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The triazole antifungals posaconazole and itraconazole can cause pseudohyperaldosteronism with hypertension and hypokalemia, edema, and gynecomastia by inhibiting steroid synthesis and metabolism. Mechanisms underlying pseudohyperaldosteronism include inhibition of adrenal 11β-hydroxylase cytochrome-P450 (CYP) 11B1 and 17α-hydroxylase (CYP17A1) as well as peripherally expressed 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). To enhance specificity for fungal CYP51, tetrazoles have been developed. This study employed H295R adrenocortical cells and enzyme activity assays to assess the potential risk of oteseconazole and two other tetrazoles, VT-1598 and quilseconazole, to inhibit adrenal steroidogenesis or 11β-HSD2. Steroidomic footprint analyses of H295R cell supernatants using untargeted liquid-chromatography-high-resolution mass-spectrometry (LC-HRMS) indicated overall patterns common to oteseconazole, quilseconazole and itraconazole, as well as similarities between VT-1598 and isavuconazole. Additionally, more specific features of the steroid signatures were observed. Targeted quantification of nine adrenal steroids in supernatants from treated H295R cells revealed an overall inhibition of adrenal steroidogenesis by the three tetrazoles, itraconazole and isavuconazole, providing an explanation for their similar steroidomic pattern. Applying recombinant enzymes indicated that this effect is not due to direct inhibition of steroidogenic enzymes because no or only weak inhibition could be observed. Moreover, oteseconazole and the two other tetrazoles did not inhibit 11β-HSD2, suggesting that they do not pose a risk of pseudohyperaldosteronism. Furthermore, oteseconazole did not alter steroid concentrations in a recent clinical study. Nevertheless, follow-up studies should assess the mechanism underlying the observed overall steroidogenesis inhibition by tetrazoles, itraconazole and isavuconazole, and whether concentrations achievable in a subgroup of susceptible patients might cause adrenal insufficiency and hyperplasia.

Abstract Portugal’s high public debt, its weak economic growth and its great attractiveness for foreign tourists are legend. Less well known is its unstable system of public pensions. This article addresses the underlying economic and political reasons, such as poor labour productivity, low real wages, insufficient immigration of trained people and the failure to find alternative ways of financing retirement. NextGenerationEU will effectively soften Portugal’s macroeconomic budget constraints, but it carries the risk of further postponement of necessary policy changes and reforms.

Abstract Only a few years ago, it was a widespread belief that globalisation would trigger processes of democratisation worldwide. However, even old and established democracies such as the United States have recently revealed serious weaknesses. This article shows that the US election system is heavily distorted and recommends profound and transparent Electoral College reforms in the election of US presidents. Furthermore, the article highlights the implications the challenges facing American democracy have for Europe.

Objective: We want to better understand what incentives firms to pursue innovations. For this purpose, we set up a new intertemporal principal-agent model. We then proceed to empirically assess the determinants of innovation activities unfolded by German firms between 2006 and 2019 and to also look at the causal factors – related to innovation activities – for the occurrence of patent registration in Germany. Research Design & Methods: In the theoretical part, we make use of intertemporal optimization tools based on the principal-agent model (PAM). In the empirical part, we apply the so-called DuPont decomposition and non-linear regression techniques. Findings: It seems that investment activities in conjunction with product innovations are the major determinants of innovation intensity. The latter (and other innovation related variables) in turn, is (are) responsible for the dynamics of patent registration in Germany. Implications & Recommendations: Our results highlight the importance of smart reward systems in R&D departments in order to incentivize innovative activities. Our findings also point at the significance of a patent regulation friendly to the innovator. Contribution & Value Added: Our findings deliver a new foundation of innovation activities based on an intertemporal principal agent approach which is confirmed by the empirical facts in the case of Germany.