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Objectives: This project aimed at the formulation of dual drug entrapped liposomes held as freezedried intravaginal rod insert (IVR), to be administered by vaginal route for uterine targeting. Methods Liposomes were formulated by dehydration-rehydration method using 3 : 1 molar ratio of1,2-distearoyl-sn-glycero-3-phosphocholine : Cholesterol. Characterization was done for vesicle size, zeta potential, entrapment efficiency, surface morphology and % loading. Key findings: Spherical and discrete vesicles of size 354 nm were observed in transmission electron microscopy (TEM) image. The entrapment efficiency of 90.91% and 74.3% w/w was obtained for Raloxifene Hydrochloride (RLX) and Leuprolide acetate (LA) respectively. Drug release was sustained for 6 days. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay results showed that dual drug entrapped liposomal formulation show significant cytotoxicity, as also confirmed by higher apoptosis in cell cycle analysis and apoptosis studies (FACS) analysis. Pharmacodynamic studies in New Zealand white female rabbits revealed that intravaginal administration of RLX-LA entrapped liposomal formulation shows considerable fibroid regression. Conclusions: Uterine targeting of liposomal RLX-LA suggests its potential to solve the limitations of the presently available therapeutic options. [ABSTRACT FROM AUTHOR]

Background: Pulmonary arterial hypertension (PAH) prognosis has improved with targeted therapies; however, the long-term outlook remains poor. Objective multiparametric risk assessment is recommended to identify patients at risk of early morbidity and mortality, and for optimization of treatment. The US Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) 2.0 risk score is a new model proposed for the follow-up of patients with PAH but has not been externally validated.Methods: The REVEAL 2.0 risk score was applied to a mixed prevalent and incident cohort of patients with PAH (n = 1,011) from the Pulmonary Hypertension Society of Australia and New Zealand (PHSANZ) Registry. Kaplan-Meier survival was estimated for each REVEAL 2.0 risk score strata and for a simplified three-category (low, intermediate, and high risk) model. Sensitivity analysis was performed on an incident-only cohort.Results: The REVEAL 2.0 model effectively discriminated risk in the large external PHSANZ Registry cohort, with a C statistic of 0.74 (both for full eight-tier and three-category models). When applied to incident cases only, the C statistic was 0.73. The three-category REVEAL 2.0 model demonstrated robust separation of 12- and 60-month survival estimates (all risk category comparisons P < .001). Although the full eight-tier REVEAL 2.0 model separated patients at low, intermediate, and high risk, survival estimates overlapped within some of the intermediate- and high-risk strata.Conclusions: The REVEAL 2.0 risk score was validated in a large external cohort from the PHSANZ Registry. The REVEAL 2.0 model can be applied for risk assessment of patients with PAH at follow-up. The simplified three-category model may be preferred for clinical use and for future comparison with other prognostic models. [ABSTRACT FROM AUTHOR]

Context: Raloxifene hydrochloride (RLH), a selective estrogen receptor modulator, shows antiproliferative and apoptotic effects on Leiomyoma. Its extensive first pass metabolism leads to oral bioavailability of 2%. Objective: The aim of this investigation was to formulate RLH-loaded liposomes and study its uterine-targeting efficiency after intravaginal administration. Materials and methods:Liposomes were prepared by thin film hydration method using 1:1 molar ratio of DSPC:Cholesterol and characterized for vesicle size, zeta potential, %entrapment efficiency, loading, drug release and transmission electron microscopy. Radiolabeling of RLH was performed with reduced technetium-99m (99mTc). Binding affinity of99mTc-labeled complexes was assessed by diethylene triamine penta acetic acid (DTPA) challenge test. Biodistribution study was done in New Zealand white female rabbits by administering the formulation intravaginally. Results and discussion: Spherical and discrete liposomes of size 119 nm were seen in TEM results. Liposomes had high entrapment efficiency of 90.96% with drug loading of 27.25%w/w. Liposomes were able to sustain the drug release for 6 days.99mTc-labeled complexes showed high labeling efficiency and stability both in saline and serum. DTPA challenge test confirmed low transchelation of99mTc-labeled complexes. Biodistribution study by gamma scintigraphy revealed the preferential uptake of the formulation by uterus when administered vaginally. Compared to plain drug, liposomes were concentrated and retained within the uterus for a longer period of time. Conclusion: Uterine targeting of RLH-loaded liposomes indicates its potential to overcome the limitations of marketed formulation. Drug targeting to site of action anticipates dose reduction needed to elicit the therapeutic effect. [ABSTRACT FROM AUTHOR]

The Cardiac Society of Australia and New Zealand (CSANZ) Position Statement describes evidence-based standards of training, pre-procedural assessment, procedural conduct and post-procedure care with respect to sedation for cardiovascular procedures. It also describes the environment in which sedation for electrophysiological and other cardiac procedures may be performed. This Statement was developed by a Working Group of the Cardiac Society of Australia and New Zealand. It was reviewed by the Continuing Education and Recertification Committee and ratified at the CSANZ Board meeting held on Friday 7 March 2014. [ABSTRACT FROM AUTHOR]

Purpose. Various animal species have been used to study oxidative stress-induced cataractogenesis; however, given that differences in the expression of the lens antioxidant system may influence species susceptibility to oxidative stress, we compared and contrasted a broad spectrum of components of the lens antioxidant system in dog, rat, marmoset, and rabbit. Methods. Lenses collected from beagle dogs, Sprague-Dawley rats, marmosets, and New Zealand white rabbits were assayed for reduced glutathione (GSH), and activities of copper-zinc and manganese superoxide dismutase (CuZnSOD; Mn-SOD), catalase (CAT), glulathione peroxidase (GPX). γ-Glutamylcysteine synthetase (GCS), glutathione reductase (GR), glutathione-S-transferases (GST), and glucose-6-phosphate dehydrogenase (GPDH), and Trolox equivalent antioxidant capacity (TEAC). Results. Expression of the lens antioxidant system varied considerably between species. Marmoset lens contained the highest levels of GSH, its respective biosynthetic and recycling enzymes GCS and GR, and the associated H[SUB2]O[SUB2] dismutation enzyme GPX. Activities of both SOD isoforms were also highest in marmoset lens. However, activities of the xenobiotic-conjugating enzyme GST and NADPHgenerating enzyme GPDH were relatively low. In contrast, dog lens had the lowest levels of GSH, GCS, GR, and CuZn SOD (1/2, 1/2 and 1/33, and 1/63 that in marmoset) but highest levels of GST and GPDH Rabbit lens contained the highest CAT activity, at up to 3.5-fold that for marmoset and rat. Conclusions. These results demonstrate substantial variation in lens antiodidant systems between different laboratory animal species. Given that such variation may affect relative susceptibility to oxidative stress-mediated ocular toxicity, our findings may provide useful information when choosing different animal species for lens research. [ABSTRACT FROM AUTHOR]

[Display omitted] The current study aimed to determine the effect of inclusion of a mucoadhesive agent on the intensity and duration of intraocular pressure (IOP) lowering activity of Δ9-tetrahydrocannabinol-valine-hemisuccinate (THC-VHS) loaded in a nanoemulsion (THC-VHS-NE) formulation. THC-VHS-NE formulation with Carbopol®940NF added as a mucoadhesive agent (THC-VHS-NEC) was prepared using hot-homogenization followed by probe sonication and characterized. A comparative evaluation of the IOP lowering activity of THC-VHS-NEC, THC-VHS-NE, THC-NEC, and commercial latanoprost ophthalmic solution, was undertaken in normotensive New Zealand white rabbits. The effect of pH, surfactant concentration, and autoclave process on the IOP lowering activity of THC-VHS-NEC was also studied. The formulation demonstrated desired viscosity, physicochemical properties, and autoclave process stability. The THC-VHS-NEC formulation showed a significant (p < 0.05) improvement in the duration of IOP lowering activity, compared to THC-NEC and THC-VHS-NE. Moreover, in this model, THC-VHS-NEC was more effective than commercially available latanoprost ophthalmic formulation, in terms of both duration and intensity of IOP lowering. A change in formulation pH, surfactant concentration, or sterilization process did not impact the IOP lowering activity of THC-VHS-NEC. Overall, inclusion of a mucoadhesive agent in THC-VHS-NE formulation, significantly increased the duration of activity, and could lead to a once- or twice- a day dosing regimen. [ABSTRACT FROM AUTHOR]

Background: Epidemiology and treatment strategies continue to evolve in pulmonary arterial hypertension (PAH). We sought to define the characteristics and survival of patients with idiopathic, heritable and drug-induced PAH in the current management era.Methods: Consecutive cases of idiopathic, heritable and drug-induced PAH were prospectively enrolled into an Australian and New Zealand Registry.Results: Between January 2012 and December 2016, a total of 220 incident cases were enrolled (mean age 57.2±18.7years, female 69.5%) and followed for a median duration of 26 months (IQR17-39). Co-morbidities were common such as obesity (34.1%), systemic hypertension (30.5%), coronary artery disease (16.4%) and diabetes mellitus (19.5%). Initial combination therapy was used in 54 patients (dual, n=50; triple, n=4). Estimated survival rates at 1-year, 2-years and 3-years were 95.6% (CI 92.8-98.5%), 87.3% (CI 82.5-92.4%) and 77.0% (CI 70.3-84.3%), respectively. Multivariate analysis showed that male sex and lower 6-minute distance at diagnosis independently predicted worse survival, whereas obesity was associated with improved survival. Co-morbidities other than obesity did not impact survival. Initial dual oral combination therapy was associated with a trend towards better survival compared with initial oral monotherapy (adjusted HR=0.27, CI 0.06-1.18, p=0.082) CONCLUSIONS: The epidemiology and survival of patients with idiopathic PAH in Australia and New Zealand are similar to contemporary registries reported in Europe and North America. Male sex and poorer exercise capacity are predictive of mortality whereas obesity appears to exert a protective effect. Despite current therapies, PAH remains a life-threatening disease associated with significant early mortality. [ABSTRACT FROM AUTHOR]