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Nerve growth factor (NGF) is the protein responsible for the development and maintenance of sensory skin innervation. Given the role of appropriate innervation in skin healing, NGF has been indicated as a possible prohealing treatment in pathologic conditions characterized by nerve-ending loss, such as chronic ulcers in diabetes; however, its use as a therapeutic agent is limited by its hyperalgesic effect. We tested the effect of topical application of the nonalgogenic NGF derivative hNGFP61S/R100E in two models of skin ulcer induced in dbdb diabetic mice, investigating healing time, skin histology, reinnervation, and angiogenesis using morphologic and molecular approaches. We showed that the topical administration of CHF6467, a recombinant human NGF in which an amino acid substitution (R100E) abolished the hyperalgesic effect usually associated with NGF, accelerated skin repair in experimental wounds (full-excision and pressure-ulcer) induced in diabetic mice (dbdb). CHF6467-induced acceleration of wound healing was accompanied by increased re-epithelization, reinnervation, and revascularization as assessed by histology, immunohistochemistry, and image analysis. Bioinformatic analysis of differentially expressed genes and signaling pathways in the wound tissues showed that protein kinase B-mammalian target of rapamycin was the most regulated pathway. In spite of the transdermal absorption leading to measurable, dose-dependent increases in CHF6467 plasma levels, no systemic thermal or local mechanical hyperalgesia was observed in treated mice. When tested in vitro in human cell lines, CHF6467 stimulated keratinocyte and fibroblast proliferation and tube formation by endothelial cells. Collectively, these results support a possible use of CHF6467 as a prohealing agent in skin lesions in diabetes. SIGNIFICANCE STATEMENT: Topical application of CHF6467 accelerates reinnervation, neoangiogenesis, and wound healing in diabetic mice in both full-thickness skin-excision and pressure-ulcer models through the protein kinase B/mammalian target of rapamycin pathway and does not induce hyperalgesia.

The pharmacokinetics of rufloxacin were evaluated in patients with acute exacerbations of chronic bronchitis. The drug was administered once-a-day for 10 consecutive days following two different dosage schedules. The first group of 56 patients was given a loading dose of 300 mg on day 1 and 150 mg on the subsequent 9 days. A second group of 55 patients received a loading dose of 400 mg followed by 200 mg for the subsequent 9 days. In each patient, three blood samples were collected during and after treatment. Rufloxacin plasma levels were determined by high performance liquid chromatography. A one-compartment model for repeated doses was employed to estimate the pharmacokinetic parameters. The data were analysed by nonlinear mixed effects modelling using the NONMEM program. The apparent clearance and volume of distribution were found to depend on body weight and gender: the elimination half-life in males (mean weight 73.7 kg) being 30 h and in females (mean weight 71.7 kg) 27 h (68% prediction intervals 9.5–93.9 and 8.6–85.4 h, respectively). The calculated peak plasma concentration at steady state for the 200 mg per day regimen was 4.81 mg/l, while the trough concentration was 2.75 mg/l. The pharmacokinetic parameters of rufloxacin were close to those measured in previous formal studies in a small number of patients but with numerous blood samples. The study also showed that a 200 mg daily oral dose of rufloxacin preceded by a loading dose of 400 mg produced steady state plasma concentrations above the minimum inhibitory concentrations for most susceptible pathogens.

Rufloxacin is a new broad-spectrum fluoroquinolone antibacterial agent. The pharmacokinetics and safety of rufloxacin were evaluated after repeated oral administration to healthy volunteers. The drug was administered once a day for 6 consecutive days following two different dose schedules. The first group of 11 subjects was given a loading dose of 300 mg on the first day and 150 mg on the subsequent 5 days. The second group of 12 subjects was given a loading dose of 400 mg and 200 mg for 5 days. Serum levels and urine concentrations of rufloxacin were determined by microbiological assay. A simultaneous fit of all data points for each subject was done according to a one-compartment open model. The drug was rapidly absorbed (absorption half-life 17 +/- 6 min in the 300 + 150 mg and 11 +/- 5 min in the 400 + 200 mg dose regimen group) and reached maximal serum concentrations (2.77 +/- 0.24 and 3.62 +/- 0.35 micrograms/ml) 4.2 +/- 0.4 and 4.0 +/- 0.9 h after the first administration. Steady-state serum concentrations (3.19 +/- 0.31 and 4.06 +/- 0.33 micrograms/ml) were reached in 3.7 +/- 0.7 and 4.5 +/- 0.4 days. Elimination half-lives were 29.5 +/- 2.4 and 36.0 +/- 2.8 h. Apparent volumes of distribution were 111 +/- 8 and 136 +/- 16 liters and apparent plasma clearances were 46 +/- 5 and 44 +/- 4 ml/min. Renal clearances were 18 +/- 3 and 17 +/- 2 ml/min.(ABSTRACT TRUNCATED AT 250 WORDS)

SummaryTwo groups of 23 and 84 patients with hip fracture received intramuscularly 100 and 300 mg dermatan sulfate (MF701) b. i. d., respectively, for the prophylaxis of deep vein thrombosis. Median duration of treatment was 17 and 16 days, respectively. Four blood samples were collected from each patient while under treatment. Plasma levels of dermatan sulfate were determined by a chromogenic substrate assay. A one-compartment model for multiple doses was employed to estimate the pharmacokinetic parameters. Fitting was applied to mean plasma concentrations calculated for each sampling time and weighted according to the number of samples available at each time. Thrombin clotting time was measured on the same plasma samples. Antithrombotic efficacy was assessed by bilateral venography.Plasma levels of dermatan sulfate increased gradually throughout the treatment, indicating a marked accumulation process. Time to reach steady-state was 14 or 9 days with 100 or 300 mg b. i. d., respectively. This was due to an apparent prolonged terminal half-life (68 or 43 h), which actually reflected slow absorption from the injection sites. The clinical efficacy of MF701 in preventing DVT was found to be dependent on the plasma concentration of the drug and also, but less significantly, on the prolongation of thrombin clotting time. Dermatan sulfate plasma levels greater than 9 μ/ml are advisable to optimize efficacy in hip fracture patients.

Abnormal amyloid-β (Aβ) production and deposition is believed to represent one of the main causes of Alzheimer's disease (AD). γ-Secretase is the enzymatic complex responsible for Aβ generation from its precursor protein. Inhibition or modulation of γ-secretase represents an attractive therapeutic approach. CHF5074 is a new γ-secretase modulator that has been shown to inhibit brain plaque deposition and to attenuate memory deficit in adult AD transgenic mice after chronic treatment. To date, it is not known whether the positive behavioral effects of this compound also occur in young transgenic mice without plaque deposition. Here, we evaluated the effects of acute and subchronic treatment with CHF5074 on contextual and recognition memory and on hippocampal synaptic plasticity in plaque-free Tg2576 mice. We found that at 5 months of age, contextual memory impairment was significantly attenuated after acute subcutaneous administration of 30 mg/kg CHF5074. At 6 months of age, recognition memory impairment was fully reversed after a 4-week oral treatment in the diet (≈60 mg/kg/day). These cognitive effects were associated with a reversal of long-term potentiation (LTP) impairment in the hippocampus. A significant reduction in brain intraneuronal AβPP/Aβ levels and hyperphosphorylated tau, but no change in soluble or oligomeric Aβ levels was detected in Tg2576 mice showing functional recovery following CHF5074 treatment. We conclude that the beneficial effects of CHF5074 treatment in young transgenic mice occurred at a stage that precedes plaque formation and were associated with a reduction in intraneuronal AβPP/Aβ and hyperphosphorylated tau.