The Role of the Iron Protoporphyrins Heme and Hematin in the Antimalarial Activity of Endoperoxide Drugs

Plasmodium has evolved to regulate the levels and oxidative states of iron protoporphyrin IX (Fe-PPIX). Antimalarial endoperoxides such as 1,2,4-trioxane artemisinin and 1,2,4-trioxolane arterolane undergo a bioreductive activation step mediated by heme (FeII-PPIX) but not by hematin (FeIII-PPIX), leading to the generation of a radical species. This can alkylate proteins vital for parasite survival and alkylate heme into hematin–drug adducts. Heme alkylation is abundant and accompanied by interconversion from the ferrous to the ferric state, which may induce an imbalance in the iron redox homeostasis. In addition to this, hematin–artemisinin adducts antagonize the spontaneous biomineralization of hematin into hemozoin crystals, differing strikingly from artemisinins, which do not directly suppress hematin biomineralization. These hematin–drug adducts, despite being devoid of the peroxide bond required for radical-induced alkylation, are powerful antiplasmodial agents. This review addresses our current understanding of Fe-PPIX as a bioreductive activator and molecular target. A compelling pharmacological model is that by alkylating heme, endoperoxide drugs can cause an imbalance in the iron homeostasis and that the hematin–drug adducts formed have strong cytocidal effects by possibly reproducing some of the toxifying effects of free Fe-PPIX. The antiplasmodial phenotype and the mode of action of hematin–drug adducts open new possibilities for reconciliating the mechanism of endoperoxide drugs and for malaria intervention.

Identifiability of pharmacological models for online individualization

There is a large variability between individuals in the response to anesthetic drugs, that seriously limits the achievable performance of closed-loop controlled drug dosing. Full individualization of patient models based on early clinical response data has been suggested as a means to improve performance with maintained robustness (safety). We use estimation theoretic analysis and realization theory to characterize practical identifiability of the standard pharmacological model structure from anesthetic induction phase data and conclude that such approaches are not practically feasible.

Abstract P433: A Pharmacological Model Predicts Drug Activity In Cardiomyocyte Hypertrophy

Introduction: Cardiomyocyte (CM) hypertrophy is predictive of heart failure, however there are no clinical therapies that target its intracellular pathways. Hypertrophy is a complex process involving numerous neurohormonal and cytokine inputs, resulting in context-dependent responses that determine CM growth. In the face of this complexity, it is critical that computational models are developed. Accurate predictions of drug activity in CM hypertrophy will require a pharmacological model that is developed with and validated against experimental data. Hypothesis: We test the hypothesis that our in silico pharmacological model accurately predicts drugs that inhibit cardiac hypertrophy as well as the context-dependent mechanisms by which they work. Methods: Here we employ a previously published computational model of cardiac hypertrophy signaling. This model utilizes logic-based ordinary differential equations to simulate a network of 106 nodes. Using the DrugBank database, we constructed a pipeline for simulating FDA-approved drugs within this hypertrophy network under multiple environmental contexts. The predicted outcomes of the model were then compared to measured phenotypes from experimental findings in literature. Results: Predicted outcomes of our model were successfully validated against 29 out of 36 distinct experiments described in literature. These simulations identify the optimal drug types that inhibit hypertrophy for each of 17 different stimuli. Sensitivity analyses performed by simulating knockdowns in our model reveals context-dependent mechanisms predicted for 51 drug types. These predictions confirmed, for example, the role of celecoxib in inhibiting CM hypertrophy induced by isoproterenol. Mechanistic analysis suggests celecoxib prevents protein kinase B (Akt) inhibition of glycogen synthase kinase 3 beta (GSK3β), consistent with literature. Conclusions: Our pharmacological model accurately predicts FDA-approved drugs that show in vitro inhibition of CM hypertrophy.

Synthesis of Novel Biologically Active Proflavine Ureas Designed on the Basis of Predicted Entropy Changes

A novel series of proflavine ureas, derivatives 11a–11i, were synthesized on the basis of molecular modeling design studies. The structure of the novel ureas was obtained from the pharmacological model, the parameters of which were determined from studies of the structure-activity relationship of previously prepared proflavine ureas bearing n-alkyl chains. The lipophilicity (LogP) and the changes in the standard entropy (ΔS°) of the urea models, the input parameters of the pharmacological model, were determined using quantum mechanics and cheminformatics. The anticancer activity of the synthesized derivatives was evaluated against NCI-60 human cancer cell lines. The urea derivatives azepyl 11b, phenyl 11c and phenylethyl 11f displayed the highest levels of anticancer activity, although the results were only a slight improvement over the hexyl urea, derivative 11j, which was reported in a previous publication. Several of the novel urea derivatives displayed GI50 values against the HCT-116 cancer cell line, which suggest the cytostatic effect of the compounds azepyl 11b–0.44 μM, phenyl 11c–0.23 μM, phenylethyl 11f–0.35 μM and hexyl 11j–0.36 μM. In contrast, the novel urea derivatives 11b, 11c and 11f exhibited levels of cytotoxicity three orders of magnitude lower than that of hexyl urea 11j or amsacrine.

Addicted to Self-esteem: Understanding the neurochemistry of narcissism by using cocaine as a pharmacological model

There are pronounced behavioural and neuroimaging parallels between cocaine abuse and narcissism. Although the observed commonalities are not specific to cocaine as opposed to other types of addiction, we argue that the relatively constrained molecular actions of cocaine and, more importantly, the covariance of narcissism-like behaviours with cocaine use build a strong case for taking the known effects of cocaine as a starting point for addressing the hitherto underinvestigated neurophysiology of narcissism. In this review, we discuss the potential relevance of cocaine abuse as a pharmacological model of narcissism. We outline previous research on the role of monoamines across several domains affected in narcissistic personality disorder and subclinical narcissism, namely, selected personality traits, social behaviour, emotional empathy and self-referential processing. We propose that dysregulation in dopamine signalling might underlie addiction-like features of narcissism and that altered serotonergic signalling may account for affective components of narcissism and, in particular, explain the differences between grandiose and vulnerable subtypes. In conclusion, we provide recommendations for future research.

Evaluating artesunate-amodiaquine deployment, efficacy and safety: an in silico pharmacological model

BackgroundThe World Health Organization currently recommends artesunate-amodiaquine (AS-AQ) as a first-line treatment for uncomplicated falciparum malaria. The clinical efficacy of AS-AQ is very high but its effectiveness in the field varies considerably. This study aimed at comparing the efficacy, effectiveness and safety of AS-AQ fixed dose combination (FDC) and non-fixed formulation (non-FDC) in controlled and real-life settings using a pharmacological model of antimalarial treatment.MethodsThe effectiveness and safety of different drug formulations in different treatment scenarios were investigated using a pharmacological model of AS-AQ treatment. The model simulated multiple treatment scenarios to assess the effects of age-or weight-based dosing bands in three geographically distinct patient populations, and poor patient adherence.ResultsThe model output was consistent with clinical trials in terms of cure rates, recrudescence rates and the pattern of AQ overdosing with age- and weight-based dosing regimens. AS-AQ treatment has good efficacy and effectiveness in fully adherent patients but monotherapy of AS or AQ lead to treatment failure. The weight-based dosing regimen with FDC was the best option for patients in terms of drug safety and had similar efficacies to the other regimens. Asians were more likely to be overdosed with AQ when using age-based dosing regimens.ConclusionsWeight-based dosing is optimal but not always feasible, so age-based dosing regimens are often used as an alternative. The model outputs highlight the importance of optimising these age-based dosing regimens for specific regions, and identify an increased risk of overdosing in young children.