Nature reviews. Drug discovery
-
Nat Rev Drug Discov · Jul 2003
ReviewLovastatin and beyond: the history of the HMG-CoA reductase inhibitors.
In the 1950s and 1960s, it became apparent that elevated concentrations of plasma cholesterol were a major risk factor for the development of coronary heart disease, which led to the search for drugs that could reduce plasma cholesterol. One possibility was to reduce cholesterol biosynthesis, and the rate-limiting enzyme in the cholesterol biosynthetic pathway, 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, was a natural target. Here, I describe the discovery and development of lovastatin--the first approved inhibitor of HMG-CoA reductase--and the clinical trials that have provided the evidence for the ability of drugs in this class to reduce the morbidity and mortality associated with cardiovascular disease.
-
Nat Rev Drug Discov · May 2003
ReviewSuch stuff as dreams are made on: mediator-directed therapy in sepsis.
Sepsis, a life-threatening disorder that arises through the body's response to infection, is the leading cause of death and disability for patients in an intensive care unit. Advances in the understanding of the complex biological processes responsible for the clinical syndrome have led to the identification of many promising new therapeutic targets, including bacterial toxins, host-derived mediators, and downstream processes such as coagulation and the endocrine response. Diverse therapies directed against these targets have shown dramatic effects in animal models; however, in humans, their impact has been frustratingly modest, and only one agent--recombinant activated protein C--has achieved regulatory approval. This review summarizes the approaches that have been evaluated in clinical trials, explores the reasons for the discordance between biological promise and clinical reality, and points to approaches that may lead to greater success in the future.