Losartan and enalapril are comparable in reducing proteinuria in children with Alport syndrome.

BACKGROUND: A previous subgroup analysis of a 12-week, double-blind study demonstrated that losartan significantly lowered proteinuria versus placebo and amlodipine and was well tolerated in children (1-17 years old) with proteinuria secondary to Alport syndrome. The present subgroup analysis of the open-label, extension phase of this study assessed the long-term efficacy and tolerability of losartan versus enalapril. METHODS: Patients who had completed the double-blind study were re-randomized to losartan or enalapril and followed for proteinuria and renal function for up to 3 years. RESULTS: Twenty-seven patients with Alport syndrome were randomized to losartan (0.44-2.23 mg/kg/day; n = 15) or enalapril (0.07-0.72 mg/kg/day; n = 12). The least-squares (LS) mean percent change from week 12 in urinary protein to creatinine ratio (UPr/Cr was +1.1 % in the losartan group versus a further 13.9 % reduction in the enalapril group (GMR [95 % CI] = 1.2 [0.7, 2.0]); the LS mean change from week 12 in estimated glomerular filtration rate (eGFR) was -6.4 ml/min/1.73 m(2) in the losartan group versus -9.1 ml/min/1.73 m(2) in the enalapril group. The adverse event incidence was low and comparable in both treatment groups. CONCLUSIONS: In children with proteinuria secondary to Alport syndrome, losartan maintained proteinuria reduction, and enalapril produced a further proteinuria reduction over the 3-year study period. Both agents were generally well tolerated.

Comparison of the intrinsic vasorelaxant and inotropic effects of the antiarrhythmic agents vernakalant and flecainide in human isolated vascular and cardiac tissues.

This study explored the intrinsic vasorelaxant and inotropic effects of the mixed potassium and sodium channel blocker atrial antiarrhythmic vernakalant and the class IC antiarrhythmic agent flecainide in human isolated subcutaneous resistance artery and in ventricular trabecular muscle preparations. At test concentrations encompassing free plasma concentrations associated with clinical efficacy for conversion of atrial fibrillation, vernakalant (1-10 µM) displayed no significant direct effects on human resistance artery tone or ventricular contractility. In contrast, tested at equimolar concentrations, flecainide significantly reduced peak isometric contractile force (10 µM) and maximal rates of force development and decline (3 and 10 µM) in the human ventricular muscle preparation while displaying no significant effect on human resistance artery tone. The lack of effects of vernakalant on human resistance artery tone and ventricular muscle contractile function suggests that direct vasorelaxant and inotropic effects do not underlie the rare hypotensive events observed clinically with vernakalant, raising the possibility that secondary (eg, reflex) effects may mediate these events. The demonstration of negative inotropic effects with flecainide in the human ventricular muscle preparations in the absence of an effect on resistance artery tone suggests that the hemodynamic effects of flecainide observed clinically result primarily from direct negative inotropic effects.

Losartan and enalapril are comparable in reducing proteinuria in children.

Angiotensin-converting enzyme inhibitors and angiotensin II type I receptor blockers delay progression of chronic kidney disease and have antiproteinuric effects beyond their effects on blood pressure. They are routinely used in adults; however, their efficacy and safety in children, in whom the causes of chronic kidney disease are significantly different relative to adults, is uncertain. Here we assessed an open-label extension of a previous 3-month blinded trial, in which the efficacy and tolerability of losartan was compared to placebo or amlodipine in 306 normotensive and hypertensive children with proteinuria. In this study, 268 children were re-randomized to losartan or enalapril and followed until 100 patients completed 3 years of follow-up for proteinuria and renal function. The least squares percent mean reduction from baseline in the urinary protein/creatinine ratio was 30.01% for losartan and 40.45% for enalapril. The least squares mean change from baseline in eGFR was 3.3 ml/min per 1.73 m2 for losartan and 7.0 ml/min per 1.73 m2 for enalapril. The incidence of specific adverse events such as hyperkalemia and renal dysfunction was low and similar in both groups. Both were generally well tolerated and, overall, fewer drug-related adverse events occurred with losartan than with enalapril. Thus, in children with proteinuria, losartan and enalapril significantly reduced proteinuria without any appreciable changes in eGFR, effects that were maintained throughout the study. Both losartan and enalapril were generally well tolerated.

Efficacy and safety of losartan in children with Alport syndrome--results from a subgroup analysis of a prospective, randomized, placebo- or amlodipine-controlled trial.

BACKGROUND: No prospective, randomized, double-blind trials of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers have previously been reported in adults or children with proteinuria secondary to Alport syndrome. METHODS: This 12-week, double-blind multinational study investigated the effects of losartan 0.7-1.4 mg/kg/day compared with placebo (normotensive patients) or amlodipine 0.1-0.2 mg/kg/day up to 5 mg/day (hypertensive patients) on proteinuria [early morning-void urinary protein/creatinine ratio (UPr/Cr), baseline ≥ 34 mg/mmol] in 30 children of up to 17 years of age with Alport syndrome. RESULTS: Twelve weeks of treatment with losartan significantly reduced proteinuria compared with placebo/amlodipine: losartan -14.7 mg/mmol (interquartile range -49.7 to -5.7 mg/mmol) or 31.6% reduction using a mixed model approach versus placebo/amlodipine 2.3 mg/mmol (-26.0 to 18.1 mg/mmol), P = 0.01 or 2.3% increase using a mixed model approach. Adverse event incidence was low and comparable between losartan and placebo/amlodipine groups. CONCLUSIONS: Losartan significantly lowered proteinuria and was well tolerated after 12 weeks of treatment in children aged 1-17 years with proteinuria secondary to Alport syndrome with or without hypertension, a population that has not previously been rigorously studied.

Randomized, double-blind, controlled study of losartan in children with proteinuria.

BACKGROUND AND OBJECTIVES: No large, randomized, double-blind trials in children with proteinuria treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers have previously been reported. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This 12-week, double-blind, multinational study investigated the effects of losartan 0.7 to 1.4 mg/kg per day compared with placebo (normotensive stratum) or amlodipine 0.1 to 0.2 mg/kg per day up to 5 mg/d (hypertensive stratum) on proteinuria (morning-void urinary protein-creatinine ratio, baseline > or =0.3 g/g) in 306 children up to 17 years of age. RESULTS: Twelve weeks of treatment with losartan significantly reduced proteinuria compared with amlodipine/placebo: losartan -35.8% (95% confidence interval: -27.6% to -43.1%) versus amlodipine/placebo 1.4% (95% confidence interval: -10.3% to 14.5%), P < or = 0.001. Significance remained after adjustment for differences across treatment groups in change in BP (losartan produced incremental systolic and diastolic BP reductions versus amlodipine of 5.4 and 4.6 mmHg, respectively; and versus placebo of 3.8 and 4.0 mmHg, respectively). Proteinuria reduction was consistently observed in the normotensive (-34.4% losartan; 2.6% placebo) and hypertensive (-41.5% losartan; 2.4% amlodipine) strata, and in all prespecified subgroups, including age, gender, race, Tanner stage, weight, prior therapy with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, as well as among the most common etiologies of proteinuria. Adverse event incidence was low and comparable in all groups. CONCLUSIONS: Losartan significantly lowered proteinuria and was well tolerated after 12 weeks in children aged 1 to 17 years with proteinuria with or without hypertension, a population that has not previously been rigorously studied.

Albuminuria is a target for renoprotective therapy independent from blood pressure in patients with type 2 diabetic nephropathy: post hoc analysis from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial.

Albuminuria reduction could be renoprotective in hypertensive patients with diabetic nephropathy. However, the current use of renin-angiotensin-system intervention is targeted to BP only. Therefore, this study investigated the adequacy of this approach in 1428 patients with hypertension and diabetic nephropathy from the placebo-controlled Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. Investigated were the extent of discordance in treatment effects on systolic BP (SBP) and albuminuria and its association with renal outcome in a multivariate Cox model. Among patients with a reduced SBP during treatment, a lack of albuminuria reduction was observed in 37, 26, and 51% (total, losartan, and placebo, respectively) at month 6. SBP or albuminuria reduction was associated with a lower risk for ESRD, whereas combined SBP and albuminuria reduction was associated with the lowest risk for events. Across all categories of SBP change, a progressively lower ESRD hazard ratio was observed with a larger albuminuria reduction. A lower residual level of albuminuria was also associated with lower ESRD risk. In conclusion, changes in albuminuria are not concordant in a substantial proportion of patients when titrated for BP. Meanwhile, the ESRD risk showed a clear dependence on albuminuria reduction. The ESRD risk also showed dependence on the residual level of albuminuria, even in patients who reached the current SBP target. Antihypertensive treatment that is aimed at improving renal outcomes in patients with diabetic nephropathy may therefore require a dual strategy, targeting both SBP and albuminuria reduction.

A multicenter, randomized, double-blind, parallel-group trial of the antihypertensive efficacy and tolerability of a combination of once-daily losartan 100 mg/hydrochlorothiazide 12.5 mg compared with losartan 100-mg monotherapy in the treatment of mild to severe essential hypertension.

BACKGROUND: Because patients with hypertension may require >1 antihypertensive agent to control blood pressure (BP), physicians often prescribe a fixed combination of antihypertensive medications. OBJECTIVE: This study evaluated the effect of adding low-dose hydrochlorothiazide 12.5 mg (HCTZ12.5) to high-dose losartan 100 mg (L100) in patients with hypertension whose BP was inadequately controlled with L100 monotherapy. METHODS: Enrolled in this multicenter, randomized, double-blind, parallel-group, filter study were patients aged > or =18 years with a mean trough sitting diastolic BP (SiDBP) of 95 to 120 mm Hg. Patients were treated with L100 QD for 4 weeks. Patients who did not achieve adequate BP control were randomly assigned to receive L100/HCTZ12.5 or L100 QD for 6 weeks. The primary efficacy measure was the mean change in trough SiDBP from baseline in the 2 groups. Responders were defined as patients with a mean trough SiDBP of <90 mm Hg or patients who had a > or =10-mm Hg decrease in mean trough SiDBP. RESULTS: Demographic characteristics were similar between treatment groups. The patients randomized to the double-blind treatment period were mostly white (65.1%) and male (57.5%), with a mean age of 53.8 years. The mean (SD) duration of hypertension at baseline was 9.7 (8.5) years. The proportion of patients previously treated with antihypertensive therapy was 76.7%. Of the 367 patients enrolled in the L100 filter period, 292 patients had BP inadequately controlled with L100 monotherapy and were randomized to receive L100 (n = 145) or L100/HCTZ12.5 (n = 147). At week 6 after randomization, mean trough SiDBP was significantly lower in the L100/HCTZ12.5 group than in the L100 group (-8.3 vs -5.2, respectively; P < 0.001). The between-group difference was -3.0 mm Hg (95 % CI, -4.6 to -1.40; P < 0.001), and the proportion of responders was significantly greater in the L100/HCTZ12.5 group than in the L100 group (63.0% vs 44.4%; P < 0.001). The incidence of adverse events (AEs) occurring in >2% of patients during the double-blind period was similar for both groups. AEs occurring in the L100 group and the L100/HCTZ12.5 group included respiratory tract infection (6.2% vs 3.4%, respectively), dizziness (2.1% vs 0.7%), and headache (0.7% vs 3.4%). CONCLUSIONS: After 6 weeks of therapy, L100/HCTZ12.5 was associated with greater antihypertensive efficacy than L100, as measured by the change in mean trough SiDBP The percentage of responders was significantly greater in the L100/HCTZ12.5 group than in the L100 group.

The impact of morbid events on survival following hospitalization for complicated myocardial infarction.

BACKGROUND: Little is known about the importance of morbid events with respect to longer term survival following MI hospital discharge. AIMS: Establish the risk of death associated with morbid events following initial discharge from MI hospitalization. METHODS: We examined the rates of morbid events (reinfarction, stroke/TIA, revascularization, heart failure (HF) hospitalization, cardiovascular hospitalization and all-cause hospitalization) and the relationships of these events to subsequent death in patients who survived the initial hospitalization for MI (n = 5301) in the OPTIMAAL trial. Events were classified as Early (< or = 30 days post discharge) and Late (> 30 days post discharge) for an average of 2.7 years follow-up. RESULTS: Death rates were higher in the Early period (0.20 deaths/patient year) than in the Late period (0.05 deaths/patient year). Once a morbid event, excluding revascularization, occurred, the acute hazard ratios (HR, determined by Cox regression) for death on the day of event were higher than at time periods following the event and were highest for reinfarction and stroke/TIA. The acute HRs for death for all 6 morbid events were especially high for events occurring during the Late period. The highest chronic HR for death was associated with HF and all-cause hospitalizations. By contrast, the chronic HR for death from revascularization in both the Early (HR = 0.3) and Late (HR = 0.4) period indicated reduced risk. CONCLUSIONS: The results document event rates following hospitalization for MI, provide quantification of the associated risk for death, and may be useful in designing clinical trials. The serious morbid events examined may serve as potential surrogate endpoints in long-term studies and identify patients that should be targeted for aggressive management.

Importance of baseline distribution of proteinuria in renal outcomes trials: lessons from the reduction of endpoints in NIDDM with the angiotensin II antagonist losartan (RENAAL) study.

A key issue in the analysis of outcome trials is the adjustment for baseline covariates that influence the primary outcome. Imbalance of an important covariate between treatment groups at baseline is of considerable concern if one treatment group is favored over another with respect to the hypothesis testing outcome. With the use of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study database as an example, the influence of baseline proteinuria on the primary composite endpoint, ESRD, and ESRD or death after adjusting for baseline proteinuria as a continuous covariate was examined. Increasing baseline proteinuria was associated with increased risk for renal events, confirming that proteinuria is an important covariate for renal outcomes. When the randomization was stratified according proteinuria <2000 mg/g or >/=2000 mg/g, within the higher proteinuria stratum (>/=2000 mg/g), patients in the losartan group had a higher baseline mean proteinuria value. When the imbalance was adjusted, an increase in the magnitude and the significance of the risk reduction with losartan for each outcome was observed. No apparent interaction between treatment effect and baseline proteinuria was found, and there was no heterogeneity in the treatment response in patients with different baseline proteinuria levels. After proteinuria was adjusted as a continuous variable, greater treatment effects were observed in the RENAAL study. This effect was due solely to the imbalance in baseline proteinuria. Considering the importance of proteinuria as a risk factor, adjustment for baseline proteinuria as a continuous covariate should be prespecified in the design and analysis of clinical trials involving renal outcomes, even when patients are stratified on the basis of level of proteinuria.

Fixed-dose combinations in the management of hypertension: defining the place of angiotensin receptor antagonists and hydrochlorothiazide.

We discuss combination therapy with angiotensin receptor antagonists (angiotensin receptor blockers; ARBs) and thiazide diuretics in light of the independent actions of both types of agents, and the adverse effects of both agents independently and in the context of the physiologic synergy achieved in using these agents together. ARBs counteract many of the adverse events associated with the use of thiazide diuretics and have been shown to reduce the occurrence of new-onset diabetes mellitus. We also review outcome trials in patients with hypertension (such as LIFE [Losartan Intervention For Endpoint reduction in hypertension], VALUE [Valsartan Antihypertensive Long-term Use Evaluation], and SCOPE [Study on COgnition and Prognosis in the Elderly]), in which losartan, valsartan, and candesartan cilexetil were used in combination with hydrochlorothiazide. Fixed combination ARB/hydrochlorothiazide agents make sense as initial therapy for patients in whom BP is >20/10 mm Hg above goal.

The JNC 7 approach compared to conventional treatment in diabetic patients with hypertension: a double-blind trial of initial monotherapy vs. combination therapy.

The JNC 7 states that persons with blood pressure (BP) more than 20/10 mm Hg above goal should be started on combination drug therapy. This criterion includes patients with BP >160/100 mm Hg and diabetics with hypertension. The goal BP for persons with diabetes mellitus is <130/80 mm Hg. A randomized, double-blind trial force titrated initial combination therapy utilizing an angiotensin receptor blocker (ARB) combination (losartan/hydrochlorothiazide [LOS/HCTZ]) compared with an angiotensin-converting enzyme (ACE) inhibitor (ramipril), for 8 weeks, and tested the hypothesis that combination therapy is more likely to achieve goal BP vs. monotherapy. At 4 weeks, 30.5% of LOS/HCTZ and 14.4% of ramipril recipients achieved goal diastolic BP (p<0.001). More participants achieved goal systolic BP in the ARB/HCTZ group at 4 weeks (29.8% vs. 14.4%; p<0.001). At 4 weeks, mean diastolic BP had decreased 10.2+/-7.4 mm Hg in the LOS/HCTZ group compared with 6.4+/-6.8 mm Hg in the ramipril group (p<0.001), and systolic BP had fallen 15.4+/-13.1 mm Hg in the ARB/HCTZ compared with 9.2+/-10.2 mm Hg in the ACE-inhibitor group (p<0.001). Significant differences favoring the combination were also noted at 8 weeks. Drug-related adverse experiences were 10.3% for the combination compared with 12.7% for the monotherapy group. Initial combination therapy with an ARB/HCTZ was more effective than ACE-inhibitor monotherapy in achieving BP goals in participants with diabetes with no significant differences in the incidence of adverse experiences. These observations confirm other studies of combination therapies, such as b blocker/diuretic, ACE inhibitor/diuretic, or ACE inhibitor/calcium channel blocker. The use of two medications will achieve goal BP in more patients than monotherapy. This observation is important in treatment of high-risk patients with diabetes.

Electromyographic predictors of residual quadriceps muscle weakness after anterior cruciate ligament reconstruction.

BACKGROUND: Despite the high prevalence of residual quadriceps muscle weakness after anterior cruciate ligament reconstruction, specific predictive factors have not been identified. HYPOTHESIS: Electromyographic analysis is a better predictor of residual muscle weakness than is preoperative strength. STUDY DESIGN: Prospective cohort study. METHODS: The quadriceps muscle strength of 37 patients (25 men, 12 women) was measured before reconstruction and 5 weeks and 6 months after surgery. Quadriceps surface electromyographic signals were recorded during all of the strength tests. Integrated electromyographic analysis and median frequency measurements were computed as deficits on the involved side. Patients also performed a single-legged hop test at the 6-month follow-up examination. RESULTS: The patients had significantly lower strength, integrated electromyographic analysis, and median frequency measurements on the involved side at all three time intervals. The best predictor of the quadriceps muscle strength deficit at 6 months was the combination of the preoperative median frequency deficit and the 5-week postoperative strength deficit. The best predictor of the hop test deficit at 6 months was the combination of preoperative deficits in integrated electromyographic analysis and median frequency. CONCLUSION: Preoperative electromyographic indices of quadriceps muscle function and early postoperative strength were predictive of residual weakness and impaired function 6 months after reconstruction.

Differences in activation patterns between eccentric and concentric quadriceps contractions.

Previous studies analysing electromyograms (EMGs) from indwelling electrodes have indicated that fast-twitch motor units are selectively recruited for low-intensity eccentric contractions. The aim of this study was to compare the frequency content of surface EMGs from quadriceps muscles during eccentric and concentric contractions at various contraction intensities. Electromyograms were recorded from the rectus femoris, vastus lateralis and vastus medialis muscles of 10 men during isokinetic (1.05 rad x s(-1)) eccentric and concentric knee extension contractions at 25%, 50%, 75% and 100% of maximal voluntary contraction (MVC) for each contraction mode. Additionally, isometric contractions (70 degrees) were performed at each intensity. The mean frequency and root mean square (RMS) of the surface EMG were computed. Mean frequency was higher for eccentric than concentric contractions at 25% (P < 0.01), 50% (P < 0.01) and 75% (P < 0.05) but not at 100% MVC. It increased with increasing contraction intensity for isometric (P < 0.001) and concentric (P < 0.01) contractions but not for eccentric contractions (P = 0.27). The EMG amplitude (RMS) increased with increasing contraction intensity similarly in each contraction mode (P < 0.0001). Higher mean frequencies for eccentric than concentric contractions at submaximal contraction intensities is consistent with more fast-twitch motor units being active during eccentric contractions.

Changes in serum sodium, sodium balance, water balance, and plasma hormone levels as the result of pelvic surgery in women.

Postoperative hyponatremia in women has been associated with the development of serious neurological disorders and even death, with a predisposition for menstruant women. The objective of this study was to evaluate the immediate hormonal, water and electrolyte responses to pelvic surgery in both pre and postmenopausal women. Of the twenty-five consecutive women studied, twenty were premenopausal while five were postmenopausal. Mean age was 45.4 +/- 1.6 years. Measurements of plasma renin activity, follicular stimulating hormone and luteinizing hormone showed no significant change pre to postoperatively. There was a significant decrease in pre to postoperative values of estrogen, 97.4 +/- 20.3 to 36.3 +/- 7.5 pg/mL (p < 0.05). There was also a significant decline in postoperative values for plasma aldosterone and plasma progesterone. Data were similar in pre and postmenopausal patients. Serum sodium levels decreased from 141.5 +/- 0.5 to 137.2 +/- 0.5 mEq/L (p < 0.01). During the twenty-four hours following surgery, mean net sodium balance was positive 122 mEq and mean measured fluid balance was positive 1108 mL. Ringers lactate or normal saline were used. On the first postoperative day, plasma arginine vasopressin levels were elevated at 4.0 +/- 0.8 pg/mL, with a mean urine osmolality of 504 +/- 29 mOsm/kg H2O. The data illustrate that women undergoing pelvic surgery decrease their serum sodium in the immediate postoperative period. Despite both positive sodium and water balance, there is a stronger tendency to conserve water. Decreased estrogen levels occur and this decrease may facilitate brain cell adaptation to plasma hypotonicity. Since the administration of isotonic fluid will not protect against the decrease in serum sodium, postoperative sodium concentration should be carefully monitored.

Endurance Training.

To improve endurance athletes' performance, exercise physiologists and coaches often recommend over-distance training. Frequently, though, athletes misinterpret this recommendation and increase their risk of injury and staleness by training excessively.

Children's Sports Injuries: Are They Avoidable?

In this study of 51 children's sports injuries, 21 injuries occurred in a nonorganized setting and 32 were deemed avoidable. Preventive measures are discussed.