Systematic Review and Meta-Analyses Assessment of the Clinical Efficacy of Bismuth Subsalicylate for Prevention and Treatment of Infectious Diarrhea.

BACKGROUND: A large number of studies have evaluated the pharmacology, safety, and/or efficacy of bismuth subsalicylate for the relief of common gastrointestinal symptoms, diarrhea and vomiting due to acute gastroenteritis. In addition, short-term (48 h) medication with bismuth subsalicylate is known to be effective against infectious gastroenteritis such as travelers' diarrhea. AIMS: Previous studies have documented the bacteriostatic/bactericidal effects of bismuth subsalicylate against a variety of pathogenic gastrointestinal bacteria. However, meta-analyses of the clinical efficacy of bismuth subsalicylate for both prevention and treatment of travelers' diarrhea have not yet been published. METHODS: A total of 14 clinical studies (from 1970s to 2007) comprised the core data used in this assessment of efficacy of bismuth subsalicylate against infectious (including travelers') diarrhea. These studies allowed for statistical meta-analyses regarding prevention (three travelers' diarrhea studies) and treatment of infectious diarrhea (11 studies [five travelers' diarrhea]). RESULTS: The results show that subjects treated with bismuth subsalicylate for up to 21 days have 3.5 times greater odds of preventing travelers' diarrhea compared with placebo (95% CI 2.1, 5.9; p < 0.001). In addition, subjects with infectious diarrhea treated with bismuth subsalicylate had 3.7 times greater odds of diarrhea relief (recorded on diaries as subjective symptomatic improvement) compared to those receiving placebo (95% CI 2.1, 6.3; p < 0.001). CONCLUSIONS: This systematic review and meta-analysis suggests that bismuth subsalicylate can be beneficial for those at risk or affected by food and waterborne diarrheal disease such as traveler's (infectious) diarrhea, and may decrease the risk of inappropriate antibiotic utilization.

Satiety effects of psyllium in healthy volunteers.

Controlling hunger between meals is a challenge for many individuals. This manuscript comprises 2 sequential clinical trials investigating the effects of psyllium (Metamucil) on satiety, both using a randomized, double-blind, placebo-controlled cross-over design. The first study determined the effects of 3.4 g, 6.8 g, and 10.2 g of psyllium taken before breakfast and lunch for 3 days. The second study determined the effects of 6.8 g (taken before breakfast and lunch on Days 1 and 2 and before breakfast on Day 3) on the satiety of participants receiving an energy restricted meal in the morning (breakfast) for 3 days. Efficacy endpoints were mean inter-meal hunger, desire to eat, and Satiety Labeled Intensity Magnitude Visual Analog Scale scores. In Study 1, all 3 psyllium doses resulted in directional or statistically significant mean reductions in hunger and desire to eat, and increased fullness between meals compared to placebo, with both higher doses better than placebo or 3.4 g. The 6.8 g dose provided more consistent (p ≤ 0.013) satiety benefits versus placebo. In Study 2, satiety was assessed similarly to Study 1. A significant (p ≤ 0.004) decrease in the 3-day mean hunger and desire to eat, as well as an increase in fullness for psyllium relative to placebo was observed. Most adverse events were mild gastrointestinal symptoms and were similar for psyllium compared to placebo. These results indicate that psyllium supplementation contributes to greater fullness and less hunger between meals.

Azimilide reduces emergency department visits and hospitalizations in patients with an implantable cardioverter-defibrillator in a placebo-controlled clinical trial.

OBJECTIVES: The goal of this study was to determine whether azimilide, as compared with placebo, will reduce the number of emergency department (ED) visits and hospitalizations caused by arrhythmias or cardiac events in patients with an implantable cardioverter-defibrillator (ICD). BACKGROUND: Patients with an ICD may require ED visits and hospitalizations because of arrhythmias, which trigger ICD therapies. The effect of adjunctive antiarrhythmic therapy on these outcomes is not known. METHODS: A total of 633 patients with an ICD were randomized in the SHIELD (SHock Inhibition Evaluation with AzimiLiDe) trial, a blinded, placebo-controlled randomized trial of the investigational class III antiarrhythmic azimilide (75 and 125 mg/day), and, prospectively, cardiac and arrhythmic ED visits and hospitalization data were collected over 1 year. RESULTS: All patients had symptomatic sustained ventricular tachycardia (72%) or ventricular fibrillation (28%) before study entry. Overall, 44% (n = 276) experienced at least 1 cardiac ED visit or hospitalization. Among 214 patients assigned to placebo, 38.3% had at least 1 arrhythmic-related ED visit or hospitalization compared with 21.8% of 220 patients assigned to 75-mg azimilide (p < 0.001) and 27.6% of 199 patients assigned to 125 mg azimilide (p < 0.05). Symptomatic ventricular tachycardia treated by antitachycardia pacing, shocks, and shocks plus symptomatic arrhythmias were significant predictors of cardiac-related ED visits or hospitalizations (relative risk: 2.0, 3.0, and 3.1, respectively). In a stepwise logistic regression model, the presence of congestive heart failure (New York Heart Association functional class II/III) was the only additional independent predictor of cardiac ED visits or hospitalizations. CONCLUSIONS: Azimilide significantly reduces the number of ED visits and hospitalizations in patients with an ICD at high risk of arrhythmias.

Electrical storm in patients with an implantable defibrillator: incidence, features, and preventive therapy: insights from a randomized trial.

AIMS: The purpose of this study was to assess the incidence, features, and clinical sequelae of 'electrical storm' (ES). METHODS AND RESULTS: This study is a prospectively designed secondary analysis of SHIELD; a randomized trial of azimilide for suppression of ventricular tachycardia/fibrillation (VT/VF) leading to implanted cardioverter defibrillator (ICD) therapies. Systematic and rigorous follow-up and blinded adjudication of ICD therapy allowed identification of all ESs (>/=3 separate VT/VF episodes leading to ICD therapies within 24 h). Of 633 ICD recipients, 148 (23%) experienced at least one ES over 1-year follow-up. No clinical predictors of ES were identified. Frequent VT episodes accounted for 91% of all ESs, with the remaining being VF alone or both VT plus VF. ES led to a 3.1-fold increase in arrhythmia-related hospitalization (95% CI 2.3-4.3; P<0.0001) compared with patients with isolated VT/VF, and to a 10.2-fold increase (95% CI 6.4-16.3; P<0.0001) compared with patients without VT/VF. Compared with placebo, azimilide (75 and 125 mg/day) reduced the risk of recurrent ES by 37% (HR=0.63, 95% CI 0.35-1.11, P=0.11) and 55% (HR=0.45, 95% CI 0.23-0.87, P=0.018), respectively. However, the reduction in time-to-first ES did not reach statistical significance by both doses (75 and 125 mg) of azimilide (HR=0.82, 95% CI 0.56-1.19, P=0.29 and HR=0.69, 95% CI 0.46-1.04, P=0.07), respectively. CONCLUSION: ES is common and unpredictable in ICD recipients and it is a strong predictor of hospitalization.

Cumulative experience of azimilide-associated torsades de pointes ventricular tachycardia in the 19 clinical studies comprising the azimilide database.

OBJECTIVES: The purpose of this study was to assess the incidence, temporal characteristics, and risk factors associated with azimilide-associated torsades de pointes (TdP) ventricular tachycardia. BACKGROUND: Azimilide dihydrochloride is a class III antiarrhythmic drug possessing Ikr and Iks channel-blocking properties. METHODS: Oral azimilide (75 to 125 mg/day) was taken by 5,375 patients in 19 clinical trials conducted at 775 international centers. Of 3,964 patients in double-blind studies, 1,427 had a history of atrial fibrillation or other supraventricular arrhythmia, 510 had an implantable cardioverter-defibrillator, and 2,027 were post-myocardial infarction patients with a left ventricular ejection fraction < or =35%. RESULTS: The TdP occurred in 56 patients assigned to azimilide, was dose-related, and tended to occur earlier with an azimilide-loading regimen. Forty-three percent of TdP patients had a QT interval corrected by Bazett's formula, for heart rate, (QTc) > or =500 ms at the time of or before the TdP occurrence. Significant risk factors using logistic regression were increasing age, female gender, diuretic use, and lack of aspirin use. CONCLUSIONS: Azimilide-associated TdP has characteristics and risk factors similar to other Ikr blockers. However, there is a distinctive temporal profile. The TdP events are not concentrated in the first week. The azimilide-associated TdP rate is 1% (95% confidence interval 0.78 to 1.35) and is not increased in patients with low left ventricular ejection fraction, even in women.

Design of the SHock Inhibition Evaluation with Azimilide (SHIELD) study: a novel method to assess antiarrhythmic drug effect in patients with an implantable cardioverter-defibrillator.

This report presents the rationale and study design details of the SHock Inhibition Evaluation with Azimilide study, which is recruiting 624 patients with implantable cardioverter-defibrillators (ICDs) who are at risk for life-threatening ventricular arrhythmia, randomized to azimilide 75 mg, azimilide 125 mg, or placebo and followed for 1 year. The objective of this study is to determine the effect of azimilide versus placebo on the symptomatic ventricular arrhythmia burden using a unique statistical analysis based on the unusual temporal distribution of symptomatic ICD therapies. The primary efficacy end points are time to all-cause shocks and time to all-cause shocks plus symptomatic ventricular arrhythmic events triggering antitachycardia pacing measured from randomization.

Placebo-controlled, randomized clinical trial of azimilide for prevention of ventricular tachyarrhythmias in patients with an implantable cardioverter defibrillator.

BACKGROUND: Although implanted cardioverter defibrillators (ICDs) effectively treat sustained ventricular tachyarrhythmias, up to 50% of ICD recipients eventually require concomitant antiarrhythmic drug therapy to prevent symptomatic arrhythmia recurrences and hence reduce the number of device therapies. METHODS AND RESULTS: A total of 633 ICD recipients were enrolled in a randomized, double-blind, placebo-controlled study to evaluate the effect of daily doses of 75 or 125 mg of azimilide on recurrent symptomatic ventricular tachyarrhythmias and ICD therapies. Total all-cause shocks plus symptomatic ventricular tachycardia (VT) terminated by antitachycardia pacing (ATP) were significantly reduced by azimilide, with relative risk reductions of 57% (hazard ratio [HR]=0.43, 95% CI 0.26 to 0.69, P=0.0006) and 47% (HR=0.53, 95% CI 0.34 to 0.83, P=0.0053) at 75- and 125-mg doses, respectively. The reductions in all-cause shocks with both doses of azimilide did not achieve statistical significance. The incidence of all appropriate ICD therapies (shocks or ATP-terminated VT) was reduced significantly among patients taking 75 mg of azimilide (HR=0.52, 95% CI 0.30 to 0.89, P=0.017) and those taking 125 mg of azimilide (HR=0.38, 95% CI 0.22 to 0.65, P=0.0004). Five patients in the azimilide groups and 1 patient in the placebo group had torsade de pointes; all were successfully treated by the device. One patient taking 75 mg of azimilide had severe but reversible neutropenia. CONCLUSIONS: Azimilide significantly reduced the recurrence of VT or ventricular fibrillation terminated by shocks or ATP in ICD patients, thereby reducing the burden of symptomatic ventricular tachyarrhythmia.

The efficacy of azimilide in the treatment of atrial fibrillation in the presence of left ventricular systolic dysfunction: results from the Azimilide Postinfarct Survival Evaluation (ALIVE) trial.

OBJECTIVES: The purpose of this study was to assess the effect of oral azimilide dihydrochloride (AZ) 100 mg versus placebo on the onset, termination, and prevalence of atrial fibrillation (AF) in a subpopulation of patients in the Azimilide Postinfarct Survival Evaluation (ALIVE) trial. BACKGROUND: Previous clinical trials have demonstrated the antiarrhythmic effects of AZ in patients with AF. Azimilide was investigated for its effects on mortality in patients with depressed left ventricular (LV) function after recent myocardial infarction (MI) and in a subpopulation of patients with AF. METHODS: A total of 3,381 post-MI patients with depressed LV function were enrolled in this randomized, placebo-controlled, double-blind study of AZ 100 mg on all-cause mortality. A total of 93 patients had AF on the baseline 12-lead electrocardiogram (ECG). An additional 27 patients developed AF after initially being in sinus rhythm at randomization. These patients were identified through 12-lead ECGs obtained during routine visits at week 2, months 1, 4, 8, and 12. RESULTS: Patients with AF at baseline had a higher mortality than those without AF (p = 0.0006). Among AF patients, there was no difference in mortality between AZ patients and placebo patients (p = 0.82). Fewer AZ patients developed AF than placebo patients (p = 0.04). More AZ patients than placebo patients converted to sinus rhythm, but this difference did not achieve statistical significance (p = 0.076). Over one-year follow-up, more AZ patients were in sinus rhythm than placebo patients (p = 0.04). CONCLUSIONS: Azimilide was safe and effective AF therapy in patients with depressed LV function after an MI.

Mortality in patients after a recent myocardial infarction: a randomized, placebo-controlled trial of azimilide using heart rate variability for risk stratification.

BACKGROUND: Depressed left ventricular function (LVF) and low heart rate variability (HRV) identify patients at risk of increased mortality after myocardial infarction (MI). Azimilide, a novel class III antiarrhythmic drug, was investigated for its effects on mortality in patients with depressed LVF after recent MI and in a subpopulation of patients with low HRV. METHODS AND RESULTS: A total of 3717 post-MI patients with depressed LVF were enrolled in this randomized, placebo-controlled, double-blind study of azimilide 100 mg on all-cause mortality. Placebo patients with low HRV had a significantly higher 1-year mortality than those with high HRV (>20 U; 15% versus 9.5%, P<0.0005) despite nearly identical ejection fractions. No significant differences were observed between the 100-mg azimilide and placebo groups for all-cause mortality in either the "at-risk" patients identified by depressed LVF (12% versus 12%) or the subpopulation of "high-risk" patients identified by low HRV (14% versus 15%) or for total cardiac or arrhythmic mortality. Significantly fewer patients receiving azimilide developed atrial fibrillation than did patients receiving placebo (0.5% versus 1.2%, P<0.04). The incidences of torsade de pointes and severe neutropenia (absolute neutrophil count < or =500 cells/microL) were slightly higher in the azimilide group than in the placebo group (0.3% versus 0.1% for torsade de pointes and 0.9% versus 0.2% for severe neutropenia). CONCLUSIONS: Azimilide did not improve or worsen the mortality of patients after MI. Low HRV independently identified a subpopulation at high risk of mortality.

Cardioplegia retrógrada seqüencial / Sequencial retrograde cardioplegy

Estudou-se o padrao de distribuiçao miocárdica de soluçao cardioplégica (SC) cristalóide gelada (3 graus Celsius - 4 graus Celsius) perfundida nos coraçoes de 15 caes mestiços com pesos variáveis entre 10-15 kg. Após anestesia e toracotomia mediana anterior, o pericárdio foi aberto, sendo estabelecida circulaçao extracorpórea. As seguintes vias foram empregadas para injeçao cardioplégica: 1) Anterógrada - por canulaçao da aorta ascendente a montante da pinça de oclusao; 2) Retrógrada Seletiva - através de cânula com balao auto-inflável introduzido no seio coronário (SCo); 3) Retrógrada Total - através de cânula introduzida no átrio direito (AD); 4) Retrógrada Seqüencial SCo-AD - com a SC injetada primeiro pelo seio coronário até a temperatura do septo interventricular atingir l6 graus Celsius e, em seqüência, pela cânula no átrio direito como na técnica retrógrada total, com o tronco arterial pulmonar ocluído; 5)Retrógrada Seqüencial SCo-VD - com a cavidade do ventrículo direito perfundida por cânula passada através da valva tricúspide. Controlou-se a variaçao da temperatura miocárdica no ventrículo esquerdo, VD, AD e regiao do no sinoatrial, por meio de teletermômetro Omega com termistor de agulha. Pode-se constatar que o esfriamento cardíaco uniforme, o menor volume e o menor tempo de injeçao ocorreram com a técnica anterógrada, seguida em excelência pelas técnicas retrógradas seqüenciais SCo-AD e SCo-VD. Concluiu-se que a técnica de cardioplegia retrógrada seqüencial é significantemente melhor que as retrógradas seletivas pelo SCo e total pelo AD, como usualmente empregadas para proteçao miocárdica, quando comparadas com a técnica de perfusao anterógrada pela aorta.

Aplicação do laser no sistema cardiovascular / Use of lasers in the cardiovascular system

Foi o raio laser aplicado em caes, em quatro tipos de experiencia: 1)lesao da intima e media das arterias, provando-se a inexistencia de estenose e formacao de trombos ate com 20 dias de evolucao; 2) "sutura" arterial ou arteriopatia, demonstrando-se a completa hemostasia e a alta resistencia a rotura, em experiencias agudas e cronicas de ate 17 dias; 3) anastomoses arterio-arteriais e arterio-venosas, mostrando-se a permeabilidade da luz dos vasos, a nao producao de estenose e trombos; 4) a - possibilidade de usar o laser, conduzido por cateter, sem necessidades de interromper a circulacao no sistema cardiovascular; b - eliminacao da estenose pulmonar, atraves do cateterismo cardiaco. Com estes resultados, acreditam os autores que o uso do laser em Cardiologia-Clinica possa ser iniciado

Parada cardiaca anoxica - tres horas de protecao - nova solucao cardioplegica. / Anoxic cardiac arrest - 3 hours of protection - new cardioplegic solution

O efeito de nova solucao cardioplegica foi estudado experimentalmente em caes, submetidos a toracotomia e circulacao extracorporea.Foram controladas as variacoes pressoricas em ventriculo esquerdo, modificacao da forca e do deslocamento miocardio bem como estudada a dinamica do ventriculo esquerdo por cineangiocardiografia. A solucao cardioplegica foi infundida em volumes correspondentes a 6 ml/ kg, repetido a intervalos de 40 minutos de anoxia. Os resultados obtidos demonstram protecao miocardica eficaz com normalizacao dos parametros controlados apos o reinicio da circulacao coronaria normal