A meta-analysis of bone cement mediated antibiotic release: Overkill, but a viable approach to eradicate osteomyelitis and other infections tied to open procedures.

A number of clinical studies have highlighted the success of antibiotics formulated at concentrations between 0 and 6% w/w into bone cements to address localized infections. Separately, some commercial manufacturers have produced gentamycin-infused bone cement mixtures as a countermeasure to infection. The anecdotal evidence suggests that antibiotic infused cements can help eradicate or delay the onset of infections. Quantifying the functionality of that response is more challenging. We have surveyed the literature to identify studies in which controlled drug release or mechanical behavioral assessments have been conducted on drug-infused cements. The focus here is on vancomycin (VAN) in part due to its higher potency relative to gentamycin and its more common usage for staph infections. Takeaways from the limited pool of research studies indicate that large fractions (>99%) of the infused vancomycin remain sequestered in the cement and aren't bioavailable after solidification. Antibiotic fluence ranged from 1 to 283 µg/cm2hr. The initial strength of the various antibiotic loaded samples as produced were 52-96 MPa. Simulated exposures in a fluid environment by submersion reduced the antibiotic loaded strengths between 3 and 29%. Some strength measurements were noted below the ASTM F451 standard for acrylic bone cement although drug releasing spacers likely have different requirements. The glassy behavior of the cured cement led to both vancomycin and gentamicin having low permeability and a burst response. Smaller drug molecules and more gel-like immobilization matrices with lower glass transition temperatures offer higher potential for larger and more comprehensive drug bioavailability.

The effect of cisplatin on the nanoscale structure of aqueous PEO-PPO-PEO micelles of varying hydrophilicity observed using SAXS.

Aqueous solutions of polyethylene oxide-polypropylene oxide-polyethylene oxide (PEO-PPO-PEO) copolymers form micelles and cubic lattices as their temperature is raised. The presence of added solutes within the dispersions can also affect the kinetics of structure formation. Here, we investigate the structures formed in the amphiphiles P104, P105, and F108 solutions at 31% mass per v both neat and co-formulated with the drug cisplatin (0.02% to 0.1% mass per v) using small-angle X-ray scattering. P104 formed BCC colloidal crystals while P105 and F108 formed FCC structures. Cisplatin had a minor influence of the formation and stability of the crystals during these thermal excursions. The largest interaction between the amphiphiles and cisplatin was P104 where there was a 2% reduction in the BCC lattice parameter of P104 as cisplatin loading rose to 0.1% at 28 °C. The F108 unit cell swelled ∼2% upon cisplatin loading of 0.1%. A progressive evolution and breakdown of these structures was noted as the temperature rose from 10 °C to 35 °C. For the different amphiphiles, crystal thermal expansion coefficients of ∼1 × 10-2 °C-1 were determined in neat and loaded amphiphiles with cisplatin and all the crystals swelled with increasing temperature.

A Ligand-Based Drug Design. Discovery of 4-Trifluoromethyl-7,8-pyranocoumarin as a Selective Inhibitor of Human Cytochrome P450 1A2.

In humans, cytochrome P450 1A2 is the major enzyme metabolizing environmental arylamines or heterocyclic amines into carcinogens. Since evidence shows that planar triangle-shaped molecules are capable of selectively inhibiting P450 1A2, 16 triangular flavone, and coumarin derivatives were designed and synthesized for these studies. Among these compounds, 7,8-furanoflavone time-dependently inhibits P450 1A2 with a K(I) value of 0.44 µM. With a 5 min preincubation in the presence of NADPH, 0.01 µM 7,8-furanoflavone completely inactivates P450 1A2 but does not influence the activities of P450s 1A1 and 1B1. Another target compound, 7,8-pyrano-4-trifluoromethylcoumarin, is found to be a competitive inhibitor, showing high selectivity for the inhibition of P450 1A2 with a K(i) of 0.39 µM, 155- and 52-fold lower than its K(i) values against P450s 1A1 and 1B1, respectively. In yeast AhR activation assays, 7,8-pyrano-4-trifluoromethylcoumarin does not activate aryl hydrocarbon receptor when the concentration is lower than 1 µM, suggesting that this compound would not up-regulate AhR-caused P450 enzyme expression. In-cell P450 1A2 inhibition assays show that 7,8-pyrano-4-trifluoromethylcoumarin decreases the MROD activity in HepG2 cells at concentrations higher than 1 µM. Thus, using 7,8-pyrano-4-trifluoromethylcoumarin, a selective and specific P450 1A2 action suppression could be achieved, indicating the potential for the development of P450 1A2-targeting cancer preventive agents.

Ethynylflavones, highly potent, and selective inhibitors of cytochrome P450 1A1.

The flavone backbone is a well-known pharmacophore present in a number of substrates and inhibitors of various P450 enzymes. In order to find highly potent and novel P450 family I enzyme inhibitors, an acetylene group was incorporated into six different positions of flavone. The introduction of an acetylene group at certain locations of the flavone backbone lead to time-dependent inhibitors of P450 1A1. 3'-Ethynylflavone, 4'-ethynylflavone, 6-ethynylflavone, and 7-ethynylflavone (KI values of 0.035-0.056 µM) show strong time-dependent inhibition of P450 1A1, while 5-ethynylflavone (KI value of 0.51 µM) is a moderate time-dependent inhibitor of this enzyme. Meanwhile, 4'-ethynylflavone and 6-ethynylflavone are highly selective inhibitors toward this enzyme. Especially, 6-ethynylflavone possesses a Ki value of 0.035 µM for P450 1A1 177- and 15-fold lower than those for P450s 1A2 and 1B1, respectively. The docking postures observed in the computational simulations show that the orientation of the acetylene group determines its capability to react with P450s 1A1 and 1A2. Meanwhile, conformational analysis indicates that the shape of an inhibitor determines its inhibitory selectivity toward these enzymes.