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To evaluate the pharmacokinetics, pharmacodynamics (PD), safety, and tolerability of epidural SP-102 (10 mg dexamethasone sodium phosphate injectable gel) compared to an intravenous injection of 10 mg dexamethasone sodium phosphate, USP (IV USP).Subjects with lumbosacral radiculopathy received a single dose of epidural SP-102, followed by a single dose of IV USP 4 weeks later. Dexamethasone plasma levels, cortisol levels, white blood cells (WBC), and blood glucose levels were assessed.Twelve subjects entered and completed the study. The mean total dexamethasone exposure (AUCIn this small study, epidural SP-102 injection was well tolerated, was not associated with greater systemic dexamethasone exposure than IV USP, and both treatments had similar PD effects on cortisol suppression, blood glucose, and WBC levels.

The combination of 4-hydroxbenzoic acid with metal ions Li+, Mg2+ and Cu2+ leads to the formation of novel 2D and 3D networks.

Ongoing maintenance and upkeep of bywashes can be expensive and difficult to justify, particularly in the context of other maintenance costs; in many cases made even more difficult as the structures are only rarely, if ever used. Using experience from the widely reported incident at Toddbrook Reservoir in August 2019 can help to quantify the benefit that bywash structures provide. A hydraulic model was developed to analyse the impact of the bywash in detail. Simulating the passage of the storm of August 2019, this paper demonstrates that the bywash reduced the duration of overtopping the auxiliary spillway by 40 hours (33%), compared to not having it in place. This is likely to have reduced the risk of even more widespread damage to the structure. For the ongoing management of the reservoir, the modelling showed the bywash can pass 2.5 m3/s, which provides the undertaker with operational cost savings (principally from pumping) to maintain the current drawdown. This paper provides an examination of the benefits of an operational bywash during a significant incident. The hydraulic modelling approach adopted has provided a unique opportunity to quantify and demonstrate the benefit for undertakers of maintaining their bywash assets.

On 1st August 2019, Toddbrook reservoir became, overnight, the most photographed UK reservoir for the last decade. After a series of sequential flood events led to localised failure of a section of the 1970s concrete auxiliary spillway, which passes spill flows over the face of the dam, residents were evacuated from the downstream town of Whaley Bridge due to fears of dam collapse. A multi-agency response was launched, with experts working around the clock to drop the reservoir level and allow residents to return home. The news crews have now moved on and the reservoir sits nearly empty, in wait of a new spillway. Modelling and design work has continued behind the scenes to allow a detailed understanding of the response of the reservoir basin to a range of storm events. A comprehensive water level control plan has been developed, and associated temporary works installed on site, to allow the reservoir to be safely managed in its transitory state. This paper details the ‘make safe’ works installed after the incident, and the ongoing design work to bring the reservoir back into operation and ensure its future resilience.

The elucidation of mechanisms to modulate the properties of multifunctional electroactive, conductive, and magnetic porous materials is desirable to aid their future application. The synthesis and ...

An investigation of the adsorption properties of two structurally related, 3D coordination polymers of composition Zn(2-Mehba) and Zn(2,6-Me2hba) (2-Mehba = the dianion of 2-methyl-4-hydroxybenzoic acid and 2,6-Me2hba = the dianion of 2,6-dimethyl-4-hydroxybenzoic acid) is presented. A common feature of these structures are parallel channels that are able to accommodate appropriately sized guest molecules. The structures differ with respect to the steric congestion within the channels arising from methyl groups appended to the bridging ligands of the network. The host network, Zn(2-Mehba), is able to take up appreciable quantities of H2 (77 K) and CO2 and CH4 (298 K) in a reversible manner. In regard to the adsorption of N2 by Zn(2-Mehba), there appears to be an unusual temperature dependence for the uptake of the gas such that when the temperature is increased from 77 to 298 K the uptake of N2 increases. The relatively narrow channels of Zn(2,6-Me2hba) are too small to allow the uptake of N2 and CH4, but H2 molecules can be adsorbed. A pronounced step at elevated pressures in CO2 and N2O isotherms for Zn(2,6-Me2hba) is noted. Calculations indicate that rotation of phenolate rings leads to a change in the available intraframework space during CO2 dosing.

The synthesis, structure and properties of a 2D FeIII network material of composition [Fe(O-bipy)2Cl](TCNQ)2 (O-bipy = 4,4'-bipyridyl N,N'-dioxide; TCNQ = 7,7,8,8-tetracyanoquinodimethane) are presented. The structure consists of a square grid in which square pyramidal FeIII centers are linked to four equivalent centers through O-bipy ligands. Pairs of TCNQ radical anions are located within rectangular cavities of the 2D network. The apical position on each Fe center is occupied by a chloride ion. Magnetic studies are indicative of weak antiferromagnetic coupling. Electrical conductivity measurements reveal that the compound is a semiconductor and on the basis of DFT calculations it is proposed that electrical conduction occurs via charge hopping between interlayer TCNQ anions. Mossbauer spectra indicate a rare example of the Goldanskii–Karyagin effect and are suggestive of unusual dynamic processes.

Redox-active ligands are of interest for their ability to link metal centres and generate electroactive materials. We report the synthesis of 9-hydrogen-2,3,7-trihydroxyfluorone, which is able to serve as a bridging ligand and has the potential to exist in multiple oxidation states. Anionic [4+4] metallocycles in which Mo or W centres are linked by the trianion of this ligand are also described.

A remarkably flexible, multifunctional, 2D coordination polymer exhibiting an unprecedented mode of reversible mechanical motion, enabling pores to open and close, is reported. Such multifunctional materials are highly sought after, owing to the potential to exploit coexisting electronic and mechanical functionalities that underpin useful technological applications such as actuators and ultrasensitive detectors. The coordination polymer, of composition Mn(F4TCNQ)(py)2 (F4TCNQ = 2,3,5,6-tetrafluoro-7,7,8,8-tetracycanoquinodimethane; py = pyridine), consists of Mn(II) centers bridged by F4TCNQ dianions and coordinated by py molecules that extend above and below the 2D network. Exposure of Mn(F4TCNQ)(py)2, in its collapsed state, to carbon dioxide results in a pore-opening process at a threshold pressure for a given temperature. In addition to carbon dioxide, a variety of volatile guests may be incorporated into the pores, which are lined with electron-rich F4TCNQ dianions. The inclusion of electron-deficient guests such as 1,4-benzoquinone, nitrobenzene, maleic anhydride, and iodine into the pores is accompanied by a striking color change associated with a new host-guest charge-transfer interaction and an improvement in the semiconductor behavior, with the iodine adduct showing an increase in conductivity of almost 5 orders of magnitude. Experimental and density functional theory calculations on this remarkable multifunctional material demonstrate a reduction in the optical band gap with increasing electron affinity of the guest.

Introduction: Apabetalone, a small molecule inhibitor, targets epigenetic readers termed BET proteins that contribute to gene dysregulation in human disorders. Apabetalone has in vitro and in vivo anti-inflammatory and antiatherosclerotic properties. In phase 2 clinical trials, this drug reduced the incidence of major adverse cardiac events in patients with cardiovascular disease. Chronic kidney disease is associated with a progressive loss of renal function and a high risk of cardiovascular disease. We studied the impact of apabetalone on the plasma proteome in patients with impaired kidney function. Methods: Subjects with stage 4 or 5 chronic kidney disease and matched controls received a single dose of apabetalone. Plasma was collected for pharmacokinetic analysis and for proteomics profiling using the SOMAscan 1.3k platform. Proteomics data were analyzed with Ingenuity Pathway Analysis to identify dysregulated pathways in diseased patients, which were targeted by apabetalone. Results: At baseline, 169 plasma proteins (adjusted P value

In 2008 a new approach to generating tetracyanoquinodimethane (TCNQ)-based materials was described which involved the use of the diprotonated, reduced form of TCNQ (TCNQH2) as a reactant. Since the initial work, the dianionic forms of TCNQH2 and F4TCNQH2 have been incorporated into a wide assortment of coordination polymers in which the ligand, with four potential donor atoms, binds to a variety of metal centres. The structures of neutral 1D, 2D and 3D coordination polymers are described, in addition to the structures of anionic networks. Not surprisingly, the oxidation state of the metal ion as well as its preference for certain coordination geometries has a major influence upon the topology and geometry of the polymeric material. In addition to the identity of the metal centre, the type of structure obtained depends upon the nature of the co-ligand in the case of neutral polymers. For anionic networks the shape, charge and size of the counter-cation impacts upon the network connectivity. The large number of metal compounds formed with the dianions is in contrast with the relatively small number of metal complexes involving TCNQ and F4TCNQ in the 0 and −1 oxidation states. In addition to coordination polymers, organic salts of TCNQ2− and F4TCNQ2− have also been investigated. The packing within these crystalline salts has been categorised into four types. In both the case of the coordination polymers and the organic salts, charge transfer interactions are common with the electron-rich TCNQ2− and F4TCNQ2− dianions often serving as electron donors. The presence of various species in the crystal that can act as electron acceptors normally leads to intensely coloured crystals. Whilst TCNQ2− and F4TCNQ2− dianions have been shown to be versatile building blocks capable of yielding a variety of unusual and aesthetically appealing structures, the redox activity of these dianions offers the prospect of creating materials that possess fascinating electronic properties. An overview of the types of structures obtained since 2008 using the TCNQH2/F4TCNQH2 synthetic approach is presented.

The reaction of Mn(BF4 )2 ⋅x H2 O with (Pr4 N)2 TCNQF4 (TCNQF4 =2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane) in a mixture of CH3 OH/CH2 Cl2 gives a 2:3 stoichiometric complex of (Pr4 N)2 [Mn2 (TCNQF4 )3 (CH3 OH)2 ] (1). If the solvent system used for the crystallisation of 1 is changed to CH3 OH/DMF, then a different product, [Mn(TCNQF4 )(DMF)2 ]⋅(CH3 OH)2 (2), is obtained. The use of Li2 TCNQF4 instead of (Pr4 N)2 TCNQF4 leads to the generation of [Mn2 (TCNQF4 )2 (DMF)4 ]⋅3 DMF (3). An unexpected mixed oxidation state network with a composition of [MnII4 MnIII16 O10 (OH)6 (OCH3 )24 (TCNQF4 )2 ](NO3 )2 ⋅24 CH3 OH (4), is formed if Mn(NO3 )2 ⋅x H2 O is used in place of Mn(BF4 )2 ⋅x H2 O in the reaction that leads to the formation of 3. Compounds 1-3 have been characterised by X-ray crystallography; FTIR, Raman and UV/Vis spectroscopy; and electrochemistry. Compound 4 has only been analysed by X-ray crystallography and vibrational spectroscopy (Raman, FTIR), owing to rapid deterioration of the compound upon exposure to air. These results indicate that relatively minor changes in reaction conditions have the potential to yield products with vastly different structures. Compound 1 adopts an anionic 2D network with unusual π-stacked dimers of the TCNQF42- dianion, whereas 2 and 3 are composed of similar neutral sheets of [Mn(TCNQF4 )(DMF)2 ]. Interestingly, the solvent has a significant influence on the stacking of the sheets in the structures of 2 and 3. In compound 4, clusters with a composition of [MnII4 MnIII16 O10 (OH)6 (OCH3 )24 (CH3 OH)4 ]6+ serve as eight-connecting nodes, whereas TCNQF42- ligands act as four-connecting nodes in a 3D network that has the same topology as fluorite. Compound 3 exhibits an exceptionally high super-catalytic activity for the electron-transfer reaction between ferricyanide and thiosulfate ions in aqueous media.

Analysis of in situ neutron powder diffraction data collected for the porous framework material Zn(hba) during gas adsorption reveals a two-stage response of the host lattice to increasing CO2 guest concentration, suggesting progressive occupation of multiple CO2 adsorption sites with different binding strengths. The response of the lattice to moderate CH4 guest concentrations is virtually indistinguishable from the response to CO2, demonstrating that the influence of host–guest interactions on the Zn(hba) framework is defined more strongly by the concentration than by the identity of the guests.

A pair of coordination polymers of composition (NBu4)2[M2(fan)3] (fan = fluoranilate; M = Fe and Zn) were synthesized and structurally characterized. In each case the compound consists of a pair of interpenetrating three-dimensional, (10,3)-a networks in which metal centers are linked by chelating/bridging fluoranilate ligands. Tetrabutylammonium cations are located in the spaces between the two networks. Despite the structural similarity, significant differences exist between (NBu4)2[Fe2(fan)3] and (NBu4)2[Zn2(fan)3] with respect to the oxidation states of the metal centers and ligands. For (NBu4)2[Fe2(fan)3] the structure determination as well as Mossbauer spectroscopy indicate the oxidation state for the Fe is close to +3, which contrasts with the +2 state for the Zn analogue. The differences between the two compounds extends to the ligands, with the Zn network involving only fluoranilate dianions, whereas the average oxidation state for the fluoranilate in the Fe network lies somewhere between −2 and ...

A 2-D coordination framework, (NEt4)2[Fe2(fan)3] (1·5(acetone); H2fan = 3,6-difluoro-2,5-dihydroxy-1,4-benzoquinone), was synthesized and structurally characterized. The compound is structurally analogous to a formerly elucidated framework, (NEt4)2[Fe2(can)3] (H2can = 3,6-dichloro-2,5-dihydroxy-1,4-benzoquinone), and adopts a 2-D (6,3) topology with the symmetrical stacking of [Fe2(fan)3]2- sheets that are held in position by the NEt4+ cations between the sheets. The investigation of the dc and ac magnetic properties of 1·5(acetone) revealed ferromagnetic ordering behavior and slow magnetization relaxation, as evinced from ac susceptibility measurements. Furthermore, the exposure of 1·5(acetone) to air led to the formation of a heptahydrate 1·7H2O which displayed distinct magnetic properties. The study of the redox state and extent of delocalization in 1·5(acetone) was undertaken via crystallography, in combination with Mossbauer and vis-NIR spectroscopy, to reveal the mixed-valence and delocalized nature of the as-synthesized material. As a result, the conductivity studies conducted on a pressed pellet showed a relatively high conductivity of 1.8 × 10-2 S cm-1 (300 K). In order to compare structurally related anilate-based structures, a relationship among the redox state, spectroscopic properties, and electronic properties was elucidated in this work. A preliminary investigation of 1·5(acetone) as a candidate anode material in lithium ion batteries revealed a high reversible capacity of 676.6 mAh g-1 and high capacity retention.

Summary Background There is a medical need for highly effective, safe, and well tolerated treatments for patients infected with hepatitis C virus (HCV) with severe renal impairment. We investigated the safety and efficacy of sofosbuvir with ribavirin or ledipasvir combined with sofosbuvir in a prospective study of patients with genotype 1 or 3 HCV infection and stage 4–5 chronic kidney disease (creatinine clearance by Cockcroft-Gault ≤30 mL/min) who were not on dialysis. Methods This phase 2b, open-label, non-randomised, multicentre study in the USA and New Zealand investigated three sequentially enrolled cohorts of patients. Patients were recruited from ten hospitals and clinical research centres and were included if they had genotype 1 or 3 HCV infection, a creatinine clearance less than or equal to 30 mL/min, and were not on dialysis. In cohorts 1 and 2, patients received sofosbuvir (200 mg in cohort 1 and 400 mg in cohort 2) plus ribavirin 200 mg once per day for 24 weeks. In cohort 3, 18 patients received ledipasvir combined with sofosbuvir (90 mg ledipasvir and 400 mg sofosbuvir) once per day for 12 weeks. The primary efficacy endpoint was the proportion of patients achieving sustained virological response 12 weeks after the end of treatment (SVR12). Safety and pharmacokinetic data were also collected. The trial is registered with ClinicalTrials.gov , number NCT01958281 , and is completed. Findings This study was done between Oct 7, 2013, and Oct 29, 2017. In the sofosbuvir plus ribavirin cohorts, 32 patients were screened, of whom 20 were enrolled and assessed for efficacy and safety (ten patients in each cohort). In the ledipasvir plus sofosbuvir cohort, 33 patients were screened, of whom 18 were enrolled and assessed for treatment efficacy and safety. Four (40%, 95% CI 12–74) of ten patients in cohort 1 and six (60%, 26–88) of ten patients in cohort 2 achieved SVR12. All 18 (100%, 82–100) patients in cohort 3 achieved SVR12. Adverse events were mostly mild or moderate in severity. The most commonly reported adverse events overall were headache (eight [21%] of 38 patients), anaemia (seven [18%] of 38 patients), and fatigue (six [16%] of 38 patients). Eight patients had serious adverse events, none of which were treatment related. There were no treatment-related cardiac events or clinically significant changes in echocardiographic parameters or creatinine clearance by Cockcroft-Gault. Interpretation In this phase 2b study, ledipasvir combined with sofosbuvir for 12 weeks was safe and effective in patients with genotype 1 HCV infection and stage 4–5 chronic kidney disease who were not on dialysis. Funding Gilead Sciences.

In the presence of the Et4N+ cation the chloranilate dianion (can2–) associates with a range of divalent cations, M2+, to yield an isomorphous series of crystalline compounds of composition (Et4N)2[M2(can)3] (M = Mg, Mn, Fe, Co, Ni, Cu, and Zn). The fluoranilate dianion (fan2–) likewise affords the closely related (Et4N)2[Zn2(fan)3]. The structures of (Et4N)2[Zn2(can)3], (Et4N)2[Fe2(can)3], and (Et4N)2[Zn2(fan)3] were determined by single crystal X-ray diffraction. Powder X-ray diffraction indicates that all the members of the can2– series are isomorphous. The structure of (Et4N)2[Zn2(fan)3] is very closely related to the structures of the can2– compounds. The [M2(can)32–]n component is present as chicken-wire-like sheets with (6,3) topology. The Et4N+ cation binds sheet to sheet and aligns them so that the large holes within the sheets are arranged one above another, thereby generating spacious channels running perpendicular to the sheets. The solvent molecules present in the channels are ill-defined and...

The combination of lightweight metal cations with a range of dicarboxylate ligands has led to the generation of ionic network materials that possess channels occupied by solvent molecules. The compounds [Li2 (2,2-bpdc)(DMF)2 ] and [Mg(2,2-bpdc)(DMF)2 ] (2,2-bpdc=2,2-dipyridyl-4,4-dicarboxylate) adopt a similar structure in which parallel metal-carboxylate chains are linked to four equivalent chains to generate a 3 D network in which DMF molecules occupy channels. [Li4 (3,5-pdc)2 (DMF)]⋅solvate (3,5-pdc=3,5-pyridine dicarboxylate) adopts a similar structure but the chains are more complex. As with the other structures, coordinated DMF molecules occupy network channels. [Li4 (3,5-pdc)2 (DMF)]⋅solvate is able to adsorb carbon dioxide at elevated pressures with the adsorption following a type V isotherm; hysteresis is apparent upon desorption. The final compound, Li[Mg3 OH(2,2-bqdc)3 (DMF/H2 O)3 ]⋅solvate (2,2-bqdc=2,2-biquinoline-4,4-dicarboxylate) has a distinctly different structure in which a trio of magnesium centres bound to a central μ3 -hydroxide ion serves as a 6-connecting, trigonal prismatic node within a 3 D network that has the point symbol, 49 66 . Solvent-filled intraframework spaces represent over 50 % of the crystal volume and are occupied by highly disordered solvent and Li+ ions. Immersion of Li[Mg3 OH(2,2-bqdc)3 (DMF/H2 O)3 ]⋅solvate in a solution of Fe(2,2-bipyridine)32+ results in the incorporation of the FeII complex into the large channels of the anionic network.

Reaction of the chloranilate dianion with Y(NO3 )3 in the presence of Et4 N+ in the appropriate proportions results in the formation of (Et4 N)[Y(can)2 ], which consists of anionic square-grid coordination polymer sheets with interleaved layers of counter-cations. These counter-cations, which serve as squat pillars between [Y(can)2 ] sheets, lead to alignment of the square grid sheets and the subsequent generation of square channels running perpendicular to the sheets. The crystals are found to be porous and retain crystallinity following cycles of adsorption and desorption. This compound exhibits a high affinity for volatile guest molecules, which could be identified within the framework by crystallographic methods. In situ neutron powder diffraction indicates a size-shape complementarity leading to a strong interaction between host and guest for CO2 and CH4 . Single-crystal X-ray diffraction experiments indicate significant interactions between the host framework and discrete I2 or Br2 molecules. A series of isostructural compounds (cat)[MIII (X-an)2 ] with M=Sc, Gd, Tb, Dy, Ho, Er, Yb, Lu, Bi or In, cat=Et4 N, Me4 N and X-an=chloranilate, bromanilate or cyanochloranilate bridging ligands have been generated. The magnetic properties of representative examples (Et4 N)[Gd(can)2 ] and (Et4 N)[Dy(can)2 ] are reported with normal DC susceptibility but unusual AC susceptibility data noted for (Et4 N)[Gd(can)2 ].

A robust, nano-sized covalent cage, of composition, [(PhSi)6(ctc)4]6- (H6ctc = cyclotricatechylene) has been prepared in a simple reaction in good yield. The tetrahedral anionic cage is stable in both the solid and solution state and exhibits an affinity for Cs+ ions which bind to the internal surface of the cage.

Coordination frameworks containing DCNQI2– (DCNQI = N,N′-dicyanoquinonediimine ligand) are produced by deprotonation of DCNQIH2 in the presence of a metal center and a co-ligand. This approach has yielded two-dimensional (2D) sheet compounds [Cd(DCNQI)(L)2] (where L = pyridine (py) or isoquinoline (isoquin)) that can be partially oxidized via solid-state electrochemical and in situ spectroelectrochemical methods to materials that contain DCNQI as its radical monoanion. The new frameworks display charge-transfer bands that are indicative of interligand charge-transfer interactions as supported by TD-DFT computational calculations. The redox-state dependent spectral properties of the frameworks have been probed using a newly developed solid-state spectroelectrochemical cell. Coupled with computational calculations, the experimental data provide an understanding of the fundamental charge-transfer processes that may underpin long-range functional properties such as conductivity in framework materials.

The structures and optical band gaps of twelve radical anionic 7,7,8,8-tetracyanoquinodimethane (TCNQ) and 7,7,8,8-tetracyano-2,3,4,5-tetrafluoroquinodimethane (F4TCNQ) based charge-transfer complexes are reported. The compounds described have been categorised into three general types based upon solid-state arrangements of the donor and acceptor molecules. Crystallographic, EPR and IR spectroscopic investigations indicated that both TCNQ and F4TCNQ in each of the compounds described exist in the radical monoanion form. Visible-NIR absorption measurements indicate optical band gaps in the range of 0.79 to 1.08 eV. Whilst the packing arrangements in CT complexes are known to affect the band gap, in the cases considered here no clear relationship between the packing arrangement and the optical band gap is apparent. The results suggest that in the absence of mixed valency the packing arrangement does not impact significantly upon the magnitude of the optical band gap.

Two cationic networks, [Cu(I)Cu(II)(4,4'bipy)4(H2O)2](3+) and [Cu(II)(4,4'bipy)2(H2O)2](2+) have been formed from a solution in which Cu(I) undergoes aerial oxidation. Whilst the topologies of the two networks are different the arrangement of Cu centres is almost identical, a structural feature which presumably allows for [Cu(I)Cu(II)(4,4'bipy)4(H2O)2](3+) to serve as a crystalline template for [Cu(II)(bipy)2(H2O)2](2+).

The structure of Li(inox)⋅2/3 DMF (inox(-) =the N-oxide of the isonicotinate anion) consists of a 3D framework with solvent-filled, square cross-section channels of approximate dimensions 5.5×5.5 Å. Unfortunately, the Li(inox) framework is unstable upon removal of DMF from the channels. When the structurally related 4-hydroxybenzoic acid (H2 hba) was used in place of Hinox, and Zn(2+) in place of the Li(+) , a structurally similar but more robust network, Zn(hba), was obtained; the isostructural compound, Co(hba), may also be prepared. Longer ligands with phenolate and carboxylate functional groups at opposite ends, such as the dianions of 4-coumaric acid (H2 cma) and 4'-hydroxy-4-biphenylcarboxylic acid (H2 hbpc), in combination with Zn(2+) yield Zn(cma) and Zn(hbpc) frameworks, respectively, with the same PtS topology but with larger channels. The coordination polymers remain intact after desolvation and exhibit microporosity, showing the ability to sorb significant quantities of CO2 , CH4 , and H2 .

End-stage renal disease (ESRD) patients receiving hemodialysis (HD) are at heightened risk for influenza, but the optimal oseltamivir dosage regimen for treating or preventing influenza in this high-risk population is still uncertain. Pharmacokinetic data for 24 adults with ESRD were pooled from a single-dose and a multiple-dose study to develop a population pharmacokinetic model using nonlinear mixed-effects modeling. The final model comprised five compartments, two each to describe the systemic pharmacokinetics of oseltamivir phosphate and its metabolite, oseltamivir carboxylate (OC), and a delay compartment to describe oseltamivir metabolism. Estimated OC clearance in the model was markedly faster during HD sessions (7.43 liters/min) than at other times (0.19 liter/min). Model simulations showed that 30 mg oseltamivir given after every HD session is the most suitable regimen for influenza treatment, producing trough OC concentrations above the median value achieved with the 75-mg twice-daily regimen in patients with normal renal function and peak concentrations below the highest oseltamivir exposures known to be well tolerated (median exposures after twice-daily dosing of 450 mg). Administration of the first dose following diagnosis of influenza need not wait until after the next HD session: addition of a single 30-mg dose during the 12 h before the next HD session raises OC exposures quickly without posing any safety risk. Further simulation showed that 30 mg oseltamivir given after every other HD session is the most suitable regimen for influenza prophylaxis.

Coordination polymer strips of composition ...Cu+2·lig2–·Cu+2·lig2–·Cu+2·lig2–... (where lig2– = TCNQ2– or its 2,3,4,5-tetrafluoro analogue) are observed with a wide range of coligands (monodentate, bidentate, and tridentate). Interdigitation of “thin”, planar N-heteroaromatic coligands on one strip with those on a neighbor is a common structural feature. Coligands too bulky to allow interdigitation give either non-interdigitating strips or 2D sheet structures. Both strips and sheets have 2-connecting Cu centers and 4-connecting tetracynano ligands. As a consequence of the great flexibility of the Cu/tetracyano ligand association, the geometries of the sheet structures vary widely from almost coplanar to highly corrugated and convoluted, despite which the same topology is present in all.

This work characterizes the pharmacokinetics (PK) of oseltamivir phosphate (OP) and its active metabolite, oseltamivir carboxylate (OC), and investigates oseltamivir i.v. dosing regimens for treatment of influenza in patients with normal renal function and with various degrees of renal impairment. Initially, data collected from 149 subjects with normal renal function and mild to severe renal impairment who were administered 40-200 mg oseltamivir i.v. were described by a four-compartment model. Two compartments described OP, one compartment described OC and one compartment described OP to OC metabolism. Then, data of 128 subjects administered 20-1,000 mg oseltamivir orally were added. The absorp- tion model included three first-order processes with direct (via first-pass) input in the OC compartment and two (di- rect and delayed) inputs in the OP compartment. Simula- tions and PK bridging were used to recommend i.v. dosing regimens. The analysis demonstrated that renal function had a major effect on OC clearance (CLM) and exposure. CLM for subjects with mild, moderate and severe renal impairment was 18, 50, and 84 % lower than for subjects with normal renal function. Simulations were used to select i.v. dosing regimens that provide OC Cmin coverage and exposures comparable to those achieved in subjects with normal renal function administered 75 mg b.i.d. orally. The oseltamivir dose depended on the degree of renal impair- ment and was independent of route of administration. Specifically, 75 mg b.i.d. is recommended for subjects with normal renal function or mild renal impairment, 30 mg b.i.d. for subjects with moderate renal impairment, and 30 mg q.d. for subjects with severe renal impairment. Recommended i.v. doses were the same as those recom- mended for oral administration in corresponding renal impairment groups.

AIMS Patients with end-stage renal disease (ESRD) are at increased risk of developing complications associated with influenza infection. Oseltamivir is indicated for influenza treatment in ESRD patients, but the disposition is poorly understood in this patient population. This study aimed to characterize the pharmacokinetics and tolerability of oseltamivir in automated peritoneal dialysis (APD) and construct a pharmacokinetic model to assist with optimized dosing.

The reaction of Mn(BF

Crystals of [Li(inox)(H2O)] (where inox- = the isonicotinate-N-oxide ion) are obtained from aqueous solution. The Li + cations and the carboxylate anions form a two-dimensional (2D) sheet containing four-membered (-Li-O-Li-O-) rings and 16-membered (-Li-O-C-O-)4 rings; the sheets are linked to adjacent parallel sheets through hydrogen bonds. Crystals of solvent-free [Li(inox)], obtained from t-butanol, consist of a three-dimensional network which can also be prepared in microcrystalline form by dehydration of [Li(inox)(H2O)] at 200 °C. Crystals of [Ca(inox)2(H2O)2] contain 2D sheets with 4,4 topology in which Ca2+ ions, bound by trans water molecules, provide the 4-connecting nodes. The Ca(H 2O)22+ units are linked by carboxylate groups to generate 16-membered (-Ca-O-C-O-)4 rings. Sheets are bound together by hydrogen bonds between the pyridine-N-oxide units and coordinated water molecules. [Ca(inox)2(H2O)2] can be dehydrated at 190 °C in a single crystal-to-single crystal transformation to give [Ca(inox)2] whose structure is related to that of the hydrated precursor. A proposed solid-state mechanism for this single crystal-to-single crystal transformation, in which the N-oxide takes up the site on calcium vacated by water is proposed. © 2014 American Chemical Society.

The new compound Cu2I(TCNQF4II–)(MeCN)2 (TCNQF42– = dianion of 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane) has been synthesized by electrochemically directed synthesis involving reduction of TCNQF4 to TCNQF42– in acetonitrile containing [Cu(MeCN)4]+(MeCN) and 0.1 M Bu4NPF6. In one scenario, TCNQF42– is quantitatively formed by reductive electrolysis of TCNQF4 followed by addition of [Cu(MeCN)4]+ to form the Cu2I(TCNQF4II–)(MeCN)2 coordination polymer. In a second scenario, TCNQF4 is reduced in situ at the electrode surface to TCNQF42–, followed by reaction with the [Cu(MeCN)4]+ present in the solution, to electrocrystallize Cu2I(TCNQF4II–)(MeCN)2. Two distinct phases of Cu2I(TCNQF4II–)(MeCN)2 are formed in this scenario; the kinetically favored form being rapidly converted to the thermodynamically favored Cu2I(TCNQF4II–)(MeCN)2. The postulated mechanism is supported by simulations. The known compound CuITCNQF4I– also has been isolated by one electron reduction of TCNQF4 and reaction with [Cu(MeC...

The trianion Z(3-) obtained from 9-phenyl 2,3,7-trihydroxyfluor-6-one, ZH3, affords dioxomolybdenum and dioxotungsten derivatives which contain [4 + 4] metallocycles of composition [(MO2)4Z4](4-) (M = Mo, W) in combination with a variety of counter cations. The syntheses, structures and ESMS of the following compounds are presented: compound 1, (MePPh3)3(NBu4)[(MoO2)4Z4]; compound 2, (MePPh3)3(NBu4)[(WO2)4Z4]; compound 3, (MePPh3)4[(WO2)4Z4]; compound 4, (PPh4)2(NBu4)2[(MoO2)4Z4]; compound 5, (AsPh4)3(NBu4)[(MoO2)4Z4]; compound 6, (AsPh4)2(NBu4)2[(WO2)4Z4]; compound 7, (Ph3PNPPh3)(NBu4)3[(MoO2)4Z4]; compound 8, (Ph3PNPPh3)(NBu4)3[(WO2)4Z4]; compound 9, (NEt4)(NBu4)3[(MoO2)4Z4]. The metallocycles in all of these compounds have similar structures, with the four metal centers located at the corners of a square slightly distorted, to varying degrees, toward a rhombus and also toward a tetrahedron. Various cations are bound inside the anionic metallocycles. ESI mass spectrometry shows that the metallocycles remain intact in the gas phase, forming [(MO2)4Z4](4-), {X-[(MO2)4Z4]}(3-) and in some cases {X2-[(MO2)4Z4]}(2-) where X(+) is an organic cation.

Clinical Development Phases I-III Regulatory, Quality, Manufacturing Mericitabine is the prodrug of RO4995855, a selective inhibitor of the hepatitis C virus (HCV) NS5B polymerase. This study assessed the effect of renal impairment on RO4995855 pharmacokinetics. In this open-label study, HCV-negative volunteers (18–75 years) with normal renal function (NRF: creatinine clearance [CLCR] >80 mL/min, n = 10) or stable renal impairment (mild: CLCR 50–80 mL/min, n = 10; moderate: CLCR 30–49 mL/min, n = 10) received oral mericitabine 1000 mg twice daily (BID) (500 mg BID for moderate renal impairment) for 5 days. Primary outcome measures were renal clearance, maximum plasma concentration (Cmax), and area under the concentration-time curve (0–12 h) (AUC0–12) for RO4995855. Renal clearance decreased as renal function decreased. Relative to subjects with NRF, the geometric mean ratios (GMR) for AUC0–12 and Cmax in mild renal impairment subjects were 1.45 (90% confidence interval [CI], 1.26–1.66) and 1.14 (1.02–1.28), respectively. For moderate renal impairment subjects, the dose-normalized GMR for AUC0–12 and Cmax relative to NRF subjects were 2.51 (90% CI, 2.19–2.88) and 1.76 (1.56–1.97), respectively. Renal clearance of RO4995855 declined in subjects with mild/moderate renal impairment following mericitabine. Dose adjustment of mericitabine may be required in patients with moderate renal impairment.

A series of compounds of composition A[CuI(F4TCNQII–)] (A = a quaternary ammonium or phosphonium cation, F4TCNQII– = the dianionic form of 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane) have been synthesized and structurally characterized. In each structure, an anionic [CuI(F4TCNQII–)]− framework possessing the topology of PtS is formed with the Cu(I) center serving as a tetrahedral 4-connecting center and the F4TCNQ2– anion acting as a planar 4-connecting unit. Although a PtS topology is observed for six different compounds, the anionic framework shows significant geometric variation depending upon the identity of the cation. Very similar structures are obtained when the organic cation is NMe4+, NMe2Pr2+, or NMe2Bu2+. A distorted anionic structure possessing the same connectivity is generated when the cation is NEt4+, and anionic frameworks with a different connectivity, but still related to PtS, are obtained when the much larger quaternary phosphonium cations are employed. Of interest in the stru...

Previous studies have shown that some lipoglycopeptide and lipopeptide antimicrobial agents may cause falsely elevated values for some phospholipid-dependent coagulation tests. The effect of oritavancin, a lipoglycopeptide antibiotic, on coagulation test results was explored using pooled human plasma samples spiked with drug and in a clinical study after an infusion of a single 1,200-mg intravenous dose of oritavancin in normal healthy volunteers. Pooled plasma with oritavancin added ex vivo showed concentration-dependent prolongation of prothrombin time/international normalized ratio (PT/INR), activated partial thromboplastin time (aPTT), and dilute Russell viper venom time (DRVVT) test results. In contrast, oritavancin had no effect on the activated protein C resistance assay, chromogenic anti-factor Xa assay (anti-FXa), thrombin time, and an immunoassay for the laboratory diagnosis of heparin-induced thrombocytopenia. In participants that received a single dose of oritavancin, elevations in PT/INR result, aPTT, DRVVT, activated clotting time, and silica clotting time occurred, with the maximum times to resolution of test interference determined to be 12, 120, 72, 24, and 18 h, respectively. The anti-FXa assay was unaffected, whereas transient elevations in D dimer levels were observed in 30% of participants, with a maximum time to resolution of 72 h. Although oritavancin has no impact on the coagulation system in vivo , a single dose of oritavancin can produce falsely elevated values of some coagulation tests used to monitor hemostasis. The interference of oritavancin on affected tests is transient, and the test results revert to normal ranges within specified times after dosing.

The uptake of inhalation anesthetics by three topologically identical frameworks is described. The 3D network materials, which possess square channels of different dimensions, are formed from the relatively simple combination of ZnII centres and dianionic ligands that contain a phenolate and a carboxylate group at opposite ends. All three framework materials are able to adsorb N2 O, Xe and isoflurane. Whereas the framework with the widest channels is able to adsorb large quantities of the various guests from the gas phase, the frameworks with the narrower channels have superior binding enthalpies and exhibit higher levels of retention. The use of ligands in which substituents are bound to the aromatic rings of the bridging ligands offers great scope for tuning the adsorption properties of the framework materials.

The combination of lightweight metal cations with a range of dicarboxylate ligands has led to the generation of ionic network materials that possess channels occupied by solvent molecules. The compounds [Li

The dianion of tetracyanoquinodimethane, TCNQ2−, is able to act as a ligand capable of binding four metal ions at the corners of a rectangle. When the ligand is combined with divalent metal ions in the presence of appropriate counterions, infinite anionic networks may be formed of composition [M2TCNQ3]2− (M = Mn, Zn, Cd). In the structures reported here the cyano groups from six separate TCNQ dianions provide an octahedral coordination environment around the metal centres. Large hexagonal channels in the anionic network are occupied by highly disordered countercations.

Menopause and increasing age are associated with a decrease in calcium absorption that can contribute to the pathogenesis of osteoporosis. We hypothesized that alendronate plus vitamin D3 (ALN + D) would increase fractional calcium absorption (FCA). In this randomized, double-blind, placebo-controlled multicenter clinical trial, 56 postmenopausal women with 25-hydroxyvitamin D [25(OH)D] concentrations of 25 ng/mL or less and low bone mineral density (BMD) received 5 weekly doses of placebo or alendronate 70 mg plus vitamin D3 2800 IU (ALN + D). Calcium intake was stabilized to approximately 1200 mg/d prior to randomization. FCA was determined using a dual-tracer stable-calcium isotope method. FCA and 25(OH)D were similar between treatment groups at baseline (0.31 ± 0.12 ng/mL and 19.8 ± 4.7 ng/mL, respectively). After 1 month of treatment, subjects randomized to ALN + D experienced a significant least squares (LS) mean [95% confidence interval (CI)] increase in FCA [0.070 (0.042, 0.098)], whereas FCA did not change significantly in the placebo group [−0.016 (−0.044, 0.012)]. After ALN + D treatment, patients had higher 25(OH)D levels (LS mean difference 7.3 ng/mL, p

Crystalline compounds of general composition (NBu4)2[MII2(dhbq)3] (where M = Mn, Fe, Co, Ni, Zn, and Cd and dhbq2– is the dianion of 2,5-dihydroxybenzoquinone) are obtained by reaction of the divalent metal acetate (or the sulfate in the case of Fe) with 2,5-diaminobenzoquinone and an excess of NBu4Br in aqueous solution at 115 °C in sealed tubes. The dhbq2– ligand is generated in situ by hydrolysis of the 2,5-diaminobenzoquinone. We have been unable to obtain these compounds in a crystalline form suitable for single crystal X-ray diffraction studies directly from H2dhbq itself. A structural feature common to this series is the presence of two interpenetrating [MII2(dhbq)3]2– coordination networks, each with the chiral (10,3)-a topology, with the two independent nets being of opposite hand—unprecedented circumstances for dhbq-based coordination polymers. Crystals of the same zinc compound as that obtained above from 2,5-diaminobenzoquinone can alternatively be obtained by in situ aerial oxidation of 1,2,4...

The 16th biennial conference of the British Dam Society (BDS) took place at the University of Strathclyde in the heart of Glasgow city. It was held early this year (2010), taking place in June between Wednesday the 23rd and Saturday the 26th.

Readily available, air-stable TCNQH2 affords numerous crystalline derivatives containing discrete TCNQ2− anions, until now a very rare redox level. The work opens the way for the generation of an almost unlimited number of TCNQ-based materials, in a very simple manner, with new structural features and properties.

2,3,7-Trihydroxy-9-phenyl-fluorone (hereafter H 3 Z) has been synthesised in its H 4 Z + , H 3 Z, H 2 Z − and Z 3− protonation states. X-ray crystal structure determinations have been carried out for (H 4 Z)(HSO 4 ), H 3 Z, [Et i Pr 2 NH]H 2 Z, solvated (PPh 4 )H 2 Z and solvated K 3 Z. In each of these salts the 9-phenyl group adopts a different orientation so as to be involved in intermolecular aromatic interactions. The 3- and 6-phenolic carbon–oxygen bond lengths show that double bond character can be delocalised from the ketone to the deprotonated phenoxide across the conjugated π system of the fluorone.

The rigid, angular ligand 3,3,3',3'-tetramethyl-1,1'spirobisindane-5,5',6,6'-tetrol, LH4, in the form of its tetra-anion, L(4-), affords crystalline compounds containing the triangular macrocyclic boron derivative [B3L3](3-) with the counter cations, triethylammonium, imidazolium, tetraethylammonium, and protonated dabco (dabco = 1,4-diazabicyclo[2,2,2]octane). Within a triangular unit all three chiral L(4-) ligands have the same hand although the crystal does contain a racemic mixture of macrocycles. In all four compounds, one out of the three counter-cations per macrocycle is bound inside the macrocycle.

In a follow-up study of the cobalt(II) member 1 of a family of isostructural cubane clusters of type [C(NH2)3]8[MII4(cit)4]·8H2O (cit = citrate, M = Mg, Mn, Fe, Co, Ni, Zn) by measuring AC magnetic susceptibilities, as a function of frequency, this compound clearly displays behaviour typical of magnetization reversal and slow magnetic relaxation (ΔE = 13.1 K, τo = 8.4 × 10–7 s). A related octanuclear cluster [Co8(C4O7)4(H2O)12]·24H2O (2) that contains a [Co4(C4O7)4] cubane moiety, behaves likewise (ΔE = 20.5 K, τo = 1.0 × 10–7 s).(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)