Anti-androgenic properties of Compound A, an analog of a non-steroidal plant compound.

We investigated the interactions between Compound A (CpdA), an analog of a hydroxyphenyl aziridine precursor found in an African shrub, and the androgen receptor (AR). CpdA represses androgen-induced activation of both specific and non-specific androgen DNA response elements. While a similar effect was obtained for the progesterone receptor (PR) via a non-specific hormone response element, CpdA had no effect on the actions of the glucocorticoid and mineralocorticoid receptors. CpdA represses the ligand-dependent interaction between the NH(2)- and COOH-terminal domains of the AR, similar to well-characterised anti-androgens. CpdA also interferes with the interaction of steroid receptor co-activator 1 (SRC1) with the activation domain AF2 but not with AF1. However, CpdA does not compete with androgen for binding to the AR. These results demonstrate that CpdA elicits anti-androgenic actions by a mechanism other than competitive binding for the AR.

Initial experience with beating heart surgery: comparison with fast-track methods.

Cardiopulmonary bypass (CPB) in coronary artery bypass grafting (CABG) may increase postoperative complications in high-risk patients. The goal of this study is to retrospectively review a series of consecutive patients undergoing conventional CABG using a fast-track recovery method and to compare this series with the initial series of patients undergoing beating heart surgery using either the single-vessel minimally invasive approach or the off-pump multivessel bypass technique with a median sternotomy. One hundred fifty-eight consecutive patients underwent CABG. One hundred four patients underwent conventional CABG using CPB with a short-pump fast-track recovery method (Group A). Twenty-nine patients underwent a single-vessel bypass via a left anterior thoracotomy off pump [Group B, minimally invasive direct coronary artery bypass (MIDCAB)]. Twenty-five patients underwent multivessel CABG with a median sternotomy off pump (Group C). Short-pump fast-track (Group A) patients exhibited minimal complications and expedient recovery and received extensive revascularization. Off-pump multivessel patients (Group C) received fewer bypass grafts, had more preoperative comorbidity, and recovered as quickly as lower-risk fast-track short-pump patients (Group A). Single-vessel off-pump patients (Group B, MIDCAB) were younger elective patients and demonstrated no recovery advantage. The overall mortality was 1.8 per cent. The conversion rates from beating heart surgery to CPB for groups B and C were 10.3 and 16 per cent, respectively. The postoperative hospital length of stay for groups A, B, and C were 4.8+/-2.4, 3.9+/-1.8, and 5.2+/-2.3 days, respectively. Eliminating CPB is not as important as reducing exposure for minimizing operative risk. Beating heart surgery is an adjunct to conventional CABG with CPB. The off-pump multivessel bypass technique is best suited for high-risk patients requiring three grafts or fewer, whereas MIDCAB is best suited for single-vessel bypass that cannot be managed using interventional percutaneous techniques; however, the recovery advantage with MIDCAB is not apparent. Patients requiring more than three bypass grafts should undergo conventional CABG with CPB.

Aggressive preoperative use of intraaortic balloon pump in elderly patients undergoing coronary artery bypass grafting.

BACKGROUND: The use of the intraaortic balloon pump (IABP) in patients undergoing coronary artery bypass grafting has been traditionally associated with a high complication rate and adverse outcomes. However, recent reports show that many of these catastrophic outcomes can be avoided by preoperatively placing the IABP in high-risk patients. To further validate these reports, we defined a set of liberal criteria for preoperative IABP insertion and applied them to a series of elderly patients (70 years or older) undergoing isolated coronary artery bypass grafting. METHODS: Two hundred six consecutive patients who underwent isolated coronary artery bypass grafting with cardiopulmonary bypass were retrospectively reviewed. A rapid recovery protocol emphasizing reduced cardiopulmonary bypass time, an anesthetic protocol for early extubation, perioperative administration of corticosteroids and thyroid hormone, and aggressive diuresis was applied to all patients. Patients who required an urgent operation because of failed percutaneous transluminal coronary angioplasty, a critical left main stenosis (70% or greater), pronounced left ventricular dysfunction (left ventricular ejection fraction 40% or less), or unstable angina refractory to medical therapy or who required an emergency reoperation received preoperative IABP support. RESULTS: The 30-day mortality rate for the entire group was 4.4%. There were 97 patients (47%) who received a preoperative IABP (group II) in comparison with 109 patients (53%) who did not fulfill the preoperative insertion criteria (group I). Patients in group II had a lower left ventricular ejection fraction (mean, 46% versus 59%, p<0.001) and a higher incidence of congestive heart failure (35% versus 17%, p<0.01) and acute myocardial infarction (37% versus 17%, p<0.01) than patients in group I. The average postoperative hospital length of stay for patients in group II was slightly longer than for those in group I (9.0+/-10.5 versus 6.0+/-3.7 days, p<0.01). However, there were no statistically significant differences in complication or mortality rates between the two groups. Only 2 patients (2.2%) had complications related to IABP insertion. Lower extremity ischemia occurred in both patients, and both were treated successfully with thromboembolectomy. CONCLUSIONS: Liberal preoperative insertion of the IABP can be performed safely in high-risk elderly patients undergoing coronary artery bypass grafting, with results comparable to those in lower risk patients.

Reduced postoperative atrial fibrillation using multidrug prophylaxis.

BACKGROUND: Atrial fibrillation (AFIB) is the most common complication following coronary artery bypass grafting (CABG). Despite three decades of recognition, efforts to reduce the high incidence reported (15%-30%) have been largely unsuccessful. Reasons for postoperative AFIB are likely multifactorial. As a result, we defined a multidrug prophylaxis based on agents known to be individually effective. This method was applied prospectively to a series of consecutive CABG patients with the goal of reducing the incidence of new-onset postoperative AFIB. METHODS: Isolated CABG with cardiopulmonary bypass was performed on 517 consecutive patients. A rapid recovery protocol emphasizing AFIB multidrug prophylaxis was applied to all patients. All patients received 10 microg of triiodothyronine intraoperatively when the clamp on the aorta was released. Immediately following CABG, parenteral magnesium was administered to assure a serum magnesium > 2.2 mEq/dL. Thyroxine 200 microg was administered parenterally to all patients on postoperative days 1 and 2. Metoprolol (25 mg to 100 mg/day) was begun on all patients after extubation provided: heart rate > 85 beats/min and systolic blood pressure > 130 mmHg. Parenteral procainamide (12 mg/kg) loading dose, followed by a maintenance dose (2 mg/min), was used for patients who developed premature atrial contractions (> 1/min), nonsustained supraventricular tachycardia, or any episodes of atrial fibrillation. All patients also received postoperative digitalization, steroids, and aggressive diuresis. RESULTS: The 30-day operative mortality was 3.7%. The overall incidence of new-onset postoperative AFIB was 10.3% (53 patients). There was no major difference in operative mortality (7.5% vs 3.2%, p = 0.23), Parsonnet risk score, or intraoperative variables between AFIB patients and the non-AFIB patients. Patients presenting with a preoperative acute myocardial infarction (p < 0.05), left main stenosis > or = 70% (p < 0.01), and advanced age > or = 70 years (p < 0.05) were at increased risk of developing AFIB. The length of stay for patients with AFIB was 9.9 +/- 9.6 days versus 5.9 +/- 5.2 days (p < 0.001). CONCLUSION: Application of a multidrug prophylaxis can reduce postoperative AFIB to a low incidence. Identification of associated clinical features can help predict patients at risk for postoperative AFIB. Additional strategies to target postoperative AFIB may include treatment at the earliest recognition of atrial rhythm instability.

Coronary artery bypass grafting "on pump": role of three-day discharge.

BACKGROUND: A new emphasis has been directed toward "off-pump" coronary artery bypass grafting to avoid the morbidity of cardiopulmonary bypass and further reduce the postoperative hospital length of stay. With the intent of achieving a hospital discharge for "on-pump" coronary artery bypass grafting procedures comparable with the same procedures "off pump," we applied a rapid-recovery protocol with particular attention paid to patients eligible for discharge on the third postoperative day. METHODS: The cases of 104 consecutive patients who underwent isolated coronary artery bypass grafting using cardiopulmonary bypass were retrospectively reviewed. A rapid-recovery protocol emphasizing reduced cardiopulmonary bypass time, an anesthesia protocol for early extubation, perioperative administration of corticosteroids and thyroid hormone, and aggressive diuresis was applied to all patients. The goal during the first 24 hours postoperatively was to achieve early extubation as well as a mild state of negative fluid balance and to ensure absence of postoperative bleeding and a safe transfer from the intensive care unit to a monitored floor. On the second postoperative day, chest drains were discontinued, and aggressive ambulation therapy was instituted. If at 72 hours postoperatively the patient was walking without assistance, had return of normal bowel function, and had no atrial fibrillation, a 3-day discharge home was planned. RESULTS: The 30-day mortality rate for the entire group was 1.9%. The average postoperative hospital length of stay for the entire series was 4.8 +/- 2.4 days. Of the 102 survivors, 30 patients (29%) were discharged within 3 days postoperatively (group 1), and 72 patients (71%) were discharged after the third postoperative day (group 2). Patients in group 1 were younger and had fewer comorbid conditions. Compared with group 2, group 1 had fewer patients with diabetes (7% versus 28%; p < 0.05), congestive heart failure (7% versus 18%), symptomatic vascular disease (0% versus 11%), chronic obstructive pulmonary disease (0% versus 10%), ambulatory difficulties (0% versus 10%), and the requirement of an intraaortic balloon pump preoperatively (13% versus 35%). Group 1 patients also had almost no complications and a lower readmission rate (3.3% versus 6.9%). CONCLUSIONS: With the application of a rapid-recovery protocol to patients undergoing "on-pump" coronary artery bypass grafting, discharge home within 3 days postoperatively is attainable and safe for patients who have minimal comorbid conditions.

Rapid recovery after coronary artery bypass grafting: is the elderly patient eligible?

BACKGROUND: Rapid recovery protocols after coronary artery bypass grafting have been applied successfully to young patients with normal ventricular function. However, the success of such protocols when applied to the elderly population has not been thoroughly validated, and at some centers there is still reluctance in allowing elderly patients to be discharged early from the hospital. METHODS: One hundred fifty-two consecutive younger patients (< 70 years) were compared retrospectively with 167 consecutive elderly patients (> or = 70 years) who underwent isolated coronary artery bypass grafting using cardiopulmonary bypass. A rapid recovery protocol emphasizing an anesthetic protocol for early extubation, reduced cardiopulmonary bypass time, and perioperative administration of corticosteroids and thyroid hormone was applied to all patients. The protocol also emphasized early identification and management of postoperative atrial fibrillation, a proactive negative fluid balance, rapid return of bowel function, mobilization of the patient, and aggressive use of the intraaortic balloon pump preoperatively. RESULTS: The 30-day mortality rate for the younger group of patients was 3.3% (Parsonnet risk 7.2 +/- 6.2), compared with 4.2% (Parsonnet risk, 17.7 +/- 6.8) for the elderly group of patients. There were no statistically significant differences in the 30-day mortality rates or postoperative complications between the elderly and younger patient groups. Rapid recovery with discharge before the fifth postoperative day was achieved in 19% of the elderly, in comparison with 48% of the younger patients (p < 0.001). The younger patients were discharged earlier after operation than the older patients (5.7 +/- 5.2 versus 8.0 +/- 8.5 days; p < 0.01). CONCLUSIONS: Application of the rapid recovery protocol helped expedite recovery for all patients regardless of age, acuity of illness, or associated conditions. Although younger patients had a significantly shorter postoperative length of hospital stay, older patients performed well and are suitable candidates for rapid recovery protocols.