ABSTRACT
The steps to produce, purify and control an immunogenic Brazilian conjugate vaccine against group C meningococcus (MenCPS-TT) using hydrazide-activated tetanus toxoid were developed. The conjugation methodology reduced the reaction time easily allowing scale-up. One freeze-dried pilot vaccine lot purified by tangential filtration, showed satisfactory quality control results including safety and stability. The pilot vaccine was immunogenic in mice in a dose-dependent fashion generating a 10-20-fold rise in IgG response in mice. The vaccine also induced high bactericidal titers. Vaccine concentrations of 1 and 0.1 microg showed higher avidity indices, suggesting induction of immunologic memory. These results support initiation of Phase I clinical studies with the MenCPS-TT conjugate vaccine.
Subject(s)
Meningococcal Vaccines/immunology , Tetanus Toxoid/immunology , Animals , Antibodies, Bacterial/blood , Antibody Affinity , Dose-Response Relationship, Immunologic , Drug Stability , Filtration/methods , Immunoglobulin G/blood , Meningococcal Vaccines/chemistry , Meningococcal Vaccines/isolation & purification , Meningococcal Vaccines/toxicity , Mice , Microbial Viability , Tetanus Toxoid/chemistry , Tetanus Toxoid/metabolismABSTRACT
A series of 5-pyrazolylhydrazone derivates (I) were designed to be mixed hybrid isosteres of both BW-755C and CBS-1108 which belong to the class of dual cyclooxygenase and 5-lipoxygenase inhibitors. Pharmacological evaluation of some members of this series (Ia, 1-formy 1-3,4-methylenedioxy-6-nitrobenzene-5-(1-phenyl-3-methyl-4-nitropyrazolil)hydrazone; Ib, 2-formylfurane-5-(1-phenyl-3-methyll-4-nitropyrazolyl)hidrazone; Ic, (E)-2-(formylethenylfurane)-5-(1-phenyl-3-methyl-4-nitropyrazolyl)hydrazone showed that they inhibit the in vitro platelet aggregation of citrated platelet-rich rabbit plasma induced by ADP (5µM), collagen (5µg/ml) and arachidonic acid (100 µM). Compounds Ia and Ic at 100 µM concentration showed 49% and 58% inhibition, respectively, of ADP-induced aggregation. In the arachidonic acid-induced aggregation, compounds Ia and Ib at 100 µM concentration fully inhibited platelet aggregation. All compounds significantly inhibited the collagen-induced aggregation. In contrast, indomethacin (10 µM) showed 100% and 85% aggregation inhibition against arachidonic acid and collagen, respectivelym, and was inactive in the ADP- induced aggregation test. These results suggest that the structure-activity relationship in this series of compounds is dependent on the hydrazone moiety at position 5 of the pyrazole ring and on the distance between the aryl ring and the pyrazole ring and that the 2-furyl ring is at the optimal distance for the maximal activity