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.

Investigation into the radiobiological consequences of pre-treatment verification imaging with megavoltage X-rays in radiotherapy

Objective: The aim of this study was to investigate the effect of pre-treatment verification imaging with megavoltage (MV) X-rays on cancer and normal cell survival in vitro and to compare the findings with theoretically modelled data. Since the dose received from pre-treatment imaging can be significant, incorporation of this dose at the planning stage of treatment has been suggested.

Methods: The impact of imaging dose incorporation on cell survival was investigated by clonogenic assay, irradiating DU-145 prostate cancer, H460 non-small cell lung cancer and AGO-1522b normal tissue fibroblast cells. Clinically relevant imaging-to-treatment times of 7.5 minutes and 15 minutes were chosen for this study. The theoretical magnitude of the loss of radiobiological efficacy due to sublethal damage repair was investigated using the Lea-Catcheside dose protraction factor model.

Results: For the cell lines investigated, the experimental data showed that imaging dose incorporation had no significant impact upon cell survival. These findings were in close agreement with the theoretical results.

Conclusions: For the conditions investigated, the results suggest that allowance for the imaging dose at the planning stage of treatment should not adversely affect treatment efficacy.

Advances in Knowledge: There is a paucity of data in the literature on imaging effects in radiotherapy. This paper presents a systematic study of imaging dose effects on cancer and normal cell survival, providing both theoretical and experimental evidence for clinically relevant imaging doses and imaging-to-treatment times. The data provide a firm foundation for further study into this highly relevant area of research.

Determining the Effect of Plasma Pre-Treatment on Antimony Tin Oxide to Support Pt@Pd and the Oxygen Reduction Reaction Activity

This article reveals the effect of plasma pre-treatment on antimony tin oxide (ATO) nanoparticles. The effect is to allow Pt@Pd to be deposited homogeneously on the ATO surface with high dispersion and narrow particle size distribution. The Pt@Pd core–shell catalyst was prepared using the polyol method and shows a dramatic improvement towards ORR activity and durability.

Adrenergic and muscarinic receptor subtypes functional regulation during diabetogenesis: Effect of curcumin and vitamin D3 pre-treatment

In the present study, the initial phase was directed to confirm the effects of curcumin and vitamin D3 in preventing or delaying diabetes onset by studying the blood glucose and insulin levels in the pre-treated and diabetic groups. Behavioural studies were conducted to evaluate the cognitive and motor function in experimental rats. The major focus of the study was to understand the cellular and neuronal mechanisms that ensure the prophylactic capability of curcumin and vitamin D3. To elucidate the mechanisms involved in conferring the antidiabetogenesis effect, we examined the DNA and protein profiles using radioactive incorporation studies for DNA synthesis, DNA methylation and protein synthesis. Furthermore the gene expression studies of Akt-1, Pax, Pdx-1, Neuro D1, insulin like growth factor-1 and NF-κB were done to monitor pancreatic beta cell proliferation and differentiation. The antioxidant and antiapoptotic actions of curcumin and vitamin D3 were examined by studying the expression of antioxidant enzymes - SOD and GPx, and apoptotic mediators like Bax, caspase 3, caspase 8 and TNF-α. In order to understand the signalling pathways involved in curcumin and vitamin D3 action, the second messengers, cAMP, cGMP and IP3 were studied along with the expression of vitamin D receptor in the pancreas. The neuronal regulation of pancreatic beta cell maintenance, proliferation and insulin release was studied by assessing the adrenergic and muscarinic receptor functional regulation in the pancreas, brain stem, hippocampus and hypothalamus. The receptor number and binding affinity of total muscarinic, muscarinic M1, muscarinic M3, total adrenergic, α adrenergic and β adrenergic receptor subtypes were studied in pancreas, brain stem and hippocampus of experimental rats. The mRNA expression of muscarinic and adrenergic receptor subtypes were determined using Real Time PCR. Immunohistochemistry studies using confocal microscope were carried out to confirm receptor density and gene expression results. Cell signalling alterations in the pancreas and brain regions associated with diabetogenesis and antidiabetogenesis were assessed by examining the gene expression profiles of vitamin D receptor, CREB, phospholipase C, insulin receptor and GLUT. This study will establish the anti-diabetogenesis activity of curcumin and vitamin D3 pre-treatment and will attempt to understand the cellular, molecular and neuronal control mechanism in the onset of diabetes.Administration of MLD-STZ to curcumin and vitamin D3 pre-treated rats induced only an incidental prediabetic condition. Curcumin and vitamin D3 pretreated groups injected with MLD-STZ exhibited improved circulating insulin levels and behavioural responses when compared to MLD-STZ induced diabetic group. Activation of beta cell compensatory response induces an increase in pancreatic insulin output and beta cell mass expansion in the pre-treated group. Cell signalling proteins that regulate pancreatic beta cell survival, insulin release, proliferation and differentiation showed a significant increase in curcumin and vitamin D3 pre-treated rats. Marked decline in α2 adrenergic receptor function in pancreas helps to relent sympathetic inhibition of insulin release. Neuronal stimulation of hyperglycemia induced beta cell compensatory response is mediated by escalated signalling through β adrenergic, muscarinic M1 and M3 receptors. Pre-treatment mediated functional regulation of adrenergic and cholinergic receptors, key cell signalling proteins and second messengers improves pancreatic glucose sensing, insulin gene expression, insulin secretion, cell survival and beta cell mass expansion in pancreas. Curcumin and vitamin D3 pre-treatment induced modulation of adrenergic and cholinergic signalling in brain stem, hippocampus and hypothalamus promotes insulin secretion, beta cell compensatory response, insulin sensitivity and energy balance to resist diabetogenesis. Pre-treatment improved second messenger levels and the gene expression of intracellular signalling molecules in brain stem, hippocampus and hypothalamus, to retain a functional neuronal response to hyperglycemia. Curcumin and vitamin D3 protect pancreas and brain regions from oxidative stress by their indigenous antioxidant properties and by their ability to stimulate cellular free radical defence system. The present study demonstrates the role of adrenergic and muscarinic receptor subtypes functional regulation in curcumin and vitamin D3 mediated anti-diabetogenesis. This will have immense clinical significance in developing effective strategies to delay or prevent the onset of diabetes.

Effect of air-drying pre-treatment on the characterization of forest soil carbon pools

Archived soils could represent a valuable resource for the spatio-temporal inventory of soil carbon stability. However, archived soils are usually air-dried before storage and the impact of a drying pretreatment on physically and chemically-defined C fractions has not yet been fully assessed. Through the comparison of field-moist and corresponding air-dried (at 25oC for 2 weeks) forest soil samples, we examined the effect of air-drying on: a) the quantity and the quality of cold- (CWEC) and hot-water (HWEC) extractable C and b) the concentration of C in physically isolated fractions (free- and intra-aggregate light and organo-mineral). Soil samples were collected from the organic (O) and mineral (A and B) horizons of three different forest soils from southeastern England: (i) Cambisol under Pine (Pinus nigra); (ii) Cambisol under Beech (Fagus sylvatica) and (iii) Gleysol under oak (Quercus robur). CWEC concentrations for dry samples were up to 2 times greater than for corresponding field moist samples and had significantly (p < 0.001) higher phenolic content. However, the effect of drying pretreatment on HWEC, its phenolic content was not significant (p > 0.05) for most samples. Dried soils had significantly (p < 0.001) higher concentrations of free light-C while having lower concentrations of intra-aggregate-C when compared to moist samples (p < 0.001). However, fine silt and clay fractions were not significantly affected by the drying pretreatment (p=0.789). Therefore, based on the results obtained from gleysol and cambisol forest soils studied here, C contents in hot-water extractions and fine particle size physical fractions (< 25µm) seem to be robust measurements for evaluating C fractions in dried stored forest soils. Further soil types should be tested to evaluate the wider generality of these findings.

Influence of aging pre-treatment on the compressive deformation of WE54 alloy

The effect of aging pre-treatment on the compressive deformation of a commercial WE54 alloy is studied. Age hardening treatments were performed at 170 °C, 250 °C and 300 °C. Compression testing was then carried out for the peak aged samples at temperatures between ambient and 450 °C. Twinning dominated the deformation at lower temperatures for all initial microstructures. This behaviour was replaced by slip dominated flow when the temperature was raised. The temperature of the transition from twinning to slip dominated flow was only mildly sensitive to the pre-treatment. It is also evident that dynamic recrystallization is retarded in this alloy.

Effect of weight reduction pre-treatment on the electrical and thermal properties of polypyrrole coated woven polyester fabrics

Weight reduction increased the amount of deposited polypyrrole (PPy) on the polyester (PET) fiber surface, leading to a considerable decrease in electrical resistance and improved heat generation capacity for the PPy coated PET fabrics. Application of dc voltages to an insulated roll of PPy-coated fabric increased the temperature to about 90 °C. This showed the suitability of these fabrics for heating applications. The optimum PPy deposition of about 2.8% was obtained in samples weight reduced by aqueous sodium hydroxide treatment. AFM images revealed a smooth surface morphology of the untreated fiber whereas the treated fiber had a high surface roughness.

Ranking of pre-treatment technologies for reverse osmosis for water recovery

Agro-industries are a life-line for sustainable future of human kind. However, the wastewater generated by agro-industries poses direct threat to the same sustainable future by polluting the freshwater sources when discharged into those freshwater sources. Thus, we need both advanced treatment technologies to treat those wastewater streams generated and better reuse practices for the treated effluents. Reverse osmosis (RO) is one of the advanced treatments to treat dissolved solids that are present in agricultural wastewater streams. But, RO is very sensitive to suspended solids (SS) present in the wastewater streams. Those SS can foul the RO membrane and make it ineffective in producing treated effluent at desired rates. Therefore, suitable pre-treatment scheme is necessary to treat the agro-wastewater streams before passing through RO. This study focuses on the qualitative and quantitative ranking of the available conventional and modern pre-treatment technologies as pre-treatment for RO. This study considers wastewater that has been treated through a secondary treatment system for example activated sludge process as the target water that needs pre-treatment. Based on qualitative ranking of conventional pre-treatment options, the Lime clarification/Granular Media filtration (GMF) option is ranked as the best; whereas finescreens/ micro-screens option ranked as the least preferred option based on the scores they attained in treating the water quality parameters that are considered essential. Based on the quantitative ranking, the low pressure membrane technology such as ultra-filtration (UF) stood first and microfiltration (MF) stood last.

A preliminary study on the volume reduction of pre-treatment sludge in seawater desalination by forward osmosis

Forward Osmosis (FO) can be applied to recover water from the pre-treatment sludge of seawater reverse osmosis process. This study investigated the effect of the concentration of two draw solutions (MgCl₂ and NaCl) in the reduction of Fe(OH)₃ sludge volume and the effect of cross flow velocity on flux through FO membrane. Higher the concentration of NaCl and MgCl₂ higher the water flux observed. However, the percentage increase was not significant due to the occurrence of internal concentration polarisation. MgCl₂ draws marginally increased water flux than NaCl, when the conditions of feed and draw solutions were similar. Increase in cross flow velocity (from 0.25 to 1.0 m/s) marginally changed the flux with both draw solutions as higher cross flow velocities were unproductive to beat the external CP effect along the membrane surface. However, at 1 m/s, highest fluxes were obtained for both draw solutions.