Pre-treatment with Depo-Provera modifies the pharmacokinetics of CMPD167 in rhesus macaques following vaginal ring administration

BACKGROUND: Vaginal ring devices are being developed to provide sustained release of HIV microbicides. To date, only limited pharmacokinetic data is available from animal or human studies. Here we report the effect of Depo-Provera (DP) pre- treatment, commonly used to thin the vaginal epithelium in challenge experiments, on the pharmacokinetic profile of CMPD167 (a small molecule CCR5 co-receptor antagonist) in rhesus macaques following vaginal ring administration.

METHODS: A single 400mg CMPD167 silicone elastomer vaginal ring was inserted into each of twelve female rhesus macaques. Six macaques were treated with (DP) 30 days before ring placement; the other six macaques were untreated. Blood, vaginal fluid and vaginal biopsies were collected prior to and at various times during 28 days of ring placement and assayed for CMPD167 levels by HPLC. Rings were assayed for residual CMPD167 at the end of the study and the calculated amount of CMPD167 released in vivo compared with in vitro release data.

RESULTS: Vaginal fluid, plasma and tissue levels of CMPD167 were detectable throughout ring placement. Significant differences were observed in mean daily vaginal fluid levels between the DP-treated (16–56 mcg/mL) and untreated groups (48–181 mcg/mL). Plasma CMPD167 levels were significantly higher peaking at 4 ng/mL and maintaining levels of 1–2 nM throughout the 14 days of testing in animals pre-treated with DP compared to non DP-treated macaques (<1 ng/mL maintained). Tissue levels were varied between 2–10 g/mL CMPD167 with no significant difference between the DP-treated and untreated macaques.

CONCLUSIONS: The study demonstrates that clinically relevant, and possibly protective doses of CMPD167 are released in the vaginal vault of rhesus macaques from vaginal rings through 28 days duration. DP is known to induce vaginal epithelial thinning and lower vaginal fluid levels, which accounts for the increased plasma levels of CMPD167. In contrast, macaques not treated with DP had minimal absorption into plasma compartments and significantly higher levels of CMPD167 in the vagina, similar to those previously shown to be protective against vaginal challenge.

Kinematics of the ring-like nebula SuWt 2

We present the first detailed spatio-kinematical analysis and modelling of the southern planetary nebula SuWt 2. This object presents a problem for current theories of planetary nebula formation and evolution, as it is not known to contain a central post-main-sequence star. Deep narrow-band [NII]6584Å images reveal the presence of faint bipolar lobes emanating from the edges of the nebular ring. Long-slit observations of the Ha and [NII]6584Å emission lines were obtained using the ESO (European Southern Observatory) Multi-Mode Instrument on the 3.6-m ESO New Technology Telescope. The spectra reveal the nebular morphology as a bright torus encircling the waist of an extended bipolar structure. By deprojection, the inclination of the ring is found to be 68° +/- 2° (cf. ~90° for the double A-type binary believed to lie at the centre of the nebula), and the ring expansion velocity is found to be 28 kms-1. Our findings are discussed with relation to possible formation scenarios for SuWt 2. Through comparison of the nebular heliocentric systemic velocity, found here to be -25 +/- 5km s-1, and the heliocentric systemic velocity of the double A-type binary, we conclude that neither component of the binary could have been the nebular progenitor. However, we are unable to rule out the presence of a third component to the system, which would have been the nebula progenitor.

A study of Heck cyclization reactions to form phenanthridine ring systems

A survey of conditions for the palladium catalyzed intramol. Heck cyclization of protected amines has shown that the Herrmann-Beller palladacycle can be exploited under 'cationic' conditions to provide a robust and rapid route (

A Ring Rearrangement Approach to the Synthesis of Benzo[b]quinolizine and Benzoindolizine Architectures

An efficient ring rearrangement metathesis (RRM) approach to the synthesis of benzo[b]quinolizine and benzoindolizine systems from N-propargyl-phenanthridine derivatives is reported. A Hovel use of flash vacuum pyrolysis (FVP) for the Boc-deprotection of acid-sensitive substrates is also disclosed.

Synthesis of the alkaloid homaline in ( ) and natural (S,S)-(-) forms, using amination and transamidative ring expansion in liquid ammonia.

Crombie, Leslie; Haigh, David; Jones, Raymond C. F.; Mat-Zin, A.Rasid. Dep. Chem., Univ. Nottingham, Nottingham, UK. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999) (1993), (17), 2047-54. CODEN: JCPRB4 ISSN: 0300-922X. Journal written in English. CAN 120:164608 AN 1994:164608 CAPLUS (Copyright (C) 2009 ACS on SciFinder (R)) Abstract The alkaloid homaline I was prepd. in (?) and natural (S,S)-(-) forms. Linking of 2-azacyclooctanone units either directly or successively using 1,4-dihalogenobutanes or 1,4-dihalogenobut-2-ynes is examd. (?)-5-Methyl-4-phenyl-1,5-diazacyclooctan-2-one is first made by a 2,2'-dithiodipyridine/triphenylphosphine-mediated cyclization, and then by amination and transamidative ring expansion from N-(3-chloropropyl)-4-phenylazetidin-2-one in liq. ammonia, followed by N-methylation. Coupling through a 1,4-dihalogenobutane of either the N-methylated azalactam, or the unmethylated azalactam followed by methylation, gave homaline in (?) and meso forms. (R)-(-)-phenylglycine was converted via (S)-?-phenyl-?-alanine into an (S)-?-lactam which was then alkylated with 1-bromo-3-chloropropane, and aminated and ring expanded in liq. ammonia. Coupling of the homochiral azalactam (2 mol) so formed with 1,4-dibromobutane, followed by N-methylation, gave (S,S)-(-)-homaline identical with the natural material.

Study of the transamidative ring expansion of N--halogenoalkyl--lactams of alkyl chain lengths 2–12 in liquid ammonia and other liquid amines: syntheses of 7-, 8- and 9-membered 1,5-diaza cyclic ketones, including routes to (±)-dihydroperiphylline and (±)-celabenzine

N-(3-Halogenopropyl)-4-phenylazetidin-2-ones undergo amination in liquid ammonia followed by transamidative ring expansion to give the eight-membered 4-phenyl -1,5-diazacyclooctan-2-one in excellent yield. Ring expansion of the amines in liquid ammonia is found to be much more effective than in hydrocarbon solvents. Formation of 7-, 8-, and 9-membered azalactams from the requisite -halogenoalkyl--lactams is an excellent synthetic process, though it is not applicable to 10membered rings. In the cases of rings of 13-, 15- and 17-members, although amination and apparent expansion takes place, the large rings appear not to be stable to ammonia and the final products are acyclic amides. N-[4-Halogenobut-2(Z)-enyl]-4-phenylazetidin-2-one satisfactorily forms a 9-membered (Z)-olefinic azalactam, but the (E)-isomer gives an acyclic amino amide. By using alkyl-substituted -lactam side-chains, C-substituted medium rings can be obtained; the relative instability of N-acyl -lactams to ammonia, however, leads to acylamino amides rather than expanded rings.Employing ethylamine in place of ammonia, it is shown that N-ethylated azalactams are formed satisfactorily, and using allylamine, N-allyl medium rings capable of further elaboration are obtained. The chemistry of these systems is discussed. Using transamidation in liquid ammonia, a short synthesis of the 9-membered spermidine alkaloid (±)-dihydroperiphylline is reported. Synthesis of key intermediates, whose transformation into the 13-membered alkaloids of the celabenzine group has already been effected, has been carried out.X-Ray single-crystal structure determinations for 4-phenyl-1,5-diazacyclononan-2-one, trans-4-phenyl-8-methyl-1,5-diazacyclooctan-2-one and (Z)-4-phenyl-1,5-diazacyclonon-7-en-2-one are reported, and comment is made on certain conformational features.

Split slot ring spatial quasi-circulator for RCS characterisation

A prototype X-band scale model for a quasi-optical three-port circulator utilising a double-layer circularly polarising frequency selective surface is proposed. The operating principles and measured characteristics of the device are discussed. A prototype device operating at 9.9 GHz has been built and validated experimentally. The port 1 to port 2 insertion loss of the quasi-circulator has been measured to be 2 dB, while port 1 to port 3 isolation is 16 dB. It is demonstrated that port 1 to 3 isolation can be increased to 25 dB by embedding the quasi-circulator in a feedforward setup.

Confirming the Existence of Gaps and Depletions in the Irish Oak Tree-Ring Record

In the course of building the 7000 year Belfast long oak chronology a series of depletion problems were encountered. These problems were overcome by 1984 when the completion of the long chronology was announced. The solution to the bridging of the various ‘gaps’ in the Irish chronology lay in the use of long sections of oak chronology from Britain. Now that a quarter of a century has elapsed and large numbers of additional oak samples, and site assemblages, have been accumulated it seems reasonable to review the ‘gaps’ in order to see if the Irish chronology could now be constructed without the use of British material. That is, are the depletion periods in the Irish chronology still evident, and if so, what might they imply about past conditions and human populations? The perhaps surprising conclusion is that the original depletions are still evident after 25 years of quasi-random sampling by archaeologists and palaeoecologists throughout Ireland.

A ring-closing metathesis approach to the bicyclo[4.3.1]decane core of caryolanes

A synthesis of highly substituted and sterically congested bicyclo[4.3.1]decenes, a structure embedded in the core 4,7,6-tricyclic system of natural caryolanes, was successfully achieved via a ring-closing metathesis (RCM) reaction of syn-1,3-diene substituted cyclohexanols. The construction of the diene substrates, starting from 4-acetoxy-3-methyl-2-cyclohexen-1-one, employed diastereoselective copper-mediated conjugate addition and Grignard reactions. An X-ray crystal structure determination of a key synthetic intermediate confirmed the relative stereochemistry of the RCM bicyclic product.

325GHz Single Layer Sub-Millimeter Wave FSS Based Split Ring Linear to Circular Polarisation Convertor

A single layer, frequency selective surface based, sub-millimeter wave transmission polarizer is presented that converts incident slant linear 45° polarization into circular polarization upon transmission. The polarization convertor consists of a 30 mm diameter 10 thick silicon reinforced metalized screen containing 2700 resonator cells and perforated with nested split ring slot apertures. The screen was designed and optimized using CST Microwave Studio and predictions were validated experimentally by transmission measurements over the 250-365 GHz frequency range. This frequency range is used for remote environmental monitoring and 325 GHz represents a molecular emission line for H2O. The results obtained show good agreement between measured and modeled predictions. The measured 3 dB axial ratio bandwidth was 11.75%, measured minimum Axial Ratio was 0.19 dB and the measured insertion loss of the single layer screen was 3.38 dB

Dielectric constant characterization using a numerical method for the microstrip ring resonator

A new method of dielectric-constant measurement is developed. The dielectric constant epsilon(r) RF/microwave substrate is extracted by combining the microstrip ring resonator measurement with Ansoft HFSS electromagnetic simulation software. The developed method has two advantages: (i) characterization of dielectric constant versus multiple frequency points, and (ii) compatibility with electronics design automation (EDA) software tools. This characterization method can reduce the design cycle of microwave circuits and devices. (C) 2004 Wiley Periodicals, Inc.

Sustained release of proteins from a modified vaginal ring device

A new vaginal ring technology, the insert vaginal ring (InVR), is presented. The InVR overcomes the current shortfall of conventional vaginal rings (VRs) that are generally ineffectual for the delivery of hydrophilic and/or macromolecular actives, including peptides, proteins and antibodies, due to their poor permeation characteristics in the hydrophobic polymeric elastomers from which VRs are usually fabricated. Release of the model protein BSA from a variety of insert matrices for the InVR is demonstrated, including modified silicone rods, directly compressed tablets and lyophilised gels, which collectively provided controlled release profiles from several hours to beyond 4 weeks. Furthermore, the InVR was shown to deliver over 1 mg of the monoclonal antibody 2F5 from a single device, offering a potential means of protecting women against the transmission of HIV.