Polypharmacy, therefore, is the clinical practice of combining two or more medications in a patient’s medication profile, with a view to treat one specific disease. For example, the combination use of salmeterol (a β2-adrenergic agonist) and see more fluticasone (a glucocorticoid steroid) in asthma

has led to the combination of these two medications in one (Advair®). Also, the combination (in Vytorin®) of simvastatin [an 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor] and ezetimibe (an inhibitor of dietary cholesterol uptake) is used to treat hyperlipidemia.20 The major dilemma encountered in a polypharmaceutical approach is a significant chance of increases in side-effects, which may be reduced statistically Inhibitors,research,lifescience,medical with the use of only one compound. Inhibitors,research,lifescience,medical The recent appearance on the market of drugs that display two mechanisms to treat a particular disease has been a clear move in the direction of the latter paradigm. One example, duloxetine (Cymbalta®) (Figure 1), used in the treatment of depression, inhibits both serotonin and norepinephrine uptake in the central nervous system (CNS).28–30 The introduction of drugs such as duloxetine indicates the clinical Inhibitors,research,lifescience,medical feasibility of designing multifunctional ligands to treat CNS disorders

with complex disease pathways. Figure 1 Structure of a multimodal antidepressant that acts both as serotonin and norepinephrine uptake inhibitor. In this review, Inhibitors,research,lifescience,medical we will consider examples of compounds with multifunctional neuroprotective-neurorescue (Figure 2 and see Table 1 for definitions) properties that may have promise in the treatment of PD, and similar approaches have been made for multimodal drugs for AD,31,32 but for the present discussion we shall focus mainly on PD. Some of the compounds discussed were discovered through serendipity, while others were the products of active drug design projects. Figure 2 Three approaches towards combination

drug therapy in a multi-target disease. These include: 1) giving a combination of two or three drugs, i.e. separate medicines, 2) chemically combining two drugs into one medicine, and/or 3) synthesizing one drug possessing … RASAGILINE Rasagiline is Inhibitors,research,lifescience,medical a restricted analog of selegiline (Figure 3) and is a newly approved compound for the treatment of PD.10 Rasagiline (N-propargyl-1R-aminoindan) is an anti-PD drug with selective MAO-B-inhibitory activity.33 Its S-isomer, TVP1022 (N-propargyl-1S-aminoindan), is more Ketanserin than a 1,000 times less potent as an MAO inhibitor than rasagiline but still retains neuroprotective activity, which suggests that the propargylamine moiety (even when ostensibly not involved in Michael reaction chemistry at the flavin adenine nucleotide (FAD) co-factor within the MAO catalytic site as the processing group in suicide inhibition) is responsible for the neuroprotective activity seen in both these compounds.34–37 Figure 3 Structures of the anti-Parkinson MAO-B inhibitors selegiline and rasagiline as monomodal drugs.