Physicians' assessment of the Bavarian drug-expenditure control system: a qualitative study.

BACKGROUND: In 2014 a new system for drug expenditures, the Wirkstoffvereinbarung (WSV, English: Active substance agreement) was implemented in Bavaria. In pre-defined indication groups, economic prescription of medications shall be enabled based on the selection, quantity, and proportion of an individual drug. Ambulatory care physicians receive quarterly trend reports on their prescribing behavior. This study examines physicians' perceptions of the WSV. METHODS: Qualitative interviews (n = 20) and seven focus groups (n = 36) were conducted with ambulatory care physicians (e.g. general practitioners, cardiologists, pulmonologists). The methodology followed Qualitative Content Analysis. RESULTS: Physicians generally accepted the necessity of prescribing economically. The majority of them rated the WSV positively and better than the previous system. As an improvement, they especially named timely feedback in form of easily understandable trend reports, encouraging self-reflection as well as allowing early control options. Problems perceived were drug discount contracts that were strongly criticized as leading to patients mixing up medications. Some perceived constraints of therapeutic freedom. CONCLUSIONS: The implementation of the WSV is mostly viewed positively by physicians. The restrictions of therapeutic freedom partially perceived might be met by improved information on the reasons why some drugs are rated as less economical than others. TRIAL REGISTRATION NUMBER: Main ID: DRKS00019820 (German Register of Clinical Studies and World Health Organization).

[PHARAO study: drug treatment of inflammatory rheumatic diseases : Guideline-conform treatment with biologics follows availability of biosimilars]. / PHARAO-Studie: Arzneimittelversorgung entzündlich rheumatischer Erkrankungen : Leitliniengerechte Versorgung mit Biologika folgt Verfügbarkeit von Biosimilars.

BACKGROUND: With the introduction of tumor necrosis factor (TNF) alpha inhibitors, the treatment of inflammatory rheumatic diseases (IRD) has undergone a fundamental change. Several of the originally high-priced biologics are now accessible as lower cost biosimilars, removing a significant impediment to prescription. OBJECTIVE: The present study investigated whether the availability of biosimilars is associated with an improvement in the care of IRD. Moreover, the subjective acceptance of biosimilars by physicians and patients was investigated and compared with objectifiable parameters. MATERIAL AND METHODS: Pseudonymized claims data of the Bavarian Association of Statutory Health Insurance Physicians from 2014 to 2019 as well as a paper and pencil survey of patients and rheumatologists formed the data basis of the study. RESULTS: During the observation period, the proportion of diagnosed patients receiving drug therapy increased from 38.5% to 43.2%. Also, the care changed in terms of the prescribed agents. Conventional drug therapy declined overall and, in particular, glucocorticoid prescriptions decreased from 39.3% in 2014 to 34.3% in 2019. At the same time, the proportion of targeted treatments increased from 12.3% to 20.4%. The median duration of basic treatment before first-time bDMARD use dropped from 3.15 years in 2014 to 2.17 years in 2019. CONCLUSION: Over the observation period, in which three biosimilars entered the market, the care of patients with IRD improved both quantitatively and qualitatively. The market share of biosimilars increased in parallel with this development. With an overall high acceptance of biosimilars, the assessment of the disease course by physicians and patients indicates a slight subjectively perceived advantage of therapy with originals compared to biosimilars, which, however, is not confirmed when standardized scores are applied. A possible explanation for this might be a nocebo effect, which could be minimized by suitable communication strategies.

[Prescribing behavior of Bavarian general practitioners at the inpatient-outpatient interface within the context of the Bavarian active substance agreement-qualitative results of the WirtMed Study]. / Verordnungsverhalten von bayerischen Hausärzt*innen an der stationär-ambulanten Schnittstelle vor dem Hintergrund der Bayerischen Wirkstoffvereinbarung ­ Qualitative Ergebnisse der WirtMed-Studie.

BACKGROUND AND OBJECTIVES: In 2014, the Association of Statutory Health Insurance Physicians of Bavaria introduced the active substance agreement (WSV) for the transparent control of pharmaceutical expenditure within the framework of the efficiency principle (§ 12 of the Fifth Book of the German Social Code [SGB V]). It replaced the prescribing target scheme. Regarding the role of the WSV, the article presents the reasons of the general practitioners (GPs) for or against a further prescription of drugs from the hospital. MATERIALS AND METHODS: In a qualitative study design, individual interviews (n = 18) and two focus groups (n = 10) were conducted with Bavarian GPs between November 2019 and March 2020 and evaluated according to qualitative content analysis. RESULTS: With the introduction of the WSV, recourse concerns decreased for GPs overall. Patient-oriented care and the professional correctness of therapy decisions are of great importance in prescribing, ahead of cost-effectiveness. Economic challenges arise with discharge medication, especially with the lead substance target of oral anticoagulants, the generic targets for antidiabetics, and for therapeutics for the cardiovascular system. Generally criticized are drug discount contracts, which often lead to drug changes after hospital discharge. There are individual reports of a "predominance" of hospital physicians when prescribing, which is contrary to their own economic actions as GPs. According to the GPs, there is a lack of cross-sectoral cost responsibility. CONCLUSIONS: In the view of GPs, a smooth interface transition is not yet available in the outpatient sector despite a framework agreement on discharge management and the new control system of the WSV. An economical supply of drugs continues to require political discussion across sectors, but also across federal states.

The Role of Curcumin in Prevention and Management of Metastatic Disease.

In the last two decades, targeted therapies have enhanced tumor patient care and treatment success, however, metastatic growth still cannot be stopped efficiently and, therefore, mortality rates remain high. Prevention strategies against formation of metastases are the most promising approach we have, however, due to lack of clinical validation studies, they have not yet entered routine clinical care. In order to smooth the way for efficient prevention, further preclinical and large clinical studies are required. In this context, the underlying molecular mechanisms and factors that lead to metastatic growth have to be explored, and potential preventive agents have to be tested. Thereby, special attention has to be paid to natural bioactive compounds which do not exert major adverse effects, like the plant-derived polyphenol Curcumin, which is known to be a powerful antitumor agent. So far, most of the preclinical studies with Curcumin have focused on its effect on inhibiting tumor cell proliferation and invasion, although, it is known that it also inhibits metastatic spread in vivo. This review discusses the preventive potential of this natural compound not only against tumor onset, but also against formation of metastases.

A highly invasive subpopulation of MDA-MB-231 breast cancer cells shows accelerated growth, differential chemoresistance, features of apocrine tumors and reduced tumorigenicity in vivo.

The acquisition of an invasive phenotype is a prerequisite for metastasization, yet it is not clear whether or to which extent the invasive phenotype is linked to other features characteristic of metastatic cells. We selected an invasive subpopulation from the triple negative breast cancer cell line MDA-MB-231, performing repeated cycles of preparative assays of invasion through Matrigel covered membranes. The invasive sub-population of MDA-MB-231 cells exhibits stronger migratory capacity as compared to parental cells confirming the highly invasive potential of the selected cell line. Prolonged cultivation of these cells did not abolish the invasive phenotype. ArrayCGH, DNA index quantification and karyotype analyses confirmed a common genetic origin of the parental and invasive subpopulations and revealed discrete structural differences of the invasive subpopulation including increased ploidy and the absence of a characteristic amplification of chromosome 5p14.1-15.33. Gene expression analyses showed a drastically altered expression profile including features of apocrine breast cancers and of invasion related matrix-metalloproteases and cytokines. The invasive cells showed accelerated proliferation, increased apoptosis, and an altered pattern of chemo-sensitivity with lower IC50 values for drugs affecting the mitotic apparatus. However, the invasive cell population is significantly less tumorigenic in orthotopic mouse xenografts suggesting that the acquisition of the invasive capacity and the achievement of metastatic growth potential are distinct events.

miR181b is induced by the chemopreventive polyphenol curcumin and inhibits breast cancer metastasis via down-regulation of the inflammatory cytokines CXCL1 and -2.

Chronic inflammation is a major risk factor for the development and metastatic progression of cancer. We have previously reported that the chemopreventive polyphenol Curcumin inhibits the expression of the proinflammatory cytokines CXCL1 and -2 leading to diminished formation of breast and prostate cancer metastases. In the present study, we have analyzed the effects of Curcumin on miRNA expression and its correlation to the anti-tumorigenic properties of this natural occurring polyphenol. Using microarray miRNA expression analyses, we show here that Curcumin modulates the expression of a series of miRNAs, including miR181b, in metastatic breast cancer cells. Interestingly, we found that miR181b down-modulates CXCL1 and -2 through a direct binding to their 3'-UTR. Overexpression or inhibition of miR181b in metastatic breast cancer cells has a significant impact on CXCL1 and -2 and is required for the effect of Curcumin on these two cytokines. miR181b also mediates the effects of Curcumin on inhibition of proliferation and invasion as well as induction of apoptosis. Importantly, over-expression of miR181b in metastatic breast cancer cells inhibits metastasis formation in vivo in immunodeficient mice. Finally, we demonstrated that Curcumin up-regulates miR181b and down-regulates CXCL1 and -2 in cells isolated from several primary human breast cancers. Taken together, these data show that Curcumin provides a simple bridge to bring metastamir modulation into the clinic, placing it in a primary and tertiary preventive, as well as a therapeutic, setting.

Curcumin inhibits prostate cancer metastasis in vivo by targeting the inflammatory cytokines CXCL1 and -2.

In America and Western Europe, prostate cancer is the second leading cause of death in men. Emerging evidence suggests that chronic inflammation is a major risk factor for the development and metastatic progression of prostate cancer. We previously reported that the chemopreventive polyphenol curcumin inhibits the expression of the proinflammatory cytokines CXCL1 and -2 leading to diminished formation of breast cancer metastases. In this study, we analyze the effects of curcumin on prostate carcinoma growth, apoptosis and metastasis. We show that curcumin inhibits translocation of NFκB to the nucleus through the inhibition of the IκB-kinase (IKKß, leading to stabilization of the inhibitor of NFκB, IκBα, in PC-3 prostate carcinoma cells. Inhibition of NFκB activity reduces expression of CXCL1 and -2 and abolishes the autocrine/paracrine loop that links the two chemokines to NFκB. The combination of curcumin with the synthetic IKKß inhibitor, SC-541, shows no additive or synergistic effects indicating that the two compounds share the target. Treatment of the cells with curcumin and siRNA-based knockdown of CXCL1 and -2 induce apoptosis, inhibit proliferation and downregulate several important metastasis-promoting factors like COX2, SPARC and EFEMP. In an orthotopic mouse model of hematogenous metastasis, treatment with curcumin inhibits statistically significantly formation of lung metastases. In conclusion, chronic inflammation can induce a metastasis prone phenotype in prostate cancer cells by maintaining a positive proinflammatory and prometastatic feedback loop between NFκB and CXCL1/-2. Curcumin disrupts this feedback loop by the inhibition of NFκB signaling leading to reduced metastasis formation in vivo.

Development of resistance towards artesunate in MDA-MB-231 human breast cancer cells.

Breast cancer is the most common cancer and the second leading cause of cancer death in industrialized countries. Systemic treatment of breast cancer is effective at the beginning of therapy. However, after a variable period of time, progression occurs due to therapy resistance. Artesunate, clinically used as anti-malarial agent, has recently revealed remarkable anti-tumor activity offering a role as novel candidate for cancer chemotherapy. We analyzed the anti-tumor effects of artesunate in metastasizing breast carcinoma in vitro and in vivo. Unlike as expected, artesunate induced resistance in highly metastatic human breast cancer cells MDA-MB-231. Likewise acquired resistance led to abolishment of apoptosis and cytotoxicity in pre-treated MDA-MB-231 cells. In contrast, artesunate was more cytotoxic towards the less tumorigenic MDA-MB-468 cells without showing resistance. Unraveling the underlying molecular mechanisms, we found that resistance was induced due to activation of the tumor progression related transcription factors NFκB and AP-1. Thereby transcription, expression and activity of the matrix-degrading enzyme MMP-1, whose function is correlated with increased invasion and metastasis, was up-regulated upon acquisition of resistance. Additionally, activation of the apoptosis-related factor NFκB lead to increased expression of ant-apoptotic bcl2 and reduced expression of pro-apoptotic bax. Application of artesunate in vivo in a model of xenografted breast cancer showed, that tumors growth was not efficiently abolished as compared to the control drug doxorubicin. Taken together our in vitro and in vivo results correlate well showing for the first time that artesunate induces resistance in highly metastatic breast tumors.

Reference profile correlation reveals estrogen-like trancriptional activity of Curcumin.

BACKGROUND: Several secondary metabolites from herbal nutrient products act as weak estrogens (phytoestrogens), competing with endogenous estrogen for binding to the estrogen receptors and inhibiting steroid converting enzymes. However, it is still unclear whether these compounds elicit estrogen dependent transcription of genes at physiological concentrations. METHODS: We compare the effects of physiological concentrations (100 nM) of the two phytoestrogens Enterolactone and Quercetin and the suspected phytoestrogen Curcumin on gene expression in the breast cancer cell line MCF7 with the effects elicited by 17-beta-estradiol (E2). RESULTS: All three phytocompounds have weak effects on gene transcription; most of the E2 genes respond to the phytoestrogens in the same direction though to a much lesser extent and in the order Curcumin > Quercetin > Enterolactone. Gene regulation induced by these compounds was low for genes strongly induced by E2 and similar to the latter for genes only weakly regulated by the classic estrogen. Of interest with regard to the treatment of menopausal symptoms, the survival factor Birc5/survivin and the oncogene MYBL1 are strongly induced by E2 but only marginally by phytoestrogens. CONCLUSION: This approach demonstrates estrogenic effects of putative phytoestrogens at physiological concentrations and shows, for the first time, estrogenic effects of Curcumin.

Novel aspects for the application of Curcumin in chemoprevention of various cancers.

Chemoprevention of malignant tumor growth is a novel and potentially powerful approach for tumor therapy. Recent in vitro and in vivo investigations provide increasing evidence that naturally occurring substances may exhibit significant chemopreventive activities. To this regard, the spice Curcumin, widely used in Indian cuisine, has been identified to show considerable anti-tumor effects. Most interestingly, numerous studies have not shown toxic side effects of this substance. Curcumin induces tumor cell apoptosis along with a reduction of tumor cell invasion and metastasis. Recent molecular studies provide evidence that Curcumin acts via a control of the NFkappaB pathway exerting most of the various modulating and moderating effects on malignant cells. Along with these in vitro studies, ex vivo and first clinical investigations confirm the anti-tumor effects of Curcumin, either as an isolated chemoprevention substance or in combination with chemotherapeutic agents as supportive measure reducing pharmaceutical resistance of tumor cells to certain chemotherapeutics. Despite our increasing knowledge on this interesting substance there still remain many unknown effects that deserve intense investigation.

Overexpression of the ATP binding cassette gene ABCA1 determines resistance to Curcumin in M14 melanoma cells.

BACKGROUND: Curcumin induces apoptosis in many cancer cells and it reduces xenograft growth and the formation of lung metastases in nude mice. Moreover, the plant derived polyphenol has been reported to be able to overcome drug resistance to classical chemotherapy. These features render the drug a promising candidate for tumor therapy especially for cancers known for their high rates concerning therapy resistance like melanoma. RESULTS: We show here that the melanoma cell line M14 is resistant to Curcumin induced apoptosis, which correlates with the absence of any effect on NFkappaB signaling. We show that CXCL1 a chemokine that is down regulated in breast cancer cells by Curcumin in an NFkappaB dependent manner is expressed at variable levels in human melanomas. Yet in M14 cells, CXCL1 expression did not change upon Curcumin treatment. Following the hypothesis that Curcumin is rapidly removed from the resistant cells, we analyzed expression of known multi drug resistance genes and cellular transporters in M14 melanoma cells and in the Curcumin sensitive breast cancer cell line MDA-MB-231. ATP-binding cassette transporter ABCA1, a gene involved in the cellular lipid removal pathway is over-expressed in resistant M14 melanoma as compared to the sensitive MDA-MB-231 breast cancer cells. Gene silencing of ABCA1 by siRNA sensitizes M14 cells to the apoptotic effect of Curcumin most likely as a result of reduced basal levels of active NFkappaB. Moreover, ABCA1 silencing alone also induces apoptosis and reduces p65 expression. CONCLUSION: Resistance to Curcumin thus follows classical pathways and ABCA1 expression should be considered as response marker.

Sustained-release delivery of leupeptin in the chinchilla: hearing results.

Transtympanic medical therapy is becoming an increasingly popular modality for the treatment of "inner-ear disorders." While investigators continue to examine the best dosing paradigms for gentamicin in the treatment of Ménière's disease and for steroids in the treatment of hearing loss, they have also begun to focus on the use of other agents. In particular, transtympanic therapy has been advocated as a plausible route for the treatment of tinnitus. Transtympanic therapy for tinnitus is not new, and a number of groups have reported success in the past. Despite this success, a number of laboratories have been focusing on newer agents that might yield higher success rates in the treatment of tinnitus and other inner-ear disorders. Many of these agents could have systemic side effects when delivered in high enough doses; therefore, they are ideal candidates for transtympanic administration. The goal of this study is to begin to define the effects of one of these agents--leupeptin, a calpain antagonist--on the normal inner ear of an animal model. In this investigation, we demonstrate the effects of sustained-release delivery of leupeptin (2.5 micrograms/ml) on the hearing of chinchillas. The medicine produced no hearing loss at the early time points but did produce some hearing loss at later time points. We discuss these results and begin to outline the next steps in the investigation of this agent.