Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2.

We report the characterization of BMS-911543, a potent and selective small-molecule inhibitor of the Janus kinase (JAK) family member, JAK2. Functionally, BMS-911543 displayed potent anti-proliferative and pharmacodynamic (PD) effects in cell lines dependent upon JAK2 signaling, and had little activity in cell types dependent upon other pathways, such as JAK1 and JAK3. BMS-911543 also displayed anti-proliferative responses in colony growth assays using primary progenitor cells isolated from patients with JAK2(V617F)-positive myeloproliferative neoplasms (MPNs). Similar to these in vitro observations, BMS-911543 was also highly active in in vivo models of JAK2 signaling, with sustained pathway suppression being observed after a single oral dose. At low dose levels active in JAK2-dependent PD models, no effects were observed in an in vivo model of immunosuppression monitoring antigen-induced IgG and IgM production. Expression profiling of JAK2(V617F)-expressing cells treated with diverse JAK2 inhibitors revealed a shared set of transcriptional changes underlying pharmacological effects of JAK2 inhibition, including many STAT1-regulated genes and STAT1 itself. Collectively, our results highlight BMS-911543 as a functionally selective JAK2 inhibitor and support the therapeutic rationale for its further characterization in patients with MPN or in other disorders characterized by constitutively active JAK2 signaling.

Kinase drug discovery approaches in chronic myeloproliferative disorders.

Myeloproliferative disorders (MPDs) are clonal malignancies that arise from hematopoietic progenitors and characterized by overproduction of mature, functional blood cells. These disorders can be broadly characterized into Philadelphia chromosome-positive (Ph(+)) or negative (Ph(-)) genetic groupings. Chronic myeloid leukemia (CML) is a Ph(+) MPD that is defined on the basis of its molecular lesion, the BCR-ABL fusion gene. Inhibitors directed at the constitutive kinase activity of BCR-ABL have been shown to be disease modifying in CML and have dramatically altered the standard of care for this leukemia. The three main Ph(-) MPDs are polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). The key features of these Ph(-) MPDs are an increased red blood cell mass in PV, a high platelet count in ET and bone marrow fibrosis in PMF, respectively. These disorders also share many clinical features such as long clinical course, increased risk for thrombosis, hemorrhage and elevated risk of leukemic transformation. Interest in these disorders has been ignited by the recent discovery of activating mutations in the tyrosine kinase gene, JAK2, in the predominance of Ph(-) MPD patients and has highlighted JAK2 as a therapeutic intervention point for drug discovery efforts with selective kinase inhibitors. This review will focus on the comparison of Ph(+) and Ph(-) MPDs, drug discovery and development efforts targeting these disorders, and will assess the new opportunities for targeted therapies for these diseases.

Ketogenic diet in Indian children with uncontrolled epilepsy.

OBJECTIVE: To evaluate the efficacy of the ketogenic diet in Indian children with uncontrolled epilepsy. STUDY DESIGN: Prospective observational study. SETTING: Hospital based. PATIENTS: 105 children (age 4 months to 18 years) with uncontrolled epilepsy enrolled in the ketogenic diet program over a period of 9 years and followed up for 25.7+/- 20.3 months (median:17 months) on the ketogenic diet. MAIN OUTCOME MEASURES: Reduction in seizure frequency and comparison of improvement in two main groups of epilepsies, namely epileptic encephalopathies and localization related epilepsies. RESULTS: Thirty seven (35%) out of 105 children dropped out of the study and 68 remained on the diet. Thirty nine (37%) achieved 100% control, 23 (22%) achieved between 90 and 99% control, 7 (6.8%) achieved between 75 and 90% control, and 16 (15.2%) achieved between 50 and 75% control. Twenty (19%) achieved less than 50% control. Epileptic encephalopathies had a better response than localization related epilepsies. CONCLUSION: The Indian version of ketogenic diet used is well tolerated and efficacious in controlling difficult-to-control epilepsy in children. Epileptic encephalopathies respond better than localization related epilepsies.

Effect of hyperthyroidism on insulin-like growth factor-I (IGF-I) and IGF-binding proteins in adolescent children.

A study was performed on adolescent hyperthyroid patients to determine the effects of hyperthyroidism on insulin-like growth factor (IGF)-I and its binding proteins. Serum concentrations of immunoreactive total and free IGF-I, and IGF binding protein (IGFBP)-2 and IGFBP-3 were determined before and after correction of hyperthyroidism in eight patients with Grave's disease and compared to control patients matched for age, sex and pubertal stage. The concentration of serum total IGF-I was not significantly different in the hyperthyroid state and euthyroid state, and did not differ significantly from euthyroid controls. IGFBP-2 levels were elevated three-fold in hyperthyroid patients at the time of diagnosis of hyperthyroidism compared to control subjects, and fell significantly during treatment. There was also a significant positive correlation between serum IGFBP-2 concentrations and thyroxine (T4) concentrations in all subjects. Serum IGFBP-3 concentrations were also elevated in hyperthyroid subjects and normalized with correction of the hyperthyroidism. There was also a positive correlation between serum T4 and IGFBP-3 concentrations in all subjects. Despite the hyperthyroid-induced elevations in IGFBP-2 and -3, no significant difference in the serum concentration of free IGF-I before or after correction of the hyperthyroid condition was observed. We conclude that hyperthyroidism does not cause alterations in the serum concentrations of either free or total IGF-I. However, both serum IGFBP-2 and IGFBP-3 concentrations were elevated during hyperthyroidism and correlated with serum T4 levels. These abnormalities reversed with normalization of thyroid function.

Congenital nasal pyriform aperture stenosis associated with central diabetes insipidus.

We describe a child who has central diabetes insipidus associated with congenital nasal pyriform aperture stenosis without any apparent anterior pituitary dysfunction. This association further strengthens the concept that congenital nasal pyriform aperture stenosis may be a microform of holoprosencephaly.

HLA frequency, HLA sharing and immunotherapy in the management of recurrent miscarriage.

OBJECTIVE: To test couples with three or more consecutive recurrent miscarriages for suitability of the mother for immunization with paternal lymphocytes. SETTING: Regional transfusion centre, patients referred by local obstetricians. PATIENTS AND INTERVENTIONS: Women treated were from 103 couples with > or = 3 consecutive recurrent miscarriages and no more than one live birth. HLA sharing and frequencies were investigated, and contrasted with control data. Patients showed increased sharing versus control (but not in comparison with gene frequencies of the county population). Sixty-eight mothers were finally found suitable and immunized with paternal lymphocytes. OUTCOME MEASURES: Pregnancy and live births. RESULTS: 55/68 conceived, with 30 live births resulting; 8/13 additional successes after repeat (booster) immunization. CONCLUSIONS: This treatment still suffers from the lack of clear criteria for patient selection, and it should be submitted to a prospective controlled double-blind trial.