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Clinical Pharmacology in Drug... Sep 2018Tedizolid phosphate is approved for the treatment of acute bacterial skin and skin structure infections in adults. We evaluated the pharmacokinetics of tedizolid in... (Comparative Study)
Comparative Study
Tedizolid phosphate is approved for the treatment of acute bacterial skin and skin structure infections in adults. We evaluated the pharmacokinetics of tedizolid in elderly subjects to guide dosing recommendations. In an open-label phase 1 study (ClinicalTrials.gov identifier NCT01496677), 14 elderly (≥65 years) and 14 younger control (18-45 years) subjects each received a single oral dose of tedizolid phosphate 200 mg. Blood samples were collected before dose and more than 72 hours after dose. The pharmacokinetic parameters of tedizolid after a single dose were similar in both age groups. Geometric mean ratios (elderly/younger controls) and corresponding 90% confidence intervals were maximum observed plasma concentration (C ), 1.091 (0.917-1.297); AUC from time 0 extrapolated to infinity (AUC ), 1.132 (0.954-1.343). Tedizolid plasma exposure was similar in elderly and younger control subjects. The findings indicated that after intravenous or oral administration of tedizolid phosphate 200 mg once daily, no dose adjustment was warranted in elderly subjects to achieve therapeutic levels.
Topics: Administration, Intravenous; Administration, Oral; Adult; Aged; Area Under Curve; Biological Availability; Drug Administration Schedule; Female; Humans; Male; Organophosphates; Oxazoles
PubMed: 29319932
DOI: 10.1002/cpdd.426 -
Journal of the American Chemical Society May 2002Knowledge of the pK(a) of phosphoranes is important for the interpretation of phosphate ester hydrolysis. Calculated pK(a)'s of the model phosphorane, ethylene...
Knowledge of the pK(a) of phosphoranes is important for the interpretation of phosphate ester hydrolysis. Calculated pK(a)'s of the model phosphorane, ethylene phosphorane, are reported. The method of calculation is based on the use of dimethyl phosphate as a reference state for evaluating relative pK(a) values, and on the optimization of the oxygen and acidic hydrogen van der Waals radii to give reasonable pK(1)(a), pK(2)(a), and pK(3)(a) for phosphoric acid in solution. Density functional theory is employed to calculate the gas-phase protonation energies, and continuum dielectric methods are used to determine the solvation corrections. The calculated pK(1)(a) and p(2)(a) for the model phosphorane are 7.9 and 14.3, respectively. These values are within the range of proposed experimental values, 6.5-11.0 for pK(1)(a), and 11.3-15.0 for pK(2)(a). The mechanistic implications of the calculated pK(a)'s are discussed.
Topics: Hydrolysis; Kinetics; Models, Chemical; Models, Molecular; Organophosphates; Phosphoranes
PubMed: 11982365
DOI: 10.1021/ja011373i -
Macromolecular Rapid Communications Dec 2017A photoregulated phosphoramidite iterative process is studied for the synthesis of non-natural, digitally encoded oligo(phosphodiester)s. The oligomers are prepared...
A photoregulated phosphoramidite iterative process is studied for the synthesis of non-natural, digitally encoded oligo(phosphodiester)s. The oligomers are prepared using two reactive phosphoramidite monomers containing a 2-(2-nitrophenyl)propoxycarbonyl (NPPOC) protected OH group. The stepwise synthesis is performed on an OH-functional soluble polystyrene support, which allows recycling by precipitation in a nonsolvent. Repeating cycles involving phosphoramidite coupling, oxidation of phosphite to phosphate, and NPPOC deprotection by light irradiation at λ = 365 nm are performed in order to prepare oligomers with different lengths and sequences. Synthesis is conducted on a micromolar scale and good recycling yields are obtained in all cases. The use of a soluble polymer support allows an in-depth characterization of the NPPOC photo-deprotection step by H NMR, UV spectroscopy, and size exclusion chromatography, and thus identification of optimal synthesis conditions. After cleavage from the support, the oligo(phosphodiester)s are characterized by tandem mass spectrometry, which confirms preparation of uniform sequence-coded oligomers.
Topics: Molecular Structure; Organophosphates; Photochemical Processes
PubMed: 29144013
DOI: 10.1002/marc.201700651 -
IARC Monographs on the Evaluation of... 1999
Review
Topics: Animals; Carcinogenicity Tests; Carcinogens; Flame Retardants; Humans; Mutagenicity Tests; Mutagens; Neoplasms; Neoplasms, Experimental; Occupational Exposure; Organophosphates; Salmonella typhimurium
PubMed: 10476477
DOI: No ID Found -
Biology of Reproduction Sep 2022The endocrine disruptive effects of bisphenol A (BPA) and brominated flame retardants (BDE-47) have led to restrictions on their use and increased the pressure to...
The endocrine disruptive effects of bisphenol A (BPA) and brominated flame retardants (BDE-47) have led to restrictions on their use and increased the pressure to identify safe replacements for these chemicals. Although there is evidence that some of these alternatives may be toxic to spermatogonial and Leydig cells, little is known about the toxicity of emerging replacements on Sertoli cells. We used high-content imaging to compare the effects of legacy chemicals, BPA and BDE-47, to their corresponding replacements. TM4 Sertoli cells were exposed for 48 h to each chemical (0.001-100 μM) followed by cytotoxicity and phenotypic endpoint assessment. The benchmark concentration potency ranking for bisphenols based on cytotoxicity was BPTMC > bisphenol M > BPAF>BPF > BPS > BPA. Human administered equivalent dose (AED) determination ranked BPS as the most potent alternative replacement. The benchmark concentration potency ranking of BDE-47 and organophosphate esters based on cytotoxicity was TDtBPP>BDMPP>TBOEP>TDCPP>TMPP>TPHP>BDE47>IPPP=BPDP=TCPP. Additionally, TM4 cell exposure to BDE-47 increased Calcein intensity (57.9 μM) and affected lysosomes (21.6 μM), while exposure to TPHP and TMPP resulted in cellular oxidative stress changes at benchmark concentration values as low as 0.01 and 0.4 μM, respectively. Overall bioactivity considerations of the chemicals on TM4 via ToxPi analyses and AED modeling further validated emerging replacements as highly potent chemicals in comparison to BPA and BDE-47. These findings demonstrate that many bisphenol and flame retardant replacements are more potent in Sertoli cells than the legacy chemical they are replacing and that phenotypic parameter assessment is an effective tool in chemical toxicity assessment.
Topics: Animals; Benzhydryl Compounds; Esters; Flame Retardants; Halogenated Diphenyl Ethers; Humans; Male; Mice; Organophosphates; Phenols; Sertoli Cells
PubMed: 35596243
DOI: 10.1093/biolre/ioac101 -
Bioorganic & Medicinal Chemistry Sep 2014The bioactive metabolite sphingosine-1-phosphate (S1P), a product of sphingosine kinases (SphKs), mediates diverse biological processes such as cell differentiation,...
The bioactive metabolite sphingosine-1-phosphate (S1P), a product of sphingosine kinases (SphKs), mediates diverse biological processes such as cell differentiation, proliferation, survival and angiogenesis. A fluorinated analogue of S1P receptor agonist has been synthesized by utilizing a ring opening reaction of oxacycles by a lithiated difluoromethylphosphonate anion as the key reaction. In vitro activity of this S1P analogue is also reported.
Topics: Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Halogenation; Humans; Male; Molecular Structure; Organophosphates; Receptors, Lysosphingolipid; Sphingosine; Sphingosine-1-Phosphate Receptors; Structure-Activity Relationship
PubMed: 25047939
DOI: 10.1016/j.bmc.2014.06.038 -
Journal of Natural Products Apr 2017Isoliquiritigenin (1) possesses a variety of biological activities in vitro. However, its poor aqueous solubility limits its use for subsequent in vivo experimentation....
Isoliquiritigenin (1) possesses a variety of biological activities in vitro. However, its poor aqueous solubility limits its use for subsequent in vivo experimentation. In order to enable the use of 1 for in vivo studies without the use of toxic carriers or cosolvents, a phosphate prodrug strategy was implemented relying on the availability of phenol groups in the molecule. In this study, a phosphate group was added to position C-4 of 1, leading to the more water-soluble prodrug 2 and its ammonium salt 3, which possesses increased stability compared to 2. Herein are reported the synthesis, characterization, solubility, and stability of phosphate prodrug 3 in biological medium in comparison to 1, as well as new results on its anti-inflammatory properties in vivo. As designed, the solubility of prodrug 3 was superior to that of the parent natural product 1 (9.6 mg/mL as opposed to 3.9 μg/mL). Prodrug 3 as an ammonium salt was also found to possess excellent stability as a solid and in aqueous solution, as opposed to its phosphoric acid precursor 2.
Topics: Animals; Chalcones; Glycyrrhiza; Molecular Structure; Organophosphates; Prodrugs; Quaternary Ammonium Compounds; Solubility; Water
PubMed: 28252963
DOI: 10.1021/acs.jnatprod.6b00600 -
The Science of the Total Environment Dec 2022Several organophosphorus compounds such as organophosphate pesticides (OPPs) and trialkylphosphates (TAPs) are suspected to inhibit cholinesterase activities, to affect...
Several organophosphorus compounds such as organophosphate pesticides (OPPs) and trialkylphosphates (TAPs) are suspected to inhibit cholinesterase activities, to affect endocrine systems or to possibly be carcinogenic. To evaluate their adverse effects on health with chronic exposure in the general population, especially in children, we measured the household exposure to OPPs and TAPs by Japanese children via all exposure pathways and the contribution of indoor air quality. First-morning void urine was collected from subjects aged 6 to 15 years (n = 132), and airborne organophosphorus compounds were sampled in the subject's bedroom for 24 h. Airborne levels of nine OPPs and three TAPs and their urinary metabolites were determined. No significant correlations were detected for any compounds between their airborne concentrations and the urinary excretion amounts of their corresponding metabolites. The estimated daily intakes were as follows (median, μg/kg b.w./d): chlorpyrifos, 0.042; diazinon, 0.067; tri-n-butylphosphate, 0.094. The 95th percentiles of the intakes for fenthion, fenitrothion and the above three compounds did not exceed their reference limit values, although one subject had a daily intake of tri-n-butylphosphate that was about twice its reference limit value. The concentration levels of the urinary metabolite of tri-n-butylphosphate in our subjects tended to be higher than those for children in many other countries. The fractions of the amounts absorbed by inhalation to the amounts absorbed via all of the exposure pathways was only 2.3 % (median) for tri-n-butylphosphate. Inhalation did not seem to contribute very much as an absorption pathway of the organophosphorus compounds in these Japanese children while they were at home. The exposure amounts of OPPs were not suggested to be high enough to adversely affect the health of these children at present on the basis of their daily intakes compared to their reference limit values.
Topics: Adolescent; Air Pollution, Indoor; Child; Chlorpyrifos; Cholinesterases; Diazinon; Environmental Exposure; Fenitrothion; Fenthion; Humans; Insecticides; Japan; Organophosphates; Organophosphorus Compounds; Pesticides
PubMed: 35973537
DOI: 10.1016/j.scitotenv.2022.158020 -
Methods in Enzymology 2018Recent years have seen an explosion of interest in understanding the mechanisms of phosphate ester hydrolysis in biological systems, using a range of computational...
Recent years have seen an explosion of interest in understanding the mechanisms of phosphate ester hydrolysis in biological systems, using a range of computational approaches, each with different advantages and limitations. In this contribution, we present the empirical valence bond (EVB) approach as a powerful tool for modeling biochemical reactivity, using the example of organophosphate hydrolysis by diisopropyl fluorophosphatase as our model reaction. We walk the reader through the protocol for setting up and performing EVB simulations, as well as key technical considerations that need to be taken into account. Finally, we provide examples of the applications of the EVB approach to understanding different experimental observables.
Topics: Computer Simulation; Cryoelectron Microscopy; Crystallography, X-Ray; Hydrolysis; Models, Molecular; Nuclear Magnetic Resonance, Biomolecular; Organophosphates; Phosphoric Triester Hydrolases; Protein Structure, Tertiary; Thermodynamics
PubMed: 30149862
DOI: 10.1016/bs.mie.2018.06.007 -
Carbohydrate Research Feb 2007An anomeric phosphodiester linkage formed by a glycosyl phosphate unit and a hydroxyl group of another monosaccharide is found in many glycopolymers of the outer... (Review)
Review
An anomeric phosphodiester linkage formed by a glycosyl phosphate unit and a hydroxyl group of another monosaccharide is found in many glycopolymers of the outer membrane in bacteria (e.g., capsular polysaccharides and lipopolysaccharides), yeasts and protozoa. The polymers (phosphoglycans) composed of glycosyl phosphate (or oligoglycosyl phosphate) repeating units could be chemically classified as poly(glycosyl phosphates). Their importance as immunologically active components of the cell wall and/or capsule of numerous microorganisms upholds the need to develop routes for the chemical preparation of these biopolymers. In this paper, we (1) present a review of the primary structures (known to date) of natural phosphoglycans from various sources, which contain glycosyl phosphate units, and (2) discuss different approaches and recent achievements in the synthesis of glycosyl phosphosaccharides and poly(glycosyl phosphates).
Topics: Animals; Bacteria; Carbohydrate Sequence; Cell Wall; Glycosylation; Leishmania; Molecular Sequence Data; O Antigens; Organophosphates; Polysaccharides; Yeasts
PubMed: 17092493
DOI: 10.1016/j.carres.2006.10.006