Advancement of Imidazo[1,2-a]pyridines With Improved Pharmacokinetics and Nanomolar Activity Against Mycobacterium Tuberculosis.

Advancement of Imidazo[1,2-a]pyridines with Improved Pharmacokinetics and Nanomolar Activity Against Mycobacterium tuberculosis.

ACS Med Chem Lett. 2013 Jul 11; 4(7): 675-679
Moraski GC, Markley LD, Cramer J, Hipskind PA, Boshoff H, Bailey M, Alling T, Ollinger J, Parish T, Miller MJ

A set of fourteen imidazo[1,2-a]pyridine-3-carboxamides was synthesized and screened against Mycobacterium tuberculosis H37Rv. The minimum inhibitory concentrations of twelve of these agents were ? 1 ?M against replicating bacteria and five compounds (9, 12, 16, 17 and 18) had MIC values ? 0.006 ?M. Compounds 13 and 18 were screened against a panel of MDR and XDR drug resistant clinical Mtb strains with the potency of 18 surpassing that of clinical candidate PA-824 by nearly 10 fold. The in vivo pharmacokinetics of compounds 13 and 18 were evaluated in male mice by oral (PO) and intravenous (IV) routes. These results indicate that readily synthesized imidazo[1,2-a]pyridine-3-carboxamides are an exciting new class of potent, selective anti-TB agents that merit additional development opportunities. HubMed – drug

A proposal for a drug information database and text templates for generating package inserts.

Drug Healthc Patient Saf. 2013; 5: 161-9
Okuya R, Kimura M, Ohkura M, Tsuchiya F

To prevent prescription errors caused by information systems, a database to store complete and accurate drug information in a user-friendly format is needed. In previous studies, the primary method for obtaining data stored in a database is to extract drug information from package inserts by employing pattern matching or more sophisticated methods such as text mining. However, it is difficult to obtain a complete database because there is no strict rule concerning expressions used to describe drug information in package inserts. The authors’ strategy was to first build a database and then automatically generate package inserts by embedding data in the database using templates. To create this database, the support of pharmaceutical companies to input accurate data is required. It is expected that this system will work, because these companies can earn merit for newly developed drugs to decrease the effort to create package inserts from scratch. This study designed the table schemata for the database and text templates to generate the package inserts. To handle the variety of drug-specific information in the package inserts, this information in drug composition descriptions was replaced with labels and the replacement descriptions utilizing cluster analysis were analyzed. To improve the method by which frequently repeated ingredient information and/or supplementary information are stored, the method was modified by introducing repeat tags in the templates to indicate repetition and improving the insertion of data into the database. The validity of this method was confirmed by inputting the drug information described in existing package inserts and checking that the method could regenerate the descriptions in the original package insert. In future research, the table schemata and text templates will be extended to regenerate other information in the package inserts. HubMed – drug

Relationship between antibiotic resistance and sickle cell anemia: preliminary evidence from a pediatric carriage study in Ghana.

Infect Drug Resist. 2013; 6: 71-7
Donkor ES, Foster-Nyarko E, Enweronu-Laryea CC

Antibiotics are frequently used among people with sickle cell anemia (homozygous SS or HbSS disease), especially for prophylaxis. However, the relationship between antibiotic resistance and people with HbSS disease has not been adequately studied, especially in the developing world. The objectives of the study were (1) to compare antibiotic resistance patterns of nasal Staphylococcus aureus between children with HbSS disease and children without HbSS disease (healthy children) and (2) to evaluate nasopharyngeal carriage of antibiotic-resistant Streptococcus pneumoniae among children with HbSS disease.This was a prospective cross-sectional study, and the subjects were children under 12 years old. Nasal swabs were collected from 50 children with HbSS disease and 50 children without HbSS disease. Nasopharyngeal swabs were collected from another group of 92 children with HbSS disease. The nasal and nasopharyngeal swabs were cultured for S. aureus and S. pneumoniae, respectively. Susceptibility testing was carried out on the S. aureus and S. pneumoniae isolates for various antibiotics, including penicillin, ampicillin, cefuroxime, erythromycin, cloxacillin, and cotrimoxazole.The carriage rates of S. aureus among pediatric subjects with HbSS disease and those without HbSS disease were 48% and 50%, respectively (P > 0.05). S. pneumoniae carriage among the pediatric subjects with HbSS disease was 10%. Antibiotic resistance patterns of S. aureus carried by children with HbSS disease and children without HbSS disease were similar, and the S. aureus resistance rates were >40% for the various antibiotics, with the exception of erythromycin and cloxacillin. Low levels of S. pneumoniae resistance (0%-11%) were observed for the various antibiotics tested except cotrimoxazole, which showed an extremely high-percentage resistance (100%).Sickling status is not a risk factor for carriage of S. aureus. In this cohort of Ghanaian children with HbSS disease, S. aureus is higher in carriage and more antibiotic-resistant, compared to S. pneumoniae. HubMed – drug

Mycobacterium marinum: a potential immunotherapy for Mycobacterium tuberculosis infection.

Drug Des Devel Ther. 2013; 7: 669-80
Tian WW, Wang QQ, Liu WD, Shen JP, Wang HS

The aim of the present study was to investigate the immune response induced by Mycobacterium marinum infection in vitro and the potential of M. marinum as an immunotherapy for M. tuberculosis infection.The potential human immune response to certain bacillus infections was investigated in an immune cell-bacillus coculture system in vitro. As a potential novel immunotherapy, M. marinum was studied and compared with two other bacilli, Bacillus Calmette-Guérin (BCG) and live attenuated M. tuberculosis. We examined the changes in both the bacilli and immune cells, especially the time course of the viability of mycobacteria in the coculture system and host immune responses including multinuclear giant cell formation by Wright-Giemsa modified staining, macrophage polarization by cell surface antigen expression, and cytokines/chemokine production by both mRNA expression and protein secretion.The M. marinum stimulated coculture group showed more expression of CD209, CD68, CD80, and CD86 than the BCG and M. tuberculosis (an attenuated strain, H37Ra) groups, although the differences were not statistically significant. Moreover, the M. marinum group expressed more interleukin (IL)-1B and IL-12p40 on day 3 (IL-1B: P = 0.003 and 0.004, respectively; IL-12p40: P = 0.001 and 0.011, respectively), a higher level of CXCL10 on day 1 (P = 0.006 and 0.026, respectively), and higher levels of chemokine (C-X-C motif) ligand (CXCL) 8 and chemokine (C motif) ligand (XCL) 1 on day 3 (CXCL8: P = 0.012 and 0.014, respectively; XCL1: P = 0.000 and 0.000, respectively). The M. marinum stimulated coculture group also secreted more tumor necrosis factor (TNF)-?, IL-1?, and IL-10 on day 1 (TNF-?: P = 0.000 and 0.000, respectively; IL-1?: P = 0.000 and 0.000, respectively; IL-10: P = 0.002 and 0.019, respectively) and day 3 (TNF-?: P = 0.000 and 0.000, respectively; IL-1?: P = 0.000 and 0.001, respectively; IL-10: P = 0.000 and 0.000, respectively). In addition, the colony-forming units (an index of viability) of M. marinum in the M. marinum stimulated coculture group was significantly less than that of BCG and H37Ra in their corresponding bacillus stimulated groups (P = 0.037 and 0.013, respectively).Our results indicated that M. marinum could be a potentially safe and effective immunotherapy. HubMed – drug

The Cycle of Addiction: The Treatment Center
When you do not have a lot of prior knowledge about addiction and recovery, it can be difficult to grasp what is happening. Family members and patients often…