Complex diseases demand novel treatment strategies: understanding drug combination

For many multigene or multifactorial diseases,the one-drug therapy for inhibiting a defined molecular target is often less effective than combined treatments.Typically,drug combination therapies are multitargeted,so the mechanisms or even interactions are often complementary.These drug-drug interactions may promote alteration of pharmacokinetic or pharmacodynamic activities of one drug by another drug.Other interactions may change the expected effect of medications through polymorphisms that alter the expression or activity of the drug-mediated enzyme and the cell signaling cascade,such as drug-gene interactions and drug-drug-gene interactions.The number of possible existing interactions requires appropriate methods of study.In this review,we summarized combination therapies for cancer,as well as for viral,cardiovascular,and neurological diseases.Here,we also highlight known methodologies,such as in vitro methods based on Loewe’s and Bliss’s pioneer models and in silico methods based on online available data.With more elaborate methods and reliable results,multitarget therapies through drug combinations may increasingly benefit patients suffering from complex diseases.

Purinergic Receptors in Basal Ganglia Diseases:Shared Molecular Mechanisms between Huntington’s and Parkinson’s Disease

Huntington’s(HD)and Parkinson’s diseases(PD)are neurodegenerative disorders caused by the death of GABAergic and dopaminergic neurons in the basal ganglia leading to hyperkinetic and hypokinetic symptoms,respectively.We review here the participation of purinergic receptors through intracellular Ca^2+signaling in these neurodegenerative diseases.The adenosine A2A receptor stimulates striatopallidal GABAergic neurons,resulting in inhibitory actions on GABAergic neurons of the globus pallidus.A2A and dopamine D2 receptors form functional heteromeric complexes inducing allosteric inhibition,and A2A receptor activation results in motor inhibition.Furthermore,the A2A receptor physically and functionally interacts with glutamate receptors,mainly with the mGlu5 receptor subtype.This interaction facilitates glutamate release,resulting in NMDA glutamate receptor activation and an increase of Ca2+influx.P2X7 receptor activation also promotes glutamate release and neuronal damage.Thus,modulation of purinergic receptor activity,such as A2A and P2X7 receptors,and subsequent aberrant Ca^2+signaling,might present interesting therapeutic potential for HD and PD.