Increasing knowledge of molecular signaling processes has enabled the identification of drug targets that synergistically address multifactorial symptoms along several contributing pathways. The idea behind 'polypills' is that minor doses of pharmacodynamically interacting drugs would selectively achieve intended clinical effects. Analogously, monofactorial symptoms could be addressed vertically along their main pathway. Clinical selectivity follows from successive incomplete inhibitions of the pathological pathway at several steps. Here, we discuss and exemplify of how successive inhibitions in the prostaglandin E2 (PGE(2)) signaling pathway could achieve anti-inflammatory and analgesic effects while preserving physiological PGE(2) signaling in organs of major toxicity. Intentionally using intelligent low-dose drug combinations might provide an innovative therapeutic concept that directs combined small-drug effects towards a large, selective clinical effect with minor collateral damage.
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