Urinary concentrations and antimicrobial activity of tobramycin in healthy volunteers receiving a single oral dose of a novel formulation for improved absorption.

Oral antibiotics for the treatment of urinary tract infections are scarce. In this ex vivo phase 1 annex study, the clinical safety, urinary concentrations and bactericidal activity of a new formulation for improved oral absorption of tobramycin (Tobrate™) were evaluated. Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of five test strains, one reference strain and four clinical uropathogenic strains were determined in cation-adjusted Mueller-Hinton broth (CA-MHB) and in pooled antimicrobial agent-free subjects' urine at different pH values (5.5, 6.5, 7.5 and 8.5). Urinary concentrations and urinary bactericidal titres (UBTs) following single oral administration of 600 mg Tobrate™ were measured in nine healthy volunteers up to 24 h. The MIC/MBC values in CA-MHB were 2-4/2-4 mg/L for two Escherichia coli strains, 2/2 mg/L for Klebsiella pneumoniae, 0.5/1 mg/L for Pseudomonas aeruginosa and 8/1 mg/L for Proteus mirabilis. MBCs in pooled alkaline urine were significantly lower than those in acidic urine. The mean maximum urinary concentration following 600 mg tobramycin was 83.9 mg/L (2-4 h collection period). The highest reciprocal median UBT values for each test strain were between 2 and 4 during the collection periods 2-4 h and 4-8 h, respectively. The new enteric oral tobramycin formulation significantly improved the very poor oral absorption of standard tobramycin salt. For all pathogens tested, maximum urinary concentrations of tobramycin were at least two times above the urinary MBC. A twice- or three-times daily dosage regimen and alkalising co-medication may further improve urinary bactericidal activity.

Knowledge and attitudes towards disability in Moldova: A qualitative study of young people's views.

BACKGROUND: People with disabilities in the Republic of Moldova continue to experience considerable discrimination and social exclusion. The Moldovan government recently affirmed their commitment to promote community integration. However, there remains limited evidence to facilitate understanding of these issues, and barriers to the integrative process. OBJECTIVE: This study explored the knowledge and attitudes towards disability of young people within Moldova. METHODS: A qualitative approach was adopted and 3 semi-structured focus group interviews were conducted with schoolchildren (n = 12), aged 13-15 years. These interviews focussed on different aspects of disability, and community integration. Pictorial and written vignettes were used to stimulate discussion. The interviews were conducted and recorded in Romanian, and were subsequently translated into English to facilitate thematic data analysis. RESULTS: Identified themes included: (1) Knowledge and understanding of disability. The young people's knowledge was limited and framed by the medical model of disability; (2) Attitudes towards community integration. A bias against long-term care institutions, but differing views regarding integration; (3) Perceptions of barriers to community integration: (i) Cultural barriers. Negative, even hostile attitudes towards disability; (ii) Policy barriers. Poor support services; and (iii) Physical barriers. Ongoing issues regarding accessibility. CONCLUSIONS: People with disabilities in Moldova experience negative cultural attitudes linked to an outdated conception of disability itself. There are inadequate community support services and infrastructure which act as barriers to inclusion. At present, there can be limited interaction and participation of people with disabilities within local communities, and so few opportunities to refute persistent stereotypes and stigma surrounding disability.

Production of salmon calcitonin by direct expression of a glycine-extended precursor in Escherichia coli.

The export of heterologous products into the conditioned medium of an Escherichia coli culture offers the advantages of a higher product yield, an increased probability of recovering an intact recombinant protein, proper folding for biological activity, and greater stability of a secreted product. In this report, we describe the development of an optimized direct expression system, designed to maximize the extracellular accumulation of recombinant glycine-extended salmon calcitonin peptide (sCTgly). We have used dual promoters, an ompA signal sequence, co-expression of homologous secretion factor genes, and multiple gene cartridges to express the sCTgly. High-density fermentation conditions have been developed that allow for the selective secretion and accumulation of the expressed sCTgly at very high levels. Purification and in vitro enzymatic conversion by peptidylglycine alpha-amidating monooxygenase yields authentic, biologically active salmon calcitonin. This recombinant production technology is applicable to a variety of amidated peptide hormones.