The effect of ravuconazole on the pharmacokinetics of nelfinavir in healthy male volunteers.

An open-label, nonrandomized study was conducted to assess the effect of ravuconazole on the pharmacokinetics of concomitantly administered nelfinavir. Healthy volunteers received 750 mg nelfinavir on day 1, 750 mg nelfinavir and 400 mg ravuconazole on day 2, 400 mg ravuconazole on days 3 to 28, and 750 mg nelfinavir and 400 mg ravuconazole on day 29. The geometric means of C(max) and area under the curve of nelfinavir coadministered with ravuconazole were 30.7% and 31.9% higher on day 2 and 7.9% and 16.2% lower on day 29, respectively, compared to the corresponding values on day 1. These findings are consistent with the potential for ravuconazole to both inhibit and induce CYP3A isozymes. The alterations in the systemic exposure to nelfinavir were within the range defined by the 90% confidence interval. The study data indicate that coadministration of ravuconazole did not result in a clinically significant change in the plasma levels of nelfinavir.

High thoracic epidural anesthesia for off-pump coronary artery bypass surgery.

OBJECTIVE: To assess the feasibility of high thoracic epidural anesthesia combined with sevoflurane for off-pump coronary artery bypass surgery and to evaluate the postoperative pain control, side effects, and perioperative hemodynamics. DESIGN: Retrospective review of prospectively collected data. SETTING: A university teaching hospital. PARTICIPANTS: One hundred six consecutive patients receiving thoracic epidural combined with sevoflurane. INTERVENTION: From November 1999, the patients undergoing off-pump coronary artery bypass grafting were offered the epidural-inhalation anesthetic approach. MEASUREMENTS AND MAIN RESULTS: Insertion of the epidural catheter was successful in all but 2 patients; 1 bloody tap occurred and the dura was never punctured, although 1 patient presented with postoperative paraplegia. An emergency spinal cord nuclear magnetic resonance excluded signs of medullary compression caused by epidural or spinal hematoma. Visual analog scale scores for pain during the first 24-hour period were < 2 in all patients. Mean time to extubation was 4.6 +/- 2.9 hours. The average intensive care unit stay was 1.5 +/- 0.8 days. Incidences of perioperative myocardial infarction, myocardial ischemia, and atrial fibrillation were 2.8%, 7.5%, and 10.6%, respectively. Two patients died: 1 from multiorgan failure and the other from myocardial infarction. Heart rate, mean arterial pressure, cardiac index, and systemic vascular resistance were not affected by thoracic epidural alone. Mean arterial pressure and cardiac index decreased (p < 0.05) when general anesthesia was induced and remained stable thereafter. Neither heart rate nor systemic vascular resistance changed from baseline during operation. CONCLUSIONS: Thoracic epidural as an adjunct to general anesthesia is a feasible technique in off-pump coronary artery bypass surgery. It induces intense postoperative analgesia and does not compromise central hemodynamics.

Adverse gastrointestinal complications after cardiopulmonary bypass: can outcome be predicted from preoperative risk factors?

UNLABELLED: Adverse gastrointestinal (GI) outcome after cardiac surgery is an infrequent event but is a clinically important health care problem because of associated increased morbidity and mortality. The ability to identify patients at greatest risk before surgery may be helpful in planning appropriate perioperative management strategies. We examined the pre- and intraoperative characteristics of 2417 patients from 24 diverse United States medical centers enrolled in the Multicenter Study of Perioperative Ischemia Study who were undergoing cardiac surgery using cardiopulmonary bypass as predictors for adverse GI outcome. Resource utilization was evaluated for patients with and without adverse GI outcomes. Adverse GI outcomes occurred in 5.5% of patients (133 of 2417), increased in-hospital mortality 6.5-fold, prolonged the mean intensive care unit length of stay by 1 wk, and more than doubled the mean postoperative hospital stay (P < 0.0001). Predictors of adverse GI outcome included decreased left ventricular function, hyperbilirubinemia, thrombocytopenia, prolonged partial thromboplastin time, prior cardiovascular surgery, combined coronary artery bypass graft surgery and intracardiac or proximal aortic surgery, pharmacological cardiovascular support, and intraoperative transfusion. The literature suggests that adverse GI outcome after cardiac surgery is secondary to poor splanchnic perfusion, which many of these risk factors may predict. Therefore, patients deemed to be at risk before surgery may benefit from tightly controlled hemodynamic management and other strategies that optimize perioperative organ perfusion. IMPLICATIONS: We identified the preoperative and intraoperative predictors associated with an increased incidence of postoperative gastrointestinal complications after cardiac surgery using cardiopulmonary bypass. Because these complications are associated with frequent morbidity and mortality, these predictors may be helpful in identifying patients at increased risk so that risk stratification can be modified and perioperative management can be appropriately adjusted.

Pharmacokinetics of irbesartan are not altered in special populations.

Studies were conducted to determine whether pharmacokinetics of irbesartan (IRBE), a potent, long-acting angiotensin (AT)-II receptor antagonist selective for AT-II type 1 receptor subtype, are altered in patients with renal impairment (RI), hepatic impairment (HI), or heart failure (HF) or by patient gender, age, or race. IRBE pharmacokinetics and blood pressure (BP) response in hypertensive (HT) children and adolescents were also studied. HI or RI (including end-stage renal disease requiring hemodialysis) had no effect on IRBE pharmacokinetics after single or repeated dosing. IRBE was not removed by hemodialysis. In patients with New York Heart Association class II or III HF, IRBE single-dose pharmacokinetics were not altered following either oral or IV administration. There were no clinically significant differences in IRBE pharmacokinetics between men and women, elderly and young, or black and white patients. No accumulation of IRBE occurred with repeated dosing in RI or HI patients or in HT men or women. In a pediatric study, IRBE pharmacokinetics were comparable between 6- to 12-year and 13- to 16-year age groups and to that previously determined for adult subjects receiving the same dose; accumulation of IRBE was minimal during multiple dosing. IRBE lowered BP in the pediatric population. Adverse event profile with IRBE was similar in all patient groups. Based on these pharmacokinetic and safety data, no dosage adjustments of IRBE are necessary for patients with RI, HI, or HF, or based on patient age, gender, or race. IRBE may be a treatment option for pediatric HT patients. The pharmacokinetic profile of IRBE and lack of necessary dosage adjustments in special populations suggest that IRBE is an excellent choice for management of hypertension across all patient groups.