Pharmacokinetics of UC781-loaded intravaginal ring segments in rabbits: a comparison of polymer matrices

UC781 is a potent and poorly water-soluble nonnucleoside reverse transcriptase inhibitor being investi- gated as a potential microbicide for preventing sexual transmission of HIV-1. This study was designed to evaluate the in vivo release and pharmacokinetics of UC781 delivered from matrix-type intravaginal ring segments in rabbits. Three polymer matrices (polyurethane, ethylene vinyl acetate copolymer, and silicone elastomer) and two drug loadings (5 and 15 mg/segment) were evaluated in at least one of two independent studies for up to 28 days in vivo. Inter-study comparison of in vivo release, vaginal tissue, and plasma concentrations for similar formulations demonstrated good reproducibility of the animal model. Mean estimates for a 28-day in vivo release ranged from 0.35 to 3.17 mg UC781 per segment. Mean proximal vaginal tissue levels (adjacent to the IVR segment) were 8– 410 ng/g and did not change significantly with time for most formulations. Distal vaginal tissue levels of UC781 were 6- to 49-fold lower than proximal tissue levels. Mean UC781 plasma levels were low for all formulations, at 0.09–0.58 ng/mL. All formulations resulted in similar UC781 concentrations in vaginal tissue and plasma, except the low loading polyurethane group which provided significantly lower levels. Loading dependent release and pharmacokinetics were only clearly observed for the polyurethane matrix. Based on these results, intravaginal ring segments loaded with UC781 led to vaginal tissue concen- trations ranging from below to approximately two orders of magnitude higher than UC781’s EC50 under in vitro conditions (2.8 ng/mL), with little influence by polymer matrix or UC781 loading. Moreover, these findings support the use of rabbit vaginal pharmacokinetic studies in preclinical testing of microbicide intravaginal rings.

Alternating ring-opening metathesis copolymerization of bicyclo[2.2.1]hept-2-ene and cyclopentene

Almost alternating copolymers of bicyclo[2.2.1]hept-2-ene and cyclopentene have been formed by ring-opening metathesis polymerization using a RuCl3-phenol catalyst system; this highly novel result is attributed to differential steric influences exerted by a hydrogen-bonded solvent cage which encloses the catalyst site.

Double cyclometalation via carbon-silicon bond cleavage by palladium(II) acetate. X-ray structure of a cationic 1,4-dipalladated benzene ring and selective synthesis of heterobimetallic 1,4-phenylene-bridged platinum(II)-palladium(II) complexes

The disilylated compound 1,4-bis(trimethylsilyl)-2,3,5,6-tetrakis((dimethylamino)methyl)benzene, (Me(3)Si)(2)C2N4, 4, can be electrophilically palladated selectively at the C-Si bonds to afford the neutral 1,4-bis(palladium) complex [(AcOPd)(2)(C2N4)], from which the dicationic [(LPd)(2)(C2N4)](2+) (L = MeCN) organometallic species are accessible. The monosilylated species (Me(3)Si)(H)C2N4, 5, can be used for the preparation of the dicationic heterodinuclear platinum(II)-palladium(II) species [(LPd)(LPt)(C2N4)](2+) (L = MeCN) via a sequence of transmetalation of the organolithium derivative of 5 with [PtCl2(SEt(2))(2)], followed by a C-Si bond palladation reaction.

Frequency selective surface using nested split ring slot elements as a lens with mechanically reconfigurable beam steering capability

The design is described of a double layer frequency selective surface which can produce a differential phase shift of 180 ° as the wave propagates through it at normal incidence. The hand of an applied circularly polarized signal is reversed due to the 180° phase shift, and it is demonstrated that the exit circularly polarized output signal can be phase advanced or phase retarded by 180 ° upon rotation of the elements comprising the structure. This feature allows the surface to act as a spatial phase shifter. In this paper the beam steering capabilities of a 10 × 10 array of such elements are demonstrated. Here the individual elements comprising the array are rotated relative to each other in order to generate a progressive phase shift. At normal incidence the 3 dB Axial Ratio Bandwidth for LHCP to RHCP conversion is 5.3% and the insertion loss was found to be -2.3 dB, with minimum axial ratio of 0.05 dB. This array is shown to be able to steer a beam from -40 ° to +40 ° while holding axial ratio at the pointing angle to below 4 dB. The measured radiation patterns match the theoretical calculation and full-wave simulation results. © 2010 IEEE.

Geometric-phase backaction in a mesoscopic qubit-oscillator system

We illustrate a reverse Von Neumann measurement scheme in which a geometric phase induced on a quantum harmonic oscillator is measured using a microscopic qubit as a probe. We show how such a phase, generated by a cyclic evolution in the phase space of the harmonic oscillator, can be kicked back on the qubit, which plays the role of a quantum interferometer. We also extend our study to finite-temperature dissipative Markovian dynamics and discuss potential implementations in micro-and nanomechanical devices coupled to an effective two-level system.

Non-Markovian effects on the nonlocality of a qubit-oscillator system

Non-Markovian evolutions are responsible for a wide variety of physically interesting effects. Here, we study nonlocality of the nonclassical state of a system consisting of a qubit and an oscillator exposed to the effects of non-Markovian evolutions. We find that the different facets of non-Markovianity affect nonlocality in different and nonobvious ways, ranging from pronounced insensitivity of the Bell function to quite spectacular evidence of information kickback.

Free-space optoelectronic switching cores with MPLS for SANs over WDM ring networks

With increasing demands on storage devices in the modern communication environment, the storage area network (SAN) has evolved to provide a direct connection allowing these storage devices to be accessed efficiently. To optimize the performance of a SAN, a three-stage hybrid electronic/optical switching node architecture based on the concept of a MPLS label switching mechanism, aimed at serving as a multi-protocol label switching (MPLS) ingress label edge router (LER) for a SAN-enabled application, has been designed. New shutter-based free-space multi-channel optical switching cores are employed as the core switch fabric to solve the packet contention and switching path conflict problems. The system-level node architecture design constraints are evaluated through self-similar traffic sourced from real gigabit Ethernet network traces and storage systems. The extension performance of a SAN over a proposed WDM ring network, aimed at serving as an MPLS-enabled transport network, is also presented and demonstrated.

Amplified optomechanics in a unidirectional ring cavity

We investigate optomechanical forces on a nearly lossless scatterer, such as an atom pumped far off-resonance or amicromirror, inside an optical ring cavity. Our model introduces two additional features to the cavity: an isolator is used to prevent circulation and resonant enhancement of the pump laser field and thus to avoid saturation of or damage to the scatterer, and an optical amplifier is used to enhance the effective Q-factor of the counterpropagating mode and thus to increase the velocity-dependent forces by amplifying the back-scattered light. We calculate friction forces, momentum diffusion, and steady-state temperatures to demonstrate the advantages of the proposed setup.

A silicone elastomer vaginal ring for HIV prevention containing two microbicides with different mechanisms of action

Vaginal rings are currently being developed for the long-term (at least 30 days) continuous delivery of microbicides against human immunodeficiency virus (HIV). Research to date has mostly focused on devices containing a single antiretroviral compound, exemplified by the 25 mg dapivirine ring currently being evaluated in a Phase III clinical study. However, there is a strong clinical rationale for combining antiretrovirals with different mechanisms of action in a bid to increase breadth of protection and limit the emergence of resistant strains. Here we report the development of a combination antiretroviral silicone elastomer matrix-type vaginal ring for simultaneous controlled release of dapivirine, a non-nucleoside reverse transcriptase inhibitor, and maraviroc, a CCR5-targeted HIV-1 entry inhibitor. Vaginal rings loaded with 25 mg dapivirine and various quantities of maraviroc (50– 400 mg) were manufactured and in vitro release assessed. The 25 mg dapivirine and 100 mg maraviroc formulation was selected for further study. A 24-month pharmaceutical stability evaluation was conducted, indicating good product stability in terms of in vitro release, content assay, mechanical properties and related substances. This combination ring product has now progressed to Phase I clinical testing.