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Aims To investigate the effect of acute P-glycoprotein inhibition by the multidrugresistance (MDR) modulator valspodar (SDZ PSC 833; PSC) on the pharmacokinetics, and potentially adverse pharmacodynamic effects of morphine, and its principal pharmacologically active metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Methods In a double-blind, three-way crossover study, the pharmacokinetic and potentially adverse pharmacodynamic effects (reaction time, transcutaneous PCO 2 , blood pressure) of morphine were compared with and without acute inhibition of P-glycoprotein by PSC. The effects of PSC alone were also evaluated. The study was performed in 18 healthy male volunteers and pharmacodynamic effects analysed by measuring the area under the effect (AUE) curve. 150 mg PSC (or its placebo) was given as an i.v. infusion over 2 h. With the expected inhibition of Pgp 1 h after starting PSC infusion, 7.5 morphine HCl (or its placebo) was infused over 2 h. Results The infusion of PSC resulted in blood concentrations expected to inhibit Pgp mediated transport. While the pharmacokinetics of plasma morphine and M6G. were unaffected there was a small but statistically signi®cant increase in the AUC and C max of M3G (11.8 and 8.3%, respectively). The t K and t max were unaffected. The pharmacokinetic parameters of PSC were not affected by coadministration with morphine. PSC did not signi®cantly affect the adverse events of morphine, as assessed by spontaneous reporting. Compared with PSC alone, morphine elicited an increase in reaction time (E max 48 ms, compared with the predose absolute reaction time of 644 ms), which was not detected by the alertness-drowsiness score, indicating only slight sedation. There was a signi®cant decrease in systolic blood pressure (E min x9 mmHg), and a trend for a fall in diastolic blood pressure (E min x14.5 mmHg) and respiratory rate (E min x1.8 breathemin ). For all these parameters, the effects of PSC/morphine were similar to that of PSC alone, suggesting some attenuation of morphine's effect. In contrast, morphine caused a signi®cant increase in PCO 2 (E max 0.69 kPa) compared to PSC alone, indicating slight respiratory depression. This increase was similar to that of the PSC/morphine combination. Conclusions Acute inhibition of P-glycoprotein by PSC in this setting does not affect the pharmacokinetic or safety-related pharmacodynamic pro®le of morphine in a clinically signi®cant manner.

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The EU Commission has introduced the instrument of National Energy and Climate Plans (NECP) to better achieve energy and climate policy targets. In Germany, a comprehensive study was commissioned for this purpose. Its methods and main results are presented here. It starts with a set of energy system models that maps the necessary changes in the energy system, together with corresponding measures bottom-up. The results then enter the PANTA RHEI macroeconometric top-down model as scenario inputs to determine the socioeconomic effects. According to the bottom-up models, achieving the target of 55% GHG reduction by 2030 will not be easy. The macroeconomic effects are mostly positive. Driven by additional investment, GDP and the number of jobs will be higher than in the baseline. The construction and service sectors can benefit from energy and climate policy measures. The share of final consumer expenditures on energy in GDP declines by 2030 compared to today. However, the direction and magnitude of the effects are not undisputed in the literature. The results show that ambitious climate policies are possible in Germany, which can also improve the achievement of economic and social goals.

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