Population Pharmacokinetic Modeling and Simulation of TV-46000: A Long-Acting Injectable Formulation of Risperidone.

TV-46000 is a long-acting subcutaneous antipsychotic that uses a novel copolymer drug delivery technology in combination with a well-characterized molecule, risperidone, that is in clinical development as a treatment for schizophrenia. A population pharmacokinetic (PPK) modeling and simulation approach was implemented to identify TV-46000 doses and dosing schedules for clinical development that would provide the best balance between clinical efficacy and safety. The PPK model was created by applying pharmacokinetic data from a phase 1 study of 97 patients with a diagnosis of schizophrenia or schizoaffective disorder who received either single or repeated doses of TV-46000.

Molecular characterization of co-transcribed genes from Streptomyces tendae Tü901 involved in the biosynthesis of the peptidyl moiety and assembly of the peptidyl nucleoside antibiotic nikkomycin.

Six genes (nikP1, nikP2, nikS, nikT, nikU, and nikV) from Streptomyces tendae Tu901 were identified by analysis of the nucleotide sequence of the nikkomycin gene cluster. These genes, together with the previously described nikQ and nikR, span 9.39 kb and are transcribed as a polycistronic mRNA in a growth-phase-dependent manner.

Production of nikkomycins Bx and Bz by mutasynthesis with genetically engineered Streptomyces tendae Tü901.

The previously described Streptomyces tendae nikC::aph mutant was used to mutasynthesize nikkomycins Bx and Bz. The mutant is deficient in L-lysine 2-aminotransferase, which transaminates lysine to form piperideine 2-carboxylate, the precursor of the peptidyl side chain of the biologically active nikkomycins I, J, X, and Z, and is therefore unable to produce these nikkomycins. The mutant accumulates the biologically inactive biosynthetic nucleoside precursors nikkomycins Cx and Cz.

Evidence of a role for NAD+-glycohydrolase and ADP-ribosyltransferase in growth and differentiation of Streptomyces griseus NRRL B-2682: inhibition by m-aminophenylboronic acid.

m-Aminophenylboronic acid (APBA) inhibited the germination, growth and sporulation of Streptomyces griseus NRRL B-2682 in an age- and concentration-dependent manner in submerged and solid cultures. When added to cells or cell extracts it irreversibly inhibited NAD+-glycohydrolase and ADP-ribosyltransferase activity. ADP-ribosyltransferase was more sensitive, but inhibition was not complete, even in the presence of 10 mM APBA.