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.

Non-invasive measurement of cardiac output: evaluation of new infrared absorption spectrometer.

The mass spectrometer (MS) traditionally has been the instrument of choice for measuring cardiac output (Q (T)) non-invasively using the foreign gas uptake method. However, the size and cost of the MS has hampered widespread adoption of this technique outside of the laboratory. Here, we present results, from six normal human subjects at rest and during exercise, of simultaneous Q (T) measurements by an MS and a new, portable infrared (IR) device developed in our laboratories. These measurements are made using on the open-circuit acetylene uptake method. The IR device measures inspired and end-tidal concentrations of acetylene, sulfur hexafluoride, and carbon dioxide by IR absorption spectroscopy with a 10-90% response time of 43 ms; accurate measurements were made down to sample flow rates of 50 mL min(-1). Excellent correlation [Q (T)(IR)=0.98 Q (T)(MS), R(2)=0.94] was observed between instruments across the range from rest to heavy exercise. These results suggest that the IR device, which is small, light-weight, and rugged may enable the foreign gas uptake method to be used in clinical, field, and point-of-care settings for Q (T) measurement.

Multicomponent remote sensing of vehicle exhaust by dispersive absorption spectroscopy. 2. Direct on-road ammonia measurements.

Remote sensing was employed for the first time to measure NH3 levels in the exhaust of on-road light duty motor vehicles. The sensor also measured the concentration of CO2, CO, hydrocarbons, and NO, among other pollutants, in the emitted exhaust. Field measurements were conducted at a Los Angeles freeway on-ramp; vehicles traveled at cruise speeds between 20 and 25 m s(-1) (45-55 mi h(-1)). Mean fleet NH3 levels of 44.7 +/- 4.1 ppm were observed. These emissions exhibited a highly skewed distribution: 50.1% of the emitted NH3 was contributed by 10% of the sampled fleet. The pollutant distribution among high NH3 emitters is analyzed to identify the conditions that lead to three-way catalyst malfunction and, hence, NH3 formation. In contradiction with previous reports, we found that high NH3 emissions could not be attributed to vehicles running under rich air-fuel conditions. We estimate a mean fleet NH3 mass emission rate of 667 +/- 57 mg L(-1) (Er = 94 +/- 8 mg km(-1)). These findings could have significant implications on air quality in the South Coast Air Basin (SoCAB) of California, since they support the hypothesis that emissions from motor vehicles constitute a dominant regional source of NH3, between 20 and 27% of total daily emissions. As NH3 is the predominant atmospheric base, tropospheric levels play a key role in the buffering capacity of the atmosphere and, hence, the formation of fine aerosol. Our results could explain the ubiquitous distribution of ammonium fine particles observed during fall stagnation conditions in the SoCAB.