The classification of receptors for adenosine, ATP and ADP (collectively called purinoceptors) has seen a number of developments in the past three years. The important division of receptors into two major classes 1 (1) adenosine (P 1 ) receptors and (2) P 2 purinoceptors, first suggested by Burnstock in 1978 (Ref.2), has been an abiding one that has set the stage for further subdivision of P 2 purinoceptors into P 2X and P 2Y subtypes on the basis of pharmacological properties 3 . Later, Dubyak 4 summarized the evidence that ATP worked through two different transduction mechanisms: intrinsic ion channels and G protein-coupled receptors. This information, coupled with the cloning of purinoceptors in 1993/94, led Abbracchio and Burnstock 5 to propose that purinoceptors should be classified in two families: G protein-coupled receptors termed P2Y purinoceptors, and intrinsic ion channels termed P2X purinoceptors. Developments in recent years have borne out these expectations and a revised nomenclature, essentially adopting the Abbracchio and Burnstock proposal, can now be proposed.

This cross-national study has demonstrated considerable variation in the utilization and expenditure of PPIs and statins across Europe, providing opportunities to further improve prescribing efficiency. The '4 Es' do provide an understandable methodology to document and compare the influence of different demand-side measures, with the influence varying by their extent and intensity. Further reforms are essential given current financial pressures. Consequently, further research will concentrate on the potential to develop a scoring system to help predict the possible impact of different demand-side measures on future utilization patterns.

The properties of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) as an antagonist ligand for A1 adenosine receptors were examined and compared with other radioligands for this receptor. DPCPX competitively antagonized both the inhibition of adenylate cyclase activity via A1 adenosine receptors and the stimulation via A2 adenosine receptors. The Ki-values of this antagonism were 0.45 nM at the A1 receptor of rat fat cells, and 330 nM at the A2 receptor of human platelets, giving a more than 700-fold A1-selectivity. A similar A1-selectivity was determined in radioligand binding studies. Even at high concentrations, DPCPX did not significantly inhibit the soluble cAMP-phosphodiesterase activity of human platelets. [3H]DPCPX (105 Ci/mmol) bound in a saturable manner with high affinity to A1 receptors in membranes of bovine brain and heart, and rat brain and fat cells (KD-values 50-190 pM). Its nonspecific binding was about 1% of total at KD, except in bovine myocardial membranes (about 10%). Binding studies with bovine myocardial membranes allowed the analysis of both the high and low agonist affinity states of this receptor in a tissue with low receptor density. The binding properties of [3H]DPCPX appear superior to those of other agonist and antagonist radioligands for the A1 receptor.

Introduction: European countries need to learn from each other to address unsustainable increases in pharmaceutical expenditures. Objective: To assess the influence of the many supply and demand-side initiatives introduced across Europe to enhance prescribing efficiency in ambulatory care. As a result provide future guidance to countries. Methods: Cross national retrospective observational study of utilization (DDDs – defined daily doses) and expenditure (Euros and local currency) of proton pump inhibitors (PPIs) and statins among 19 European countries and regions principally from 2001 to 2007. Demand-side measures categorized under the “4Es” – education engineering, economics, and enforcement. Results: Instigating supply side initiatives to lower the price of generics combined with demand-side measures to enhance their prescribing is important to maximize prescribing efficiency. Just addressing one component will limit potential efficiency gains. The influence of demand-side reforms appears additive, with multiple initiatives typically having a greater influence on increasing prescribing efficiency than single measures apart from potentially “enforcement.” There are also appreciable differences in expenditure (€/1000 inhabitants/year) between countries. Countries that have not introduced multiple demand side measures to counteract commercial pressures to enhance the prescribing of generics have seen considerably higher expenditures than those that have instigated a range of measures. Conclusions: There are considerable opportunities for European countries to enhance their prescribing efficiency, with countries already learning from each other. The 4E methodology allows European countries to concisely capture the range of current demand-side measures and plan for the future knowing that initiatives can be additive to further enhance their prescribing efficiency.

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Introduction: The appreciable growth in pharmaceutical expenditure has resulted in multiple initiatives across Europe to lower generic prices and enhance their utilization. However, considerable variation in their use and prices.Objective: Assess the influence of multiple supply and demand-side initiatives across Europe for established medicines to enhance prescribing efficiency before a decision to prescribe a particular medicine. Subsequently utilize the findings to suggest potential future initiatives that countries could consider.Method: An analysis of different methodologies involving cross national and single country retrospective observational studies on reimbursed use and expenditure of PPIs, statins, and renin-angiotensin inhibitor drugs among European countries.Results: Nature and intensity of the various initiatives appreciably influenced prescribing behavior and expenditure, e.g., multiple measures resulted in reimbursed expenditure for PPIs in Scotland in 2010 56% below 2001 levels despite a 3-fold increase in utilization and in the Netherlands, PPI expenditure fell by 58% in 2010 vs. 2000 despite a 3-fold increase in utilization. A similar picture was seen with prescribing restrictions, i.e., (i) more aggressive follow-up of prescribing restrictions for patented statins and ARBs resulted in a greater reduction in the utilization of patented statins in Austria vs. Norway and lower utilization of patented ARBs vs. generic ACEIs in Croatia than Austria. However, limited impact of restrictions on esomeprazole in Norway with the first prescription or recommendation in hospital where restrictions do not apply. Similar findings when generic losartan became available in Western Europe.Conclusions: Multiple demand-side measures are needed to influence prescribing patterns. When combined with supply-side measures, activities can realize appreciable savings. Health authorities cannot rely on a “spill over” effect between classes to affect changes in prescribing.

Pharmaceutical expenditures in ambulatory care rose rapidly in Europe in the 1990s and early 2000s. This was typically faster than other components of healthcare spending, leading to reforms to moderate future growth. A number of these centered on generic medicines with measures to lower reimbursed prices as well as enhance their prescribing and dispensing. The principal objective of this paper is to review additional measures that some European countries can adopt to further reduce reimbursed prices for generics. Secondly, potential approaches to address concerns with generics when they arise to maximize savings. Measures to enhance the prescribing of generics will also briefly be discussed. A narrative review of the extensive number of publications and associated references from the co-authors was conducted supplemented with known internal or web-based articles. In addition, health authority and health insurance databases, principally from 2001 to 2007, were analyzed to assess the impact of the various measures on price reductions for generic omeprazole and generic simvastatin vs. pre-patent loss prices, as well as overall efficiency in Proton Pump Inhibitor (PPI) and statin prescribing. The various initiatives generally resulted in considerable lowering of the prices of generics as well as specifically for generic omeprazole and generic simvastatin vs. pre-patent loss prices. At one stage in the UK, generic simvastatin was just 2% of the originator price. These measures also led to increased efficiency for PPI and statin prescribing with reimbursed expenditure for the PPIs and statins either falling or increasing at appreciably lower rates than increases in utilization. A number of strategies have also been introduced to address patient and physician concerns with generics to maximize savings. In conclusion, whilst recent reforms have been successful, European countries must continue learning from each other to fund increased volumes and new innovative drugs as resource pressures grow. Policies regarding generics and their subsequent impact on reimbursement and utilization of single sourced products will continue to play a key role to release valuable resources. However, there must continue to be strategies to address concerns with generics when they exist.