Postoperative analgesia is not different after local vs systemic administration of meloxicam in patients undergoing inguinal hernia repair.

Purpose: To distinguish between local and systemic drug effects, we compared pain scores, analgesic consumption and plasma concentrations after local vs i.v. administration of meloxicam 7.

Association of acylated cationic decapeptides with dipalmitoylphosphatidylserine-dipalmitoylphosphatidylcholine lipid membranes.

The interaction of three acylated and cationic decapeptides with lipid membranes composed of dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylserine (DPPS) has been studied by means of fluorescence spectroscopy and differential scanning calorimetry (DSC). The synthetic model decapeptides that are N-terminally linked with C(2), C(8), and C(14) acyl chains contain four basic histidine residues in their identical amino acid sequence. A binding model, based on changes in the intrinsic fluorescent properties of the peptides upon association with the DPPC-DPPS membranes, is used to estimate the peptide-membrane dissociation constants.

Comparison of total oral bioavailability and the lymphatic transport of halofantrine from three different unsaturated triglycerides in lymph-cannulated conscious rats.

The lymphatic transport and the portal absorption of the lipophilic drug halofantrine were investigated in a conscious rat model. The rats were dosed with 0.1 g with triolein, trilinolein or trilinolenin containing 2 mg halofantrine.

Separation of hypericins and hyperforins in extracts of Hypericum perforatum L. using non-aqueous capillary electrophoresis with reversed electro-osmotic flow.

The separation of the lipophilic compounds in extracts of Hypericum perforatum L. is demonstrated in a non-aqueous capillary electrophoresis system with reversed electro-osmotic flow. Solvent mixtures of methanol, dimethylsulfoxide and N-methylformamide were used for the electrophoresis media, with addition of ammonium acetate and sodium acetate as electrolytes.

Melt agglomeration with polyethylene glycol beads at a low impeller speed in a high shear mixer.

This study was performed in order to evaluate the possibility of obtaining spherical agglomerates with a high content of meltable binder by a melt agglomeration process in a high shear mixer. Lactose monohydrate was melt agglomerated with polyethylene glycol (PEG) 1500 or 6000 in a 10-l high shear mixer at an impeller speed of 400 rpm. The PEG 1500 was used as a size fraction of beads, and the PEG 6000 as a fine powder, a powder, unfractionated beads, and size fractions of beads.

Determination of the disappearance rate of iodine-125 labelled oils from the injection site after intramuscular and subcutaneous administration to pigs.

The rate of disappearance of clinically used vegetable oils, Viscoleo, sesame oil, castor oil and isopropyl myristate, from the injection site after intramuscular (i.m.) or subcutaneous (s.

Resolution, configurational assignment, and enantiopharmacology at glutamate receptors of 2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA) and demethyl-ACPA.

We have previously described (RS)-2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA) as a potent agonist at the (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor subtype of (S)-glutamic acid (Glu) receptors. We now report the chromatographic resolution of ACPA and (RS)-2-amino-3-(3-carboxy-4-isoxazolyl)propionic acid (demethyl-ACPA) using a Sumichiral OA-5000 column. The configuration of the enantiomers of both compounds have been assigned based on X-ray crystallographic analyses, supported by circular dichroism spectra and elution orders on chiral HPLC columns.

A dynamic in vitro lipolysis model. II: Evaluation of the model.

A lipolysis model was characterised and evaluated by investigating the composition of the aqueous phase and the concentration of probucol and danazol in the aqueous phase. Effects of bile salt levels at 5, 10, 20, and 30 mM were investigated. Samples were taken at 0%, 50%, 75% and 95% hydrolysis of the triglycerides, and the aqueous phases were isolated by ultra-centrifugation, whereby the concentrations of bile salts, fatty acids, mono-, di-, triglycerides, and drug substances were measured.

Application of enzymatically stable dipeptides for enhancement of intestinal permeability. Synthesis and in vitro evaluation of dipeptide-coupled compounds.

Transport across the intestinal barrier of compounds with low permeability may be facilitated by targeting the human oligopeptide transporter, hPepT1. A flexible synthetic pathway for attaching compounds to dipeptides through ester or amide bonds was developed. Furthermore, a synthetic approach to functionalize model drugs from one key intermediate was generated and applied to a glucose-6-phosphatase active model drug.

Dipeptide model prodrugs for the intestinal oligopeptide transporter. Affinity for and transport via hPepT1 in the human intestinal Caco-2 cell line.

The human intestinal di/tri-peptide carrier, hPepT1, has been suggested as a drug delivery target via increasing the intestinal transport of low permeability compounds by designing peptidomimetic prodrugs. Model ester prodrugs using the stabilized dipeptides D-Glu-Ala and D-Asp-Ala as pro-moieties for benzyl alcohol have been shown to maintain affinity for hPepT1. The primary aim of the present study was to investigate if modifications of the benzyl alcohol model drug influence the corresponding D-Glu-Ala and D-Asp-Ala model prodrugs' affinity for hPepT1 in Caco-2 cells.

Inhibition of aerobic growth and nitrification of bacteria in sewage sludge by antibacterial agents.

Toxicity of antibacterial agents on environmentally relevant bacteria was investigated using activated sludge. The growth and nitrifying inhibiting effects for activated sludge of benzyl penicillin (penicillin G) (BP), tetracycline (TC), chlortetracycline (CTC), oxytetracycline (OTC), olaquindox (O), streptomycin (ST), tiamulin (TI), tylosin (TYL) sulfadiazine (SDZ), metronidazole (MET), and oxolinic acid (OXA) was investigated. Studies were performed in accordance to the ISO 15522 (1999) and ISO 9509 (1989) test guidelines, respectively.

Comparison of effects of DL-threo-beta-benzyloxyaspartate (DL-TBOA) and L-trans-pyrrolidine-2,4-dicarboxylate (t-2,4-PDC) on uptake and release of [3h]D-aspartate in astrocytes and glutamatergic neurons.

Uptake and release processes in cerebellar astrocytes and granule neurons (glutamatergic) for glutamate were investigated by the use of [3H]D-aspartate, a non-metabolizable glutamate analog. The effects of DL-threo-beta-benzyloxyaspartate (DL-TBOA) and L-trans-pyrrolidine-2,4-dicarboxylate (t-2,4-PDC) on uptake and release of [3H]D-aspartate were studied. Both compounds inhibited potently uptake of [3H]D-aspartate in neurons and astrocytes (IC50 values 10-100 microM), DL-TBOA being slightly more potent than t-2,4-PDC.

Investigation of a new mathematical model for compression of pharmaceutical powders.

A new compaction equation, the log-exp model: V=V(l)-w log(P)+V(e) exp(P/P(m)) is presented. The model presumes that two compaction processes: a logarithmic and an exponential decline may be active simultaneously. Using non-linear regression techniques the model gives an excellent fit to a number of model substances with wide differences in compaction behaviour.

Effects of physical properties of powder particles on binder liquid requirement and agglomerate growth mechanisms in a high shear mixer.

A study was performed in order to elucidate the effects of the physical properties of small powder particles on binder liquid requirement and agglomerate growth mechanisms. Three grades of calcium carbonate having different particle size distribution, surface area, and particle shape but approximately the same median particle size (4-5 microm), were melt agglomerated with polyethylene glycol (PEG) 3000 or 20,000 in an 8-l high shear mixer at three impeller speeds. The binder liquid requirement was found to be very dependent on the packing properties of the powder, a denser packing resulting in a lower binder liquid requirement.

A dynamic in vitro lipolysis model. I. Controlling the rate of lipolysis by continuous addition of calcium.

Lipolysis by pancreatic lipase was investigated with the aim to establish an in vitro lipolysis model, which can be used to investigate the dissolution of poorly soluble lipophilic drug substances at controlled hydrolysis rates. The effects of three experimental parameters -- the concentrations of bile salts and Ca(2+) and the lipase activity -- were investigated. The effect on the rate of hydrolysis of emulsified soybean oil was investigated in experiments in a pH-stat at pH 6.

Role of GluR2 expression in AMPA-induced toxicity in cultured murine cerebral cortical neurons.

alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R)-mediated neurotoxicity was studied in relation to subunit expression and the presence of Ca(2+)-permeable receptor channels. AMPA-mediated toxicity had two components: 1) a direct AMPA-R-mediated component, which was not due to Ca(2+) influx through voltage-gated Ca(2+) channels, reversal of the Na(+)/Ca(2+) exchanger or release of calcium from dantrolene-sensitive intracellular Ca(2+) stores, and 2) a minor, indirect component involving activation of NMDA receptor channels, because of glutamate release and removal of the Mg(2+) block of the NMDA receptor on AMPA-R stimulation. The involvement of Ca(2+) influx through AMPA-R was also examined.

Influence of a microemulsion vehicle on cutaneous bioequivalence of a lipophilic model drug assessed by microdialysis and pharmacodynamics.

Purpose: The aim of the study was to investigate the cutaneous bioequivalence of a lipophilic model drug (lidocaine) applied in a novel topical microemulsion vehicle, compared to a conventional oil-in-water (O/W) emulsion, assessed by a pharmacokinetics microdialysis model and a pharmacodynamic method.

Methods: Dermal delivery of lidocaine was estimated by microdialysis in 8 volunteers. Absorption coefficients and lag times were determined by pharmacokinetic modelling of the microdialysis data.

Model prodrugs designed for the intestinal peptide transporter. A synthetic approach for coupling of hydroxy-containing compounds to dipeptides.

The human peptide transporter, hPepT1, situated in the small intestine, may be exploited to increase absorption of drugs or model drugs by attaching them to a dipeptide, which is recognised by hPepT1. A synthetic protocol for this kind of model prodrugs was developed, in which model drugs containing a hydroxy group were attached to enzymatically stable dipeptides by hydrolysable ester linkages. Furthermore, a number of benzyl alcohols with various substituents in the 4-position of the phenyl ring were coupled to D-Asp-Ala and D-Glu-Ala.

Solid-phase directed ortho-lithiation and the preparation of a phthalide library.

An efficient solid-phase synthesis of phthalides is described in which aromatic carboxylic acids or acid chlorides and ketones are used as building blocks. The carboxylic acid or acid chloride is tethered to aminomethylated polystyrene resin, forming a secondary amide, which functions as both the linker and the directing metalation group. This allows the resin-bound benzamides to be ortho-lithiated at 0 degrees C.

Dermal pharmacokinetics of microemulsion formulations determined by in vivo microdialysis.

Purpose: To investigate the potential of improving dermal drug delivery of hydrophilic and lipophilic substances by formulation in microemulsion vehicles and to establish a reliable pharmacokinetic model to analyze cutaneous microdialysis data.

Methods: After a topical application of microemulsions, commercially available creams, and a hydrogel, unbound cutaneous concentrations of lidocaine and prilocaine were determined by in vivo microdialysis in rats. Recovery was monitored during the experiments via retrodialysis by calibrator.

Bioisosteric determinants for subtype selectivity of ligands for heteromeric GABA(A) receptors.

The potency and efficacy of a series of bioisosterically modified GABA analogues were determined electrophysiologically using heteromeric GABA(A) receptors expressed in Xenopus oocytes. These agonist parameters were shown to be strongly dependent on the receptor subunit combination. On the other hand, the antagonist potencies of the classical GABA(A) antagonists SR 95531 (7) and BMC (8) and also of 5g and the phosphinic acid bioisosteres of 5a, compounds 5f and 6, were essentially independent of the receptor subunit combinations.

Addition of hydrogen bond donating excipients to oil solution: effect on in vitro drug release rate and viscosity.

In oily vehicles containing different hydrogen bond donating excipients rates of transfer of the weak electrolytes naproxen and lidocaine from the oil phase to the aqueous medium were measured by using the rotating dialysis cell. A logarithmic linear correlation was established between the apparent partition coefficient, P(app), and the first-order rate constant related to attainment of equilibrium between the two phases, k(obs), which fitted well with results from former publications. Further, release data for the non-electrolyte testosterone were found to fit into this linear correlation.

Novel anionic annelation tactics for construction of fused heteroaromatic frameworks. 1. Synthesis of 4-substituted pyrazolo[3,4-c]quinolines, 9-substituted pyrazolo[3,4-c]quinolines, and 1,4-dihydrochromeno[4,3-c]pyrazoles.

4-Substituted pyrazolo[4,3-c]quinolines 4a-i and 6a-b were prepared from pyrazole 3 whereas 9-substituted pyrazolo[3,4-c]quinolines 9a-d and 17 were prepared from pyrazole 13 utilizing anionic annelation techniques. 1,4-dihydrochromeno[4,3-c]pyrazoles 7a-c were accessed from pyrazole 3, extending the method for the synthesis of 4a-i.

Synthesis and receptor binding affinity of new selective GluR5 ligands.

Two hybrid analogues of the kainic acid receptor agonists, 2-amino-3-(5-tert-butyl-3-hydroxy-4-isoxazolyl)propionic acid (ATPA) and (2S,4R)-4-methylglutamic acid ((2S,4R)-4-Me-Glu), were designed, synthesized, and characterized in radioligand binding assays using cloned ionotropic and metabotropic glutamic acid receptors. The (S)-enantiomers of E-4-(2,2-dimethylpropylidene)glutamic acid ((S)-1) and E-4-(3,3-dimethylbutylidene)glutamic acid ((S)-2) were shown to be selective and high affinity GluR5 ligands, with Ki values of 0.024 and 0.

Model prodrugs for the intestinal oligopeptide transporter: model drug release in aqueous solution and in various biological media.

The human intestinal di/tri-peptide carrier, hPepT1, has been suggested as a target for increasing intestinal transport of low permeability compounds by creating prodrugs designed for the transporter. Model ester prodrugs using the stabilized dipeptides D-Glu-Ala and D-Asp-Ala as pro-moieties for benzyl alcohol have been shown to have affinity for hPepT1. Furthermore, in aqueous solution at pH 5.