Aromatase Inhibitors and Musculoskeletal Symptoms: Prevalence, Predictors, and Impact on Adherence and Persistence to Therapy Among Older Women with Early-stage HR+/HER2- Breast Cancer

Background: Randomized clinical trials and cross-sectional studies have shown that musculoskeletal adverse events associated with aromatase inhibitor (AI) therapy are prevalent, and these have a negative impact on adherence and persistence, but the current literature lacks information from real-world settings. Methods: This was a retrospective cohort study conducted using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data from 2010-2017 in older women with early-stage HR+/HER2- breast cancer (BC). The prevalence and predictors of musculoskeletal symptoms (MSS) in the 180 days after initiation of AI therapy were evaluated and the impact of MSS on subsequent adherence and persistence was determined. Chi-square tests and logistic regression were used to determine the predictors of MSS. Adherence to therapy was calculated using proportion of days covered (PDC). Monthly PDCs were modeled using group-based trajectory modeling (GBTM) and a multinomial logistic regression was conducted comparing the lower adherence groups to the adherent group. Time to discontinuation (defined as a gap in medication fills of ≥90 days) differences between the group with MSS diagnosis and the group without MSS diagnosis were examined using Kaplan–Meier (KM) analysis and log-rank test. An extended multivariable Cox proportional hazard model was employed to evaluate the association of diagnosis of MSS with time to discontinuation of therapy. Results: Among the 28,896 patients who initiated AI therapy, 46.0% reported MSS within 180 days of therapy initiation. The GBTM identified a 4-group model that best described the adherence patterns in this cohort. The 4 groups were: (1) patients who were consistently adherent (61.4%); (2) patients who were moderately adherent (22.1%); (3) patients whose adherence gradually declined (5.3%); (4) patients who were non-adherent (11.2%). MSS were a strong predictor for membership in lower adherence groups. The rate of discontinuation was higher among patients with MSS diagnosis when compared to those without any MSS diagnosis (20.8% vs 16.6%, respectively). The diagnosis of MSS was significantly associated with treatment discontinuation (aHR: 1.28 (1.20 - 1.36), p <0.0001). Conclusions: There is a high prevalence of MSS within 180 days of treatment initiation with AIs and this was a strong predictor of lower medication adherence and early treatment discontinuation. Factors associated with patients at risk for poor adherence and persistence to therapy will help inform customized interventions to improve adherence and persistence

A naturalistic observation study of medication counseling practices at retail chain pharmacies

Objective: This study evaluated medication counseling procedures and trends at retail pharmacies in the Houston metropolitan area through a naturalistic observational study. Methods: A blinded cross-sectional observational study was conducted at retail pharmacies in the Houston metropolitan area. Data were collected by trained observers utilizing an observational log, to record various parameters that could have an impact on the duration of patient-pharmacist interaction in a naturalistic pharmacy practice setting. Additionally, indicators of counseling such as utilization of the counseling window and performance of show-and-tell were recorded. Statistical analyses included descriptive statistics, t-tests, Pearson correlations, ANOVAs, and multiple linear regressions. Results: One hundred and sixty-five interactions between patients and pharmacy staff were recorded at 45 retail pharmacies from 7 retail pharmacy chains. The counseling window was utilized in only 3 (1.81%) out of 165 observations and the show-and-tell process was observed in just 1(0.61%) interaction during this study. Mean (SD) interaction time between patient and pharmacists [159.50 (84.50)] was not statistically different (p>0.05) from the mean interaction time between patients and pharmacy technicians [139.30 (74.19)], irrespective of type of the retail chain observed. However, it was influenced by the number of patients waiting in queue. Patient wait time significantly differed by the time of the day the interaction was observed, weekends and weekdays had significantly different wait times and patient interaction times Multiple linear regression analyses indicated that, patient interaction time, pharmacy chain type, initial contact (pharmacist/technician), and time of the day, were significantly associated with patient wait time whereas patient wait time, pharmacy chain type, number of patients in queue, and number of pharmacy technician were significantly associated with interaction time. Conclusions: Our study found that the key indicators of counseling including the use of the counseling window and the show-and-tell process were absent, suggesting lack of adequate pharmacists counseling. Further studies are needed to evaluate the validity of this conclusion and the role of pharmacy services and its value towards medication use and safety

Discovery and Development of LX7101, a Dual LIM-Kinase and ROCK Inhibitor for the Treatment of Glaucoma

The structure of LX7101, a dual LIM-kinase and ROCK inhibitor for the treatment of ocular hypertension and associated glaucoma, is disclosed. Previously reported LIM kinase inhibitors suffered from poor aqueous stability due to solvolysis of the central urea. Replacement of the urea with a hindered amide resulted in aqueous stable compounds, and addition of solubilizing groups resulted in a set of compounds with good properties for topical dosing in the eye and good efficacy in a mouse model of ocular hypertension. LX7101 was selected as a clinical candidate from this group based on superior efficacy in lowering intraocular pressure and a good safety profile. LX7101 completed IND enabling studies and was tested in a Phase 1 clinical trial in glaucoma patients, where it showed efficacy in lowering intraocular pressure

Discovery of LX2761, a Sodium-Dependent Glucose Cotransporter 1 (SGLT1) Inhibitor Restricted to the Intestinal Lumen, for the Treatment of Diabetes

The increasing number of people afflicted with diabetes throughout the world is a major health issue. Inhibitors of the sodium-dependent glucose cotransporters (SGLT) have appeared as viable therapeutics to control blood glucose levels in diabetic patents. Herein we report the discovery of LX2761, a locally acting SGLT1 inhibitor that is highly potent in vitro and delays intestinal glucose absorption in vivo to improve glycemic control

Genetic Deletion of Mst1 Alters T Cell Function and Protects against Autoimmunity

<div><p>Mammalian sterile 20-like kinase 1 (Mst1) is a MAPK kinase kinase kinase which is involved in a wide range of cellular responses, including apoptosis, lymphocyte adhesion and trafficking. The contribution of Mst1 to Ag-specific immune responses and autoimmunity has not been well defined. In this study, we provide evidence for the essential role of Mst1 in T cell differentiation and autoimmunity, using both genetic and pharmacologic approaches. Absence of Mst1 in mice reduced T cell proliferation and IL-2 production in vitro, blocked cell cycle progression, and elevated activation-induced cell death in Th1 cells. Mst1 deficiency led to a CD4⁺ T cell development path that was biased toward Th2 and immunoregulatory cytokine production with suppressed Th1 responses. In addition, Mst1^−/− B cells showed decreased stimulation to B cell mitogens in vitro and deficient Ag-specific Ig production in vivo. Consistent with altered lymphocyte function, deletion of Mst1 reduced the severity of experimental autoimmune encephalomyelitis (EAE) and protected against collagen-induced arthritis development. Mst1^−/− CD4⁺ T cells displayed an intrinsic defect in their ability to respond to encephalitogenic antigens and deletion of Mst1 in the CD4⁺ T cell compartment was sufficient to alleviate CNS inflammation during EAE. These findings have prompted the discovery of novel compounds that are potent inhibitors of Mst1 and exhibit desirable pharmacokinetic properties. In conclusion, this report implicates Mst1 as a critical regulator of adaptive immune responses, Th1/Th2-dependent cytokine production, and as a potential therapeutic target for immune disorders.</p></div

Mst1^−/− mice exhibit decreased incidence and severity of CIA.

<p>(<b>A</b>) Mice of indicated genotype (n = 11–13) were immunized with CII in CFA and observed for clinical signs of arthritis at the time points depicted on the X axis. Histological scores of synovial inflammation and cartilage/bone erosion were analyzed on day 45 after immunization. Data are expressed as mean (± SEM); * (p<0.05) indicates significant differences in comparison to WT littermates (Mann–Whitney U test). Similar data were obtained in two additional independent experiments. (<b>B</b>) Representative pictures of histological and radiographic signs of arthritis in the same mice as in (A), obtained on day 45 after immunization with CII (left and middle panels). Arrows of the H&E-stained sections of paw joints point to severe synovial inflammation and cartilage erosion in the Mst1^−/− animals. Representative µCT images of subchondral bone changes characteristic of arthritis were taken on day 45 after immunization (right panels).</p

Analysis of T cell apoptosis and functional immune responses in Mst1^−/− mice.

<p>(<b>A</b>) Increased apoptosis of activated Mst1^−/− splenic T cells in vitro. Early apoptotic T cells were quantitated by flow cytometry in after stimulation with the indicated mAbs for 48 hrs (n = 5 per genotype). (<b>B</b>) Analysis of apoptosis in unstimulated MST^−/− T cells. Early apoptotic T cells were quantitated by flow cytometry in CD44^low and CD44^high subsets of freshly isolated splenocytes (n = 5 per genotype). (<b>C</b>) The percentages of naïve (CD62L^highCD44^low), effector memory (CD62L^lowCD44^high), and CD279-, CD25-, and CD69-positive splenic CD4⁺ T cells were examined by flow cytometry (n = 5 per genotype). (<b>D</b>) Cytokine production by splenic CD62L^highCD44⁻ CD4⁺ T cells from WT and Mst1^−/− mice (n = 5 per genotype) was examined 48 hrs after stimulation with mAbs to CD3 and CD28 (both at 1 µg/ml). (<b>E</b>) Th1 and Th2 polarized cells were generated from naïve splenic CD62L^highCD44⁻ CD4⁺ T cells after in vitro culture in polarizing conditions for 5 days. The percentages of effector memory (CD62L^lowCD44^high) CD4⁺ T cells were examined by flow cytometry (n = 5 per genotype). The percentage of sub-G0/G1 apoptotic cells was determined by the BrdU/7-AAD Flow kit and flow cytometry (n = 5 per genotype) following restimulation in vitro with plate-bound CD3 mAb (5 µg/ml) for 48 hrs. (<b>F</b>) Mst1^−/− deficiency leads to decreased Ag-specific adaptive immune responses in vivo. Mst1^−/− and WT mice (n = 6 and 9, respectively) were immunized with OVA in CFA. On day 14, serum samples were analyzed for OVA-specific IgG1 and IgG2a concentrations. Values and statistical significance are expressed as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0098151#pone-0098151-g002" target="_blank">Fig. 2</a> and are representative of at least two independent experiments. Pre, preimmune serum.</p