Dynamics of driven translocation of semiflexible polymers.

We study translocation of semiflexible polymers driven by force f_{d} inside a nanometer-scale pore using our three-dimensional Langevin dynamics model. We show that the translocation time τ increases with increasing bending rigidity κ. Similarly, the exponent β for the scaling of τ with polymer length N,τ∼N^{β}, increases with increasing κ as well as with increasing f_{d}.

Rigidity-induced scale invariance in polymer ejection from capsid.

While the dynamics of a fully flexible polymer ejecting a capsid through a nanopore has been extensively studied, the ejection dynamics of semiflexible polymers has not been properly characterized. Here we report results from simulations of ejection dynamics of semiflexible polymers ejecting from spherical capsids. Ejections start from strongly confined polymer conformations of constant initial monomer density.

Quantification of tension to explain bias dependence of driven polymer translocation dynamics.

Motivated by identifying the origin of the bias dependence of tension propagation, we investigate methods for measuring tension propagation quantitatively in computer simulations of driven polymer translocation. Here, the motion of flexible polymer chains through a narrow pore is simulated using Langevin dynamics. We measure tension forces, bead velocities, bead distances, and bond angles along the polymer at all stages of translocation with unprecedented precision.

Uniform description of polymer ejection dynamics from capsid with and without hydrodynamics.

We use stochastic rotation dynamics (SRD) to examine the dynamics of the ejection of an initially strongly confined flexible polymer from a spherical capsid with and without hydrodynamics. The results obtained using stochastic rotation dynamics (SRD) are compared to similar Langevin simulations. Inclusion of hydrodynamic modes speeds up the ejection but also allows the part of the polymer outside the capsid to expand closer to equilibrium.

Chaperone-assisted translocation of flexible polymers in three dimensions.

Polymer translocation through a nanometer-scale pore assisted by chaperones binding to the polymer is a process encountered in vivo for proteins. Studying the relevant models by computer simulations is computationally demanding. Accordingly, previous studies are either for stiff polymers in three dimensions or flexible polymers in two dimensions.

Criteria for minimal model of driven polymer translocation.

While the characteristics of the driven translocation for asymptotically long polymers are well understood, this is not the case for finite-sized polymers, which are relevant for real-world experiments and simulation studies. Most notably, the behavior of the exponent α, which describes the scaling of the translocation time with polymer length, when the driving force fp in the pore is changed, is under debate. By Langevin dynamics simulations of regular and modified translocation models using the freely jointed-chain polymer model we find that a previously reported incomplete model, where the trans side and fluctuations were excluded, gives rise to characteristics that are in stark contradiction with those of the complete model, for which α increases with fp.

Dynamics of polymer ejection from capsid.

Polymer ejection from a capsid through a nanoscale pore is an important biological process with relevance to modern biotechnology. Here, we study generic capsid ejection using Langevin dynamics. We show that even when the ejection takes place within the drift-dominated region there is a very high probability for the ejection process not to be completed.

Pharmacokinetics of oxycodone after intravenous, buccal, intramuscular and gastric administration in children.

Objective: To evaluate the pharmacokinetics of four administration routes of oxycodone parenteral liquid (10 mg/mL), single intravenous and intramuscular injections and buccal and gastric administration, in children.

Patients And Participants: Forty generally healthy children, aged 6-93 months, undergoing inpatient surgery.

Methods: After induction of anaesthesia, children received a single dose of oxycodone 0.

Paracellular and passive transcellular permeability in immortalized human corneal epithelial cell culture model.

A cell culture model of human corneal epithelium (HCE-model) was recently introduced [Invest. Ophthalmol. Vis.

Pharmacokinetics of intravenous and rectal ketoprofen in young children.

Objective: To evaluate the relative bioavailabilities of ketoprofen after intravenous and rectal administration to young children.

Design: Open-label prospective parallel-group study.

Patients: Participants were 28 children aged 7 to 93 months.

Extracellular and intracellular factors influencing gene transfection mediated by 1,4-dihydropyridine amphiphiles.

Double-charged 1,4-dihydropyridine (1,4-DHP) amphiphiles have been shown to condense DNA and efficiently transfect it into cells in vitro [Hyvönen et al., Biochim. Biophys.

Culture model of human corneal epithelium for prediction of ocular drug absorption.

Purpose: The main purpose of this study was to develop a cell culture model of immortalized epithelium from the human cornea for drug permeability testing.

Methods: Immortalized human corneal epithelial (HCE) cells were grown on filters, with various filter materials and coating procedures. In the optimal case, HCE cells were grown on polyester filters coated with rat tail collagen gel containing fibroblast cells.

Different effects of pH on the permeation of pilocarpine and pilocarpine prodrugs across the isolated rabbit cornea.

Ocular absorption of pilocarpine and many other ophthalmic drugs can be improved by prodrug derivatization. For stability and solubility reasons basic prodrugs must be formulated at acidic pH, which may affect the corneal drug permeability. We studied the effects of pH on in vitro permeation of pilocarpine, pilocarpic acid benzyl diester prodrugs [O-propionyl (I) and O-valeryl (II)] and O,O'-(1, 4-xylylene) bispilocarpic acid diester prodrugs [O,O'-diacetyl (III), O,O'-dipropionyl (IV) and O,O'-divaleryl (V)] through albino rabbit cornea.

Comparison of enzymatic hydrolysis of pilocarpine prodrugs in human plasma, rabbit cornea, and butyrylcholinesterase solutions.

Various bispilocarpic acid diesters (double prodrugs of pilocarpine) were synthesized, and their in vitro esterase catalyzed hydrolysis was evaluated in diluted human plasma, rabbit cornea homogenate, and specific butyrylcholinesterase solution. The structural changes greatly affected the rate of enzymatic hydrolysis of the prodrugs. Bispilocarpic acid with 2 cyclopropane substituents was the most stable derivative, whereas bispilocarpic acid with 2 cyclobutane substituents was the most labile derivative.

Ocular absorption and irritation of pilocarpine prodrug is modified with buffer, polymer, and cyclodextrin in the eyedrop.

The influence of buffer, viscosity and cyclodextrin on the ocular absorption and irritation of a pilocarpine prodrug, O,O'-dipropionyl-(1,4-xylylene) bispilocarpic acid diester, was studied in albino rabbits. The prodrug solutions, equivalent to 0.5% pilocarpine, were prepared in 0, 10, 20, 50, or 75 mM citrate buffer at pH 5.

Synthesis and analysis of O,O'-dicarboxylate (dibenzyl) bispilocarpates as possible prodrugs of pilocarpine.

As a part of a series of studies to develop prodrug derivatives of pilocarpine, the O,O'-succinyl (dibenzyl), O,O-adipoyl (dibenzyl), O,O-fumaryl (dibenzyl), and O,O-terephthaloyl (dibenzyl) bispilocarpate fumarates were synthesized as a new class of pilocarpine prodrugs. The compounds were prepared from pilocarpic acid benzyl monoester by coupling two pilocarpic acid benzyl monoesters together with spacer chains by usual esterification methods. Liquid chromatography, thermospray liquid chromatography-mass spectrometry, high-resolution mass spectrometry, and NMR spectroscopy were applied to the identification and the purity evaluation of the synthetic products.

Improved corneal pilocarpine permeability with O,O'-(1,4-xylylene) bispilocarpic acid ester double prodrugs.

O,O'-(1,4-Xylylene) bispilocarpic acid esters are pilocarpine prodrugs containing two pilocarpic acid monoesters linked with one pro-moiety. Each mole of prodrug forms two pilocarpine moles in the presence of esterases. Corneal uptake and permeability of various bispilocarpic acid diesters were investigated in vitro using isolated albino rabbit corneas.

Determination of physicochemical properties, stability in aqueous solutions and serum hydrolysis of pilocarpic acid diesters.

New alkyl and aralkyl pilocarpic acid diesters, prodrugs of pilocarpine, were synthesized with the aim of improving the bioavailability of pilocarpine by increasing its corneal permeability. These esters were several orders of magnitude more lipophilic than pilocarpine as determined by their apparent partition coefficients between 1-octanol and phosphate buffer (pH 7.40) (log P).

Synthesis and identification of pilocarpic acid diesters, prodrugs of pilocarpine.

A series of new pilocarpic acid diesters were synthesized to obtain prodrugs for pilocarpine with varying physico-chemical properties. Thermospray liquid chromatography-mass spectrometry (TSP-LC-MS), liquid chromatography with UV-detection (LC-UV) and NMR-spectroscopy were used for the identification of the synthetic products and for evaluation of their purity including typical impurities (pilocarpic acid monoester, pilocarpine). TSP-LC-MS-analysis was performed in the reversed-phase mode using acetonitrile (60%)-0.