Discovery of Clinical Candidate AZD5462, a Selective Oral Allosteric RXFP1 Agonist for Treatment of Heart Failure.

Optimization of the highly potent and selective, yet metabolically unstable and poorly soluble hRXFP1 agonist AZ7976 led to the identification of the clinical candidate, AZD5462. Assessment of RXFP1-dependent cell signaling demonstrated that AZD5462 activates a highly similar panel of downstream pathways as relaxin H2 but does not modulate relaxin H2-mediated cAMP second messenger responsiveness. The therapeutic potential of AZD5462 was assessed in a translatable cynomolgus monkey heart failure model. Following 8 weeks of treatment with AZD5462, robust improvements in functional cardiac parameters including LVEF were observed at weeks 9, 13, and 17 without changes in heart rate or mean arterial blood pressure. AZD5462 was well tolerated in both rat and cynomolgus monkey and has successfully completed phase I studies in healthy volunteers. In summary, AZD5462 is a small molecule pharmacological mimetic of relaxin H2 signaling at RXFP1 and holds promise as a potential therapeutic approach to treat heart failure patients.

Educational improvement in Medical English Practice: Questionnaire survey to sophomore medical students of Hokkaido University.

In the past, we made several efforts making curriculum changes to Medical English Practice, however, these changes did not improve motivation effectively. We have completely modified the curriculum in 2012, and performed a questionnaire survey to 112 sophomore medical students. In the final exam, students answered a questionnaire assessing all classes of the course by scoring 3 points (no change required), 2 points (minor change required), and 1 point (major change required or discontinue). In addition, students could write free comments about potential contents they would like to add to the curriculum. Each class was assessed as more than or equal to 2.5 points on average (range: 2.50-2.96). Potential contents students want to add are: 1. Speaking (45 students [55%]), 2. Listening (30 students [37%]), 3. Reading (6 students [7%]), 4. Writing (1 student [1%]). The most frequent suggestion was to include group discussions in speaking (27 students [33%]), followed by listening on topics of healthcare systems (11 students [13%]). Many students suggested to include conversation classes in small groups, or classes in which international students introduce the structure of healthcare systems of their home countries to the curriculum. Increasing the participation of international faculty, staff and students in the Medical English Practice might contribute to the improvement of medical students' motivation.

Role of gustation in the recognition of oleate and triolein in anosmic rats.

Recent studies suggest a chemical perception of dietary fat in the oral cavity. To examine the role of gustation for the recognition of oleate and triolein, very short-term (5-min), two-bottle preference tests were conducted in anosmic rats. To minimize the effects of olfaction, texture and postingestive effects, rats were rendered anosmic with intranasal zinc sulfate, test substances were suspended in 0.3% xanthan gum solution and test fluids were offered for 5 min. Rats preferred oleate fluid but not triolein fluid to the control of 0.3% xanthan gum solution. The preference threshold for oleate in the rat oral cavity was between 0.2% and 0.5%. In the two-bottle preference tests between oleate and triolein, rats preferred oleate fluid to triolein fluid, showing discrimination of oleate and triolein. The results suggest that rat recognizes oleate by a gustatory cue and that fatty acid but not triglyceride is important for gustatory recognition of fat.