@article{ShityakovSohajdaPuskasetal.2014,
  author    = {Shityakov, Sergey and Sohajda, Tam{\´a}s and Puskas, Istav{\´a}n and Roewer, Norbert and F{\"o}rster, Carola and Broscheit, Jens-Albert},
  title     = {Ionization States, Cellular Toxicity and Molecular Modeling Studies of Midazolam Complexed with Trimethyl-β-Cyclodextrin},
  series = {Molecules},
  volume    = {19},
  journal   = {Molecules},
  number    = {10},
  doi       = {10.3390/molecules191016861},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119186},
  pages     = {16861-76},
  year      = {2014},
  abstract  = {We investigated the ionization profiles for open-ring (OR) and closed-ring (CR) forms of midazolam and drug-binding modes with heptakis-(2,3,6-tri-O-methyl)-β-cyclodextrin (trimethyl-β-cyclodextrin; TRIMEB) using molecular modeling techniques and quantum mechanics methods. The results indicated that the total net charges for different molecular forms of midazolam tend to be cationic for OR and neutral for CR at physiological pH levels. The thermodynamic calculations demonstrated that CR is less water-soluble than OR, mainly due to the maximal solvation energy (ΔG(CR)(solv = -9.98 kcal·mol ⁻¹), which has a minimal ΔG(OR)(solv) of -67.01 kcal·mol⁻¹. A cell viability assay did not detect any signs of TRIMEB and OR/CR-TRIMEB complex toxicity on the cEND cells after 24 h of incubation in either Dulbecco's Modified Eagles Medium or in heat-inactivated human serum. The molecular docking studies identified the more flexible OR form of midazolam as being a better binder to TRIMEB with the fluorophenyl ring introduced inside the amphiphilic cavity of the host molecule. The OR binding affinity was confirmed by a minimal Gibbs free energy of binding (ΔG(bind)) value of -5.57 ± 0.02 kcal·mol⁻¹, an equilibrium binding constant (K(b)) of 79.89 ± 2.706 μM, and a ligand efficiency index (LE(lig)) of -0.21 ± 0.001. Our current data suggest that in order to improve the clinical applications of midazolam via its complexation with trimethyl-β-cyclodextrin to increase drug's overall aqueous solubility, it is important to concern the different forms and ionization states of this anesthetic. All mean values are indicated with their standard deviations.},
  language  = {en}
}
@article{ShityakovPuskasPapaietal.2015,
  author    = {Shityakov, Sergey and Pusk{\´a}s, Istv{\´a}n and P{\´a}pai, Katalin and Salvador, Ellaine and Roewer, Norbert and F{\"o}rster, Carola and Broscheit, Jens-Albert},
  title     = {Sevoflurane-sulfobutylether-\(\beta\)-cyclodextrin complex: preparation, characterization, cellular toxicity, molecular modeling and blood-brain barrier transport studies},
  series = {Molecules},
  volume    = {20},
  journal   = {Molecules},
  doi       = {10.3390/molecules200610264},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148543},
  pages     = {10264-10279},
  year      = {2015},
  abstract  = {The objective of the present investigation was to study the ability of sulfobutylether-\(\beta\)-cyclodextrin (SBECD) to form an inclusion complex with sevoflurane (SEV), a volatile anesthetic with poor water solubility. The inclusion complex was prepared, characterized and its cellular toxicity and blood-brain barrier (BBB) permeation potential of the formulated SEV have also been examined for the purpose of controlled drug delivery. The SEV-SBE\(\beta\)CD complex was nontoxic to the primary brain microvascular endothelial (pEND) cells at a clinically relevant concentration of sevoflurane. The inclusion complex exhibited significantly higher BBB permeation profiles as compared with the reference substance (propranolol) concerning calculated apparent permeability values (P\(_{app}\)). In addition, SEV binding affinity to SBE\(\beta\)CD was confirmed by a minimal Gibbs free energy of binding (ΔG\(_{bind}\)) value of -1.727 ± 0.042 kcal・mol\(^{-1}\) and an average binding constant (K\(_{b}\)) of 53.66 ± 9.24 mM indicating rapid drug liberation from the cyclodextrin amphiphilic cavity.},
  language  = {en}
}