Long-acting injectable naltrexone for the treatment of alcohol dependence

Combining pharmacotherapy with psychosocial and behavioral interventions has helped improve the treatment of alcohol dependence. However, the clinical use of effective medications, such as naltrexone, is limited by poor adherence to a daily oral regimen. Recently, a once monthly extended-release injectable formulation of naltrexone (Vivitrol, Alkermes, Inc.) became the first FDA-approved long-acting formulation of naltrexone for alcohol dependence. Compared with the oral preparation, extended-release naltrexone shows reduced peaks and minimal fluctuations in plasma levels that may possibly lead to a more benign adverse-event profile. The administration of long-acting naltrexone in conjunction with psychosocial support has been associated with significant improvement in drinking outcome measures, especially among patients who are abstinent entering treatment. Additional studies are warranted to increase the knowledge on the clinical applications of long-acting naltrexone in other addictive disorders and to compare extended-release naltrexone with other long-acting formulations that are in development. The clinical availability of extended-release naltrexone has the potential to enhance treatment outcomes for alcohol and other drug dependence disorders.     

Quinone oxidoreductase (NQO1) gene polymorphism may not confer a susceptibility to mood disorders

Quinone oxidoreductase (NQO1) plays a key role in the cellular antioxidant defense by detoxifying quinine derivatives. Case-control association study of the possible relationship between the NQO1 gene polymorphism and mood disorders (patients with major depressive disorder, n=61; patients with bipolar I disorder, n=80; control, n=106) was carried out using PCR-based techniques. These preliminary results showed that the NQO1 gene polymorphism was not related to a susceptibility to mood disorders.     

Biologically active aspidofractinine, rhazinilam, akuammiline, and vincorine alkaloids from Kopsia

Eleven new indole alkaloids, in addition to the previously reported rhazinal (1), and 14 other known alkaloids, were obtained from the Malayan Kopsia singapurensis, viz., kopsiloscines A-F (2-7), 16-epikopsinine (8), kopsilongine- N-oxide (9), 16-epiakuammiline (10), aspidophylline A (11), and vincophylline (12). The structures of these alkaloids were determined using NMR and MS analyses. Rhazinal (1), rhazinilam (17), and rhazinicine (18) showed appreciable cytotoxicity toward drug-sensitive as well as vincristine-resistant KB cells, while kopsiloscines A (2), B (3), and D (5) and aspidophylline A (11) were found to reverse drug-resistance in drug-resistant KB cells.     

Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones

PPAR gamma is required for fat cell development and is the molecular target of antidiabetic thiazolidinediones (TZDs), which exert insulin-sensitizing effects in adipose tissue, skeletal muscle, and liver. Unexpectedly, we found that inactivation of PPAR gamma in macrophages results in the development of significant glucose intolerance plus skeletal muscle and hepatic insulin resistance in lean mice fed a normal diet. This phenotype was associated with increased expression of inflammatory markers and impaired insulin signaling in adipose tissue, muscle, and liver. PPAR gamma-deficient macrophages secreted elevated levels of factors that impair insulin responsiveness in muscle cells in a manner that was enhanced by exposure to FFAs. Consistent with this, the relative degree of insulin resistance became more severe in mice lacking macrophage PPAR gamma following high-fat feeding, and these mice were only partially responsive to TZD treatment. These findings reveal an essential role of PPAR gamma in macrophages for the maintenance of whole-body insulin action and in mediating the antidiabetic actions of TZDs.     

Impaired opsonization with C3b and phagocytosis of Streptococcus pneumoniae in sera from subjects with defects in the classical complement pathway

Results from studies using mice deficient in specific complement factors and clinical data on patients with an inherited deficiency of the classical complement pathway component C2 suggest that the classical pathway is vital for immunity to Streptococcus pneumoniae. However, the consequences of defects in classical pathway activity for opsonization with C3b and the phagocytosis of different S. pneumoniae serotypes in human serum are not known, and there has not been a systematic analysis of the abilities of sera from subjects with a C2 deficiency to opsonize S. pneumoniae. Hence, to investigate the role of the classical pathway in immunity to S. pneumoniae in more detail, flow cytometry assays of opsonization with C3b and the phagocytosis of three capsular serotypes of S. pneumoniae were performed using human sera depleted of the complement factor C1q or B or sera obtained from C2-deficient subjects. The results demonstrate that, in human serum, the classical pathway is vital for C3b-iC3b deposition onto cells of all three serotypes of S. pneumoniae and seems to be more important than the alternative pathway for phagocytosis. Compared to the results for sera from normal subjects, C3b-iC3b deposition and total anti-S. pneumoniae antibody activity levels in sera obtained from C2(-/-) subjects were reduced and the efficiency of phagocytosis of all three S. pneumoniae strains was impaired. Anticapsular antibody levels did not correlate with phagocytosis or C3b-iC3b deposition. These data confirm that the classical pathway is vital for complement-mediated phagocytosis of S. pneumoniae and demonstrate why subjects with a C2 deficiency have a marked increase in susceptibility to S. pneumoniae infections.