The use of complementary and alternative medicine by patients in routine care and the risk of interactions.

BACKGROUND: Patients suffering from cancer often make use of complementary and alternative medicine (CAM). Only few data exist on the prevalence and clinical significance of interactions of a biological CAM method and conventional drugs. METHODS: From February 2014 to March 2016, consecutive patients from five oncological practices in Germany were asked to fulfill a standardized questionnaire regarding use of CAM. Data on diagnosis, date of first diagnosis, ECOG and the past and current treatment were derived from the patients' files. Interactions were evaluated by systematically using a database on potential interactions. RESULTS: From 1000 patients asked to participate, we received a total of 720 questionnaires of which 711 were completed and eligible for evaluation. 29% of the patients reported any CAM usage. Women showed a significantly higher use of CAM with 35.6 versus 23.6% of men. For 54.9% of CAM users (15.9% of all patients), we found a combination of conventional drugs and biological based CAM methods with a risk for interactions. Vitamins A, C and E were the most frequently used CAM substances in these cases (39.3%), followed by herbs with 17.5%. CONCLUSION: There was a risk of interactions between a biological CAM method and conventional drugs in 54.9% of the patients using CAM. To raise knowledge on interactions a better training for doctors with respect to CAM is strongly needed. Furthermore, patients' awareness should also be raised and communication between physician and patient on the topic improved.

Estrogen Enhances Linkage in the Vascular Endothelial Calmodulin Network via a Feedforward Mechanism at the G Protein-coupled Estrogen Receptor 1.

Estrogen exerts many effects on the vascular endothelium. Calmodulin (CaM) is the transducer of Ca(2+) signals and is a limiting factor in cardiovascular tissues. It is unknown whether and how estrogen modifies endothelial functions via the network of CaM-dependent proteins. Here we show that 17ß-estradiol (E2) up-regulates total CaM level in endothelial cells. Concurrent measurement of Ca(2+) and Ca(2+)-CaM indicated that E2 also increases free Ca(2+)-CaM. Pharmacological studies, gene silencing, and receptor expression-specific cell studies indicated that the G protein-coupled estrogen receptor 1 (GPER/GPR30) mediates these effects via transactivation of EGFR and subsequent MAPK activation. The outcomes were then examined on four distinct members of the intracellular CaM target network, including GPER/GPR30 itself and estrogen receptor α, the plasma membrane Ca(2+)-ATPase (PMCA), and endothelial nitric-oxide synthase (eNOS). E2 substantially increases CaM binding to estrogen receptor α and GPER/GPR30. Mutations that reduced CaM binding to GPER/GPR30 in separate binding domains do not affect GPER/GPR30-Gßγ preassociation but decrease GPER/GPR30-mediated ERK1/2 phosphorylation. E2 increases CaM-PMCA association, but the expected stimulation of Ca(2+) efflux is reversed by E2-stimulated tyrosine phosphorylation of PMCA. These effects sustain Ca(2+) signals and promote Ca(2+)-dependent CaM interactions with other CaM targets. Consequently, E2 doubles CaM-eNOS interaction and also promotes dual phosphorylation of eNOS at Ser-617 and Ser-1179. Calculations using in-cell and in vitro data revealed substantial individual and combined contribution of these effects to total eNOS activity. Taken together, E2 generates a feedforward loop via GPER/GPR30, which enhances Ca(2+)/CaM signals and functional linkage in the endothelial CaM target network.