ALBERT

Description: The lateral amygdala (LA) acquires differential coding of predictive and non-predictive fear stimuli that is critical for proper fear memory assignment. The neurotransmitter dopamine is an important modulator of LA activity and facilitates fear memory formation, but whether dopamine neurons aid in the establishment of discriminative fear coding by the LA is unknown. NMDA-type glutamate receptors in dopamine neurons are critical for the prevention of generalized fear following an aversive experience, suggesting a potential link between a cell autonomous function of NMDAR in dopamine neurons and fear coding by the LA. Here, we utilized mice with a selective genetic inactivation functional NMDARs in dopamine neurons (DAT-NR1 KO mice) combined with behavior, in vivo electrophysiology, and ex vivo electrophysiology in LA neurons to demonstrate that plasticity underlying differential fear coding in the LA is regulated by NMDAR signaling in dopamine neurons and alterations in this plasticity is associated non-discriminative cued-fear responses.

Description: Syk kinase is central to FcR and B-cell signaling in inflammatory cells. By inhibiting syk, and thereby IgG signaling, R788 (a small molecule prodrug for biologically active R406), inhibits the downstream activation of mast cells, macrophages and B-cells. (Braselmann S. Pharm Exp Ther. 2006). Preclinical study showed that R788 minimized thrombocytopenia in mice treated with anti-platelet antibodies (Crow, A.R. Blood 2005). In this study, adult, refractory ITP patients (pts) were treated with escalating doses of R788 in cohorts of ≥3 pts to evaluate safety and efficacy. After a cohort completed four weeks, the next cohort could be initiated. Pts completed 2 weeks of dosing before the dose could be increased (by 25 mg twice daily). Dosing was initiated at 75mg PO BID to 150 mg PO BID. Pts who responded and then had their platelet (plt) counts (cts) decline, could have their dose increased to a maximum of 175mg bid. Safety: 14 pts entered the study, 10 after failed splenectomy and 5 who were 〉70 yo. Six pts withdrew due to failure to respond (4) or gastrointestinal (GI) symptoms (2). GI symptoms (vomiting & diarrhea) were seen in 5 of 14 pts with mild elevations in ALT in 2 pts (2 〉2XULN, one of whom had pre-existing hepatitis). Two pts were hospitalized for GI side effects (dehydration) and one developed an unrelated UTI with subsequent diagnosis of DVT. R788 also elevated blood pressure in some pts but appeared to not have a significant effect on neutrophil counts. Efficacy: By protocol standards, 9/14 pts are considered responders with stable platelet counts 〉 30,000/ul (30k). Six pts had peak counts 〉 100k. The mean change from pre treatment to the peak count in the 8 on study pts was 125k. Two pts, who previously had failed a wide range of other treatments, have maintained counts generally above 20k completing 〉 20 weeks of study with 0 and 1 IVIG treatments respectively, in each for the first time in 〉 10 years that they achieved prolonged avoidance of IVIG. Five had not responded to a thrombopoietic agent, 2 of whom responded to R788. Two responders discontinued the study because of nausea and vomiting at the dose that provided a response. Conclusions: The effects of R788 treatment are preliminary but, despite GI toxicity in certain patients, nonetheless impressive in this very refractory ITP population. Certain pts have had important clinical although numerically unimpressive benefit. Further studies are ongoing including studies of FcR expression before and after treatment. Patients Currently On Study Patient Baseline Plt Count x 109/L Peak Plt Count x 109/L (w/o IVIG) Most Recent Plt Count x 109/L Total Wks On Study Current Dose 001 14 49 20 30 175mg BID 002 22 222 18 24 175mg BID 003 32 158 37 24 150mg BID 007 20 111 40 21 100mg BID 008 22 205 205 19 125mg BID 009 46 329 329 14 100mg BID 011 45 124 124 11 125mg BID 014 107 107 36 6 125mg BID Mean 38 163 Patients Withdrawn From Study Patients Baseline Plt Count x 109/L Peak Plt Count x 109/L (w/o IVIG) End Of Study Plt Count x 109/L Total Wks On Study Highest Dose 004 12 11 11 19 175mg BID 005 12 66 11 14 150mg BID 010 18 13 21 11 175mg BID 012 17 17 14 3 125mg BID 013 25 159 97 5 150mg BID 015 3 13 13 4 125mg BID Mean 14 46