Cardiovascular Tolerability Research Articles

Cardiovascular events reported in patients with B-cell malignancies treated with zanubrutinib

AbstractFirst-generation Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, has been associated with an increased risk of cardiovascular toxicities. Zanubrutinib is a more selective, next-generation BTK inhibitor. In this analysis, incidence rates of atrial fibrillation, symptomatic (grade ≥2) ventricular arrhythmia, and hypertension were evaluated in a pooled analysis of 10 clinical studies with zanubrutinib monotherapy in patients (N = 1550) with B-cell malignancies and a pooled analysis of head-to-head studies comparing zanubrutinib with ibrutinib (ASPEN cohort 1; ALPINE). Among the 10 studies, most patients (median age, 67 years) were male (66.3%) and had CLL/SLL (60.5%). Overall incidence and exposure-adjusted incidence rates (EAIR) for atrial fibrillation, symptomatic ventricular arrhythmia, and hypertension were lower with zanubrutinib than ibrutinib. Despite a similar prevalence of preexisting cardiovascular events in ASPEN and ALPINE, atrial fibrillation/flutter incidence rates (6.1% vs 15.6%) and EAIR (0.2 vs 0.64 persons per 100 person-months; P < .0001) were lower with zanubrutinib than with ibrutinib. Symptomatic ventricular arrhythmia incidence was low for both zanubrutinib (0.7%) and ibrutinib (1.7%) with numerically lower EAIR (0.02 vs 0.06 persons per 100 person-months, respectively) for zanubrutinib. The hypertension EAIR was lower with zanubrutinib than ibrutinib in ASPEN but similar between treatment arms in ALPINE. The higher hypertension EAIR in ALPINE was inconsistent with other zanubrutinib studies. However, fewer discontinuations (1 vs 14) and deaths (0 vs 6) due to cardiac disorders occurred with zanubrutinib versus ibrutinib in ALPINE. These data support zanubrutinib as a treatment option with improved cardiovascular tolerability compared with ibrutinib for patients with B-cell malignancies in need of BTK inhibitors. These trials were registered at www.ClinicalTrials.gov as # NCT03053440, NCT03336333, NCT03734016, NCT04170283, NCT03206918, NCT03206970, NCT03332173, NCT03846427, NCT02343120, and NCT03189524.

Efficacy and safety of tofacitinib in the treatment of rheumatoid arthritis: results of 10 years of use

The article presents a review of the basic data on the efficacy and safety of the drug tofacitinib, the place of the drug in the treatment of rheumatoid arthritis (RA) patients according to current international and Russian recommendations. Data on the mechanism of action of Janus kinase inhibitors, the spectrum of cytokines inhibited by tofacitinib is presented. The results of major randomised controlled trials demonstrating high clinical efficacy in patients who have not responded to methotrexate (MT) and other synthetic classical anti-rheumatic drugs (SCARDs), genetically engineered biologic drugs, are presented, with equal efficacy of tofacitinib when given as monotherapy or in combination with MT or other SCARDs, with adalimumab. The safety of tofacitinib with long-term treatment (up to 9.5 years) is analysed. The cardiovascular tolerability of tofacitinib is presented separately, considering the proposals discussed at the last EULAR 2022 Congress. The low incidence of serious cardiovascular adverse events, including venous thrombosis and thromboembolism over the long-term follow-up period, and the risk of these adverse events, which was no higher than on the selective Janus kinase inhibitor baricitinib, are presented. Changes in laboratory parameters (haemoglobin, neutrophil count, aminotransferase concentration) during tofacitinib administration are described. Domestic data on the use of tofacitinib in the treatment of RA patients is demonstrated. An association was shown between early clinical response to tofacitinib (5 mg twice daily) and a reduction in RA activity after 3 and 6 months in RA patients. Tofacitinib in real clinical practice showed early development of effect (by week 12) in the group of patients who did not respond to MT and in 60% of cases to genetically engineered biologic drugs, with respect to indicators of inflammatory activity of RA and functional status of patients. Domestic authors have noted the high safety of tofacitinib. A domestic generic version of the original drug tofacitinib has been reported to be registered for the same indications: RA, psoriatic arthritis, plaque psoriasis, ulcerative colitis.

Design and optimisation of dendrimer-conjugated Bcl-2/xL inhibitor, AZD0466, with improved therapeutic index for cancer therapy

Dual Bcl-2/Bcl-xL inhibitors are expected to deliver therapeutic benefit in many haematological and solid malignancies, however, their use is limited by tolerability issues. AZD4320, a potent dual Bcl-2/Bcl-xL inhibitor, has shown good efficacy however had dose limiting cardiovascular toxicity in preclinical species, coupled with challenging physicochemical properties, which prevented its clinical development. Here, we describe the design and development of AZD0466, a drug-dendrimer conjugate, where AZD4320 is chemically conjugated to a PEGylated poly-lysine dendrimer. Mathematical modelling was employed to determine the optimal release rate of the drug from the dendrimer for maximal therapeutic index in terms of preclinical anti-tumour efficacy and cardiovascular tolerability. The optimised candidate is shown to be efficacious and better tolerated in preclinical models compared with AZD4320 alone. The AZD4320-dendrimer conjugate (AZD0466) identified, through mathematical modelling, has resulted in an improved therapeutic index and thus enabled progression of this promising dual Bcl-2/Bcl-xL inhibitor into clinical development.

Cardiovascular outcomes, safety, and tolerability with oral semaglutide: insights for managed care.

It is important to consider the safety profile of new medications in type 2 diabetes (T2D) when selecting the most appropriate treatment option for each patient. This can help ensure that patients achieve optimal response, that those experiencing adverse events are appropriately managed, and that treatment is tailored for those with pre-existing conditions such as cardiovascular disease (CVD), which is the leading cause of death in patients with T2D. The American Diabetes Association and American Association of Clinical Endocrinologists/American College of Endocrinology recommend a glucagon-like peptide-1 receptor agonist (GLP-1RA) or sodium-glucose cotransporter 2 inhibitor with proven cardiovascular (CV) benefit in patients with established CVD or those at high risk of CVD. Injectable semaglutide is approved by the FDA for reducing the risk of major CV events in adults with T2D and established CVD. In PIONEER 6, the CV safety of the first GLP-1RA tablet, oral semaglutide, was noninferior to placebo, and a longer-term study (SOUL; NCT03914326) powered to assess a potential CV benefit is ongoing. The safety and tolerability profile of oral semaglutide across the PIONEER clinical trial program was consistent with the GLP-1RA class. The most common adverse events were gastrointestinal (GI) (eg, nausea, diarrhea, and vomiting), which were typically mild to moderate and transient. In clinical practice, oral semaglutide expands the treatment options available to patients with T2D and can be considered in patient populations suitable for injectable GLP-1RAs.

A pilot study on secondary anemia in "frailty" patients treated with Ferric Sodium EDTA in combination with vitamin C, folic acid, copper gluconate, zinc gluconate and selenomethionine: safety of treatment explored by HRV non-linear analysis as predictive factor of cardiovascular tolerability.

Iron deficiency anemia (IDA) in patients with heart disease is correlated with decreased exercise capacity and poor health-related quality of life, and predicts worse cardiovascular outcomes, especially for elderly patients. IDA can worsen cardiac function that can be monitored with Heart Rate Variability (HRV) analysis, providing important information about cardiac health. In a recent study we explored the effect and the tolerability of the administration of Ferric Sodium EDTA in combination with vitamin C, folic acid, copper gluconate, zinc gluconate and selenomethionine (Ferachel Forte®) in "frailty" patients with secondary anemia and low kidney failure, by analysing the HRV frequency domain. The aim of the present study is the further confirmation of the safety of the already evaluated intervention, by analysing non-linear domain of HRV. In this pilot study we enrolled 52 "frailty" elderly patients, with a recent diagnosis of secondary anemia due to iron deficiency, with Class II New York Heart Association (NYHA) hypertensive heart disease, low kidney failure, and atherosclerosis. The patients were divided in 2 groups: Group A (N=23 patients) received oral administration of Ferric Sodium EDTA in combination with vitamin C, folic acid, copper gluconate, zinc gluconate and selenomethionine (Ferachel Forte®) 2 tabs/day, containing 60 mg of Fe3+, for 24 days; Group B (N=29 patients) received intravenous administration of ferrous gluconate 63 mg/day added to saline solution, while they were hospitalized (15±5 days). We evaluated laboratory values of hemoglobin (Hb) and sideremia levels. Furthermore, we measured ECG signals before and after treatment, using non-linear analysis techniques. Both intravenous and oral treatments evaluated in this study, were effective and safe about the cardiovascular risk in "frailty" elderly patients, as resulted from non-linear HRV analysis. Efficacy results showed that hemoglobin and sideremia levels after treatments are significantly increased. The HRV non-linear analysis showed that all parameters evaluated, except for the SD1 values in the Group A, were not affected by treatments, confirming the absence of cardiovascular risk of the therapy. Non-linear HRV evaluation confirmed that oral administration of Ferric Sodium EDTA, in combination with vitamin C, folic acid, copper gluconate, zinc gluconate and selenomethionine (Ferachel forte®) did not impact the cardiovascular risk, without causing adverse events typically reported with other iron supplementation therapies, both oral and intravenous.

Long-term treatment with supraphysiologic doses of levothyroxine in treatment-refractory mood disorders – A prospective study of cardiovascular tolerability

BackgroundTo investigate long-term effects of adjunctive prophylactic treatment with supraphysiologic doses of levothyroxine (L-T4) on cardiovascular tolerability in 23 patients with treatment-refractory mood disorders. MethodsStarting point for a comprehensive cardiovascular assessment in patients was the indication for long-term maintenance treatment with L-T4 (mean dose 463 mcg/day). Prospective longitudinal assessment of the cardiovascular risk profile included in addition to a physical examination and blood pressure measurement, several technical investigations: resting electrocardiogram, transthoracic echocardiogram, cardiac stress test, and holter electrocardiogram. Statistical analysis was performed by linear mixed effects models (LMM) for evaluation of longitudinal changes in various heart measures. ResultsDuring the mean observational period of 20.4 months none of the heart measures reached statistical significance in change over time. None of the assessed cardiac parameters of each single patient was in a range predictive for cardiac dysfunction. LimitationsSmall sample size, no technical cardiac investigations prior to L-T4 initiation, no patient control group with mood disorders who did not receive L-T4. ConclusionsResults of this study indicated no increased risk for cardiovascular disorders during treatment with supraphysiologic L-T4 doses in patients with refractory mood disorders.

Renal Support for Acute Kidney Injury in the Developing World

There is wide variation in the management of acute kidney injury (AKI) and the practice of renal replacement therapy (RRT) around the world. Clinicians in developing countries face additional challenges due to limited resources, reduced availability of trained staff and equipment, cultural and socioeconomic aspects, and administrative and governmental barriers. In this article, we report the consensus recommendations from the 18th Acute Dialysis Quality Initiative conference in Hyderabad, India. We provide the minimal requirements for provision of acute RRT in developing countries, including patient selection, choice of RRT modality and monitoring, transition, and termination of acute RRT. We also discuss areas of uncertainty and propose themes for future research. These recommendations can serve as a foundation for clinicians to implement renal support for AKI in low resource settings.

Evaluation of the Effects of CHF6001, an Inhaled PDE4 Inhibitor, on Cardiac Repolarization and Cardiac Arrhythmias in Healthy Volunteers.

Chronic obstructive pulmonary disease (COPD) is a multicomponent condition characterized by airway inflammation and associated to comorbidities, including cardiovascular diseases. Among anti-inflammatory agents in development for COPD, the phosphodiesterase inhibitors administrated by inhalation have the potential for increased efficacy and reduced systemic side effects. CHF6001 is an inhaled PDE4 inhibitor with proven anti-inflammatory properties in animal models. This randomized, double-blind, placebo-controlled study was aimed to demonstrate its cardiovascular safety and tolerability in healthy male volunteers with normal electrocardiogram and cardiac parameters. Single and multiple ascending doses (7 days of administration) of CHF6001 were administered. Three electrocardiograms were recorded at several pharmacokinetic time points and at each time points, postdose heart rate, QRS and PR intervals, and presence of arrhythmia were evaluated. In single ascending dose, QTcF intervals did not increase more than 30 milliseconds from the baseline, all heart rate was between 45 and 100 bpm, and no statistically significant differences were observed in PR and QRS intervals. In multiple ascending dose, cardiac parameters did not differ significantly from baseline. In the pharmacokinetic/pharmacodynamic analysis, no medically or clinically significant changes were found. Further studies are ongoing to demonstrate that CHF6001 is safe and well tolerated in COPD patients as well.

Direct inhibition of plasmatic renin activity with aliskiren: a promising but under-investigated therapeutic option for non-diabetic glomerulonephritis.

Non-diabetic glomerulonephritis is a frequent cause of end-stage renal disease. The use of renin-angiotensin-aldosterone system blockers is a fundamental therapeutic approach. However, converting enzyme inhibitors (ACE-is) and angiotensin receptor blockers do not always achieve the desired target of proteinuria. The induction of the prorenin and renin up-regulation is a possible explanation. Aliskiren is the first drug acting as direct inhibitor of plasmatic renin activity, also able to interfere with the prorenin and renin profibrotic escape. We aimed at reviewing the literature for the assessment of potential efficacy and safety of aliskiren in the treatment of non-diabetic glomerulonephritis. The data on this topic are limited; however, we concluded for a possible usefulness of aliskiren. The renal safety profile appears potentially acceptable in non-diabetic patients although extreme carefulness, particularly with respect to long-term renal and cardiovascular tolerability, is recommended.

Pharmacokinetics, safety, and cardiovascular tolerability of phenylephrine HCl 10, 20, and 30 mg after a single oral administration in healthy volunteers.

Background and ObjectivesPhenylephrine HCl 10 mg has been used as a nasal decongestant for over 50 years, yet only limited pharmacokinetic and metabolic data are available. The purpose of this study was to evaluate single-dose pharmacokinetics and safety of phenylephrine HCl 10, 20, and 30 mg and to assess cardiovascular tolerability compared with baseline and placebo in healthy volunteers.MethodsTwenty-eight adults were enrolled in this randomized, double-blind, placebo-controlled, single-dose, four-treatment crossover study. Subjects remained housed for 6 days to permit time-matched, serial measurements of pulse, blood pressure, and electrocardiograms (ECGs) for baseline and complete treatments on consecutive days. After fasting overnight, subjects were dosed with oral phenylephrine HCl 10, 20, or 30 mg or placebo. Pharmacokinetic blood samples were collected over 7 h, whereas pulse, blood pressure, and ECGs were measured over 12 h. Urine was collected over each 24-h period to quantify phenylephrine and metabolites.ResultsAfter oral administration, phenylephrine was rapidly absorbed with median times to maximum plasma concentrations (tmax) from 0.33 to 0.5 h. For phenylephrine HCl 10, 20, and 30 mg, the mean (standard deviation) maximum concentration (Cmax) was 1354 (954), 2959 (2122), and 4492 (1978) pg/mL, and total systemic exposure [area under the plasma concentration–time curve from time zero to infinity (AUC∞)] was 955.8 (278.5), 2346 (983.8), and 3900 (1764) pg·h/mL, respectively. Both parameters increased disproportionally with increasing dose, as β >1 in the power model. Negligible amounts of phenylephrine and phenylephrine glucuronide were excreted in urine. With increasing dose, percentages by dose of phenylephrine sulfate decreased, whereas percentages of 3-hydroxymandelic acid increased. Eight subjects reported nine mild adverse events; one (somnolence) was deemed to be treatment related. Means of time-matched differences in pulse and blood pressure from baseline showed similar fluctuations over 12 h among phenylephrine HCl doses and placebo, although small differences in systolic pressure were observed during the initial 2 h. No apparent dose-related effects were observed for Fridericia-corrected QT interval (QTcF) values, and individual changes from time-matched baseline (DQTcF).ConclusionsMaximum and total systemic exposures following singe doses of phenylephrine HCl 10, 20, and 30 mg increased disproportionally with increasing dose. Safety and cardiovascular tolerability were comparable among doses and placebo.

Oral contraception for midlife women

Midlife women are women short before or within the perimenopause who need especially effective contraception since unwanted pregnancies are risk pregnancies due to the higher age and often due to increasing cardiovascular risk. Weight gain, tendency to hypertension, lipid disturbance and diabetic conditions often are seen, but even in healthy women the risk of venous thromboembolism (VTE) is increased. The choice could be using progestin-only contraception like levonorgestrel-IUDs, progestin-only pills or implants, potentially combined with transdermal estradiol especially since climacteric symptoms or risk of osteoporosis are frequent in this age-group. However, often bleeding problems lead to the question if combined oral contraceptives (COC) also may be used. Up to recently all preparations available throughout the world have used only ethinylestradiol (EE). In cardiovascular healthy women these COC can be used also in perimenopause, recommended up to 52 (−54) years. If the combination with levonorgestrel should be preferred remains controversial due to the different results of studies on the VTE risk. Two COC now are available containing Estradiol(E2)valerat and dienogest (DNG) in a four-phasic pill or E2 and nomegestrol acetate (NOMAC) in a 24/28 monophasic regimen. Hepatic and cardiovascular tolerability is expected to be better than with EE, for example. During the development of E2-derived COC irregular bleedings have been the main problem which is solved with those two pills due to endometrial stability caused by low, but constant continuous E2-levels and strong progestagenic efficacy of DNG and NOMAC, resp., leading to short or even missing withdrawal bleedings in most women. The E2-derived COC are expected to provide further benefits which, however, have to be verified in the future through targeted studies on larger populations than those studied during clinical development.

Aripiprazole (ABILIFY MAINTENA®): a review of its use as maintenance treatment for adult patients with schizophrenia.

Aripiprazole (ABILIFY(®)) is an atypical antipsychotic drug that is proposed to act via partial agonism of dopamine D2 receptors. Trials with oral aripiprazole have shown that, compared with some other atypical antipsychotics, aripiprazole is associated with fewer metabolic disturbances and has a favourable cardiovascular tolerability profile. Recently, an intramuscular long-acting injectable (LAI) depot formulation of aripiprazole (ABILIFY MAINTENA(®)) (aripiprazole LAI) has been approved for use as a treatment for schizophrenia in adults. The efficacy of aripiprazole LAI as a maintenance treatment for schizophrenia has been demonstrated in randomized clinical trials. In the trials, aripiprazole LAI was more effective than placebo, and noninferior to oral aripiprazole, in delaying relapse and in reducing relapse rates in schizophrenia. Aripiprazole LAI was generally well tolerated, with a tolerability profile consistent with that of oral aripiprazole. Thus, aripiprazole LAI is a valuable new treatment option for adult patients with schizophrenia. It may be of particular use for patients stable on oral aripiprazole who would prefer, or are likely to benefit from, a long-acting formulation.

STATINS IN THE TREATMENT AND PREVENTION OF CARDIOVASCULAR DISEASES: REPETITION OF THE PAST AND OPTIMISM FOR THE FUTURE

Statins, the most common drugs for reduction in lipid levels, are “strategic” medicinal products for the treatment and prevention of cardiovascular diseases caused by atherosclerosis. The milestones of lipid-lowering therapy history are presented as well as its contemporary aims and their implementation with focus on rosuvastatin. Data of recent metaanalysis regarding statins efficacy in primary and secondary prevention of cardiovascular complications, good safety and tolerability profile were presented. Treatment of patients with acute coronary syndrome with modern statins in high doses is discussed specially. Clinical case study of long-term treatment with rosuvastatin 20 mg/day is described. Frequency of statin prescriptions and achievements of target lipid levels in real medical practice among population of Russian patients is evaluated according to results of LIS study and PROFILE registry. Results of Russian studies of therapeutic equivalence of generic drug with original rosuvastatin are presented.

Lurasidone (Latuda®): An Atypical Antipsychotic

Lurasidone is a new atypical antipsychotic that has demonstrated positive effects on psychosis, mood, and cognition. This improved efficacy and safety profile for the treatment of schizophrenia. Its overall tolerability profile seems to be comparable to the other atypical antipsychotics. Perhaps its more potent blockade on the 5HT7 receptor will give it more of an advantage in treating the negative symptoms as well as improve cognitive and depressive symptoms associated with schizophrenia. Additionally, it does not appear to have any significant adverse impact on the metabolic profile, such as weight, glucose, or lipid metabolism. Lurasidone is also associated with good cardiovascular tolerability without widening of the QT interval. The use of this medication may be of particular interest in patients presenting with endocrine or cardiovascular abnormalities. The average price for a 30-day supply of lurasidone is $475.98.

Cardiovascular Effects and Safety of Fingolimod in Clinical Practice (P04.138)

Objective: To describe the cardiovascular safety and tolerability of fingolimod in a clinical/academic practice. Background Fingolimod is approved by the FDA for relapsing multiple sclerosis (RRMS). Bradycardia and slowing of AV conduction were observed with fingolimod initiation in clinical trials. Screening electrocardiogram (EKG) and a first dose observation (FDO) period is recommended in all patients starting this medication. Design/Methods: Patients starting fingolimod from December 2010 to August 2011 were identified through the electronic medical record database. Demographics, cardiovascular history, screening EKG, cardiology consultation notes, FDO experience and 3 month follow-up data were retrieved and tabulated. Results: A total of 318 patients were identified. A history of hypertension was present in 30 (9.4%) of patients and a history of cardiac disease was present in 8 (2.5%) patients. Betablockers, calcium channel blockers, and digoxin were used by 3.7%, 2.8%, and 0.6% of patients respectively. Pretreatment EKG studies were available in 300 (94.3%) patients and were abnormal in 80 (25.2%) cases. Cardiology consultation was requested in 33 (10.4%) patients and use of fingolimod was cleared for all. During FDO mean heart rate change was -11.5 bpm (p Conclusions: Screening EKG showed abnormalities in a quarter of patients starting fingolimod, and identified patients at risk for symptomatic bradycardia. Fingolimod was well tolerated and no severe or serious cardiovascular adverse effects were encountered during FDO. Disclosure: Dr. Bermel has received personal compensation for activities with Astellas, Biogen Idec, Novartis, and Teva Neuroscience as a consultant and/or speaker. Dr. Ontaneda has nothing to disclose. Dr. Hara-Cleaver has received personal compensation for activities with Biogen Idec, Novartis, Serono, Inc., and TEVA Neuroscience as a consultant. Dr. Rudick has received personal compensation for activities with Biogen Idec, Genzyme, and Wyeth/Pfizer. Dr. Rudick has received research support from Biogen Idec through the Cleveland Clinic. Dr. Cohen has received personal compensation for activities with Biogen Idec, Eli Lilly & Company, Novartis, and Vaccinex. Dr. Cohen has received research support for activities with Biogen Idec, BioMS, Genzyme Corporation, Novartis, Synthon, and Teva Neuroscience.

Silodosin: a guide to its use in benign prostatic hyperplasia

The highly selective α1A-adrenergic receptor antagonist silodosin rapidly improves the signs and symptoms of benign prostatic hyperplasia (BPH). Oral silodosin is generally well tolerated in men with BPH, with a favourable cardiovascular tolerability profile. Abnormal ejaculation is the most commonly reported adverse effect associated with silodosin therapy; however, only 3.9% of patients discontinued treatment due to this event.

Aripiprazole

Oral aripiprazole (Abilify®) is an atypical antipsychotic agent that is approved worldwide for use in adult patients with schizophrenia. It is a quinolinone derivative that has a unique receptor binding profile as it exhibits both partial agonist activity at dopamine D(2) receptors and serotonin 5-HT(1A) receptors and antagonist activity at 5-HT(2A) receptors. In several well designed, randomized, clinical trials of 4-6 weeks duration, aripiprazole provided symptomatic control for patients with acute, relapsing schizophrenia or schizoaffective disorder. Furthermore, following 26 weeks' treatment, the time to relapse was significantly longer for patients with chronic, stabilized schizophrenia receiving aripiprazole compared with those receiving placebo. Using a variety of efficacy outcomes, aripiprazole showed a mixed response when evaluated against other antipsychotic agents in randomized clinical trials. Longer-term data showed that improvements in remission rates and response rates favoured aripiprazole over haloperidol, although, the time to failure to maintain a response was not significantly different between the treatment arms. On the other hand, improvements in positive and negative symptom scores mostly favoured olanzapine over aripiprazole, although, the time to all-cause treatment discontinuation was not significantly different between the two treatments. Several open-label, switching trials showed that aripiprazole provided continued control of symptoms in patients with schizophrenia or schizoaffective disorder. Using a variety of efficacy outcomes or quality-of-life scores, longer-term treatment generally favoured patients switched to receive aripiprazole compared with standard-of-care oral antipsychotics. Aripiprazole was generally well tolerated in patients with schizophrenia. In particular, its use seems to be associated with a lower incidence of extrapyramidal symptoms than haloperidol and fewer weight-gain issues than olanzapine. Aripiprazole also showed a favourable cardiovascular tolerability profile and its use was associated with a reduced risk of metabolic syndrome than placebo or olanzapine. As a consequence, aripiprazole may provide a more cost-effective treatment option compared with other atypical antipsychotics. In conclusion, oral aripiprazole provides an effective and well tolerated treatment alternative for the acute and long-term management of patients with schizophrenia.

Tolerance and Durability of Abacavir/Lamivudine (Abc/3tc) Containing Regimens: Results from a large French Prospective Cohort

Background: Abacavir is considered as a potent and well tolerated drug but recent controversial data have raised questions concerning cardiovascular tolerability and virological efficacy in antiretroviral initial regimen with abacavir/lamivudine (ABC/3TC). Methods: Patients were selected from the Dat’AIDS french prospective cohort if they were prescribed a regimen containing ABC/3TC free or fixed dose combination for the first time between 01/01/2004 and 31/12/2007 before HLA screening recommendation or routine usage. All causes of treatment discontinuation were recorded, as well as immuno-virological and clinical data during follow-up. Results: Among the 1704 patients included in the study (male 69%, mean age 43 years) 407 (24%) were antiretroviral naive, 696 (41%) had viral load (VL) below detection on ARV treatment (switch), and 601 (35%) were on treatment with detectable VL (failure) at time of ABC/3TC initiation. Overall 565 patients (33%) discontinued ABC/3TC combination during follow-up, among them 26% have used ABC in the next regimen. Reasons for discontinuation were intolerance in 14% of the cases - including suspected hypersensitivity (HSR) in 7% of the overall population - treatment failure in 20%, and other causes in 39%. The median time to treatment discontinuation was 52 months for the overall population. After 2 years, the probability of receiving ABC/3TC was at 62%, 77%, and 60% respectively for the defined groups. Finally, the VL on treatment was below detection for 86%, 90%, and 71%, respectively. Conclusion: In this population ABC/3TC containing regimens were maintained with virological success for more than 2 years. Tolerance issues including HSR were the main reason for early discontinuation.

Efficacy and cardiovascular tolerability of continuous veno-venous hemodiafiltration in acute decompensated heart failure: A randomized comparative study

Background and ObjectivesRecently, continuous veno-venous hemodiafiltration (CVVHDF) has received increased attention in the treatment of congestive heart failure (CHF). The aim of this study is to assess the safety and efficacy of CVVHDF compared with intravenous furosemide in patients with CHF. MethodsForty patients having CHF were included in this prospective, randomized, comparative trial. We randomized patients to treatment for 72 hours with CVVHDF or intravenous furosemide. Outcomes assessed were weight loss, total fluid output, length of stay (LOS) in the intensive care unit (ICU), 30-day mortality, and cardiovascular stability. ResultsDemographic data were comparable in both groups. Weight loss (P ≤ .05) and total fluid output (P ≤ .01) were greater in the CVVHDF group. Length of stay in the ICU was significantly reduced in the CVVHDF group (P ≤ .05). The mortality rates were comparable in both groups. The cardiac output and the stroke volume significantly increased, whereas the pulmonary capillary wedge pressure significantly decreased (P ≤ .05) in both groups compared with the baseline. A transient attack of hypotension occurred in 1 patient in the CVVHDF group. ConclusionIn CHF, the use of CVVHDF effectively and safely produced greater weight and fluid loss and decreased LOS in the ICU more than the intravenous furosemide with no hemodynamic instability.

Silodosin for the Treatment of Benign Prostatic Hyperplasia: Pharmacology and Cardiovascular Tolerability

Relief of benign prostatic hyperplasia (BPH)-related lower urinary tract symptoms by α-blockers (α₁-adrenoceptor antagonists) is mediated primarily through the blockade of α(1A)-receptors, leading to relaxation of smooth muscle in the prostate and bladder neck. Early α-blockers that were nonselective for adrenoceptor subtypes have been associated with blood pressure-related adverse effects, such as orthostatic hypotension, that may be attributed at least in part to the blockade of α(1B)-adrenoceptors in arterial vessels. Silodosin, a novel α-blocker with exceptionally high selectivity for α(1A-) versus α(1B)-adrenoceptors, was recently approved in the United States for the treatment of urinary symptoms related to BPH. The unique receptor selectivity profile likely accounts for some of the desirable clinical features of the drug. Silodosin possesses an excellent cardiac- and blood pressure-related safety profile, and data have demonstrated that it does not promote QT-interval prolongation. Therapeutic doses of silodosin are safe for men with mild-to-moderate liver dysfunction; dosage adjustment is recommended in those with moderate renal impairment. The drug should not be taken with potent cytochrome P450 3A4 inhibitors. Silodosin may be especially beneficial in patients who need to maximize cardiovascular tolerability.