Doll therapy intervention for women with dementia living in nursing homes: a randomized single-blind controlled trial protocol.

BACKGROUND: Doll therapy is a non-pharmacological intervention for people with dementia aimed to reduce distressing behaviours. Reliable results on the efficacy of Doll therapy for people with dementia are needed. The concept of attachment theorised by Bowlby has been proposed to explain the Doll therapy process, but it has not been proven to influence the response to doll presentation. METHODS/DESIGN: This single-blind, randomised controlled trial will involve people with dementia living in nursing homes of the Canton Ticino (Switzerland). Participants will be randomised to one of two interventions: Doll Therapy Intervention or Sham Intervention with a non-anthropomorphic object, using a 1:1 allocation ratio. The two interventions will consist of 30 daily sessions lasting an hour at most, led by a trained nurse for an hour at most. We will enrol 64 participants per group, according to power analysis using an estimated medium effect size (f = 0.25), an alpha level of 0.05, and a power of 0.8. The primary goal is to test the efficacy of the Doll Therapy Intervention versus the Sham Intervention as the net change in the following measures from baseline to 30 days (blinded outcomes): the Neuropsychiatric Inventory-Nursing Home administered by a trained psychologist blinded to group assignment, the professional caregivers' perceived stress scale of the Neuropsychiatric Inventory-Nursing Home, patients' physiological indices of stress (salivary cortisol, blood pressure and heart rate) and interactive behaviours. The secondary goal is to assess the relationship between attachment styles of people with dementia (detected by means of the Adult Attachment Interview to the patients' offspring) and their caregiving behaviours shown during the Doll Therapy Intervention. DISCUSSION: This is the first single-blind, randomised controlled trial on the efficacy of Doll therapy for dementia and an explanatory model of the response of people with dementia to doll presentation. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03224143. Retrospectively registered on 21 July 2017.

Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH).

The farnesoid X receptor (FXR) is a nuclear receptor that acts as a master regulator of bile acid metabolism and signaling. Activation of FXR inhibits bile acid synthesis and increases bile acid conjugation, transport, and excretion, thereby protecting the liver from the harmful effects of bile accumulation, leading to considerable interest in FXR as a therapeutic target for the treatment of cholestasis and nonalcoholic steatohepatitis. We identified a novel series of highly potent non-bile acid FXR agonists that introduce a bicyclic nortropine-substituted benzothiazole carboxylic acid moiety onto a trisubstituted isoxazole scaffold. Herein, we report the discovery of 1 (tropifexor, LJN452), a novel and highly potent agonist of FXR. Potent in vivo activity was demonstrated in rodent PD models by measuring the induction of FXR target genes in various tissues. Tropifexor has advanced into phase 2 human clinical trials in patients with NASH and PBC.

Lead identification to clinical candidate selection: drugs for Chagas disease.

Chagas disease affects 8 million people worldwide and remains a main cause of death due to heart failure in Latin America. The number of cases in the United States is now estimated to be 300,000, but there are currently no Food and Drug Administration (FDA)-approved drugs available for patients with Chagas disease. To fill this gap, we have established a public-private partnership between the University of California, San Francisco and the Genomics Institute of the Novartis Research Foundation (GNF) with the goal of delivering clinical candidates to treat Chagas disease. The discovery phase, based on the screening of more than 160,000 compounds from the GNF Academic Collaboration Library, led to the identification of new anti-Chagas scaffolds. Part of the screening campaign used and compared two screening methods, including a colorimetric-based assay using Trypanosoma cruzi expressing ß-galactosidase and an image-based, high-content screening (HCS) assay using the CA-I/72 strain of T. cruzi. Comparing molecules tested in both assays, we found that ergosterol biosynthesis inhibitors had greater potency in the colorimetric assay than in the HCS assay. Both assays were used to inform structure-activity relationships for antiparasitic efficacy and pharmacokinetics. A new anti-T. cruzi scaffold derived from xanthine was identified, and we describe its development as lead series.