Development and optimization of an ultra-fast microextraction followed by HPLC-UV of tetracycline residues in milk products.

The present study developed a new ultra-fast microextraction (within 8 min) with acetonitrile followed by gradient reversed-phase HPLC-UV method to determinate six tetracyclines simultaneously in various milk products with HPLC analysis time of 9 min. Chromatographic separations were achieved with a phenomenex™ Synergi 4 µm Fusion-RP (150 × 4.60 mm) column at 220 nm, using acetonitrile/KHPO buffer (4 mmol·L, pH 2.

Adverse Drug Events in Patients with Chronic Kidney Disease Associated with Multiple Drug Interactions and Polypharmacy.

Background And Purpose: Chronic kidney disease (CKD) is associated with adverse drug events due to medication errors and the risks of polypharmacy. The aim of this study was to investigate whether multiple pharmacodynamic interactions are a significant problem in CKD patients to improve medication safety.

Methods: The discharge medication of 200 elderly patients with stage 3, 4 and 5/5D CKD was analysed in a retrospective observational study with respect to kidney-related medication errors and multiple pharmacodynamic interactions.

Discovery of Novel 5-Lipoxygenase-Activating Protein (FLAP) Inhibitors by Exploiting a Multistep Virtual Screening Protocol.

Leukotrienes (LTs) are proinflammatory mediators derived from arachidonic acid (AA), which play significant roles in inflammatory diseases. The 5-lipoxygenase-activating protein (FLAP) is an integral membrane protein, which is essential for the initial step in LT biosynthesis. The aim of this study was to discover novel and chemically diverse FLAP inhibitors for treatment of inflammatory diseases requiring anti-LT therapy.

Analysis of secondary care data to evaluate the clinical relevance of the drug-drug interaction between amlodipine and simvastatin.

Background: Pharmacokinetic analyses revealed an increase in the bioavailability of simvastatin when co-administered with amlodipine [Nishio S et al. Hypertensin research 2005; Son H et al. Drug metabolism and pharmacokinetics 2014].

In Vitro Studies on Physiological and Chemical Stability of New LE404-Derivatives with Extended Half-Life.

Dibenzoazecines are a class of potential neuroleptics with high affinity to dopamine and serotonin receptors. The efficacy and high therapeutic range has already been demonstrated in vivo with the lead structure 7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-ol (LE404: ) and selected derivatives. There is a variety of new synthesized structurally different dibenzoazecine derivatives with the aim to improve pharmacokinetic parameters, all of which contain the lead structure LE404: .

Synthesis and Characterization of new Azecine-Derivatives as Potential Neuroleptics.

Dibenzo- and benzindolo-azecines represent a class of potential neuroleptics. To characterize the effectiveness at the dopamine and 5-HT-receptor representative structures were synthesized and tested by radio ligand binding studies, in vivo and in vitro studies.Neuroleptic potency and the risk of side effects of the prodrug 7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-yl isobutyrate, an ester derivative of the most promising azecine 7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-ol (LE404), was tested in vivo concerning conditioned avoidance response inhibition, locomotor activity and triggering of catalepsy vs.

Impact of pharmacokinetics on the toxicity and efficacy of clofarabine in patients with relapsed or refractory acute myeloid leukemia.

Common side effects of clofarabine (CFB) are liver toxicity, particularly a transient elevation of transaminases and skin toxicity. We studied the correlation of pharmacokinetic (PK) parameters with these toxicities and the efficacy of CFB in patients with relapsed or refractory acute myeloid leukemia. Clofarabine PK parameters showed large inter-individual variability.

Simultaneous determination of clofarabine and cytarabine in human plasma by LC-MS/MS.

Combination of cytostatic agents is a basic principle in the treatment of cancer. For the treatment of acute myeloid leukemia (AML), purine analogs, like clofarabine and cytarabine act synergistically. Little is known, however, on their interaction in vivo.

Stereoselective plasma protein binding of amlodipine.

The binding of the (R)- and (S)-enantiomers of amlodipine to bovine serum albumin (BSA), human serum albumin (HSA), alpha(1)-acid glycoprotein (AGP), and human plasma (HP) was studied by equilibrium dialysis over the concentration range of 75-200 microM at a protein concentration of 150 microM. Unbound drug concentrations were determined by enantioselective capillary electrophoresis using 50 mM phosphate buffer, pH 2.5, containing 18 mM alpha-cyclodextrin as background electrolyte.

NO donors. Part 18: Bioactive metabolites of GTN and PETN--synthesis and vasorelaxant properties.

The vasodilators glyceryl trinitrate (GTN) and pentaerythrityl tetranitrate (PETN) are supposed to be degraded in vivo to the lower nitrates PETriN, PEDN, PEMN, 1,2-GDN, 1,3-GDN, 1-GMN, and 2-GMN. We synthesized these bioactive metabolites as reference compounds for pharmacokinetic studies. The use of HPLC-methods for monitoring the stepwise reduction of PETN to lower nitrates and the syntheses of the glyceryl dinitrates proved advantageous.

A synopsis on different homologous series of fomocaine derivatives. In vitro interactions with the cytochrome P450 system, toxicity, and local anaesthetic effects in rats--Part 1.

Fomocaine (CAS 56583-43-6) is a basic ether-type local anaesthetic used in dermatological practice for surface anaesthesia. For many years, modifications of the fomocaine molecule have been pursued, e.g.

Heme oxygenase-1: a novel key player in the development of tolerance in response to organic nitrates.

Objective: Nitrate tolerance is likely attributable to an increased production of reactive oxygen species (ROS) leading to an inhibition of the mitochondrial aldehyde dehydrogenase (ALDH-2), representing the nitroglycerin (GTN) and pentaerythrityl tetranitrate (PETN) bioactivating enzyme, and to impaired nitric oxide bioactivity and signaling. We tested whether differences in their capacity to induce heme oxygenase-1 (HO-1) might explain why PETN and not GTN therapy is devoid of nitrate and cross-tolerance.

Methods And Results: Wistar rats were treated with PETN or GTN (10.

Number of nitrate groups determines reactivity and potency of organic nitrates: a proof of concept study in ALDH-2-/- mice.

Background And Purpose: Mitochondrial aldehyde dehydrogenase (ALDH-2) has been shown to provide a pathway for bioactivation of organic nitrates and to be prone to desensitization in response to highly potent, but not to less potent, nitrates. We therefore sought to support the hypothesis that bioactivation by ALDH-2 critically depends on the number of nitrate groups within the nitrovasodilator.

Experimental Approach: Nitrates with one (PEMN), two (PEDN; GDN), three (PETriN; glyceryl trinitrate, GTN) and four (pentaerithrityl tetranitrate, PETN) nitrate groups were investigated.

NO-donors, part X [1] : investigations on the stability of pentaerythrityl tetranitrate (PETN) by HPLC-chemoluminescence-N-detection (CLND) versus UV-detection in HPLC.

HPLC in combination with chemoluminescence-N-detection (CLND) is very useful for the analysis of pentaerythrityl tetranitrate (PETN) and its possible biological and chemical degradation products pentaerythrityl trinitrate (PETriN), pentaerythrityl dinitrate (PEDiN) and pentaerythrityl mononitrate (PEMonoN). Quantification is more convenient and sensitivity of this method is about four times higher compared to UV-detection. The present study demonstrates that PETN is a chemically more stable compound in vitro than expected.

Investigations on the thermal behavior of omeprazole and other sulfoxides.

Thermoanalytical and chromatographic investigations were performed to elucidate the reason for the uncommon thermal behavior of omeprazole prepared according to a newly developed route of synthesis. Differential scanning calorimetry revealed that the position of the melting endotherm of omeprazole strongly depended on the heating rate. High heating rates (20-30 degrees C/min) led to endothermic peaks at high temperatures (comparable to literature data), while lower rates induced a shift of the signal to lower temperatures.

Investigations of interactions of chlormezanone racemate and its enantiomers on human keratinocytes and human leucoytes in vitro.

Chlormezanone is a centrally acting muscle relaxant introduced in human therapy as a racemic substance. The following investigation was performed in order to investigate whether the racemate and both enantiomers differ in their potential cytotoxicty in vitro. We investigated antiproliferative effects and cytotoxicity (PicoGreen and ATP assay) for human HaCaT keratinocytes, production of oxygen radicals (ROS) by human interleukin-3-stimulated leukocytes (Lucigenin assay) and production of sulfoleukotrienes (Cellular Antigen Stimulation Test - CAST) by human leukocytes.

[Simultaneous photometric determination of covalently bound fluorine and fluoride ion contamination adsorbed on drugs in the low ppm range after alkaline pulping].

The simultaneous determination of fluorine resulting from inorganic fluoride as well as fluorine-containing solvents adsorbed to drugs was achieved in the 0.1-30 ppm range by a combination of decomposition with magnesium oxide at 800 degrees C and steam distillation of the resulting fluoride followed by photometric measurement of the aminomethylalizarindiacetic acid-cerium(III) complex at 620 nm. The inevitable loss of fluoride occurring during the decomposition and distillation processes was corrected using factors derived from authorized calibrations.

[Photometric determination of iron contamination of drugs and biological matrices].

The Ph. Eur. detects colorimetrically the limiting value of iron by formation of a complex with thioglycolic acid in ammoniacal solution.

[Conjugation reactions of ciprofibrate with human and laboratory animals].

An open problem of the lipid lowering agent ciprofibrate (rac-2-[4-(2,2-dichlorocyclopropyl)-phenoxy]-2-methylpropanoic acid, CAS 52214-84-3) is its metabolism concerning the conjugation with amino acids and glucuronic acid. It could be solved by syntheses of the needed reference compounds--unknown up to now--and administration of ciprofibrate to volunteers and rats. Unexpectedly the conjugation compounds with amino acids are stable in vitro and in metabolism.

[New findings on the synthesis of the centrally acting muscle relaxant chlormezanone and its resolution of a gram scale using a Chiralcel OD column].

2-(4-Chlorophenyl)-4-metathiazanone (2) is the intermediate product for the two step-synthesis of chlormezanone (1), a centrally acting muscle relaxant. The second step includes the oxidation of its sulfur atom. It has been found that the foregoing reaction of 4-chlorobenzaldehyde with methylamine forming the hemiaminale and the subsequent addition of beta-mercaptopropionic acid leads to a remarkable better yield (67% of th.

[Synthesis and pharmacologic action of chiral fomocaine ((4-[2-methyl-3-(morpholin-4-yl)propyl)benzyl)-phenyl-ether and (4-(1-methyl-3-(morpholin-4-yl)propyl]benzyl)-phenyl-ether). 13. Synthesis of new compounds with local anesthetic action].

The syntheses of two chiral fomocaines namely rac ((4-[2-methyl-3-(morpholin-4-yl)propyl]-benzyl)-phenyl-ether (O/G 3) and rac (4-[1-methyl-3-(morpholin-4-yl)propyl]benzyl)-phenyl-ether) (O/G 5) are reported. These compounds are part of a new research program concerning the relation between chirality and local anaesthetic activity in the group of fomocaines. The yield over five steps is in the range of 9% (O/G 3) up to 19.

Local anaesthetic effectivity and toxicity of fomocaine, five N-free fomocaine metabolites and two chiralic fomocaine derivatives in rats compared with procaine.

Until now, no optimal local anaesthetic drug with long lasting effect and low toxicity has been developed. Fomocaine (CAS 17692-39-6), introduced in the German extrapharmacopoela (DAC) in 1979, is a local anaesthetic, which is largely in accordance with these aspects. Now the basic ether fomocaine, its metabolites O/Se 9 (CAS 3006-96-0), O/Se 10 (CAS 31719-76-3), O/Se 11, O/Se 12 (CAS 64264-21-7) and M5 and its chiralic derivatives O/G 3 and O/G 5 were compared with procaine (CAS 59-46-1) and characterised more in detail in rats.

[[Physical chemical, pharmacological and toxicologic properties of fomocaine metabolites] ].

Fomocaine (4-[3-(4-phenoxymethylphenyl)-propyl]-morpholine, CAS 17692-39-6) is a highly effective local anaesthetic of low toxicity. The drug, which causes no allergic response, was introduced in the German Extrapharmacopoeia (DAC). Fourteen metabolites are formed after oral administration to rat and beagle dog.