Cardiovascular Tolerability Research Articles

Efficacy and cardiovascular tolerability of continuous venovenous hemodiafiltration in acute decompensated heart failure: a randomized comparative study

Efficacy and cardiovascular tolerability of continuous venovenous hemodiafiltration in acute decompensated heart failure: a randomized comparative study

The Forefront for Novel Therapeutic Agents Based on the Pathophysiology of Lower Urinary Tract Dysfunction: α-Blockers in the Treatment of Male Voiding Dysfunction — How Do They Work and Why Do They Differ in Tolerability?

α1-Adrenoceptor antagonists are the mainstay of medical treatment of male voiding dysfunction which typically is attributed to benign prostatic hyperplasia. While original concepts have assumed that they relieve voiding dysfunction by relaxing prostatic smooth muscle, newer data indicate that their therapeutic effects at least partly occur independent of prostatic relaxation, perhaps involving direct effects on blood vessels, urothelium, afferent nerves, and/or smooth muscle of the urinary bladder. The adverse event profiles differ among α1-adrenoceptor antagonists, with tamsulosin having a particularly good cardiovascular tolerability. While this was originally attributed to its selectivity for α1A-adrenoceptors, it appears that alfuzosin which lacks subtype-selectivity, has a very similar tolerability. In contrast, doxazosin and terazosin, which are chemically and pharmacologically more closely related to alfuzosin than to tamsulosin, appear to have more side effects attributable to the cardiovascular system. More recent data indicate that tolerability differences between α1-adrenoceptor antagonists may at least partly relate to pharmacokinetic rather than to pharmacodynamic differences. Taken together, these data emphasize the idea that concepts about drug efficacy and tolerability despite being highly plausible may not necessarily be true and always require thorough experimental testing.

Prucalopride

Prucalopride, a first-in-class dihydrobenzofuran-carboxamide derivative, is a potent, selective and specific serotonin 5-HT(4) receptor agonist with enterokinetic properties. Over a 12-week treatment period, prucalopride 2 and 4 mg once daily significantly improved bowel habit assessments (based on patient diary data) relative to placebo in three large, randomized, double-blind, multicentre trials in patients (aged 17-95 years) with severe chronic constipation, the majority of whom were women who experienced inadequate relief with previous therapies. There was no additional benefit with the 4 mg/day over the 2 mg/day dosage of prucalopride. Patient assessments of constipation symptoms and severity, treatment efficacy, satisfaction with bowel habit and treatment, and health-related quality of life were also significantly improved with prucalopride compared with placebo. The improvement in patient satisfaction with bowel habit and treatment was maintained for up to 24 months in open-label, multicentre, long-term follow-up studies. Prucalopride therapy was generally well tolerated; most adverse events in the 12-week studies were transient and of mild to moderate severity. In terms of cardiovascular tolerability, the incidence of QT interval prolongation with prucalopride at dosages of 2 and 4 mg/day was low and similar to that with placebo. Moreover, prucalopride at dosages up to 20 mg/day (10-fold higher than the recommended therapeutic dosage) had no clinically relevant effects on cardiovascular parameters in healthy volunteers.

Novel anesthetics and other treatment strategies for refractory status epilepticus

Novel anesthetics and other treatment strategies for refractory status epilepticus

Effective Bilirubin Reduction by Single‐Pass Albumin Dialysis in Liver Failure

Albumin dialysis is widely accepted as a liver-support technique for patients with liver failure. The Molecular Adsorbent Recirculating System, the widely accepted albumin dialysis technique, has limited use in developing countries because of its technical difficulties and high cost. Therefore, we assessed the efficacy of the more practical modality, the single-pass albumin dialysis (SPAD), in terms of bilirubin reduction, as a marker of albumin-bound toxins removal, as well as the patient outcomes. Twelve acute or acute-on-chronic patients with liver failure who had hyperbilirubinemia (total bilirubin > 20 mg/dL) were treated with SPAD by using 2% human serum albumin dialysate for 6 h. SPAD treatment significantly improved the levels of total bilirubin, conjugated bilirubin, urea, and creatinine (P < 0.001 for all parameters). The reduction ratios of these four parameters were 22.9 +/- 3.8%, 20.9 +/- 5%, 19.0 +/- 4.1%, and 27.7 +/- 3.2%, respectively. No significant difference was observed between serum ammonia before and after treatment. No significant changes in mean arterial pressures were noted during the maneuver, representing cardiovascular tolerability. No treatment-related complications were found. The 15-day in-hospital survival was 16.7%. However, a subgroup of the patients who had moderate severity showed 100% 15-day-survival rate (2 of 2 patients). In conclusion, SPAD is salutarily effective in reducing bilirubin in patients with liver failure. The procedure is safe and simply set up.

Pharmacokinetics of ertapenem in critically ill patients with acute renal failure undergoing extended daily dialysis

Extended (daily) dialysis (EDD) is an increasingly popular mode of renal replacement therapy in the ICU (intensive care unit) as it combines the advantages of intermittent haemodialysis (IHD) and continuous renal replacement therapy (CRRT), i.e. excellent detoxification accompanied by cardiovascular tolerability. The aim of this study was to evaluate pharmacokinetics (PK) of ertapenem, the newest carbapenem with once-daily dosing, in critically ill patients with anuric acute renal failure (ARF) undergoing EDD. In a single-centre, prospective, open-label study six ICU patients with ARF undergoing EDD were treated with 1 g ertapenem given as a single intravenous dose. EDD was performed using a high-flux dialyzer (polysulphone, 1.3 m(2)). Blood and dialysate flow were 160 mL/min, and the length of treatment was 480 min. Plasma samples were collected at different time-points up to 24 h after medication. Drug concentrations were determined by a validated LC-MS method. Free drug concentrations were estimated using a two-class binding site equation. After a single dose of 1000 mg free ertapenem, protein-unbound plasma concentrations exceeded a MIC(90) value of 2 mg/L for >20 h after dosing. The clearance of the tested dialyzer was 38.5 +/- 14.2 mL/min. In contrast to patients undergoing regular IHD, in which a dose reduction is required, our data suggest that in patients treated with EDD a standard dose of ertapenem (1 g/day), i.e. dose for patients without renal failure, is required to maintain adequate plasma drug levels.

Integration of Blood Volume, Blood Pressure, Heart Rate and Bioimpedance Monitoring for the Achievement of Optimal Dry Body Weight during Chronic Hemodialysis

Achieving optimal dry body weight in hemodialysis is challenging. Clinical assessment alone is inadequate, and methods such as bioimpedance monitoring may be impractical for every patient treatment. Continuous blood volume monitoring, blood pressure and heart rate variability inform clinical decision-making, but integrated use of multiple methodologies to achieve dry weight and understand patient factors has not yet been described. Nineteen chronic hemodialysis patients underwent thrice-weekly treatments for two weeks. Baseline hydration status and target weight were determined by bioimpedance. During subsequent treatments, ultrafiltration was adjusted and relative blood volume, blood pressure and pulse were recorded non-invasively. Bioimpedance was repeated to assess hydration. Response of variables to progressive change in weight was assessed and selected patients underwent additional autonomic function testing. Four distinct hemodynamic patterns emerged. Profile A: 4 patients demonstrated overhydration at baseline. With decreasing target, pulse and blood pressure remained stable while blood volume and bioimpedance demonstrated achievement of dry weight. Profile B: 8 patients demonstrated overhydration at baseline. With decreasing target, blood pressure remained stable while pulse increased. Profile C: 5 patients were overhydrated, but as weight decreased, blood pressure became unstable and heart rate failed to compensate. Further testing confirmed autonomic dysfunction. Profile D: 2 patients were dehydrated, and with increasing target demonstrated stable pulse and pressure, while blood volume and bioimpedance revealed achievement of dry weight. Integrating existing non-invasive, continuous monitoring during hemodialysis enabled achievement of dry weight and identified distinct profiles of the patients, some with autonomic dysfunction. This strategy may contribute to achieving optimum dry weight while improving cardiovascular tolerability of hemodialysis.

Response to Daily 10 Mg Alfuzosin Predicts Acute Urinary Retention and Benign Prostatic Hyperplasia Related Surgery in Men With Lower Urinary Tract Symptoms

We analyzed the influence of treatment response on the risk of acute urinary retention and benign prostatic hyperplasia related surgery in 5,792 men complaining of lower urinary tract symptoms who were treated for 6 months with the selective alpha1-blocker alfuzosin at 10 mg once daily. The influence of dynamic variables (International Prostate Symptom Score change and bother during treatment) and baseline variables (patient age, prior acute urinary retention managed conservatively, prostate specific antigen, International Prostate Symptom Score and bother severity) on the risk of acute urinary retention and benign prostatic hyperplasia related surgery was estimated using the Kaplan-Meier method and log rank test. The associated HR and 95% CI were calculated using Cox proportional hazard models. During alfuzosin treatment International Prostate Symptom Score improved by 3 or greater and greater than 6 points in 74.8% and 50.3% of men, respectively. In this unselected population, including 3.8% with prior unoperated acute urinary retention, the rate of acute urinary retention and benign prostatic hyperplasia related surgery events during treatment was low (0.5% and 1.1%, respectively). Men with stable or worsening International Prostate Symptom Score were at increased risk for acute urinary retention or surgery (HR 3.75, 95% CI 1.58 to 8.89, p = 0.003 and HR 4.71, 95% CI 2.69 to 8.24, p <0.001, respectively). Prior acute urinary retention was a strong predictor of acute urinary retention relapse and surgery (HR 10.35, 95% CI 4.29 to 26.08, p <0.001 and HR 3.57, 95% CI 1.59 to 7.98, p = 0.002, respectively). Bother score greater than 3 during treatment was the strongest predictor of surgery (HR 7.61, 95% CI 4.16 to 13.93, p <0.001). Prostate specific antigen had much less predictive value. This 6-month real life practice study shows that alfuzosin is associated with a low incidence of acute urinary retention and benign prostatic hyperplasia related surgery. It also suggests that responder status is the most important predictor of acute urinary retention and benign prostatic hyperplasia related surgery. Thus, first line treatment with alfuzosin may help select patients at risk for benign prostatic hyperplasia progression to optimize treatment.

La dysfonction érectile, un nouveau symptôme pour le cardiologue

During many years, the symptom of erectile dysfunction was a matter for the urologist or the sexologist without efficacious treatment. Since 1999, the unexpected efficacy of sildenafil initially tested as a coronary vasodilatator emphasized the major role of an endothelial dysfunction potentially corrected by type 5 phosphodiesterase inhibitors (5-PDEI), which are able to reinforce the NO-dependant vasodilatation of cavernous arteries. Due to the medicalisation and the mediatisation of erectile dysfunction during the past five years, this symptom is now a matter for the cardiologist. The first reason was the query of cardiovascular safety of 5-PDEI. American and Britannic registries have established a good cardiovascular tolerability of these drugs including in patients with coronary heart disease according to the respect of contraindication in cases of coprescription with nitrates. The second was the association of erectile dysfunction with many cardiovascular risk factors concerned by the cardiologist. The third reason was the observation that erectile dysfunction could be a potential marker to identify patients with silent myocardial ischemia and relevant coronary artery disease. The Princeton consensus provides guidelines to help the cardiologist in the evaluation of patients with erectile dysfunction according to the cardiovascular risk level. Henceforth, erectile dysfunction should be considered by the cardiologist as “a sound of silence” of myocardial ischemia and should encourage to more aggressive evaluation and treatment of cardiovascular risk factors.

Age, Comorbidity and Hypertensive Co-Medication do Not Affect Cardiovascular Tolerability of 10 Mg Alfuzosin Once Daily

We assessed in real-life practice the impact of age, cardiovascular comorbidity and co-medication on the tolerability and efficacy of 10 mg alfuzosin OD in men with lower urinary tract symptoms suggestive of benign prostatic obstruction. A total of 6,523 men with a mean age of 64.7 years were enrolled in a 6-month open label study of 10 mg alfuzosin OD. They were stratified by age quartile (younger than 60, 60 to 64, 65 to 70 and older than 70 years), comorbidity (hypertension, ischemic heart disease and diabetes) and antihypertensive co-medication (diuretics, beta-blockers, angiotensin converting enzyme inhibitors, angiotensin II inhibitors and calcium channel antagonists). Alfuzosin was effective and well tolerated. Despite an increased prevalence of cardiovascular comorbidity and antihypertensive co-medication with age changes in blood pressure did not significantly differ among age groups. In controls, ie those with no cardiovascular comorbidity or co-medication, alfuzosin produced minimal decreases in sitting systolic (mean -2.6 to -2.8 mm Hg) and diastolic (mean -1.7 to -1.8 mm Hg) blood pressure. In men with cardiovascular comorbidity mean decreases in systolic (-3.5 to 5.8 mm Hg) and diastolic (-2.0 to -3.3 mm Hg) blood pressure remained marginal. Of the 6,523 exposed patients 19.3% withdrew from the study, mainly for adverse events (6.4%) or a lack of efficacy (5.3%), while 229 (3.5%) experienced serious adverse events and 1,558 (23.9%) reported at least 1 treatment emergent adverse event. The most commonly reported adverse event was dizziness/postural dizziness (4.8%). Hypotension/postural hypotension was uncommon (0.7%). Age, cardiovascular comorbidity and antihypertensive co-medication had no impact on the safety profile of 10 mg alfuzosin OD. Alfuzosin (10 mg) OD is effective and well tolerated, and it has marginal effects on blood pressure, including in elderly patients and those with hypertension, ischemic heart disease or diabetes and those receiving antihypertensive agents.

Pharmacokinetics and total elimination of meropenem and vancomycin in intensive care unit patients undergoing extended daily dialysis*

Extended daily dialysis (EDD) combines the advantage of both intermittent hemodialysis and continuous renal replacement therapy: excellent detoxification accompanied by cardiovascular tolerability. The aim of this study was to evaluate pharmacokinetics of meropenem and vancomycin in critically ill patients with renal failure undergoing EDD. Prospective clinical study. Surgical intensive care unit in a tertiary care center. We studied intensive care patients with anuric acute renal failure being treated with EDD and receiving meropenem (n = 10) or vancomycin (n = 10) therapy. The antibiotics were administered 6 hrs (1.0 g meropenem) or 12 hrs (1.0 g vancomycin) before EDD was started in order to study the pharmacokinetics before and during EDD. In addition to the application of different methods to calculate pharmacokinetic parameters, the total dialysate concentration of both drugs was measured. Based on the amount of the drug recovered from the collected spent dialysate, the fraction of drug removed by one dialysis treatment was 18% for meropenem and 26% for vancomycin. Dosing regimes for intermittent hemodialysis and continuous renal replacement therapy cannot be used for critically ill patients treated with EDD. Our data suggest that patients treated with EDD by means of a high-flux dialyzer (polysulphone; surface area, 1.3 m; blood and dialysate flow, 160 mL/min; EDD time, 480 mins) and current dosing regimens run the risk of being significantly underdosed, which may have detrimental effects on critically ill patients with life-threatening infections. The exact dose has to be tailored according to weight and severity of illness as well as the current minimal inhibitory concentration against the incriminated bacteria. Whenever possible, therapeutic drug monitoring should be performed.

Effects of ??1-Adrenoceptor Antagonists on Male Sexual Function

alpha(1)-Adrenoceptor antagonists such as alfuzosin, doxazosin, tamsulosin and terazosin are first-line agents for the treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH), but are only second-line agents (doxazosin and terazosin only) for the treatment of arterial hypertension. Sexual function is complex and includes multiple domains such as sexual desire (libido), erectile function and ejaculatory function. Erectile and ejaculatory functions are frequently reduced in patients with BPH and can impact on their quality of life. Therefore, the treatment of BPH should aim to maintain or even restore sexual function.alpha(1)-Adrenoceptor antagonists lack major effects on sexual desire in placebo-controlled studies. Reports on erectile function are inconsistent, with both beneficial and adverse effects being reported, but impotence can occur in some patients without clear differences between drugs. Ejaculatory dysfunction during treatment may represent (relative) an ejaculation. It occurs more frequently with tamsulosin than with other drugs of this class, but the differences are not big enough to be consistently detectable in directly comparative studies. We propose that such differences between drugs should be weighed against differences in cardiovascular tolerability when choosing the optimal treatment for each patient.

Technology Insight: treatment of renal failure in the intensive care unit with extended dialysis

Sustained low-efficiency dialysis (SLED) is an increasingly popular extracorporeal renal replacement therapy for patients with renal failure in the intensive care unit (ICU). Several centers across the world employ this 'hybrid' technique, which has advantages of both intermittent and continuous methods. The goal of these centers is to provide an easy-to-perform treatment with reduced solute clearances for prolonged periods. Many centers use standard, sophisticated dialysis equipment for SLED. An increasing number of hospitals in Europe and South America employ a single-pass batch dialysis system, the procedural simplicity of which makes it an ideal modality for SLED in the ICU. All systems offer the advantages of flexible timing of treatment and reduced costs; their ease of handling means that SLED is readily accepted by ICU staff. Prospective controlled studies have shown that SLED clears small solutes with an efficacy comparable to that of intermittent hemodialysis and continuous venovenous hemofiltration (even when the latter employs high rates of fluid substitution). Cardiovascular tolerability associated with SLED is similar to that associated with continuous renal replacement therapy, even in severely ill patients. Nocturnal dialysis -- a special form of SLED -- has all the advantages outlined above, with the added benefit of unrestricted physician access to the patient during the day, minimizing the interference of renal replacement therapy with other ICU activities.

A single-pass batch dialysis system: an ideal dialysis method for the patient in intensive care with acute renal failure

Conventional intermittent hemodialysis and continuous veno-venous hemofiltration are the opposite poles of current treatment modalities for patients with acute renal failure in the intensive care unit. Because both intermittent and continuous renal replacement techniques have several disadvantages, alternative treatment strategies have been developed. This review summarizes relevant information on these new hybrid techniques, and special attention is paid to the use of a single-pass batch dialysis system in the intensive care unit. Prospective controlled studies have been published from several centers that use standard dialysis equipment for hybrid techniques, called sustained low-efficiency dialysis or slow extended dialysis. Their common therapeutic aim is to provide an easy-to-perform treatment with reduced solute clearances maintained for prolonged periods of time. These studies have documented that sustained low-efficiency dialysis offers (1) solute removal that is comparable with that obtained with intermittent hemodialysis and continuous veno-venous hemofiltration, even if high substitution fluid rates are used, (2) cardiovascular tolerability like that observed with continuous veno-venous hemofiltration, (3) significantly reduced heparin use in comparison with continuous veno-venous hemofiltration, (4) simple handling and high acceptance by the intensive care unit staff, (5) reduced treatment costs, and (6) the possibility of nocturnal treatments, allowing unrestricted patient access for daytime procedures. Sustained low-efficiency dialysis is increasingly being used as renal replacement therapy in critically ill patients in the intensive care unit. It combines several advantages of both intermittent and continuous techniques. The procedural simplicity, particularly if single-pass batch dialysis is used, makes it an ideal treatment for patients with renal failure in the intensive care unit.

Selecting against S1P 3 enhances the acute cardiovascular tolerability of 3-(N-benzyl)aminopropylphosphonic acid S1P receptor agonists

Structurally modified 3-(N-benzylamino)propylphosphonic acid S1P receptor agonists that maintain affinity for S1P 1, and have decreased affinity for S1P 3 are efficacious, but exhibit decreased acute cardiovascular toxicity in rodents than do nonselective agonists.

Cardiovascular tolerability and safety of triptans: a review of clinical data.

Triptans are not widely used in clinical practice despite their well-established efficacy, endorsement by the US Headache Consortium, and the demonstrable need to employ effective intervention to reduce migraine-associated disability. Although the relatively restricted use of triptans may be attributed to several factors, research suggests that prescribers' concerns about cardiovascular safety prominently figure in limiting their use. This article reviews clinical data--including results of clinical trials, postmarketing studies and surveillance, and pharmacodynamic studies--relevant to assessing the cardiovascular safety profile of the triptans. These data demonstrate that triptans are generally well tolerated. Chest symptoms occurring during use of triptans are usually nonserious and usually not attributed to ischemia. Incidence of triptan-associated serious cardiovascular adverse events in both clinical trials and clinical practice appears to be extremely low. When they do occur, serious cardiovascular events have most often been reported in patients at significant cardiovascular risk or in those with overt cardiovascular disease. Adverse cardiovascular events also have occurred, however, in patients without evidence of cardiovascular disease. Several lines of evidence suggest that nonischemic mechanisms are responsible for sumatriptan-associated chest symptoms, although the mechanism of chest symptoms has not been determined to date. Importantly, most of the clinical trials and clinical practice data on triptans are derived from patients without known cardiovascular disease. Therefore, the conclusions of this review cannot be extended to patients with cardiovascular disease. The cardiovascular safety profile of triptans favors their use in the absence of contraindications.

Selecting against S1P3 enhances the acute cardiovascular tolerability of 3-(N-benzyl)aminopropylphosphonic acid S1P receptor agonists

Structurally modified 3-(N-benzylamino)propylphosphonic acid S1P receptor agonists that maintain affinity for S1P1, and have decreased affinity for S1P3 are efficacious, but exhibit decreased acute cardiovascular toxicity in rodents than do nonselective agonists.

In vitro and in vivo characterization of TC‐1827, a novel brain α4β2 nicotinic receptor agonist with pro‐cognitive activity

AbstractNicotine activates specific receptors that are cation‐permeable ionic channels located in the central and autonomous nervous systems, as well as at the neuromuscular junction. Administration of nicotine to animals and humans has been shown to enhance cognitive processes. However, side effects linked to the activation of peripheral nicotinic receptors limit the usefulness of nicotine for the treatment of cognitive disorders such as Alzheimer's disease (AD) or mild cognitive impairments (MCI). The synthesis and properties of TC‐1827, a novel metanicotine derivative that activates brain α4β2 nicotinic receptors is described. TC‐1827 has high affinity for nicotine‐labeled receptors in the cortex (Ki=34 nM), full‐agonist intrinsic activity in α4β2‐mediated neurotransmitter release studies in synaptosomes, and has no functional activity at nicotinic receptors in ganglionic or muscular cell lines. The compound enhances long‐term potentiation in hippocampal slices, a form of synaptic plasticity thought to be involved in information storage at the cellular level. In vivo studies demonstrate that TC‐1827 dose‐dependently occupies thalamic nicotinic receptors labeled with [3H]‐cytisine, increases cortical extracellular acetylcholine levels following oral administration, and enhances cognitive performance in rat and mice behavioral procedures of learning and memory. Pharmacokinetic studies in mice, rats, and monkeys indicated that TC‐1827 has good oral absorption with a first pass effect resulting in bioavailabilities of 13–65% across dose/species. Cardiovascular safety studies indicate good cardiovascular tolerability for this compound. The present data demonstrate that TC‐1827 is a selective and potent activator of brain α4β2 nicotinic receptors and is a prototypical member of a new class of compounds with potential utility in the symptomatic treatment of cognitive disorders including AD and MCI. Drug Dev. Res. 62:26–40, 2004. © 2004 Wiley‐Liss, Inc.

Extended-release alfuzosin hydrochloride: A new alpha-adrenergic receptor antagonist for symptomatic benign prostatic hyperplasia

Background: Extended-release (ER) alfuzosin hydrochloride is the most recently approved alpha-adrenergic receptor antagonist (AARA) for the management of symptomatic benign prostatic hyperplasia (BPH). Although new to the United States, alfuzosin has been available in immediate-release (IR) and sustained-release (SR) formulations in other countries for many years. Objective: This article reviews data on the pharmacodynamics, pharmacokinetics, efficacy, tolerability, drug-interaction potential, and dosing of alfuzosin ER. Methods: Relevant articles were identified through MEDLINE, EMBASE, and International Pharmaceutical Abstracts searches of the English-language literature published between 1986 and September 2003 using the terms alfuzosin, alpha-adrenergic receptor antagonists, and quinazolines. The reference lists of identified articles were also searched, as were abstracts from annual meetings of the American Urological Association for the past 5 years. Data regarding the ER formulation were emphasized, and data involving the IR/SR formulations were included only when data for the ER formulation were not available or as needed for clarification. Results: In comparative trials with its IR counterpart (alfuzosin ER 10 mg QD vs alfuzosin IR 2.5 mg TID), alfuzosin ER was an equieffective once-daily AARA. No comparative trials of alfuzosin ER with the SR (BID) formulation or with other AARAs were identified. Food has been found to exert a clinically important effect by enhancing the bioavailability of the ER formulation; thus, the drug should be taken on a full stomach. Hepatic impairment has been found to significantly delay the elimination of alfuzosin IF, which constitutes a contraindication to use of the ER formulation. Renal impairment does not appear to exert clinically important effects on the pharmacokinetics of alfuzosin ER. Adverse events with alfuzosin ER include dizziness, upper respiratory tract infection, headache, and fatigue, with hypotension and syncope reported rarely. Concurrent use of inhibitors of the cytochrome P450 3A4 isozyme (eg, ketoconazole, diltiazem, cimetidine, atenolol) can significantly elevate serum concentrations of alfuzosin and enhance its pharmacodynamic effects. Conclusions: In the absence of direct head-to-head comparative trials, the role of alfuzosin ER in the management of symptomatic BPH relative to that of other AARAs is unclear. Because the effect size (drug response minus placebo response) of alfuzosin ER is comparable to that of other AARAs, marked differences in efficacy are unlikely. Extrapolating from direct comparative trials between these agents and alfuzosin IR/SR, alfuzosin ER would be expected to have better cardiovascular tolerability (eg, in terms of dizziness and orthostasis) than prazosin, terazosin, or doxazosin, and to have similar tolerability to tamsulosin. However, the existing data do not suggest that alfuzosin ER is likely to represent a significant advance over tamsulosin.

Efficacy and cardiovascular tolerability of extended dialysis in critically ill patients: a randomized controlled study

Background: Extended dialysis is an increasingly used modality of renal replacement therapy that theoretically offers advantages of both intermittent and continuous therapies in the intensive care unit (ICU). Methods: We randomly treated 39 ventilated critically ill patients with oliguric acute renal failure with either continuous venovenous hemofiltration (CVVH; n = 19; age, 50.1 ± 3.2 years; Acute Physiology and Chronic Health Assessment II [APACHE II] score, 32.3 ± 1.2; 79% sepsis) and a substitution fluid rate of at least 30 mL/kg/h for 24 hours or with extended dialysis for 12 hours (n = 20; age, 50.8 ± 3.6 years; APACHE II score, 33.6 ± 1.0; 85% sepsis). The latter was performed using an easy-to-handle, single-pass, batch dialysis system. All hemodynamic parameters were monitored invasively by means of an indwelling arterial catheter. Results: Average mean arterial blood pressure, heart rate, cardiac output, systemic vascular resistance, and catecholamine dose were not significantly different in both therapies. Urea reduction rate was similar with extended dialysis compared with CVVH therapy (53% ± 2% versus 52% ± 3%; P = not significant) despite an average rate of substitution fluid with the latter of 3.2 ± 0.1 L/h. This was corroborated by the finding of similar amounts of urea eliminated in the collected spent total hemofiltration and dialysis fluid. Correction of acidosis was accomplished faster with extended dialysis than CVVH, and the amount of heparin used was significantly lower with extended dialysis (P < 0.01). Conclusion: Extended dialysis combines excellent detoxification with cardiovascular tolerability, even in severely ill patients in the ICU. The technically simple dialysis system used offers flexibility of treatment time.