Investigation of the stereoselective in vitro metabolism of the chiral antiasthmatic/antiallergic drug flezelastine by high-performance liquid chromatography and capillary zone electrophoresis.

An achiral HPLC method using a silica gel column as well as two independent chiral analytical methods by HPLC and capillary zone electrophoresis (CZE) were developed in order to investigate the in vitro metabolism of the racemic antiasthmatic/antiallergic drug flezelastine. The chiral HPLC analysis was performed on a Chiralpak AD column, which also allowed the simultaneous separation of the N-dephenethyl metabolite. The chiral separation by CZE was achieved by the addition of beta-cyclodextrin to the run buffer.

Enantioselective high-performance liquid chromatography assay of (+)R- and (-)S-alpha-lipoic acid in human plasma.

A specific plasma level assay for the enantiomers of alpha-lipoic acid is described. It makes use of liquid-liquid extraction, chemical reduction to the dithiol enantiomers, and their precolumn chiral derivatisation with o-phthalaldehyde in the presence of D-phenylalanine. The two diastereomeric derivatives are separated by reversed-phase HPLC with fluorescence detection.

In vivo incorporation of lipoic acid enantiomers and homologues in the pyruvate dehydrogenase complex from Escherichia coli.

The strain Escherichia coli JRG26, which has a defect in the lipoic acid biosynthesis, was cultivated in the presence of R-lipoic acid, S-lipoic acid, RS-dithiolane-3-caproic acid, RS-bisnorlipoic acid, and RS-tetranorlipoic acid, respectively. With the exception of the last compound the strain was able to grow with all these substances. R-lipoic acid was the most efficient factor, concentrations of 10 ng/l were sufficient to support growth of the cells, while 10(4)-fold to 10(7)-fold higher concentrations were necessary for the other compounds.

Using lipoate enantiomers and thioredoxin to study the mechanism of the 2-oxoacid-dependent dihydrolipoate production by the 2-oxoacid dehydrogenase complexes.

The thioredoxin-catalyzed insulin reduction by dihydrolipoate was applied to study the 2-oxoacid: lipoate oxidoreductase activity of 2-oxoacid dehydrogenase complexes. The enzymatic and non-enzymatic mechanisms of the transfer of reducing equivalents from the complexes to free lipoic acid (alpha-lipoic acid, 6,8-thiooctic acid) were distinguished using the high stereoselectivity of the complex enzymes to the R-enantiomer of lipoate. Unlike these enzymes, thioredoxin from E.

Interaction of alpha-lipoic acid enantiomers and homologues with the enzyme components of the mammalian pyruvate dehydrogenase complex.

Lipoic acid (alpha-lipoic acid, thioctic acid) is applied as a therapeutic agent in various diseases accompanied by polyneuropathia such as diabetes mellitus. The stereoselectivity and specificity of lipoic acid for the pyruvate dehydrogenase complex and its component enzymes from different sources has been studied. The dihydrolipoamide dehydrogenase component from pig heart has a clear preference for R-lipoic acid, a substrate which reacts 24 times faster than the S-enantiomer.

Tolerability and pharmacokinetics of single and multiple doses of azelastine hydrochloride in elderly volunteers.

The tolerability and pharmacokinetics of azelastine hydrochloride (CAS 73907-93-0, A-05610) after single and multiple dosing (4.4 mg as tablet, tau = 12 h) were investigated in 14 volunteers (6 female, 8 male) older than 65 years (70 +/- 5 years, mean +/- SD). The medication was administered as tablets in the morning of days 1 and 11, and b.

Structural and immunological reactivity of the principal neutralizing determinant V3 of glycoprotein gp120 of HIV-1.

The variable domain V3 in the outer glycoprotein gp120 of HIV-1 is a highly important region with respect to immune response during the course of viral infection. Neutralizing antibodies are produced against this domain: in addition, it has been shown to be a functionally active epitope for T helper and cytotoxic T cells. The high degree of amino acid variability in individual HIV-isolates, however, limits the use of the V3-domain in approaches to vaccine development.

Absorption of [7,8-14C]rac-a-lipoic acid from in situ ligated segments of the gastrointestinal tract of the rat.

rac-a-Lipoic acid (CAS 62-46-4, thioctic acid) is used in human therapy besides the parenteral route also orally in gastric juice soluble galenic formulations in patients suffering from diabetic polyneuropathy which also involves the gastrointestinal tract (GI) tract in about 20% of the diabetic population. In those patients the most common manifestation of the disease due to small intestine dysfunction is diarrhoea as a consequence of which malabsorption of orally administered drugs may result. Due to the importance of the knowledge on absorption characteristics, in preclinical studies on pharmacokinetics the extent of [14C]absorption from a solution of [7,8-14C]rac-a-lipoic acid was investigated in the rat after oral administration by means of comparison of the AUCs from the [14C]plasma concentrations vs those from the intravenous route, yielding 66%.

Tolerability, pharmacokinetics and dose linearity of azelastine hydrochloride in healthy subjects.

In a double-blind, randomized, 4-period crossover study, single oral doses of azelastine hydrochloride tablets (A-05610, Allergodil, Radethazin, Azeptin, CAS 79307-93-0) were ingested by 12 healthy volunteers (6 males, 6 females, mean age 25.2 +/- 3.5 years).

High-performance liquid chromatographic assay for the determination of the decapeptide cetrorelix, a novel luteinizing hormone-releasing hormone antagonist, in human plasma.

This is the first paper which describes a HPLC method for the determination of the decapeptide cetrorelix, a potent luteinizing hormone-releasing hormone (LH-RH) antagonist, in human plasma by liquid-liquid extraction, concentration by back-extraction with diluted acid into a smaller volume, and fluorescence detection, using the decapeptide D-21740 as internal standard. The excitation (227 nm) and emission wavelengths (340 nm) for cetrorelix and the internal standard are identical. The extraction yield for both peptides is ca.

Naftopidil inhibits 5-hydroxytryptamine-induced platelet aggregation and 5-hydroxytryptamine uptake in platelets of healthy volunteers.

Naftopidil exerts its antihypertensive action via alpha 1-adrenoceptor blockage and Ca2+ antagonism in vascular smooth muscle. Since the chemically similar 1-(1-naphthyl) piperazine is known to be a 5-hydroxytryptamine2 receptor antagonist, the 5-hydroxytryptamine (5-HT) antagonistic properties of naftopidil were tested by examining 5-HT-induced aggregation and 5-HT uptake in platelets from 12 healthy volunteers after oral administration of 60 mg naftopidil or placebo. Platelet aggregation in vitro was inhibited by naftopidil with a Ki value of 1.

Naftopidil, a new adrenoceptor blocking agent with Ca(2+)-antagonistic properties: interaction with adrenoceptors.

The interaction of naftopidil with adrenoceptors was studied in comparison to standard drugs. Naftopidil binds specifically to alpha 1-adrenoceptors. The Ki values are 58.

Dose-proportional plasma levels of the analgesic flupirtine maleate in man. Application of a new HPLC assay.

Single oral doses of the non-opioid, centrally-acting analgesic flupirtine maleate (Katadolon, CAS 75507-68-5) were administered to healthy volunteers and the 2 h plasma levels determined with a new specific HPLC assay. 50, 100, 200, and 300 mg were ingested as the commercial capsules in a double-blind randomized cross-over design with time intervals of at least 6 d. Dose-proportionality was observed for the median 2 h plasma levels which is in agreement with dose-proportionality previously described for multiple-dose studies.

Characterization of Ca(2+)-antagonistic effects of three metabolites of the new antihypertensive agent naftopidil, (naphthyl)hydroxy-naftopidil, (phenyl)hydroxy-naftopidil, and O-desmethyl-naftopidil.

The newly developed antihypertensive agent naftopidil blocks alpha 1-adrenoceptors and inhibits Ca2+ entry via potential-dependent channels in vascular and cardiac muscle. It is extensively metabolized in vivo. Since it is of interest whether its metabolites are still pharmacologically active, we have characterized the effects of (naphthyl)hydroxy-naftopidil (NHN), (phenyl)hydroxy-naftopidil (PHN), and O-desmethyl-naftopidil (DMN) in various isolated preparations of the guinea pig heart.

5-HT1A-agonistic properties of naftopidil, a novel antihypertensive drug.

Naftopidil, a novel antihypertensive compound, possesses 5-HT1A agonistic properties in addition to being an alpha 1-adrenoceptor antagonist. The IC50 values for alpha 1-adrenoceptors (235 nmol/l) and for 5-HT1A receptors (108 nmol/l) lie in the same concentration range. The reduction in blood pressure of anesthetized cats by 8-OH-DPAT and urapidil was completely abolished by spiroxatrine, a 5-HT1A antagonist.

Metabolic fate of the novel antihypertensive drug naftopidil.

The metabolism of 14C-naftopidil ((R,S)-1-(2-methoxyphenyl)-1-piperazinyl-3- (1-naphthyl-oxy-2-propanol, CAS 57149-07-2) and the pharmacodynamic action of the metabolites was investigated. The metabolic pathway in rat, dog, mouse and man was qualitatively similar, with preference for the hydroxylation of the phenyl or naphthyl moiety of naftopidil [phenyl)hydroxy-metabolite, (naphthyl)hydroxy-metabolite). Cleavage of the parent compound and production of the propylene glycol metabolite was a further important reaction especially for rat and man.

Pharmacokinetic fate of the novel antihypertensive drug naftopidil.

The pharmacokinetics of naftopidil (R,S)-1-[4-(2-methoxyphenyl)-1-piperazinyl]-3-(1-naphthyloxy)-2 propanol, CAS 57149-07-2) was studied in rats and dogs using 14C-labeled drug in pharmacodynamically effective doses (oral doses: 5/10 mg/kg and intravenous doses: 1/2.5 mg/kg in rats/dogs, respectively). Naftopidil (14C) was rapidly and in high extent absorbed in rats and dogs after oral administration.

Dose-related analgesic effects of flupirtine.

1. Flupirtine is a novel and, in all probability, centrally acting, analgesic. The present investigation was conducted in order to investigate dose-related effects of perorally administered flupirtine in man, with special regard to specifically analgesic actions, employing a model based on pain-related chemosomatosensory evoked potentials and subjective intensity estimates of painful stimuli.

Investigations with the novel non-opioid analgesic flupirtine in regard to possible benzodiazepine-like abuse inducing potential.

Flupirtine (D-9998, Katadolon, CAS 56995-20-1); CAS 56995-20-1), a novel non-opioid analgesic was investigated for possible benzodiazepine-like activities. In receptor binding studies flupirtine and its metabolite were found to reveal no affinity for specific 3H-flunitrazepam binding up to a concentration of 10 mumol/l. In drug discrimination studies, rats were trained to discriminate the novel analgesic flupirtine (10 mg/kg i.

Radioreceptor assay for the determination of alpha 1-adrenoceptor-binding material in rat plasma following single oral administration of naftopidil.

Naftopidil could be characterized by receptor binding studies as an alpha 1-adrenergic antagonist with a binding affinity constant (Ki) of 58.3 nmol/l. both enantiomers of naftopidil revealed similar values, indicating no stereoselective inhibition of 3H-prazosin-binding.

Effect of selegiline and desmethyl-selegiline on cortical electric activity in rats.

The pharmaco-EEG changes caused by the monoamine oxidase (MAO) B inhibitor selegiline were compared with the frequency band alterations aroused by its desmethyl metabolite after oral administration in rats. After single administration (5 mg/kg) the EEG changes caused by selegiline or desmethyl-selegiline differed significantly. Distinct decreases in delta and clear increases in theta EEG frequency bands were obvious after administration of selegiline.

Kinetic evaluation of MAO-B-activity following oral administration of selegiline and desmethyl-selegiline in the rat.

The monoamine oxidase (MAO) B activity of rat brain was inhibited by selegiline and its desmethyl-metabolite in vitro with IC50-values of 11.25 nmol/l and 625.00 nmol/l, respectively.

Pharmacological characteristics of the stereoisomers of carvedilol.

The racemic compound carvedilol possesses two complementary pharmacological effects, vasodilation and beta-blockade. The R- and S-enantiomers of carvedilol and the racemate were investigated with respect to the beta-blocking, vasodilating, and hypotensive actions. In agreement with results obtained with other beta-blockers, only the S-enantiomer of carvedilol exerts beta-blocking effects.

Mode of antinociceptive action of flupirtine in the rat.

1. Flupirtine is a novel, centrally acting, non-opioid analgesic agent. The present investigation was undertaken to ascertain which neuronal systems might be responsible for its antinociceptive effect in rodents.