Ulrike Holzgrabe

Bio: Ulrike Holzgrabe is an academic researcher from University of Würzburg. The author has contributed to research in topics: Allosteric regulation & Capillary electrophoresis. The author has an hindex of 45, co-authored 566 publications receiving 9806 citations. Previous affiliations of Ulrike Holzgrabe include Jagiellonian University & University of Illinois at Chicago.

Penetration of antibacterials into bone: pharmacokinetic, pharmacodynamic and bioanalytical considerations.

Abstract: Antibacterials play a key role in the treatment of bone infections and appropriate surgical prophylaxis. The rate and extent of penetration of antimicrobials into bone has been assessed and shown to be important for successful treatment in numerous studies. However, no recent review or critical evaluation of the analytical techniques is available. This review compares established and new sample preparation and analytical methods to measure bone concentrations. We performed a systematic literature search in MEDLINE, EMBASE, conference abstracts and references from published articles on bone penetration of antibacterials. This article focuses on the standardization of drug analysis in bone, the extent and rate of bone penetration of antibacterials, and the design, evaluation and reporting techniques of pharmacokinetic studies of bone penetration. The focus is on studies conducted between 1998 and 2007, since a previous review was published in 1999. WinNonlin® Professional version 5.0.1 software was used for statistics. Very different methods for sample preparation, drug analysis, data handling and reporting have been employed in bone penetration studies. There is substantial variability in the reported mean bone penetration between drugs and between different studies of the same drug. Quinolones, macrolides and linezolid have mean bone:serum concentration ratios that are commonly between 0.3 and 1.2, and higher ratios have been found for azithromycin (bone concentration in mg/kg of total bone). The ratios are usually between 0.15 and 0.3 for cephalosporins and glycopeptides, and between 0.1 and 0.3 for penicillins. Cephalosporins and penicillins have shown significantly lower (p<0.05) concentration ratios than linezolid. For 20 of 25 different drugs, the ratios were higher for cancellous bone than for cortical bone. The available data show a larger extent of bone penetration for quinolones, macrolides and linezolid than for β-lactams. The bone penetration of penicillins and cephalosporins was significantly lower than that of linezolid. Guidelines on sample preparation, drug analysis, study design and pharmacokinetic evaluation of bone penetration studies are vitally needed.

Quaternary Ammonium Salts and Their Antimicrobial Potential: Targets or Nonspecific Interactions?

Abstract: For more than 50 years dequalinium chloride has been used successfully as an antiseptic drug and disinfectant, particularly for clinical purposes. Given the success of dequalinium chloride, several series of mono- and bisquaternary ammonium compounds have been designed and reported to have improved antimicrobial activity. Furthermore, many of them exhibit high activity against mycobacteria and protozoa, especially against plasmodia. This review discusses the structure-activity relationships and the modes of action of the various series of (bis)quaternary ammonium compounds.

Comparison of pharmacological activities of three distinct kappa ligands (Salvinorin A, TRK-820 and 3FLB) on kappa opioid receptors in vitro and their antipruritic and antinociceptive activities in vivo.

Abstract: Salvinorin A, TRK-820 (17-cyclopropylmethyl-3,14beta-dihydroxy-4,5alpha-epoxy-6beta-[N-methyl-trans-3-(3-furyl) acrylamido]morphinan hydrochloride), and 3FLB (diethyl 2,4-di-[3-fluorophenyl]-3,7-dimethyl-3,7-diazabicyclo[3.3.1]nonane-9-one-1,5-dicarboxylate) are structurally distinctly different from U50,488H [(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methanesulfonate], the prototypic selective kappa agonist. Here, we investigated their in vitro pharmacological activities on receptors expressed in Chinese hamster ovary cells and in vivo antiscratch and antinociceptive activities in mice. All three compounds showed high selectivity for the kappa opioid receptor (KOR) over the mu opioid receptor (MOR) and delta opioid receptor (DOR) and nociceptin or orphanin FQ receptors. In the guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding assay, all three were full agonists on the KOR. The rank order of affinity and potency for the KOR was TRK-820 >> U50,488H approximately salvinorin A >> 3FLB. TRK-820 acted as a partial agonist on MOR and DOR, whereas salvinorin A and 3FLB showed no activities on these receptors. Salvinorin A, TRK-820, and 3FLB caused internalization of the human KOR in a dose-dependent manner. Interestingly, although salvinorin A and U50,488H had similar potencies in stimulating [(35)S]GTPgammaS binding, salvinorin A was about 40-fold less potent than U50,488H in promoting internalization. Following 4-h incubation, all three compounds induced down-regulation of the human KOR, with salvinorin A causing a lower extent of down-regulation. Although TRK-820 was potent and efficacious against compound 48/80-induced scratching, salvinorin A showed low and inconsistent effects, and 3FLB was inactive. In addition, salvinorin A and 3FLB were not active in the acetic acid abdominal constriction test. The discrepancy between in vitro and in vivo results may be due to in vivo metabolism of salvinorin A and 3FLB and possibly to their effects on other pharmacological targets.

PACKMOL: a package for building initial configurations for molecular dynamics simulations.

Abstract: Adequate initial configurations for molecular dynamics simulations consist of arrangements of molecules distributed in space in such a way to approximately represent the system's overall structure. In order that the simulations are not disrupted by large van der Waals repulsive interactions, atoms from different molecules must keep safe pairwise distances. Obtaining such a molecular arrangement can be considered a packing problem: Each type molecule must satisfy spatial constraints related to the geometry of the system, and the distance between atoms of different molecules must be greater than some specified tolerance. We have developed a code able to pack millions of atoms, grouped in arbitrarily complex molecules, inside a variety of three-dimensional regions. The regions may be intersections of spheres, ellipses, cylinders, planes, or boxes. The user must provide only the structure of one molecule of each type and the geometrical constraints that each type of molecule must satisfy. Building complex mixtures, interfaces, solvating biomolecules in water, other solvents, or mixtures of solvents, is straightforward. In addition, different atoms belonging to the same molecule may also be restricted to different spatial regions, in such a way that more ordered molecular arrangements can be built, as micelles, lipid double-layers, etc. The packing time for state-of-the-art molecular dynamics systems varies from a few seconds to a few minutes in a personal computer. The input files are simple and currently compatible with PDB, Tinker, Molden, or Moldy coordinate files. The package is distributed as free software and can be downloaded from http://www.ime.unicamp.br/~martinez/packmol/.

ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death

Abstract: It is important that the medical profession plays a significant role in critically evaluating the use of diagnostic procedures and therapies as they are introduced and tested in the detection, management, or prevention of disease states. Rigorous and expert analysis of the available data documenting absolute and relative benefits and risks of those procedures and therapies can produce helpful guidelines that improve the effectiveness of care, optimize patient outcomes, and favorably affect the overall cost of care by focusing resources on the most effective strategies. The American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) have jointly engaged in the production of such guidelines in the area of cardiovascular disease since 1980. The ACC/AHA Task Force on Practice Guidelines, whose charge is to develop, update, or revise practice guidelines for important cardiovascular diseases and procedures, directs this effort. The Task Force is pleased to have this guideline developed in conjunction with the European Society of Cardiology (ESC). Writing committees are charged with the task of performing an assessment of the evidence and acting as an independent group of authors to develop or update written recommendations for clinical practice. Experts in the subject under consideration have been selected from all 3 organizations to examine subject-specific data and write guidelines. The process includes additional representatives from other medical practitioner and specialty groups when appropriate. Writing committees are specifically charged to perform a formal literature review, weigh the strength of evidence for or against a particular treatment or procedure, and include estimates of expected health outcomes where data exist. Patient-specific modifiers, comorbidities, and issues of patient preference that might influence the choice of particular tests or therapies are considered as well as frequency of follow-up and cost effectiveness. When available, information from studies on cost will be considered; however, review …

Gas chromatography mass spectrometry–based metabolite profiling in plants

Abstract: The concept of metabolite profiling has been around for decades, but technical innovations are now enabling it to be carried out on a large scale with respect to the number of both metabolites measured and experiments carried out. Here we provide a detailed protocol for gas chromatography mass spectrometry (GC-MS)-based metabolite profiling that offers a good balance of sensitivity and reliability, being considerably more sensitive than NMR and more robust than liquid chromatography-linked mass spectrometry. We summarize all steps from collecting plant material and sample handling to derivatization procedures, instrumentation settings and evaluating the resultant chromatograms. We also define the contribution of GC-MS-based metabolite profiling to the fields of diagnostics, gene annotation and systems biology. Using the protocol described here facilitates routine determination of the relative levels of 300-500 analytes of polar and nonpolar extracts in approximately 400 experimental samples per week per machine.