Colony-stimulating factor therapy and febrile neutropenia induced by chemotherapy: need for economical studies

Abstract

Racemic R,S-salbutamol is taken to relieve bronchial constriction. Only the R-enantiomer has bronchodilating properties. The S-enantiomer has been proposed to cause in vitro bronchial hyperreactivity in guinea-pigs. Stereoselective elimination of salbutamol has been shown, with S-salbutamol being eliminated at a slower rate than R-salbutamol. This study questioned whether rates of stereoselective elimination were similar after oral or lung delivery, and whether the S:R ratio would increase after repeated inhalations in a situation resembling a common clinical use.Eighteen healthy volunteers received single-dose racemic salbutamol as a solution instilled in the trachea during anaesthesia, as inhaled micronized powder and/or as ingested tablets. Five volunteers inhaled repeated doses of racemic salbutamol. Concentrations in plasma and urine were measured using a technique which allowed chiral separation of samples with concentrations as low as 0.1 ng . mL -1 . The bioavailability of S-salbutamol was significantly higher than that of R-salbutamol after the different modes of administration. Stereoselective elimination was more pronounced after oral administration than after inhalation. Repeated inhalations resulted in successive increases in the S:R ratio as steady state was approached.In conclusion, the clinical consequences of increasing plasma concentrations of Ssalbutamol need to be further assessed. Eur Respir J 1999; 13: 1230±1235. Many drugs are formulated as racemic mixtures and it has become clear that the enantiomers may differ in their pharmacokinetic and pharmacodynamic properties. There are numerous examples of enantioselective differences [1], and single enantiomers have taken the place of racemic drugs in several areas of medicine. Salbutamol (albuterol) is a sympathomimetic drug, with potent b 2 -adrenoceptor stimulating properties. Racemic R,S-salbutamol is taken for the relief of reversible bronchoconstriction and the therapeutic activity is associated with the R-enantiomer [2±4]. S-salbutamol has been demonstrated to cause increased airway responsiveness to carbachol in vitro and in vivo (in guinea-pigs) [5,6]. Previously it has been shown that metabolism occurs in both airways and the gastrointestinal tract by stereoselective sulphate conjugation [7]. The rate by which the bronchodilating R-enantiomer is sulphated greatly exceeds that of the S-enantiomer in vitro [8]. Unchanged R-and S-salbutamol is excreted in urine [9]. Stereoselective elimination has been reported after administration of the racemate by oral [3, 10], intravenous or rectal routes [9], findings that were also supported by in vitro experiments [11,12]. These observations indicate a more efficient removal of the active bronchodilating R-enantiomer, exposing the body to higher concentrations of the S-enantiomer. Repeated dosing could then lead to a greater ratio of S:R salbutamol in the blood over time. Assuming that adverse effects are associated with S-salbutamol in humans, the clinical implication of stereoselective d...

Evaluation and Management of the Complications of Lung Cancer Treatment

“…The role of colony-stimulating factor (CSF) therapy in chemotherapy-induced febrile neutropenia remains unclear. 102 In patients with SCLC treated with high-dose chemotherapy, prophylactic administration of granulocyte-CSF (G-CSF) reduced the incidence of febrile neutropenia, length of hospital stay, and antibiotic use but had no effect on infectious mortality rate, response, or survival rates. 103,104 Further studies on a wider patient group with febrile neutropenia have again failed to demonstrate a significant benefit of either G-CSF or granulocyte-macrophage-CSF on morbidity or mortality.…”