Longitudinal impact of the Women's Health Initiative study on hormone therapy use in Australia.

Purpose: This study aimed to examine the longitudinal impact of evidence changes on menopausal hormone therapy (MHT) use in Australia. Methods: We analyzed two datasets of subsidized and total MHT use (2000-2016) using segmented regression analysis to explore the impact of the Women's Health Initiative (WHI) 2002 and 2007 studies. Analyses were stratified by class, route, and strength. Use was measured in defined daily dose/1000 women/day (DDD/1000/day) or packs/1000 women/month (packs/1000/month). Results: The drop in total MHT use after the WHI 2002 was substantial. The biggest decreases in class, route, and strength were estrogens (28.99 DDD/1000/day, 95% confidence interval [CI] 23.97, 34.01), oral (46.07 DDD/1000/day, 95% CI 41.13, 51.01), and medium strength (34.95 packs/1000/month, 95% CI 30.17, 39.73), respectively. However, vaginal use remained stable (-1.83 DDD/1000/day, 95% CI -3.83, 0.17). Profiles of total and subsidized use were similar over time. Utilization levels were relatively unchanged after 2007. Decreased utilization contributed to product discontinuation, with a lag of up to 4 years. Product discontinuation in 2009 further decreased utilization. Discussion and conclusions: MHT use remained low after 2002 despite evidence favoring its use in women younger than 60 years or within 10 years postmenopause. Continued low use could relate to the WHI 2002 media coverage, therapy objectives, key stakeholder uncertainty, health policies, and medicine availability.

Concise synthesis of rare pyrido[1,2-a]pyrimidin-2-ones and related nitrogen-rich bicyclic scaffolds with a ring-junction nitrogen.

Pyrido[1,2-a]pyrimidin-2-ones represent a pharmaceutically interesting class of heterocycles. The structurally related pyrido[1,2-a]pyrimidin-4-ones are associated with a broad range of useful biological properties. Furthermore, quinolizinone-type scaffolds of these sorts with a bridgehead nitrogen are expected to display interesting physico-chemical properties. However, pyrido[1,2-a]pyrimidin-2-ones are largely under-represented in current small molecule screening libraries and the physical and biological properties of the pyrido[1,2-a]pyrimidin-2-one scaffold have been poorly explored (indeed, the same can be said for unsaturated bicyclic compounds with a bridgehead nitrogen in general). Herein, we report the development of a new strategy for the concise synthesis of substituted pyrido[1,2-a]pyrimidin-2-ones from readily available starting materials. The synthetic route involved the acylation of the lithium amide bases of 2-aminopyridines with alkynoate esters to form alkynamides, which were then cyclised under thermal conditions. The use of lithium amide anions ensured excellent regioselectivity for the 2-oxo-isomer over the undesired 4-oxo-isomer, which offers a distinct advantage over some existing methods for the synthesis of pyrido[1,2-a]pyrimidin-2-ones. Notably, different aminoazines could also be employed in this approach, which enabled access to several very unusual bicyclic systems with higher nitrogen contents. This methodology thus represents an important contribution towards the synthesis of pyrido[1,2-a]pyrimidin-2-ones and other rare azabicycles with a ring-junction nitrogen. These heterocycles represent attractive structural templates for drug discovery.

Analysis of second-site mutations that suppress the multiple drug resistance phenotype of the yeast PDR1-7 allele.

The yeast PDR1 locus encodes a member of the C6 zinc cluster family of transcriptional regulatory proteins. Among the targets of PDR1 is the yeast PDR5 locus. The product of this gene is a member of the ATP-binding cassette (ABC) transmembrane protein family and plays a major role in inhibitor efflux. Mutations in PDR1 affect the relative level of PDR5 transcript and can therefore result in increased or decreased drug resistance. We isolated three second-site suppressors of a PDR1-7 semidominant hyper-resistant mutation. These mutants were drug hypersensitive, as compared with isogenic controls. Two of the three mutations contained alterations in a putative DNA-binding domain. Significantly, the mutant proteins exhibited reduced DNA-binding capacity.