher in the ACEI group than in the control group (P<0.05). Plasma renin activity and vasopressin concentration increased in both groups during CPB (P<0.05). The study demonstrates that administration of an i.v. ACEI, enalaprilat, improves cardiac output during CABG surgery in patients with ischaemic heart dysfunction. Moreover, renal perfusion was better maintained during surgery, and this effect was sustained up to post-operative day 7.
Although the survival benefits of ACEi are known for patients with DKD, the relative effects on survival of ACEi with AIIRA are unknown due to the lack of adequate direct comparison studies. In placebo controlled studies, only ACEi (at the maximum tolerable dose, but not lower so-called renal doses) were found to significantly reduce the risk of all-cause mortality. Renal and toxicity profiles of these two classes of agents were not significantly different.