Disposition of fleroxacin, a new trifluoroquinolone, and its metabolites. Pharmacokinetics in elderly patients

The pharmacokinetics of fleroxacin and its main metabolites, N-demethyl-fleroxacin and N-oxide-fleroxacin, were studied in 12 elderly patients aged 63 to 88 years. Plasma and urine samples collected at different times after drug administration were analysed by a specific reverse phase high performance liquid chromatography (HPLC) method. The peak plasma concentration (Cmax) of fleroxacin was 15.6 +/- 1.6 mg/L, time to Cmax (tmax) was about 3h, elimination half-life (t1/2) was 16 +/- 1h and the percentage of unchanged fleroxacin excreted in urine was 39 +/- 3% of the dose. The plasma concentrations of metabolites were very low and accounted for no more than 4% of the concentration of unchanged fleroxacin. Plasma parameters were mainly correlated with age and weight; urinary parameters were correlated with creatinine clearance. Compared with results in younger normal patients, no significant change in the t1/2 of fleroxacin or metabolites was observed. Assuming that the bioavailability (f) is complete, the apparent volume of distribution (Vd/f) was lower in elderly (0.9 +/- 0.1 L/kg) than in younger patients (1.3 +/- 0.1 L/kg) and a 2-fold decrease in apparent total clearance (CL/f) was noted (2.58 +/- 0.42 vs 4.86 +/- 0.72 L/h); plasma concentrations were consequently higher in elderly patients. Compared with patients with renal failure, the pharmacokinetics of fleroxacin and metabolites in the elderly were similar to those of patients with mild to moderate renal insufficiency. On the basis of the findings of this single dose study, no major dosage adjustments are needed for patients of this age range except for those with creatinine clearance less than 30 ml/min.     

Induction of Donor-Specific Allograft Tolerance by Short-Term Treatment with LF15-0195 After Transplantation. Evidence for a Direct Effect on T-Cell Differentiation

A 20-day treatment with LF15-0195, a deoxyspergualine analog, induced long-term heart allograft survival in the rat without signs of chronic rejection. LF15-0195-treated recipients did not develop an anti-donor alloantibody response. Analysis of graft-infiltrating cells, IL10, TNFalpha, IFNgamma mRNA and iNOS protein expression in allografts, 5 days after transplantation, showed that they were markedly decreased in allografts from LF15-0195-treated recipients compared with allografts from untreated recipients. Surprisingly, spleen T cells from LF15-0195 recipients, 5days after grafting, were able to proliferate strongly in vitro, when stimulated with donor cells, but had reduced mRNA expression for IFNy compared with spleen T cells from untreated graft recipients. Furthermore, when T cells from naive animals were stimulated in vitro, using anti-CD3 and anti-CD28, LF15-0195 also increased T-cell proliferation in a dose-dependent fashion: however, these cells expressed less of the Th1 -related cytokines, IFNgamma and IL2, compared with untreated cells, suggesting that LF15-0195 could act on T-cell differentiation. In conclusion, we show here that a short-term treatment with LF15-0195 induced long-term allograft tolerance, decreasing the in situ anti-donor response, and we illustrate evidence for the development of regulatory mechanisms.     

The safety of awake tracheal intubation in cervical spine injury

As a referral centre for cervical spine injuries, we have routinely performed awake tracheal intubation when intubation was indicated. A retrospective case control study was undertaken to review the frequency of neurological deterioration and aspiration associated with our approach. Neurological deterioration was assessed by a change in level of injury or neurological grade at admission and discharge. Four hundred and fifty-four patients with critical cervical spine and/or cord injuries were reviewed over an eight-year period. A case group of 165 patients underwent tracheal intubation awake within two months of injury. A control group of 289 remained unintubated during the same period. A comparison of spinal neurological status between admission and discharge revealed no statistically significant difference in neurological deterioration between the two groups. This occurred despite a greater injury severity score in the case group. No evidence of aspiration during intubation was documented. We conclude that awake tracheal intubation is a safe method of airway management in patients with cervical spine injuries.     

CAG repeat number governs the development rate of pathology in Huntington's disease

We compared the number of CAG repeats, the age at death, and the severity of neuropathology in 89 Huntington's disease brains. We found a linear correlation between the CAG repeat number and the quotient of the degree of atrophy in the striatum (the brain region most severely affected in Huntington's disease) divided by age at death, with an intercept at 35.5 repeats. The largest CAG repeat length, therefore, at which no pathology is expected to develop is 35.5. These results imply that striatal damage in Huntington's disease is almost entirely a lineaar function of the length of the polyglutamine stretch beyond 35.5 glutamines multiplied by the age of the patient. Thus, it is predicted that the pathological process develops linearly from birth. Analysis of other measures of striatal function could test this hypothesis and might determine when treatment for CAG repeat diseases should start.     

Iodomethylated fatty acid metabolism in mice and dogs

The myocardial uptake of fatty acids labeled with radioactive iodine and injected i.v. can only be evaluated with SPECT if their oxidation kinetics is slow enough. For this reason, we evaluated different iodomethylated fatty acids in mice and dogs to determine which of them shows the highest myocardial uptake and the slowest oxidation. The most suitable was found to be 16-iodo-3-methyl hexadecanoic acid (mono ) since its myocardial fixation was the same as that of the reference, i.e. 16-iodo-9-hexadecenoic acid (IHA), whereas it was degraded more slowly. Thirty min after injection of mono into dogs, the decrease in myocardial activity with respect to the maximum was two fold less than after IHA injection. The myocardial uptake of the two dimethylated fatty acids studied, i.e. 16-iodo-2,2-methyl hexadecanoic acid and 16-iodo-3,3-methyl hexadecanoic acid, was less than that of IHA in mice and dogs. In the latter, the myocardial uptake was so small that we were unable to study the time course of its activity. Consequently, these dimethylated fatty acids are not suitable for the study of the myocardial uptake of fatty acids in man.     

Epidermal growth factor receptor regulates normal urothelial regeneration

Members of the epidermal growth factor (EGF) family and their receptors are involved in many cellular processes, including proliferation, migration, and differentiation. We have previously reported that these growth factors are expressed and have specific regulatory functions in an organ-like culture model of normal human urothelial cells. Here, we used this model to investigate the involvement of EGF receptor (EGFR) in human urothelial regeneration. Three 4-mm-diameter damaged areas were made in confluent normal human urothelial cell cultures with a biopsy punch. Regeneration was measured, on fixed stained cultures, with an image analyzer, at 4, 24, and 48 hours after injury. Cell proliferation was assessed by 5-bromo-2-deoxyuridine incorporation. To identify EGF family factors potentially involved in the healing process, we studied the effect of these factors on damaged confluent cultures and the level of expression of mRNAs extracted from these cultures. EGFR inhibition of the proliferation and migration of urothelial cells was tested with (1). a specific tyrosine kinase inhibitor (AG1478) and (2). a blocking anti-EGFR antibody (LA22). Exogenously added amphiregulin, EGF, transforming growth factor-alpha and heparin-binding EGF (HB-EGF) stimulated urothelial regeneration. The damaged areas were repaired by regrowth within 48 hours. Both AG1478 and LA22 inhibited the repair (by 50% and 30%, respectively), as well as proliferation and migration. This regeneration was accompanied by increased HB-EGF mRNA expression in cultures of cells from four of six subjects, but no corresponding change in EGFR protein level was observed. These results indicate that the EGFR signaling pathway is involved in urothelial regeneration. Our data support an autocrine role of HB-EGF in this process and suggest that the EGFR pathway is a potential therapeutic target for modulating urothelial cell proliferation.     

Prevalences of herpesviruses DNA sequences in salivary gland biopsies from primary and secondary Sj?gren's syndrome using degenerated consensus PCR primers.

BACKGROUND: Sj?gren's syndrome (SS) is an autoimmune exocrinopathy associated with multiple autoantibodies, lymphocyte infiltration of various organs, and functional deficiency of T cells. Several viruses have been implicated by PCR based studies, but their contribution to the pathophysiology of SS is still controversial. OBJECTIVES: In an attempt to explore the presence of human herpesviruses DNA sequences in salivary glands biopsies from patients suffering of SS, a recently developed strategy based on PCR with consensus degenerated primers that allowed to detect known and eventually unknown herpesviruses was used. STUDY DESIGN: Salivary glands biopsies from 55 patients suffering of primary and SS syndrome were explored by herpesviruses consensus PCR primers and all the PCR products were sequenced. RESULTS: Nine out of 55 salivary glands were positive by PCR and sequence analyses allowed to identify Epstein-Barr virus (EBV) in 6 cases and herpes simplex virus (HSV)-1 in 3 cases. We did not detect any sequences that could be related to a new herpesvirus. CONCLUSION: In view of the good sensitivity of the technique used, our study is not consistent with SS being associated with an unknown herpesvirus. However, our results suggest that EBV and HSV-1 could be implicated in a subset of SS cases and this possibility needs to be explored, to assess the potential benefit of antiviral drugs in some cases.     

Predictive factors of virologic success in HIV-1-infected children treated with lopinavir/ritonavir

Predictive factors of the virologic success of the use of lopinavir/ritonavir (LPV/r) in HIV-infected children are unknown, especially in children who have been pretreated with protease inhibitors (PIs). This longitudinal, single-center, observational study included 69 children (21 PI-naive and 48 PI-experienced) who had received LPV/r for at least 3 months. The mean (+/- SD) age was 10.3 +/- 4.8 years, and the mean baseline of CD4 percentage and HIV-1 RNA was 14.9% +/- 9.8% and 4.8 +/- 1.05 log10 copies/mL, respectively. The mean duration of follow-up was 16.5 +/- 8.3 months. At 6, 12, and 18 months, 52%, 57%, and 49% of all children, respectively, had a viral load less than 50 copies/mL. The risk of virologic failure, defined as 2 consecutive viral loads greater than 1000 copies/mL, was significantly higher when the children were previously treated with PIs and when the baseline LPV mutation score exceeded 3 mutations. In the pretreated children, the ratio of the plasma LPV maximal concentration to the baseline LPV score mutation was also associated with failure, independently of resistance score. Finally, in children failing an LPV-containing regimen, accumulation of additional PI-associated resistance mutations was evidenced in viral isolates from children with prior PI treatment, even with viral replication levels less than 10,000 copies/mL. In pretreated children, LPV plasma levels should be optimized in an attempt to achieve sufficient drug concentrations to overcome the resistance level.