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.

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.

Experimental nerve injury results in exaggerated responses to tactile and thermal stimuli that resemble some aspects of human neuropathic pain. Neuronal hyperexcitability and neurotransmitter release have been suggested to promote such increased responses to sensory stimuli. Enhanced activity of Ca(2+) current is associated with increased neuronal activity and blockade of N- and P-types, but not L-type, calcium channels have been found to block experimental neuropathic pain. While T-type currents are believed to promote neuronal excitability and transmitter release, it is unclear whether these channels may also contribute to the neuropathic state. Rats were prepared with L(5)/L(6) spinal nerve ligation, and tactile and thermal hypersensitivities were established. Mibefradil or ethosuximide was administered either intraperitoneally, intrathecally (i.th.), or locally into the plantar aspect of the injured hindpaw. Systemic mibefradil or ethosuximide produced a dose-dependent blockade of both tactile and thermal hypersensitivities in nerve-injured rats; responses of sham-operated rats were unchanged. Local injection of mibefradil also blocked both end points. Ethosuximide, however, was inactive after local administration, perhaps reflecting its low potency when compared with mibefradil. Neither mibefradil nor ethosuximide given i.th. produced any blockade of neuropathic behaviors. The results presented here suggest that T-type calcium channels may play a role in the expression of the neuropathic state. The data support the view that selective T-type calcium channel blockers may have significant potential in the treatment of neuropathic pain states.

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.

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Background: Dipyrone differs from other nonsteroidal anti-inflammatory drugs with a distinctive spasmolytic effect; however, the mechanism of action is not clear yet. The possible mechanism behind this effect was investigated on airway smooth muscle tone in vitro. Method:The effect of dipyrone on inositol phosphate (IP) accumulation was evaluated on guinea pig trachea smooth muscle. Changes in intracellular free calcium levels and IP accumulation were evaluated in LTK8 cells.Results: Dipyrone (0.01, 0.1, 1 mmol/l) had a relaxing effect on histamine (0.02 mmol/l)- and adenosine triphosphate- (ATP) (0.01 mol/l)-induced contractions, but not potassium chloride (KCl)-stimulated contractions. This relaxing effect was not observed with in- domethacin. Indomethacin did not inhibit the relaxation response of dipyrone. In isolated tracheal smooth muscle, histamine- (0.02 mmol/l) and ATP (0.01 mmol/l)-induced IP accumulation was significantly inhibited by dipyrone (1 mmol/l). ATP (0.01 mmol/l)-induced IP accumulation was also significantly inhibited by dipyrone (0.01 mmol/l) in LTK8 cells. Dipyrone inhibited ATP-induced (0.01 and 0.1 mmol/l) intracellular calcium increase in LTK8 cells.Conclusion: Inhibition of the release of intracellular Ca²⁺ may play a role in the smooth muscle relaxing effect of dipyrone. The inhibitor effect of dipyrone on IP accumulation may be due to direct inhibition of phospholipase C (PLC) or impairment of the activation of PLC by G protein-coupled receptor (GPCR).

We evaluated the characteristics of headache in migraine without aura and episodic tension-type headache diagnosed according to the International Headache Society (IHS) Classification. Fifty migraine without aura and 50 tension-type headache patients were selected prospectively. Fifty-eight percent of migraineurs had pain of a pulsating quality; 88% had severe pain and 74% had unilateral pain; aggravation by routine physical activity was reported by 96%. Episodic tension-type headache was of a pressing quality in 52%, moderate in 40%, bilateral in 82% and aggravated by routine physical activity in 16%. Nausea and/or vomiting, photophobia and phonophobia were reported significantly more commonly in migraineurs than tension-type headache patients.

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