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Assessing the synergy between cholinomimetics and memantine as augmentation therapy in cognitive impairment in schizophrenia. A virtual human patient trial using quantitative systems pharmacology.

Geerts H, Roberts P, Spiros A - Front Pharmacol (2015)

Bottom Line: Smoking reduces the effect of cholinomimetics with aripiprazole and olanzapine, but enhances the effect in haloperidol and risperidone.Adding memantine to antipsychotics improves cognition except with quetiapine, an effect enhanced with smoking.Combining cholinomimetics, antipsychotics and memantine in general shows an additive effect, except for a negative interaction with aripiprazole and quetiapine and a synergistic effect with olanzapine and haloperidol in non-smokers and haloperidol in smokers.

View Article: PubMed Central - PubMed

Affiliation: In Silico Biosciences Berwyn, PA, USA ; Perelman School of Medicine, University of Pennsylvania Philadelphia, PA, USA.

ABSTRACT
While many drug discovery research programs aim to develop highly selective clinical candidates, their clinical success is limited because of the complex non-linear interactions of human brain neuronal circuits. Therefore, a rational approach for identifying appropriate synergistic multipharmacology and validating optimal target combinations is desperately needed. A mechanism-based Quantitative Systems Pharmacology (QSP) computer-based modeling platform that combines biophysically realistic preclinical neurophysiology and neuropharmacology with clinical information is a possible solution. This paper reports the application of such a model for Cognitive Impairment In Schizophrenia (CIAS), where the cholinomimetics galantamine and donepezil are combined with memantine and with different antipsychotics and smoking in a virtual human patient experiment. The results suggest that cholinomimetics added to antipsychotics have a modest effect on cognition in CIAS in non-smoking patients with haloperidol and risperidone and to a lesser extent with olanzapine and aripiprazole. Smoking reduces the effect of cholinomimetics with aripiprazole and olanzapine, but enhances the effect in haloperidol and risperidone. Adding memantine to antipsychotics improves cognition except with quetiapine, an effect enhanced with smoking. Combining cholinomimetics, antipsychotics and memantine in general shows an additive effect, except for a negative interaction with aripiprazole and quetiapine and a synergistic effect with olanzapine and haloperidol in non-smokers and haloperidol in smokers. The complex interaction of cholinomimetics with memantine, antipsychotics and smoking can be quantitatively studied using mechanism-based advanced computer modeling. QSP modeling of virtual human patients can possibly generate useful insights on the non-linear interactions of multipharmacology drugs and support complex CNS R&D projects in cognition in search of synergistic polypharmacy.

No MeSH data available.


Related in: MedlinePlus

Complex pharmacology of antipsychotics and their major metabolites (forming the active moiety of currently used antipsychotic medication) illustrated by the pKa (−10logKi) against the human receptors, where Ki is the affinity of the drug determined by tracer displacement studies. More peripheral readouts correspond to higher affinities. Data are derived from the standardized PDSP database (http://pdsp.med.unc.edu/indexR.html). It is clear that many antipsychotics have complex pharmacologies leading to non-linear interactions in the human networks. (A) pharmacology of active moiety of aripiprazole, haldoperidol, and olanzapine, (B) pharmacology of risperidone and quetiapine.
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Figure 1: Complex pharmacology of antipsychotics and their major metabolites (forming the active moiety of currently used antipsychotic medication) illustrated by the pKa (−10logKi) against the human receptors, where Ki is the affinity of the drug determined by tracer displacement studies. More peripheral readouts correspond to higher affinities. Data are derived from the standardized PDSP database (http://pdsp.med.unc.edu/indexR.html). It is clear that many antipsychotics have complex pharmacologies leading to non-linear interactions in the human networks. (A) pharmacology of active moiety of aripiprazole, haldoperidol, and olanzapine, (B) pharmacology of risperidone and quetiapine.

Mentions: The affinity parameters for each individual drug and neurotransmitter for human receptors were derived from the standardized PDSP database (http://pdsp.med.unc.edu/indexR.html) (Besnard et al., 2012). Importantly, the active moiety of antipsychotics, taking into account the pharmacology of metabolites was used (see Figure 1). We took great care in determining the functional intrasynaptic concentration of the various antipsychotics using published 11C-raclopride displacements observed with specific antipsychotic dose combinations using the receptor competition model, described above.


Assessing the synergy between cholinomimetics and memantine as augmentation therapy in cognitive impairment in schizophrenia. A virtual human patient trial using quantitative systems pharmacology.

Geerts H, Roberts P, Spiros A - Front Pharmacol (2015)

Complex pharmacology of antipsychotics and their major metabolites (forming the active moiety of currently used antipsychotic medication) illustrated by the pKa (−10logKi) against the human receptors, where Ki is the affinity of the drug determined by tracer displacement studies. More peripheral readouts correspond to higher affinities. Data are derived from the standardized PDSP database (http://pdsp.med.unc.edu/indexR.html). It is clear that many antipsychotics have complex pharmacologies leading to non-linear interactions in the human networks. (A) pharmacology of active moiety of aripiprazole, haldoperidol, and olanzapine, (B) pharmacology of risperidone and quetiapine.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585031&req=5

Figure 1: Complex pharmacology of antipsychotics and their major metabolites (forming the active moiety of currently used antipsychotic medication) illustrated by the pKa (−10logKi) against the human receptors, where Ki is the affinity of the drug determined by tracer displacement studies. More peripheral readouts correspond to higher affinities. Data are derived from the standardized PDSP database (http://pdsp.med.unc.edu/indexR.html). It is clear that many antipsychotics have complex pharmacologies leading to non-linear interactions in the human networks. (A) pharmacology of active moiety of aripiprazole, haldoperidol, and olanzapine, (B) pharmacology of risperidone and quetiapine.
Mentions: The affinity parameters for each individual drug and neurotransmitter for human receptors were derived from the standardized PDSP database (http://pdsp.med.unc.edu/indexR.html) (Besnard et al., 2012). Importantly, the active moiety of antipsychotics, taking into account the pharmacology of metabolites was used (see Figure 1). We took great care in determining the functional intrasynaptic concentration of the various antipsychotics using published 11C-raclopride displacements observed with specific antipsychotic dose combinations using the receptor competition model, described above.

Bottom Line: Smoking reduces the effect of cholinomimetics with aripiprazole and olanzapine, but enhances the effect in haloperidol and risperidone.Adding memantine to antipsychotics improves cognition except with quetiapine, an effect enhanced with smoking.Combining cholinomimetics, antipsychotics and memantine in general shows an additive effect, except for a negative interaction with aripiprazole and quetiapine and a synergistic effect with olanzapine and haloperidol in non-smokers and haloperidol in smokers.

View Article: PubMed Central - PubMed

Affiliation: In Silico Biosciences Berwyn, PA, USA ; Perelman School of Medicine, University of Pennsylvania Philadelphia, PA, USA.

ABSTRACT
While many drug discovery research programs aim to develop highly selective clinical candidates, their clinical success is limited because of the complex non-linear interactions of human brain neuronal circuits. Therefore, a rational approach for identifying appropriate synergistic multipharmacology and validating optimal target combinations is desperately needed. A mechanism-based Quantitative Systems Pharmacology (QSP) computer-based modeling platform that combines biophysically realistic preclinical neurophysiology and neuropharmacology with clinical information is a possible solution. This paper reports the application of such a model for Cognitive Impairment In Schizophrenia (CIAS), where the cholinomimetics galantamine and donepezil are combined with memantine and with different antipsychotics and smoking in a virtual human patient experiment. The results suggest that cholinomimetics added to antipsychotics have a modest effect on cognition in CIAS in non-smoking patients with haloperidol and risperidone and to a lesser extent with olanzapine and aripiprazole. Smoking reduces the effect of cholinomimetics with aripiprazole and olanzapine, but enhances the effect in haloperidol and risperidone. Adding memantine to antipsychotics improves cognition except with quetiapine, an effect enhanced with smoking. Combining cholinomimetics, antipsychotics and memantine in general shows an additive effect, except for a negative interaction with aripiprazole and quetiapine and a synergistic effect with olanzapine and haloperidol in non-smokers and haloperidol in smokers. The complex interaction of cholinomimetics with memantine, antipsychotics and smoking can be quantitatively studied using mechanism-based advanced computer modeling. QSP modeling of virtual human patients can possibly generate useful insights on the non-linear interactions of multipharmacology drugs and support complex CNS R&D projects in cognition in search of synergistic polypharmacy.

No MeSH data available.


Related in: MedlinePlus