Safety and pharmacokinetics of aciclovir in women following release from a silicone elastomer vaginal ring.

OBJECTIVES: Systemic aciclovir and its prodrug valaciclovir are effective in treating and reducing recurrences of genital herpes simplex virus (HSV) and reducing transmission. Local aciclovir delivery, if it can achieve and maintain comparable intracellular genital tract levels, may be equally effective in the treatment and suppression of genital HSV. Intravaginal ring (IVR) delivery of aciclovir may provide pre-exposure prophylaxis against HSV acquisition. METHODS: Tolerability and pharmacokinetics were evaluated in six HIV-negative women with recurrent genital HSV who switched their daily oral valaciclovir suppression to an aciclovir IVR for 7 days (n = 3) or 14 days (n = 3). Blood and cervicovaginal lavage (CVL) were collected after oral and IVR dosing to measure aciclovir concentrations and genital swabs were obtained to quantify HSV shedding by PCR. RESULTS: The rings were well tolerated. Median plasma aciclovir concentrations were 110.2 ng/mL (IQR, 85.9-233.5) 12-18 h after oral valaciclovir. Little or no drug was detected in plasma following IVR dosing. Median (IQR) CVL aciclovir levels were 127.3 ng/mL (21-660.8) 2 h after oral valaciclovir, 154.4 ng/mL (60.7-327.5) 12-18 h after oral valaciclovir and 438 ng/mL (178.5-618.5) after 7 days and 393 ng/mL (31.6-1615) after 14 days of aciclovir ring use. Median CVL aciclovir levels 2 h after oral dosing were similar to levels observed 7 (P = 0.99) and 14 (P = 0.75) days after ring use. HSV DNA was not detected in genital swabs and there was no significant change in inflammatory mediators. CONCLUSIONS: This first-in-human study demonstrated that an IVR could safely deliver mucosal levels of aciclovir similar to oral valaciclovir without systemic absorption. More intensive site-specific pharmacokinetic studies are needed to determine whether higher local concentrations are needed to achieve optimal drug distribution within the genital tract.

Acute and chronic hemodynamic effects of enhanced external counterpulsation in patients with angina pectoris.

BACKGROUND: Enhanced external counterpulsation (EECP) is an effective noninvasive treatment for patients with angina pectoris. However, the hemodynamic effects of EECP are still unknown and have been theorized to simulate the clinical use of the intra-aortic balloon pump, enhancing cardiac output, stroke volume, and retrograde aortic diastolic flow. METHODS: Twelve hemodynamic parameters were measured, using the BioZ System (CardioDynamics International Corporation, San Diego, Calif) after 1 hour (n=22) and after 35 hours (n=16) of EECP treatment compared with baseline. The BioZ System noninvasively measures hemodynamic parameters using the thoracic electrical bioimpedance method. RESULTS: One hour of EECP treatment revealed a significant decrease in cardiac output, stroke volume, contractility, afterload, preload, and myocardial energy production, but systolic time ratios and thoracic fluid content were unchanged. However, after 35 hours of therapy, stroke volume (P < or = 0.05), index of contractility (P < or = 0.05), and thoracic fluid content (P < or = 0.01) were decreased. CONCLUSIONS: The acute reduction in contractility, preload, and concurrent bradycardia may have favorable hemodynamic effects for patients with angina pectoris. Further studies are needed to elucidate the mechanism of EECP therapy and its efficacy for patients with angina pectoris.