Oral amiodarone for prevention of atrial fibrillation after open heart surgery, the Atrial Fibrillation Suppression Trial (AFIST): a randomised placebo-controlled trial.

BACKGROUND: Beta-blockers and amiodarone reduce the frequency of atrial fibrillation after open-heart surgery but the effectiveness of oral amiodarone in older patients already receiving beta-blockers is unknown. We have assessed the efficacy of oral amiodarone in preventing atrial fibrillation in patients aged 60 years or older undergoing open-heart surgery. METHODS: We did a randomised, double-blind placebo-controlled trial in which patients undergoing open-heart surgery (n=220, average age 73 years) received amiodarone (n=120) or placebo (n=100). Patients enrolled less than 5 days before surgery received 6 g of amiodarone or placebo over 6 days beginning on preoperative day 1. Patients enrolled at least 5 days before surgery received 7 g over 10 days beginning on preoperative day 5. FINDINGS: Patients on amiodarone had a lower frequency of any atrial fibrillation (22.5% vs 38.0%; p=0.01; absolute difference 15.5% [95% CI 3.4-27.6%]), and there were significant differences in favour of the active drug for symptomatic atrial fibrillation (4.2% vs 18.0%, p=0.001), cerebrovascular accident (1.7% vs 7.0%, p=0.04), and postoperative ventricular tachycardia (1.7% vs 7.0%, p=0.04). Beta-blocker use (87.5% amiodarone vs 91.0% placebo), nausea (26.7% vs 16.0%), 30-day mortality (3.3% vs 4.0%), symptomatic bradycardia (7.5% vs 7.0%), and hypotension (14.2% vs 10.0%) were similar. INTERPRETATION: Oral amiodarone prophylaxis in combination with beta-blockers prevents atrial fibrillation and symptomatic fibrillation and reduces the risk of cerebrovascular accidents and ventricular tachycardia.

The effect of testosterone on health-related quality of life in elderly males - a pilot study.

OBJECTIVE: To assess the effect of short-term testosterone supplementation on health-related quality of life in elderly males. METHOD: As part of a double-blind, placebo-controlled study, healthy males > or = 65-year-old were randomised to receive a total of four doses of 200 mg testosterone enanthanate (n = 14) or placebo (n = 8) intramuscularly every 2 weeks. Health-related quality of life (HRQOL) was assessed using the Short Form 36-item (SF-36) and Psychological General Well-Being (PGWB) scales, at baseline, week 8 and during therapy withdrawal, 6 weeks after the last dose. RESULTS: The baseline SF-36 scores were similar between the groups in seven domains; only vitality was significantly lower in the placebo group (T: 80.4, P: 65.6; P = 0.007). After the 8-week treatment period and withdrawal phase, SF-36 scores were not significantly different between the groups. The PGWB scores at baseline, on treatment and off treatment were not significantly different between the groups. Moreover, the SF-36 and PGWB scores within each group did not change significantly over time. CONCLUSION: This pilot study suggests that intramuscular testosterone, administered at a dose of 200 mg every 2 weeks, does not affect the HRQOL of elderly males.

Efficacy and cost analysis of ibutilide.

OBJECTIVE: To determine the efficacy and safety of ibutilide in atrial fibrillation (AF) and atrial flutter (AFl) in a clinical setting and to compare the cost of first-line ibutilide with that of projected first-line electrical cardioversion (EC) from a hospital and third-party payer perspective. METHODS: Medical records of all patients (n = 60) who received ibutilide from August 1996 to March 1998 were reviewed. Efficacy was defined as successful conversion to sinus rhythm within 60 minutes of the end of the infusion, and the maintenance of sinus rhythm until hospital discharge. Safety was evaluated by determining the incidence of torsade de pointes. Charges for EC and drug administration were obtained from the hospital database and converted to costs using cost/charge ratios. Hospital costs included drug, drug administration, cardiac intensive care laboratory fee, and the cost of managing torsade de pointes. The third-party payer calculation included all of the above plus the cardiologist and anesthesiologist fees. RESULTS: Fifty percent of patients with AF or AFl were successfully converted with ibutilide; 67% of these remained in sinus rhythm at hospital discharge. Three patients experienced nonsustained torsade de pointes; all resolved with pharmacologic management. From a hospital perspective, the cost of first-line ibutilide was greater than the cost of first-line EC ($280 vs. $138 per patient). However, from a third-party payer perspective, the use of ibutilide saved approximately $324 per patient ($718 vs. $1042). CONCLUSIONS: The efficacy and safety of ibutilide in the clinical setting are consistent with data reported in clinical trials. In contrast to a previous decision analysis, ibutilide was not associated with cost savings from a hospital perspective, but was from a payer perspective.

The effect of beta-blockers on health-related quality of life in patients with heart failure.

Beta-blockers reduce the risk of death in patients with heart failure and are recommended in those with stable class II or III disease despite optimal standard therapy. Health-related quality of life (HRQOL) is an increasingly important end point in clinical trials. We reviewed all studies that determined the effect of beta-blockers on HRQOL in patients with heart failure. In these trials, HRQOL was assessed by the Quality of Life Questionnaire in Severe Heart Failure and the Minnesota Living with Heart Failure Questionnaire. Three of the 10 studies that used either of these instruments reported significant improvements in scores. When HRQOL was determined by a single-question global assessment, substantial improvements were observed by patients and physicians in five of the seven studies that used the instrument. Possible reasons for the lack of consistent effect on HRQOL include lack of responsiveness of currently available instruments, incomplete data collection, and true lack of effect of beta-blockers on HRQOL in these patients.

Anaphylaxis in labor secondary to prophylaxis against group B Streptococcus. A case report.

BACKGROUND: Two strategies have been recommended by the Centers for Disease Control and Prevention and approved by the American College of Obstetrics and Gynecology to help prevent group B streptococcal disease in the newborn. Both involve using penicillin in labor. However, the potential for allergic and even anaphylactic reactions to penicillin exists. CASE: A patient was treated for risk factors for group B Streptococcus in labor and suffered a serious anaphylactic reaction to penicillin; it resulted in an emergency cesarean section. Although the patient and infant were eventually discharged, the patient developed disseminated intravascular coagulation and suffered acute tubular necrosis that required dialysis. CONCLUSION: Prophylaxis against group B streptococcal sepsis is of proven benefit, but the possible harm to the mother and fetus from treatment with penicillin must be recognized.

Reduced tetracycline bioavailability caused by magnesium aluminum silicate in liquid formulations of bismuth subsalicylate.

RATIONALE: Bismuth subsalicylate, tetracycline hydrochloride, and metronidazole are widely used in combination for the treatment of Helicobacter pylori infections. As a result, there is renewed interest in the interaction between tetracycline and bismuth subsalicylate. OBJECTIVE: To determine whether the observed decrease in tetracycline bioavailability is due to the active drug bismuth subsalicylate via complexation, or to magnesium aluminum silicate (Veegum), an inactive excipient present only in the liquid formulation of bismuth subsalicylate, which might adsorb the tetracycline, rendering it unavailable for systemic absorption. METHODS: Eleven healthy volunteers participated in a randomized three-period, three-treatment complete crossover study with a 7-day washout interval between treatments. After an overnight fast, subjects received a 500-mg capsule of tetracycline hydrochloride with either tap water, 30 mL of bismuth subsalicylate (525 mg) liquid containing Veegum (Pepto-Bismol), or 30 mL of a specially formulated bismuth subsalicylate (525 mg) liquid without Veegum. Blood was collected for 24 hours after each dose of tetracycline. Serum was assayed for tetracycline concentration by HPLC. In addition, standard in vitro ultraviolet spectrophotometric methods were used to determine the capacity for complexation of bismuth with tetracycline and for adsorption of tetracycline to Veegum. RESULTS: Compared with the reference treatment of tetracycline hydrochloride with water, the liquid formulation of bismuth subsalicylate containing Veegum decreased the maximum serum concentration (Cmax) of tetracycline by 21% and the serum tetracycline AUC by 27% (p < 0.001). The bismuth subsalicylate formulation without Veegum resulted in decreases in Cmax and AUC of 11% and 13%, respectively (p > 0.05 vs. tetracycline hydrochloride with water). Multiple linear regression analysis of the spectral absorbance data demonstrated a calculated recovery of tetracycline of 100.9% and, therefore, a lack of in vitro complexation with bismuth. At pH 1.2, the amount of tetracycline adsorbed to Veegum ranged from 91.5% to 97.2% over the concentration range of 0.25 to 2 mg/mL. At pH 7.0, the values ranged from 82.9% to 83.9% over the concentration range of 0.25 to 1 mg/mL. CONCLUSIONS: In vitro and in vivo data from this study indicate that Veegum, a suspending agent, and not the active agent bismuth subsalicylate, is the primary ingredient in liquid formulations of bismuth subsalicylate responsible for a decrease in tetracycline bioavailability. In addition, the mechanism of interaction is not likely due to complexation between tetracycline and bismuth subsalicylate, as previously postulated, but rather is caused by adsorption of tetracycline to the excipient Veegum, which is present only in the liquid formulation of bismuth subsalicylate. The clinical relevance of this interaction has not been determined.

A novel DNA repair response is induced in human cells exposed to ionizing radiation at the G1/S-phase border.

We have discovered a novel DNA repair response which is induced in cells irradiated with gamma rays at the G1/S-phase border. The induction of this repair response occurs at a stage in the cell cycle when overall levels of excision repair are reduced compared to cells irradiated in either S phase, G2/M phase or exponential growth. The induced repair is characterized by the formation of very long excision repair patches (VLERP) containing at least 150 nucleotides compared to the constitutive repair patches that are 3-5 nucleotides. These VLERP appear to be produced in response to a DNA lesion specific to ionizing radiation since they were not observed in cells irradiated with UV radiation at G1/S phase. The formation of VLERP requires both the nucleotide excision repair pathway, since they are absent in irradiated xeroderma pigmentosum group A cells, and the synthesis of new protein and mRNA. The time course for the induction of the VLERP shows an initial delay of 2 h, followed by a steady increase for up to 12 h after irradiation. By comparison, the production of the constitutive short repair patches shows an initial rapid production which levels out after 4 h.

The yeast RAD2, but not RAD1, gene is involved in the transcription-coupled repair of thymine glycols.

Transcription-coupled repair of H2O2-induced thymine glycols and UV-induced pyrimidine dimers has been shown to occur in the yeast Saccharomyces cerevisiae. In order to determine whether the preferential repair of thymine glycols is carried out by the same nucleotide excision repair complex that removes pyrimidine dimers, we examined the repair of thymine glycols in two yeast mutants, rad1 delta and rad2 delta, in which the nucleotide excision repair pathway was disrupted. We find that in both wild-type and a rad1 delta mutant, repair of thymine glycols occurs faster on the transcribed strand of the GAL7 gene than on the nontranscribed strand. This indicates that transcription-coupled repair can occur in the absence of nucleotide excision repair and that repair of oxidative DNA damage initiated by an N-glycosylase can be coupled to transcription. In contrast, the initial rate of repair of thymine glycols on the transcribed strand of the GAL7 gene in a rad2 delta mutant is significantly slower than that for the wild-type cells, with kinetics similar to that of the nontranscribed strand. However, by 60 min post-treatment, the amount of repair on the transcribed strand in the rad2 delta eventually reaches that of the wild-type cells. We conclude that repair of oxidative DNA damage, such as thymine glycols, can be coupled to transcription and that RAD2 facilitates transcription-coupled repair of oxidative DNA damage in yeast.