Bronchopulmonary disposition of the ketolide telithromycin (HMR 3647).

Telithromycin (HMR 3647) is the first member of a new family of antimicrobials, the ketolides, developed specifically for the treatment of community-acquired respiratory tract infections. Telithromycin has proven in vitro activity against both common and atypical respiratory tract pathogens. The penetration of telithromycin into bronchopulmonary tissues and subsequent elimination from these sites were evaluated in four groups (groups A, B, C, and D) of six healthy male subjects who received telithromycin at 800 mg once daily for 5 days. Subjects in groups A, B, C, and D underwent fiberoptic bronchoscopy and bronchoalveolar lavage 2, 8, 24, and 48 h after receipt of the last dose, respectively. The concentration of telithromycin in the alveolar macrophages, epithelial lining fluid (ELF), and plasma was determined by the agar diffusion method with Bacillus subtilis ATCC 6633 as the test organism. The concentration of telithromycin in alveolar macrophages markedly exceeded that in plasma, reaching up to 146 times the concentration in plasma 8 h after dosing (median concentration, 81 mg/liter). Telithromycin was retained in alveolar macrophages 24 h after dosing (median concentration, 23 mg/liter), and it was still quantifiable 48 h after dosing (median concentration, 2.15 mg/liter). Telithromycin median concentrations in ELF also markedly exceeded concentrations in plasma (median concentration in ELF, 3.7 mg/liter 8 h after dosing). Telithromycin achieves high and sustained concentrations in ELF and in alveolar macrophages, while it maintains adequate levels in plasma, providing an ideal pharmacokinetic profile for effective treatment of community-acquired respiratory tract infections caused by either common or atypical, including intracellular, respiratory tract pathogens.

Methodological problems relating to the evaluation of anti-rejection treatments.

The evaluation of anti-rejection treatments raises a variety of methodological problems depending on the clinical phase of development. The first administrations in man are carried out in order to study the profile of a drug and are sometimes performed in healthy volunteers, but more frequently in transplanted patients. It is then necessary to select and evaluate the assessment criteria which will be used in comparative studies to demonstrate the efficacy and safety of the new treatments compared with reference drugs. Factors responsible for variation may be related to the nature of the organ transplanted, the clinical condition of the donor and host and their immune compatibilities. Associated treatments and the multidisciplinary environment in which an organ transplant takes place should also be taken into consideration. After registration, knowledge about the new anti-rejection drug continues in order to identify the optimum conditions for its use, its true therapeutic efficacy and to determine possible new indications.

Autoantibodies against pancreatic beta-cells: characterization by western blot analysis in the non-obese diabetic (NOD) mouse.

The NOD mouse is a relevant model for studying autoimmune diabetes. As in human insulin-dependent diabetes mellitus, the nature of the autoantigen towards which the immune system is directed remains to be clarified. It has been shown that T cells are central to the disease process. However, autoantibodies may be used as a probe to identify islet autoantigens to which self tolerance is defective. Using Western blot analysis, we characterized autoantibodies which are specific for a 58 kDa islet antigen and a 29 kDa antigen. The 58 kDa autoantigen was present in cellular extracts prepared from rat tumoral insulin-secreting cells (Rin5F) and NOD islets but not from most other non-insulin-secreting cell lines. By contrast the 29 kDa antigen was a ubiquitous antigen expressed in all cell lines tested and was not further characterized since it is very likely to be responsible for secondary immunization rather than play any role in the NOD disease process. Anti-58 kDa autoantibodies were detected in all diabetic male and female NOD animals as well as in sera from old non-diabetic NOD animals. Anti-58 kDa antibodies were not detected in sera from young NOD mice (less than 6 weeks of age) or in sera from other conventional laboratory strains of mice including autoimmune prone animals such as MRL/lpr and (NZB x NZW)F1 mice. A monoclonal antibody (72.2) specific for the 58 kDa structure was obtained, which allowed further characterization of the corresponding islet cell antigen. The expression of the 58 kDa antigen was evidenced by Western blot analysis in normal islets and in a mouse neuroblastoma cell line.

Peripherin: an islet antigen that is cross-reactive with nonobese diabetic mouse class II gene products.

The nonobese diabetic (NOD) mouse, in which major histocompatibility complex genes may be involved in the susceptibility to diabetes, has been developed as a model of autoimmune diabetes. The NOD mouse expresses I-A-encoded class II major histocompatibility complex antigens, which differ from those of other mouse haplotypes by the presence of a serine at position 57 of the A beta chain. Identifying islet autoantigens may help elucidate the role of class II antigens in the activation of autoreactive T cells and, thus, in the development of diabetes. We have detected autoantibodies directed against a 58-kDa islet cell antigen in NOD mice but not in other strains, including lupus-prone mice. Apart from insulin-secreting cells, the 58-kDa antigen was only found to be expressed by neuroblastoma cells and was identified as peripherin, an intermediate filament protein previously characterized in well-defined neuronal populations. This autoantigen cross-reacted with I-Anod class II antigens, suggesting that it may contribute to defective self-tolerance of islet beta cells in the NOD mouse.

Medium-chain fatty acids increase glucose production in normal and low birth weight newborns.

To study the pathogenesis of hypoglycemia in low birth weight infants, glucose production was measured in five hypotrophic and four premature newborns with glycemia of 45 +/- 6 and 59 +/- 10 mg/dl, respectively. Hepatic glucose output averaged 5.7 +/- 0.4 and 5.3 +/- 0.5 mg.kg-1.min-1 in these neonates vs. 8.2 +/- 0.5 mg.kg-1.min-1 in five normal at term newborns and was correlated with glycemia (P less than 0.02). Despite normal plasma free fatty acids, the low birth weight infants had low ketone levels of 163 +/- 72 and 126 +/- 65 vs. 263 +/- 60 microM in normals. Oral administration of medium-chain triglycerides to the neonates increased their circulating ketones by two- to threefold and restored near-normal glycemia (51 +/- 9 and 76 +/- 8 mg/dl) and production of glucose (6.7 +/- 0.7 and 6.6 +/- 0.8 mg.kg-1.min-1) in the hypotrophic and premature vs. normals (8.7 +/- 0.7 mg.kg-1.min-1). Individual rates of glucose production correlated with ketone concentrations (P less than 0.02). We conclude that the hypoglycemia characterizing low birth weight neonates is primarily due to impaired glucose production. That exogenous lipids were able to increase glucose production indicates that fatty acid oxidation plays an important glucoregulatory role in the human newborn.