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Biomedical subjects

Lars I Andersson

Publications and source records attributed to Lars I Andersson.

9 recordsLinked to original sources
PubMed2005

Determination of ropivacaine in human plasma using highly selective molecular imprint-based solid phase extraction and fast LC-MS analysis.

A method for determining ropivacaine in human plasma using highly selective molecular imprint-based solid phase extraction and LC-MS analysis was developed. The imprinted extraction material was prepared using a structural analogue of ropivacaine as the template. The efficient sample cleanup achieved allowed single MS mode operation and analytical separation under isocratic conditions with a total separation time of less than two minutes. The absence of ion suppression was confirmed for both the m/z of ropivacaine and the m/z of the internal standard. The solid phase extraction protocol was optimised for elution of ropivacaine in a small volume of aqueous-rich solvent suitable for injection into a reversed phase LC-MS system. The final method measured trace levels of ropivacaine in human plasma with a limit of quantification of 2.5 nmol/L and interassay accuracy and precision of 101.7-104.4% and 2.1-7.2%, respectively.

Amides↗
PubMed2005

Renal effects of the cyclooxygenase-inhibiting nitric oxide donator AZD3582 compared with rofecoxib and naproxen during normal and low sodium intake.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) and can thereby reduce renal function, especially with respect to solute excretion and renal perfusion. AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] is a COX-inhibiting nitric oxide donator. Donation of nitric oxide by AZD3582 could preserve blood flow and thereby counteract the deleterious effects of COX inhibition in the gastrointestinal tract and possibly in other organ systems, including the kidney. The aim of this single-dose study was to assess the hypothesis that AZD3582 would not adversely affect renal function compared with NSAIDs. METHODS: In a parallel, randomized, double-blind fashion, a total of 60 healthy subjects (age range, 20-44 years) received 2 single doses of 750 mg AZD3582, 1500 mg AZD3582, 50 mg rofecoxib, 500 mg naproxen, or placebo (n = 12 per group). The first dose was given after a 5-day normal-sodium diet (150 mmol/d), and the second was given after a consecutive 3-day low-sodium diet (10 mmol/d). Urinary sodium excretion during normal sodium intake and glomerular filtration rate (GFR) (assessed by iohexol clearance) during sodium depletion were the primary variables measured. RESULTS: Urinary sodium excretion was reduced in all active treatment groups (maximal reduction of approximately 11 mmol/h during normal sodium intake, P < .05 versus placebo for all groups). GFR was also reduced in all active treatment groups. In sodium-depleted subjects, the mean (SD) maximal reduction in GFR during 0 to 6 hours for 750 mg AZD3582, 1500 mg AZD3582, 50 mg rofecoxib, and 500 mg naproxen was 28.1 mL/min (13.5 mL/min), 33.7 mL/min (23.3 mL/min), 25.2 mL/min (29.2 mL/min), and 41.7 mL/min (30.7 mL/min), respectively, with a statistically significant difference between 500 mg naproxen and placebo. Relative changes in sodium excretion and GFR were similar during normal sodium intake and sodium depletion during active treatment. CONCLUSION: The renal effects of 750 mg and 1500 mg AZD3582 were similar to those of 500 mg naproxen and 50 mg rofecoxib. Thus the potential for nitric oxide donation to create a renal-sparing agent was not found for AZD3582.

Adult↗
PubMed2005

Direct gas measurements indicate that the novel cyclooxygenase inhibitor AZD3582 is an effective nitric oxide donor in vivo.

1. AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] is a COX-inhibiting nitric oxide donor that inhibits COX-1 and COX-2. It is as effective as naproxen in models of pain and inflammation, but causes less gastroduodenal damage. Nitric oxide (NO) is generated from AZD3582 in vitro, and this study sought to show that the drug donates NO in vivo. 2. In anaesthetised male New Zealand white rabbits, the endogenous NO concentration in exhaled air was reduced by N(G)-nitro-L-arginine methyl ester (L-NAME) (30 mg kg(- 1) i.v.) from 33.5+/-1.0 ppb (mean+/-s.e.m.; n=6 per group) to 3.0+/-1.0 ppb, while increasing blood pressure and reducing heart rate. AZD3582 (0.2, 0.6, 2.0 or 6.0 micromol kg(- 1) min(- 1)) given 30 min after L-NAME increased the concentration of NO in exhaled air (P<0.05), decreased blood pressure and increased heart rate in a dose-dependent manner versus L-NAME control values. The peak mean NO concentration obtained was 44+/-8.0 ppb. 3. In in situ-perfused rabbit lungs, L-NAME (185 micromol l(- 1)) reduced the NO concentration in exhaled air from 106+/-13 to 4.0+/-0.4 ppb (n=5). Addition of AZD3582 (6 micromol min(- 1)) to the perfusate produced an initial rapid increase in the NO concentration in exhaled air, followed by a sustained, but lower plateau. Infusion of L-NAME increased, and AZD3582 decreased, pulmonary arterial pressure. 4. In both anaesthetised rabbits and in the perfused lungs, brief periods of hypoxia increased NO concentrations generated by AZD3582. 5. We conclude that, in rabbits, AZD3582 donates NO in vivo with characteristics similar to those reported for nitroglycerin and isosorbide nitrates

Acid-Base Equilibrium↗
PubMed2004

The roles of template complexation and ligand binding conditions on recognition in bupivacaine molecularly imprinted polymers.

A model for the molecular basis for ligand recognition in bupivacaine imprinted methacrylic acid-ethylene glycol dimethacrylate co-polymers has been developed based upon a series of (1)H-NMR studies in conjunction with HPLC and radioligand binding analyses. (1)H-NMR studies indicated that functional monomer-template complexes survive the polymerisation process, at least up until the stage of gelation. Polymers were synthesised and characterised by surface area analysis (BET), FT-IR and SEM. A combination of zonal and frontal chromatographic studies in aqueous and non-polar media indicate that selectivity arises from a combination of hydrophobic and electrostatic interactions. However, in the concentration regime employed for LC-based studies, ligand recognition in aqueous media was shown to be predominantly non-specific and hydrophobic in character. Radioligand binding studies, in lower ligand binding concentration regimes, permitted closer examination of the higher affinity binding sites. It was shown that the presence of a polar modifier in a non-polar solvent, or an organic modifier in water, produced enhanced selectivity. Variable temperature studies showed that the temperature of binding influences selectivity as well as the apparent number of sites available and that this effect is different in organic and aqueous environments. This indicates that the system studied is more complex in character than is generally appreciated. A comparison of the techniques employed here indicates that although chromatographic studies provide a valuable first-round screen for polymer-ligand selectivities, the level of detail obtainable using radioligand binding studies (lower concentrations and true equilibrium binding) makes them superior for detailed evaluations of molecularly imprinted polymers.

Anesthetics, Local↗
PubMed2003

Water-compatible molecularly imprinted polymers obtained via high-throughput synthesis and experimental design.

A technique allowing high-throughput synthesis and evaluation of molecularly imprinted polymer sorbents at a reduced scale (mini-MIPs) was developed and used for the optimization of MIPs for use in pure aqueous environments. The technique incorporated a 4-port liquid-handling robot for the rapid dispensing of monomers, templates, solvents and initiator into the reaction vessels of a 96-well plate. A library of 80 polymers, each ca. 50 mg, could thus be prepared in 24 h. The MIP rebinding capacity and selectivity could be rapidly assessed in the batch mode by quantifying nonbound fractions in parallel using a UV monochromator plate reader. This allowed a complete evaluation of the binding characteristics of an 80 polymer library in approximately 1 week. With the objective of optimizing a polymer imprinted with the local anaesthetic Bupivacaine for use in pure aqueous systems, a polymer library was prepared by varying the original poly(MAA-co-EDMA) MIP composition. The variable factors were the added amount of the hydrophilic comonomer, 2-hydroxyethyl methacrylate (HEMA), the cross-linking ratio, and the porogen. This optimization resulted in polymers showing high imprinting factors (IF = K(MIP)/K(NIP)) in water as a result, mainly, of reduced binding to the nonimprinted polymer. Normal scale batches of these materials showed strong retention of the template and low nonspecific binding when assessed as chromatographic stationary phases using pure phosphate buffer, pH 7.4, as mobile phase, by equilibrium batch rebinding experiments and as sorbents for extractions of the analyte from blood plasma samples.

Journal Article↗
PubMed2003

COX-inhibiting nitric oxide donators (CINODs) - a new paradigm in the treatment of pain and inflammation.

The clinical utility of non-selective non-steroidal anti-inflammatory drugs (NSAIDs) for pain relief is tempered by their propensity to cause gastrointestinal toxicity. Cyclooxygenase (COX)-inhibiting nitric oxide donators (CINODs) are a new class of drugs designed to provide analgesic efficacy through COX inhibition and gastrointestinal safety through the protective effects of controlled nitric oxide donation. Pre-clinical studies assessing the pharmacology, efficacy and gastrointestinal safety of AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] support this concept. Based on these studies, AZD3582 was the first CINOD to enter clinical development for the treatment of acute and chronic pain. The potential clinical utility of this new class is illustrated by a study of AZD3582 in healthy volunteers in which it caused significantly less acute gastrointestinal toxicity than an equimolar dose of naproxen. The results of the animal studies and the initial clinical study warrant long-term tolerability studies of AZD3582 along with evaluation of its anti-inflammatory and analgesic effects in humans.

Journal Article↗
PubMed2002

Molecularly imprinted CEC sorbents: investigations into polymer preparation and electrolyte composition.

The influence of the sorbent preparation protocol and separation parameters on the selectivity and chromatographic efficiency of super-porous molecularly imprinted polymer (MIP) monoliths in capillary electrochromatography (CEC) was studied. Chiral templates were employed and enantiomer separation and resolution were used as measures of imprint selectivity and column efficiency, respectively; the latter was in addition studied by chromatography of non-related aromatic structures. The polymer preparation was varied with respect to monomer composition in the pre-polymerisation mixture and also the use of single versus multiple template(s). The separation parameters investigated were type and content of organic solvent and surfactant modifier in the electrolyte. It was found that acetone and acetonitrile in buffer mixtures provided enantiomer separation of enantiomers of the template and also structural analogues; however, the degree of separation was greatly influenced by the content in the electrolyte. Three surfactants, sodium dodecylsulfate (SDS), cetyltrimethylammonium bromide (CTAB) and polyoxyethylene sorbitanmonolaurate (Tween 20), were examined as electrolyte modifiers. It was found that addition of SDS decreased and CTAB and Tween 20 increased the enantiomer separation. SDS and CTAB could be used up to 1 mM concentration whereas Tween could be used up to 90 mM concentration without causing baseline disturbances. The effects found and demonstrated strongly suggest that these parameters are to be considered during optimisation of an MIP-CEC system.

Journal Article↗
PubMedDate not supplied

Molecular imprinting science and technology: a survey of the literature for the years up to and including 2003.

Over 1450 references to original papers, reviews and monographs have herein been collected to document the development of molecular imprinting science and technology from the serendipitous discovery of Polyakov in 1931 to recent attempts to implement and understand the principles underlying the technique and its use in a range of application areas. In the presentation of the assembled references, a section presenting reviews and monographs covering the area is followed by papers dealing with fundamental aspects of molecular imprinting and the development of novel polymer formats. Thereafter, literature describing attempts to apply these polymeric materials to a range of application areas is presented.

Biological Assay↗