The site-specific conjugation of polymers to multiple engineered cysteine residues of a prolyl endopeptidase leads to its stabilization in the gastrointestinal tract of rats, without compromising the activity relative to the native enzyme. The importance of polymer attachment sites is investigated, as well as the significance of polymer structure.

We describe two cases of hypertension and hypokalemia due to mineralocorticoid excess caused by posaconazole treatment of coccidioidomycosis and rhinocerebral mucormycosis infections, respectively. Clinical laboratory evaluations, including a comprehensive analysis of blood and urine steroid profiles, revealed low renin and aldosterone and indicated as the underlying mechanism primarily a block of 11β-hydroxylase activity in patient 1, whereas patient 2 displayed weaker 11β-hydroxylase but more pronounced 11β-hydroxysteroid dehydrogenase 2 inhibition. The results show that both previously suggested mechanisms must be considered and emphasize significant interindividual differences in the contribution of each enzyme to the observed mineralocorticoid excess phenotype. The mineralocorticoid symptoms of patient 1 resolved after replacement of posaconazole therapy by isavoconazole, and posaconazole dosage de-escalation ameliorated the effects in patient 2. By providing a thorough analysis of the patients’ blood and urine steroid metabolites, this report adds further evidence for two individually pronounced mechanisms of posaconazole-induced hypertension and hypokalemia. The elucidation of the factors responsible for the individual phenotype warrants further research.

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Lisdexamfetamine is a novel prodrug of D-amphetamine that is used for the treatment of attention-deficit/hyperactivity disorder (ADHD). D-amphetamine releases dopamine and norepinephrine and stimulates the hypothalamic-pituitary-adrenal (HPA) axis, which may contribute to its reinforcing effects and risk of abuse. However, there is currently no data available on the effects of lisdexamfetamine on circulating steroids. The goal of the present study was to assess the effects of lisdexamfetamine on circulating steroids compared with Damphetamine and placebo. Equimolar doses of D-amphetamine (40 mg) and lisdexamfetamine (100 mg) and placebo were administered in 24 healthy subjects in a randomized, double-blind, placebo-controlled, cross-over study. Plasma concentrations of steroids and D-amphetamine were determined up to 24 h. Plasma D-amphetamine concentrations began to increase and reached peak levels later after lisdexamfetamine administration compared with D-amphetamine administration, but the maximal concentrations and total exposure (area under the curve [AUC]) were similar. Lisdexamfetamine and Damphetamine significantly increased plasma concentrations of adrenocorticotropic hormone, glucocorticoids (cortisol, cortisone, corticosterone, 11-dehydrocorticosterone, and 11deoxycortisol), androgens (dehydroepiandrosterone, dehydroepiandrosterone sulfate, and ∆4-androstene-3,17-dione [androstenedione]), and progesterone (only in men) compared with placebo. Steroid concentration-time curves were shifted to later time points because of a nonsignificantly later onset after lisdexamfetamine administration compared with D-amphetamine, but maximal plasma steroid concentrations and AUCs did not differ between the active treatments. None of the active treatments altered plasma concentrations of the mineralocorticoids aldosterone and 11-deoxycorticosterone or the androgen testosterone compared with placebo. The effects of the amphetamines on glucocorticoid production were similar to those that were previously reported for methylphenidate (60 mg) but weaker than those for the serotonin releaser 3,4-methylenedioxymethamphetamine (MDMA; 125 mg) or direct serotonin receptor agonist lysergic acid diethylamide (LSD; 0.2 mg). Lisdexamfetamine produced comparable HPA axis activation and had similar pharmacokinetics compared with D-amphetamine, with the exception of a later time of onset. Thus, serotonin (MDMA, LSD) may more effectively stimulate the HPA axis than dopamine and norepinephrine (Damphetamine).

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