ACLF carries high short-term mortality and early intervention by liver transplantation should be considered in patients who shows high risk of mortality.

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3011 Background: Cyclin-dependent kinases (Cdks) have emerged as important targets in anticancer drug development. P1446A-05 is a potent and specific inhibitor of Cdk4-D1 (IC50-0.09µM), Cdk1-B (IC50-0.025µM), and Cdk9-T (IC50-0.022µM). This study was designed to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT), safety profile, pharmacokinetics, and antitumor activity of orally administered P1446A-05 in patients with advanced refractory tumors. Methods: This study was conducted at 5 centers in India. P1446A-05 was administered in escalating doses across 5 cohorts of eligible pts starting with a dose of 75 mg once a day (OD) for 14 days in a 21 day cycle utilizing a modified Fibonacci scheme for dose escalation. 10 pts positive for cyclin D1 expression in the tumor were enrolled at MTD. Treatment was continued until unacceptable toxicity or disease progression. For pharmacokinetic analysis, blood samples were collected on days 1 and 13/14 of cycle 1 at multiple time points. In consenting pts, skin and tumor tissue biopsies were collected on days 1 (pre-dose), 8 and 15 of cycle 1. Results: A total of 29 patients were dosed. Two DLTs (abdominal pain and acute renal failure) were reported at 850 mg/d. The MTD was 600 mg/d and diarrhea was reported as 1 DLT at this dose level. Six SAEs including one death related to study drug were reported. Pharmacokinetic analysis demonstrated a median half-life of 16 to 26 h and linear increase in exposure at steady state across tested doses. Plasma concentration at 300 mg/d dose level crossed efficacy exposure of 100mg/kg of five day dosing in SCID mice. The recommended phase II dose is 600 mg OD on this schedule. Stable disease for 4 to 6 cycles was reported in 5 pts. Of them, one patient each with breast cancer, spindle cell sarcoma in neck, and nasopharyngeal carcinoma had cyclin D1 over expression. No objective responses were observed in this group of heavily pretreated patients. Conclusions: The safety profile of P1446A-05 is considered acceptable. On this dosing schedule, the MTD is determined as 600 mg/day. Further testing of P1446A-05 in phase II studies is planned.

Objective: The treatment of bipolar disorder is challenging because of its clinical complexity and availability of multiple treatment options, none of which are ideal mood stabilizers. This survey studies prescription practices of psychiatrists in India and their adherence to guidelines. Method: In total, 500 psychiatrists randomly selected from the Indian Psychiatric Society membership directory were administered a face-to-face 22-item questionnaire pertaining to the management of bipolar disorder. Results: For acute mania, most practitioners preferred a combination of a mood stabilizer and an atypical antipsychotic to monotherapy. For acute depression, there was a preference for a combination of an antidepressant and a mood stabilizer over other alternatives. Electroconvulsive therapy was preferred in the treatment of severe episodes and to hasten the process of recovery. Approximately, 50% of psychiatrists prescribe maintenance treatment after the first bipolar episode, but maintenance therapy was rarely offered lifelong. While the majority (85%) of psychiatrists acknowledged referring to various clinical guidelines, their ultimate choice of treatment was also significantly determined by personal experience and reference to textbooks. Limitations: The study did not study actual prescriptions. Hence, the responses to queries in the survey are indirect measures from which we have tried to understand the actual practices, and of course, these are susceptible to selfreport and social-desirability biases. This was a cross-sectional study; therefore, temporal changes in responses could not be considered. Conclusion: Overall, Indian psychiatrists seemed to broadly adhere to recommendations of clinical practice guidelines, but with some notable exceptions. The preference for antidepressants in treating depression is contrary to general restraint recommended by most guidelines. Therefore, the efficacy of antidepressants in treating bipolar depression in the context of Indian psychiatrists' practice needs to be studied systematically. Not initiating maintenance treatment early in the course of illness may have serious implications on the long-term outcome of bipolar disorder.

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