New Knowledge About Old Drugs: The Anti-Inflammatory Properties of Cardiac Glycosides.

In the 19th century, cardio-active steroid glycosides, shortly cardiac glycosides, were scientifically established as drugs against heart failure. Their in vivo, cellular, and molecular actions as well as their predominant target, Na+-K+-ATPase, have been comprehensively investigated in the 20th century and the discovery of endogenous cardiac glycosides has fostered this research field. In the last years, however, results from clinical trials and meta-analyses have questioned their therapeutic value due to efficacy and safety issues. This has led to a considerable decline of their usage. Beyond the cardiovascular system, cardiac glycosides have been increasingly recognized as antitumor compounds and Na+-K+-ATPase has evolved into a promising drug target in oncology. A wealth of review articles exists that intensively discuss these topics. Surprisingly, the anti-inflammatory actions of cardiac glycosides, which were discovered in the 1960s, have so far hardly been perceived and have not yet been summarized. This review provides an overview of the in vivo and in vitro actions of cardiac glycosides on inflammatory processes and of the signaling mechanisms responsible for these effects: cardiac glycosides have been found to decrease inflammatory symptoms in different animal models of acute and chronic inflammation. Regarding the underlying mechanisms most research has focused on leukocytes. In these cells, cardiac glycosides primarily inhibit cell proliferation and the secretion of proinflammatory cytokines.

Evidence-Based Phytotherapy in Europe: Where Do We Stand?

Medicinal plants represent the oldest source of pharmacotherapy used by mankind. A considerable number of traditional systems of medicine (folk medicine) have emerged over the last millennia under different cultural conditions. Even nowadays, the majority of people in less developed countries have to rely on herbal remedies as primary health care. Based on scientific and technical progress, the options to produce high quality herbal medicinal products have been largely improved in the last decades. The acceptance of phytotherapy as a "natural and mild alternative" to synthetic drugs is very high within the general public in developed countries and, from a global perspective, sales figures of herbal medicines are constantly rising. However, we still face many issues in this field. In contrast to the popularity of herbal medicinal products, physicians and their respective societies often have a very critical view of them. Besides dogmatic obstacles, this is based on the frequently missing clinical trials that clearly demonstrate their efficacy and/or safety. This perspective discusses the reasons and implications of the lack of scientific evidence and also of the wrong understanding of the principles of rational phytotherapy.

Plant-derived anti-inflammatory compounds: hopes and disappointments regarding the translation of preclinical knowledge into clinical progress.

Many diseases have been described to be associated with inflammatory processes. The currently available anti-inflammatory drug therapy is often not successful or causes intolerable side effects. Thus, new anti-inflammatory substances are still urgently needed. Plants were the first source of remedies in the history of mankind. Since their chemical characterization in the 19th century, herbal bioactive compounds have fueled drug development. Also, nowadays, new plant-derived agents continuously enrich our drug arsenal (e.g., vincristine, galantamine, and artemisinin). The number of new, pharmacologically active herbal ingredients, in particular that of anti-inflammatory compounds, rises continuously. The major obstacle in this field is the translation of preclinical knowledge into evidence-based clinical progress. Human trials of good quality are often missing or, when available, are frequently not suitable to really prove a therapeutical value. This minireview will summarize the current situation of 6 very prominent plant-derived anti-inflammatory compounds: curcumin, colchicine, resveratrol, capsaicin, epigallocatechin-3-gallate (EGCG), and quercetin. We will highlight their clinical potential and/or pinpoint an overestimation. Moreover, we will sum up the planned trials in order to provide insights into the inflammatory disorders that are hypothesized to be beneficially influenced by the compound.

Hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase.

The acylphloroglucinol derivative hyperforin is the major lipophilic constituent in the herb Hypericum perforatum (St. John's wort). The aim of the present study was to investigate if hyperforin as well as extracts of H. perforatum can suppresses the activities of 5-lipoxygenase (5-LO) and cyclooxygenases (COX), key enzymes in the formation of proinflammatory eicosanoids from arachidonic acid (AA). In freshly isolated human polymorphonuclear leukocytes stimulated with Ca(2+) ionophore A23187, hyperforin inhibited 5-LO product formation with IC(50) values of about 1-2 microM, in the absence or presence of exogenous AA (20 microM), respectively, being almost equipotent to the well-documented 5-LO inhibitor zileuton (IC(50) = 0.5-1 microM). Experiments with purified human 5-LO demonstrate that hyperforin is a direct 5-LO inhibitor (IC(50) approximately 90 nM), acting in an uncompetitive fashion. In thrombin- or ionophore-stimulated human platelets, hyperforin suppressed COX-1 product (12(S)-hydroxyheptadecatrienoic acid) formation with an IC(50) of 0.3 and 3 microM, respectively, being about 3- to 18-fold more potent than aspirin. At similar concentrations, hyperforin suppressed COX-1 activity in platelets in presence of exogenous AA (20 microM) as well as in cell-free systems. Hyperforin could not interfere with COX-2 product formation and did not significantly inhibit 12- or 15-LO in platelets or leukocytes, respectively. We conclude that hyperforin acts as a dual inhibitor of 5-LO and COX-1 in intact cells as well as on the catalytic activity of the crude enzymes, suggesting therapeutic potential in inflammatory and allergic diseases connected to eicosanoids.