Current Issue : July - September Volume : 2016 Issue Number : 3 Articles : 4 Articles
The renal excretion of gentamicin, an aminoglycoside antibiotic, was studied in the isolated perfused\nrat kidney (IPRK) model. Dose-linearity experiments were carried out at four doses (400,\n800, 1600, 3200 Ã?¼g), targeting initial perfusate levels of 5, 10, 20 and 40 Ã?¼g/ml. Additionally, gentamicin\nwas co-perfused with sodium bicarbonate (0.25 mM) and/or cimetidine (2 mM) to evaluate\nthe effect of urinary alkalization and secretory inhibition on gentamicin excretion and kidney\naccumulation. Gentamicin displayed net reabsorption in the IPRK, consistent with extensive\nluminal uptake. Kinetic analysis indicated that luminal transport of gentamicin (kidney ââ? â?? urine)\nis the rate-determining step for gentamicin urinary excretion. Clearance and cumulative excretion\ndecreased with increased gentamicin dose. Gentamicin kidney accumulation, estimated by mass\nbalance, ranged from ~20% - 30%. Urinary alkalization significantly increased gentamicin excretion,\nwith no effect on kidney accumulation. Conversely, cimetidine co-administration did not affect\ngentamicin clearance in the IPRK, but kidney accumulation was significantly reduced. When\nboth sodium bicarbonate and cimetidine were administered together, gentamicin kidney accumulation\ndecreased ~80% with corresponding increases in clearance and excretion ratio (XR)\ncompared to gentamicin alone. A main strategy to reduce the incidence of nephrotoxicity with\ngentamicin therapy (up to ~25%) involves reducing kidney accumulation of the compound. The\nresults of this research suggest that the combination of urinary alkalization and inhibition of basolateral\nsecretion (blood ââ? â?? kidney) may be a viable approach to mitigate aminoglycoside toxicity,\nand warrants further investigation....
Background: The monoclonal antibody natalizumab (NAT) inhibits the migration of lymphocytes throughout the\nbloodââ?¬â??brain barrier by blocking very late antigen (VLA)-4 interactions, thereby reducing inflammatory central\nnervous system (CNS) activity in patients with multiple sclerosis (MS). We evaluated the effects of different NAT\ntreatment regimens.\nMethods: We developed and optimised a NAT assay to measure free NAT, cell-bound NAT and VLA-4 expression\nlevels in blood and cerebrospinal fluid (CSF) of patients using standard and prolonged treatment intervals and after\nthe cessation of therapy.\nResults: In paired CSF and blood samples of NAT-treated MS patients, NAT concentrations in CSF were approximately\n100-fold lower than those in serum. Cell-bound NAT and mean VLA-4 expression levels in CSF were comparable\nwith those in blood. After the cessation of therapy, the kinetics of free NAT, cell-bound NAT and VLA-4 expression\nlevels differed. Prolonged intervals greater than 4 weeks between infusions caused a gradual reduction of free\nand cell-bound NAT concentrations. Sera from patients with and without NAT-neutralising antibodies could be\nidentified in a blinded assessment. The NAT-neutralising antibodies removed NAT from the cell surface in vivo\nand in vitro. Intercellular NAT exchange was detected in vitro.\nConclusions: Incorporating assays to measure free and cell-bound NAT into clinical practice can help to\ndetermine the optimal individual NAT dosing regimen for patients with MS...
The complexity of traditional Chinese medicines (TCMs) is related to their multi-component\nsystem. TCM aqueous decoction is a common clinical oral formulation. Between molecules in\nsolution, there exist intermolecular strong interactions to form chemical bonds or weak non-bonding\ninteractions such as hydrogen bonds and Van derWaals forces, which hold molecules together to form\nââ?¬Å?molecular aggregatesââ?¬Â. Taking the TCM Puerariae lobatae Radix (Gegen) as an example, we explored\nfour Gegen decoctions of different concentration of 0.019, 0.038, 0.075, and 0.30 g/mL, named G-1,\nG-2, G-3, and G-4. In order of molecular aggregate size (diameter) the four kinds of solution were\nranked G-1 < G-2 < G-3 < G-4 by Flow Cell 200S IPAC image analysis. A rabbit vertebrobasilar artery\ninsufficiency (VBI) model was set up and they were given Gegen decoction (GGD) at a clinical dosage\nof 0.82 g/kg (achieved by adjusting the gastric perfusion volume depending on the concentration).\nThe HPLC fingerprint of rabbit plasma showed that the chemical component absorption into blood in\norder of peak area values was G-1 < G-2 > G-3 > G-4. Puerarin and daidzin are the major constituents\nof Gegen, and the pharmacokinetics of G-1 and G-2 puerarin conformed with the two compartment\nopen model, while for G-3 and G-4, they conformed to a one compartment open model. For all four\nGGDs the pharmacokinetics of daidzin complied with a one compartment open model. FQ-PCR\nassays of rabbitsââ?¬â?¢ vertebrobasilar arterial tissue were performed to determine the pharmacodynamic\nprofiles of the four GGDs. GGD markedly lowered the level of AT1R mRNA, while the AT2R mRNA\nlevel was increased significantly vs. the VBI model, and G-2 was the most effective. In theory the\ndosage was equal to the blood drug concentration and should be consistent; however, the formation\nof molecular aggregates affects drug absorption and metabolism, and therefore influences drugsââ?¬â?¢\neffects. Our data provided references for the rational use of Chinese medicines in the clinic, such as\nthe best oral preparation and decoction concentration....
Rationale\nBronchiectasis is a condition characterised by dilated and thick-walled bronchi. The presence\nof Pseudomonas aeruginosa in bronchiectasis is associated with a higher hospitalisation\nfrequency and a reduced quality of life, requiring frequent and adequate treatment with\nantibiotics.\nObjectives\nTo assess local tolerability and the pharmacokinetic parameters of inhaled excipient free\ndry powder tobramycin as free base administered with the Cyclops dry powder inhaler to\nparticipants with non-cystic fibrosis bronchiectasis. The free base and absence of excipients\nreduces the inhaled powder dose.\nMethods\nEight participants in the study were trained in handling the device and inhaling correctly.\nDuring drug administration the inspiratory flow curve was recorded. Local tolerability was\nassessed by spirometry and recording adverse events. Serum samples were collected\nbefore, and 15, 30, 45, 60, 75, 90, 105, 120 min; 4, 8 and 12 h after inhalation.\nResults and Discussion\nDry powder tobramycin base was well tolerated and mild tobramycin-related cough was\nreported only once. A good drug dose-serum concentration correlation was obtained. Relatively small inhaled volumes were computed from the recorded flow curves, resulting in\npresumably substantial deposition in the central airwaysââ?¬â?i.e., at the site of infection.\nConclusions\nIn this first study of inhaled dry powder tobramycin free base in non-cystic fibrosis bronchiectasis\npatients, the free base of tobramycin and the administration with the Cyclops dry\npowder device were well tolerated. Our data support further clinical studies to evaluate\nsafety and efficacy of this compound in this population....
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