Discovery of Orally Active Inhibitors of Brahma Homolog (BRM)/SMARCA2 ATPase Activity for the Treatment of Brahma Related Gene 1 (BRG1)/SMARCA4-Mutant Cancers.

SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily A member 2 (SMARCA2), also known as Brahma homologue (BRM), is a Snf2-family DNA-dependent ATPase. BRM and its close homologue Brahma-related gene 1 (BRG1), also known as SMARCA4, are mutually exclusive ATPases of the large ATP-dependent SWI/SNF chromatin-remodeling complexes involved in transcriptional regulation of gene expression. No small molecules have been reported that modulate SWI/SNF chromatin-remodeling activity via inhibition of its ATPase activity, an important goal given the well-established dependence of BRG1-deficient cancers on BRM. Here, we describe allosteric dual BRM and BRG1 inhibitors that downregulate BRM-dependent gene expression and show antiproliferative activity in a BRG1-mutant-lung-tumor xenograft model upon oral administration. These compounds represent useful tools for understanding the functions of BRM in BRG1-loss-of-function settings and should enable probing the role of SWI/SNF functions more broadly in different cancer contexts and those of other diseases.

The effects of antimuscarinics on health-related quality of life in overactive bladder: a systematic review and meta-analysis.

The objective of this study was to review the effects of antimuscarinic treatments on health-related quality of life (HRQL) in patients with overactive bladder (OAB). MEDLINE, EMBASE, the Cochrane Controlled Trials Register, and the Cumulative Index to Nursing and Allied Health Literature databases were searched from 1966 through August 2004 for randomized controlled trials of antimuscarinic agents. HRQL data from included trials were extracted, and meta-analysis was performed where possible. Of 56 trials included, 25 (45%) reported HRQL and/or patient-reported outcomes. The most commonly used instruments were the Incontinence Impact Questionnaire (3 trials), the King's Health Questionnaire (KHQ; 5 trials), the Medical Outcomes Study Short Form-36 (2 trials), the Gaudenz Appraisal Questionnaire (3 trials), and the Urogenital Distress Inventory (2 trials). Results from the meta-analyses of placebo-controlled trials showed statistically significant differences in favor of antimuscarinic therapy. Differences in HRQL as assessed using the KHQ were also clinically meaningful. The meta-analysis results of active-controlled trials did not show significant differences among antimuscarinic agents. This review provides evidence that antimuscarinics provide an HRQL benefit to patients with OAB. HRQL outcomes using validated instruments are recommended for inclusion in active-controlled trials, and agreement on the most appropriate HRQL instrument is now required.

The effects of antimuscarinic treatments in overactive bladder: a systematic review and meta-analysis.

OBJECTIVES: To evaluate the tolerability, safety and efficacy of antimuscarinic drugs used to treat overactive bladder and to identify any differences between individual antimuscarinics. METHODS: Medline, Embase, CCTR and Cinahl databases were searched for published RCTs including an antimuscarinic agent from 1966 to August 2004. Data from included trials were extracted and meta-analysed where possible. RESULTS: Fifty-six trials were included. The antimuscarinics were found to be safe and efficacious. All antimuscarinics apart from oxybutynin IR were found to be well tolerated. Dry mouth was the most commonly reported adverse event and no drug was associated with an increase in any serious adverse event. There were significant differences between the antimuscarinics in rates of withdrawal and rates and range of adverse events and efficacy outcomes. CONCLUSIONS: The antimuscarinics have different tolerability and safety profiles, which are clinically significant.

Health-related quality of life in women with polycystic ovary syndrome, a self-administered questionnaire, was validated.

OBJECTIVE: We examined the measurement properties of a questionnaire (PCOSQ) measuring health-related quality of life (HRQOL) in women with the polycystic ovary syndrome (PCOS). STUDY DESIGN: This multicenter prospective randomized placebo-controlled blinded study enrolled 393 patients with PCOS at tertiary care sites. Participants were randomized to placebo or troglitazone (150 mg/d, 300 mg/d, or 600 mg/d). At baseline (n=393) and after 44 weeks of treatment (n=284) the proportion of normal menstrual cycles, the free testosterone (T) level, four objective measures of facial hair growth (hair density and hair growth rate by photography, and hair diameter and hair growth rate using plucked hairs), and a subjective assessment of the degree of hirsutism, the modified Ferriman-Gallwey (F-G) score, were determined. At both visits, patients also completed the PCOSQ. Since the trial was conducted, troglitazone has been removed from the market because of toxic effects. The PCOSQ includes 26 questions (items) that address five areas of concern (domains), including emotions, body hair, body weight, fertility, and menstruation rated on a seven-point scales in which lower scores denote higher degrees of patient concern and a lower HRQOL. RESULTS: Cronbach's alpha was >0.7 for four of five domains. Factor analysis provided moderate to strong support for the five-domain structure of the PCOSQ. Cross-sectional correlations were weak with all measures but the F-G score and hair growth (r=-.46, P < .01). The change in the F-G score showed a statistically significant (P < .01) correlation with changes in PCOSQ hair growth (r=-.22), weight (r=-.17), infertility (r=-.20), and menstruation (r=-.20). Changes in the proportion of normal menstrual cycles correlated with change in the infertility domain (r=.14, P < .03) and with the change in the menstruation domain (r=.31, P < .001). The PCOSQ proved as responsive as the F-G, and more responsive than the objective measures of hair growth, to effects of troglitazone. CONCLUSIONS: Our data provides some support for the discriminative and longitudinal validity, and appreciable support for the responsiveness, of the PCOSQ.