Niemann-Pick Type C disease (NPC) is a rare metabolic disorder characterized by disruption of normal cholesterol trafficking within the cells of the body. There are no FDA approved treatments available for NPC patients. Recently, the cycloheptaglucoside 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) has shown efficacy as a potential NPC therapeutic by extending lifetime in NPC mice, delaying neurodegeneration, and decreasing visceral and neurological cholesterol burden. Although promising, systemic HP-β-CD treatment is limited by a pharmacokinetic profile characterized by rapid loss through renal filtration. To address these shortcomings, we sought to design a family of HP-β-CD pro-drug delivery vehicles, known as polyrotaxanes (PR), capable of increasing the efficacy of a given injected dose by improving both pharmacokinetic profile and bioavailability of the HP-β-CD agent. PR can effectively diminish the cholesterol pool within the liver, spleen, and kidney at molar concentrations 10-to-100-fold lower than monomeric HP-β-CD. In addition to this proof-of-concept, use of PR scaffolds with differing physiochemical properties reveal structure-activity relationships in which PR characteristics, including hydrophobicity, threading efficiency and surface charge, were found to both decisively and subtly effect therapeutic efficacy. PR scaffolds exhibit absorption, pharmacokinetics, and biodistribution patterns that are significantly altered from monomeric HP-β-CD. In all, PR scaffolds hold great promise as potential treatments for visceral disease in NPC patients.Niemann-Pick Type C disease (NPC) is a panethnic, heterogeneous, and extremely rare metabolic disorder (estimated incidence of approximately 1:120,000 live births 1 ) characterized by a disruption of normal cholesterol trafficking within cells 2 . Natural transport is hindered by mutations in either the NPC1 or NPC2 proteins in the late endosomal/lysosomal (LE/LY) system. Genetic mutation in the NPC1 gene is implicated in ~95% of clinical cases 2,3 . These proteins are responsible for the movement of unesterified cholesterol (UC) through the LE/LY, with their disruption resulting in aberrant accumulation of UC and other lipids including glycolipids and fatty acids within these compartments [4][5][6] . This defect presents a range of visceral and neurological symptoms including organomegally of the spleen and liver, supranuclear gaze palsy, delayed motor development, seizures, and dementia 7,8 . The progression of these NPC symptoms are ultimately fatal.There are no United States Food and Drug Administration (FDA) approved treatments currently available for NPC patients. In 2009, miglustat (Zavesca), an iminosugar small molecule drug that is currently approved to treat Gaucher's disease, was approved by the European Agency of Medicines for use in NPC, despite being rejected by the FDA 9 . The treatment has been shown to slow neurodegeneration in NPC mice and NPC patients, despite ultimately being unable to alter disease progression 10,11 . Small molecule drugs known...
A family of five water-soluble Gd 3+ :1,4,7,10-tetraazacyclododecane-1,4,7-tetraacetic acid-modified polyrotaxane (PR) magnetic resonance contrast agents bearing mixtures of 2-hydroxypropyl-β-cyclodextrin and 4-sulfobutylether-β-cyclodextrin macrocycles threaded onto Pluronic cores were developed as long circulating magnetic resonance contrast agents. Short diethylene glycol diamine spacers were utilized for linking the macrocyclic chelator to the PR scaffold prior to Gd 3+ chelation. The PR products were characterized by 1 H NMR, gel permeation chromatography/ multiangle light scattering, dynamic light scattering, and analytical ultracentrifugation. Nuclear magnetic relaxation dispersion and molar relaxivity measurements at 23 °C revealed that all the PR contrast agents displayed high spin−spin T 1 relaxation and spin−lattice T 2 relaxation rates relative to a DOTAREM control. When injected at 0.05 mmol Gd/kg body weight in BALB/c mice, the PR contrast agents increased the T 1 -weighted MR image intensities with longer circulation times in the blood pool than DOTAREM. Excretion of the agents occurred predominantly via the renal or biliary routes depending on the polyrotaxane structure, with the longest circulating L81 Pluronic-based agent showing the highest liver uptake. Proteomic analysis of PR bearing different β-cyclodextrin moieties indicated that lipoproteins were the predominant component associated with these materials after serum exposure, comprising as much as 40% of the total protein corona. We infer from these findings that Gd(III)-modified PR contrast agents are promising long-circulating candidates for blood pool analysis by MRI.
Pefloxacin pharmacokinetics and serum bactericidal activities (SBA) against Escherichia coli and Staphylococcus aureus were compared after intravenous infusion of either a single 800-mg dose or twice-daily 400-mg doses into 16 healthy volunteers. Plasma pefloxacin concentrations were measured for up to 60 h, and SBAs were determined 1,12, and 24 h after the start of the infusion. The mean areas under the concentrationversus-time curve for plasma were not different (138 versus 136 h. mg/liter). The mean clearances, volumes of distribution, and half-lives were also comparable. The mean (± standard deviation) maximal concentration after the 800-mg infusion was 12.11 ± 1.35 versus 6.51 ± 0.73 mg/liter after the first 400-mg infusion and 7.42 +-0.76 mg/liter after the second 400-mg infusion. Mean trough concentrations at 24 h were significantly different: 2.77 ± 0.63 (800 mg) versus 1.93 ± 0.49 (400 mg twice) mg/liter (P = 0.0007). Mean SBAs against E. coli after 800 mg of pefloxacin were higher than 1/128 (1 h), 1/32 (12 h), and 1/16 (24 h). Mean SBAs against S. aureus under the same conditions were higher than 1/64 (1 h), 1116 (12 h), and 1/8 (24 h). Mean SBAs at 1 and 12 h were significantly higher after the 800-mg infusion than after the 400-mg infusion but were similar at 24 h for both regimens. Comparison of SBAs according to National Committee for Clinical Laboratory Standards criteria showed a similar adequacy at 24 h for both regimens against both strains. Administration of 800 mg of pefloxacin once a day is bioequivalent to 400 mg twice a day, and bactericidal activity of the 800-mg infusion is not less than that of two 400-mg infusions.Pefloxacin is a fluorinated quinolone that is especially active in vitro against gram-negative bacteria and staphylococcal strains (8). Its excellent penetration into various tissues and fluids allows its use in a wide range of infections (8). Pefloxacin is usually given as 400 mg twice a day (b.i.d.) intravenously or per os, resulting in similar maximum concentrations in plasma of approximately 10 mg/liter owing to its complete bioavailability (7). Pefloxacin is metabolized extensively to form the active N-demethylpefloxacin (norfloxacin) and inactive N-oxide metabolites (9). The elimination half-life (t1,2) of pefloxacin following administration of single doses ranged from 8 to 13 h, increasing to 14 to 15 h after multiple dosing (7).Thus, administration of 800 mg of pefloxacin once a day instead of 400 mg b.i.d. could be clinically effective and should improve compliance with treatment. The aim of this study was to compare pefloxacin pharmacokinetics and serum bactericidal activity (SBA) in 16 healthy volunteers after intravenous infusion of either a single 800-mg dose or two 400-mg doses given at a 12-h interval.MATERIALS AND METHODS Subjects. Sixteen healthy male Caucasian volunteers were enrolled in this study. Their mean weight (+ standard deviation) was 66.9 + 4.9 kg (range, 62 to 75 kg), their mean height was 176.6 + 4.8 cm (range, 169 to 185 cm), and their mean age...
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