Semi-automated in vivo solid-phase microextraction sampling and the diffusion-based interface calibration model to determine the pharmacokinetics of methoxyfenoterol and fenoterol in rats

In vivo solid-phase microextraction (SPME) can be used to sample the circulating blood of animals without the need to withdraw a representative blood sample. In this study, in vivo SPME in combination with liquid–chromatography tandem mass spectrometry (LC–MS/MS) was used to determine the pharmacokinetics of two drug analytes, R,R-fenoterol and R,R-methoxyfenoterol, administered as 5 mg kg⁻¹i.v. bolus doses to groups of 5 rats. This research illustrates, for the first time, the feasibility of the diffusion-based calibration interface model for in vivo SPME studies. To provide a constant sampling rate as required for the diffusion-based interface model, partial automation of the SPME sampling of the analytes from the circulating blood was accomplished using an automated blood sampling system. The use of the blood sampling system allowed automation of all SPME sampling steps in vivo, except for the insertion and removal of the SPME probe from the sampling interface. The results from in vivo SPME were compared to the conventional method based on blood withdrawal and sample clean up by plasma protein precipitation. Both whole blood and plasma concentrations were determined by the conventional method. The concentrations of methoxyfenoterol and fenoterol obtained by SPME generally concur with the whole blood concentrations determined by the conventional method indicating the utility of the proposed method. The proposed diffusion-based interface model has several advantages over other kinetic calibration models for in vivo SPME sampling including (i) it does not require the addition of a standard into the sample matrix during in vivo studies, (ii) it is simple and rapid and eliminates the need to pre-load appropriate standard onto the SPME extraction phase and (iii) the calibration constant for SPME can be calculated based on the diffusion coefficient, extraction time, fiber length and radius, and size of the boundary layer. In the current study, the experimental calibration constants of 338.9 ± 30 mm⁻³ and 298.5 ± 25 mm⁻³ are in excellent agreement with the theoretical calibration constants of 307.9 mm⁻³ and 316.0 mm⁻³ for fenoterol and methoxyfenoterol respectively.     

An overview on chemical derivatization and stability aspects of selected avermectin derivatives

Naturally occurring avermectins (AVMs) and its derivatives are potent endectocide compounds, well-known for their novel mode of action against a broad range of nematode and anthropod animal parasites. In this review, chemical and pharmaceutical aspects of AVM derivatives are described including stability, synthetic and purification processes, impurities and degradation pathways, and subsequent suggestions are made to improve the chemical stability. It has been found out that unique structure of AVM molecules and presence of labile groups facilitated the derivatization of AVM into various compounds showing strong anthelmintic activity. However, the same unique structure is also responsible for labile nature related to sensitive stability profile of molecules. AVMs are found to be unstable in acidic and alkaline conditions. In addition, these compounds are sensitive to strong light, and subsequently presence of photo-isomer in animals treated topically with AVM product is well known. The pharmacoepial recommendations for addition of antioxidant into drug substance, as well as its products, arises from the fact that AVM are very sensitive to oxidation. Formations of solvates, salts, epoxides, reduction of double bonds and developing liquid formulation around pH 6.2, were some chemical approaches used to retard the degradation in AVM. This coherent review will contribute towards the better understanding of the correlation of chemical processes, stability profile and biological activity; therefore, it will help to design the shelf-life stable formulations containing AVMs.     

Re-examination of the C NMR spectrum of xanthene: a revised correlation for the carbocyclic ring JCH meta-coupling constants in fused oxygen heterocycles

¹³C Chemical shifts and J_CH coupling constants are reported for xanthene and for some dimedone adducts containing a xanthene ring. A revised correlation pattern for the carbocyclic ring ³J_CH meta-couplings in fused oxygen heterocycles is proposed in which the magnitude of the interactions alternate around the ring.     

Magnetic resonance imaging of cortical bone with ultrashort TE pulse sequences

PurposeNormal adult cortical bone has a very short T₂ and characteristically produces no signal with pulse sequence echo times (TEs) routinely used in clinical practice. We wished to determine whether it was possible to use ultrashort TE (UTE) pulse sequences to detect signal from cortical bone in human subjects and use this signal to characterise this tissue.Subjects and MethodsSeven volunteers and 10 patients were examined using ultrashort TE pulse sequences (TE=0.07 or 0.08 ms). Short and long inversion as well as fat suppression pulses were used as preparation pulses. Later echo images were also obtained as well as difference images produced by subtracting a later echo image from a first echo image. Saturation pulses were used for T₁ measurement and sequences with progressively increasing TEs for T₂* measurement. Intravenous gadodiamide was administered to four subjects.ResultsSignal in cortical bone was detected with UTE sequences in children, normal adults and patients. This signal was usually made more obvious by subtracting a later echo image from the first provided that the signal-to-noise ratio was sufficiently high.Normal mean adult T₁s ranged from 140 to 260 ms, and mean T₂*s ranged from 0.42 to 0.50 ms. T₁ increased significantly with age (P<.01).Increased signal was observed after contrast enhancement in the normal volunteer and the three patients to whom it was administered.Reduction in signal from short T₂ components was seen in acute fractures, and increase in signal in these components was seen with new bone formation after fracture malunion. In a case of osteoporosis, bone cross-sectional area and signal level appeared reduced.ConclusionSignal can be detected from normal and abnormal cortical bone with UTE pulse sequences, and this can be used to measure its T₁ and T₂* as well as observe contrast enhancement. Difference images are of value in increasing the conspicuity of cortical bone and observing abnormalities in disease.     

Mechanism for twisting in polyethylene spherulites

A model is proposed to account for the regular twisting of radial ribbons in certain polymer spherulites. The model assumes that the ribbons have crystallographically regular fold surfaces and that growth of the ribbons is nucleation-controlled. The model leads directly to a possible mechanism of spherulitic growth in some polymers.     

Redox inactivation of human 15-lipoxygenase by marine-derived meroditerpenes and synthetic chromanes: archetypes for a unique class of selective and recyclable inhibitors

The selective inhibition of human 15-lipoxygenase (15-hLO) could serve as a promising therapeutic target for the prevention of atherosclerosis. A screening of marine sponges revealed that crude extracts of Psammocinia sp. exhibited potent 15-hLO inhibitory activity. Bioassay-guided fractionation led to the isolation of chromarols A-E (8-12) as potent and selective inhibitors of 15-hLO. An additional 22 structurally related compounds, including meroditerpenes from the same Psammocinia sp. (3, 4, 13-16) and our pure compound repository (17, 18), commercially available tocopherols (19-24), and synthetic chromanes (25-32), were evaluated for their ability to inhibit human lipoxygenases. The 6-hydroxychromane moiety found in chromarols A-D was identified as essential for the selective redox inhibition of 15-hLO. Furthermore, the oxidized form of the 6-hydroxychromane could be reduced by ascorbate, suggesting a potential regeneration pathway for these inhibitors in the body. This pharmacophore represents a promising paradigm for the development of a unique class of recyclable 15-hLO redox inhibitors for the treatment of atherosclerosis.     

The Synthesis and Evaluation of Quaternary Pyridinium Bisphosphonates as Potent Anti-Resorptives

Abstract

Several novel quaternary pyridinium bisphosphonates have been synthesised and their efficacy as potential anti-resorptive bone agents have been tested in Dictyostelium discoideum. This assay has been shown to accurately reflect the potency of a bisphosphonic acid as an anti-resorptive compound. All the quaternary bisphosphonates are very potent growth inhibitors but results indicate that the more potent compounds are those containing hydrophobic, bulky groups.     

Benefit of temporal fine structure to speech perception in noise measured with controlled temporal envelopes

Previous studies have assessed the importance of temporal fine structure (TFS) for speech perception in noise by comparing the performance of normal-hearing listeners in two conditions. In one condition, the stimuli have useful information in both their temporal envelopes and their TFS. In the other condition, stimuli are vocoded and contain useful information only in their temporal envelopes. However, these studies have confounded differences in TFS with differences in the temporal envelope. The present study manipulated the analytic signal of stimuli to preserve the temporal envelope between conditions with different TFS. The inclusion of informative TFS improved speech-reception thresholds for sentences presented in steady and modulated noise, demonstrating that there are significant benefits of including informative TFS even when the temporal envelope is controlled. It is likely that the results of previous studies largely reflect the benefits of TFS, rather than uncontrolled effects of changes in the temporal envelope.     

Palladium(II) and platinum(II) complexes with tridentate iminophosphine ligands; synthesis and structural studies

The previously synthesised Schiff-base ligands 2-(2-Ph(2)PC(6)H(4)N[double bond, length as m-dash]CH)-R'-C(6)H(3)OH (R'= 3-OCH(3), HL(1); 5-OCH(3), HL(2); 5-Br, HL(3); 5-Cl, HL(4)) were prepared by a faster, more efficient route involving a microwave assisted co-condensation of 2-(diphenylphosphino)aniline with the appropriate substituted salicylaldehyde. HL(1-4) react directly with M(II)Cl(2)(M = Pd, Pt) or Pt(II)I(2)(cod) affording neutral square-planar complexes of general formula [M(II)Cl(eta(3)-L(1-4))](M = Pd, Pt, 1-8) and [Pt(II)I(eta(3)-L(1-4))](M = Pd, Pt, 9-12). Reaction of complexes 1-4 with the triarylphosphines PR(3)(R = Ph, p-tolyl) gave the novel ionic complexes [Pd(II)(PR(3))(eta(3)-L(1-4))]ClO(4)(13-20). Substituted platinum complexes of the type [Pt(II)(PR(3))(eta(3)-L(1-4))]ClO(4)(R = P(CH(2)CH(2)CN)(3)21-24) and [Pt(II)(P(p-tolyl)(3))(eta(3)-L(3,4))]ClO(4)( 25 and 26 ) were synthesised from the appropriate [Pt(II)Cl(eta(3)-L(1-4))] complex (5-8) and PR(3). The complexes are characterised by microanalytical and spectroscopic techniques. The crystal structures of 3, 6, 10, 15, 20 and 26 were determined and revealed the metal to be in a square-planar four-coordinate environment containing a planar tridentate ligand with an O,N,P donor set together with one further atom which is trans to the central nitrogen atom.     

Molecular dynamics simulations of one-dimensional Lennard-Jones systems

One-dimensional Lennard-Jones systems are investigated by molecular dynamics simulations. The full Lennard-Jones potential is compared to the repulsive Lennard-Jones potential. It is found that the pair correlation function and the normalized velocity autocorrelation function agree at high densities and high temperature. However, the diffusion coefficient indicates that the attractive potential introduces additional correlations into particle dynamics which are not reflected in the statics. These results are in agreement with three-dimensional studies.