Dibenzo[a,g]quinolizin-8-ones: synthesis, estrogen receptor affinities, and cytostatic activity

A number of acetoxy-substituted dibenzo[a,g]quinolizin-8-ones were synthesized by the reaction of 1-oxoisoquinolines with substituted homophthalic acid anhydride. All of the derivatives with acetoxy groups in positions 3 and 10 bind to the estrogen receptor. Relative binding affinities (RBA) ranged from 1.8 to 5.6 (estradiol: RBA = 100) when the substituent at C-6 was a short alkyl group. Introduction of additional oxygen functions in the 2- and/or 11-position decreased binding affinities. Analyses of the enantiomers of 6-methyl (6b) and 6-ethyl (6c) derivatives revealed that the receptor binding is mainly due to one optical isomer (e.g. (-)-6b, 9.9; (+)-6b, 0.6). In hormone-sensitive human MCF-7 breast cancer cells, compounds with one acetoxy group in each aromatic ring strongly inhibited cellular growth. Despite marked differences in receptor affinity, the enantiomers displayed similar activities in this cell culture. In hormone-independent MDA-MB 231 mammary tumor cells, only a weak cytostatic effect was recorded at 10-5 M. In the immature mouse uterine weight test, minimal estrogenic activity was observed. At higher doses, a significant anti-estrogenic effect became evident. It is assumed that the estrogen antagonism is responsible for the specific cytostatic effect in MCF-7 breast cancer cells

UNITAID can address HCV/HIV co-infection

This book is a guide to the law that applies in the three international criminal tribunals, for the former Yugoslavia, Rwanda and Sierra Leone, set up by the UN during the period 1993 to 2002 to deal with atrocities and human rights abuses committed during conflict in those countries. Building on the work of an earlier generation of war crimes courts, these tribunals have developed a sophisticated body of law concerning the elements of the three international crimes (genocide, crimes against humanity and war crimes), and forms of participation in such crimes, as well as other general principles of international criminal law, procedural matters and sentencing. The legacy of the tribunals will be indispensable as international law moves into a more advanced stage, with the establishment of the International Criminal Court. Their judicial decisions are examined here, as well as the drafting history of their statutes and other contemporary sources

A win-win solution?: A critical analysis of tiered pricing to improve access to medicines in developing countries

Background: Tiered pricing - the concept of selling drugs and vaccines in developing countries at prices systematically lower than in industrialized countries - has received widespread support from industry, policymakers, civil society, and academics as a way to improve access to medicines for the poor. We carried out case studies based on a review of international drug price developments for antiretrovirals, artemisinin combination therapies, drug-resistant tuberculosis medicines, liposomal amphotericin B (for visceral leishmaniasis), and pneumococcal vaccines. Discussion: We found several critical shortcomings to tiered pricing: it is inferior to competition for achieving the lowest sustainable prices; it often involves arbitrary divisions between markets and/or countries, which can lead to very high prices for middle-income markets; and it leaves a disproportionate amount of decision-making power in the hands of sellers vis-à-vis consumers. In many developing countries, resources are often stretched so tight that affordability can only be approached by selling medicines at or near the cost of production. Policies that “de-link” the financing of R&D from the price of medicines merit further attention, since they can reward innovation while exploiting robust competition in production to generate the lowest sustainable prices. However, in special cases - such as when market volumes are very small or multi-source production capacity is lacking - tiered pricing may offer the only practical option to meet short-term needs for access to a product. In such cases, steps should be taken to ensure affordability and availability in the longer-term. Summary: To ensure access to medicines for populations in need, alternate strategies should be explored that harness the power of competition, avoid arbitrary market segmentation, and/or recognize government responsibilities. Competition should generally be the default option for achieving affordability, as it has proven superior to tiered pricing for reliably achieving the lowest sustainable prices

Focusing on Quality Patient Care in the New Global Subsidy for Malaria Medicines

Tido von Schoen-Angerer and colleagues discuss the new Affordable Medicines Facility for malaria (AMFm), which subsidizes and facilitates access to artemisinin-based combination therapy, and what mechanisms are needed to ensure it stays focused on quality patient care