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At least 19 recordsLinked to original sources

PubMed1994

Simultaneous enantioselective determination and quantification of dimethindene and its metabolite N-demethyl-dimethindene in human urine using cyclodextrins as chiral additives in capillary electrophoresis.

Capillary electrophoresis (CE) has been used for the chiral resolution of the basic racemic drug dimethindene (Fenistil) and its metabolite N-demethyl-dimethindene. After oral administration of 4 mg dimethindene maleate the enantioselective excretion in human urine was determined by capillary electrophoresis using a 50 mM phosphate run buffer (pH 3.3) containing 30 mM hydroxypropyl-beta-cyclodextrin. The determination of very low concentrations of dimethindene and N-demethyl-dimethindene in human urine was possible using sample stacking conditions to increase the amount of analyte in the capillary with good peak forms and resolutions. The detection limit of the method was approximately 1 ng ml-1 urine for each compound.

Administration, Oral↗

PubMed1991

Enantioselective determination of dimethindene in urine after oral administration of racemic dimethindene.

A sensitive high-performance liquid chromatographic determination of dimethindene and its metabolite N-demethyldimethindene in urine has been developed. The quantitative analysis was followed by determination of the enantiomeric ratio of dimethindene on an alpha 1-AGP column (EnantioPac). The urinary data for nine volunteers after oral administration of racemic dimethindene are presented. The isolation, identification and synthesis of the metabolite N-demethyldimethindene are reported.

Administration, Oral↗

PubMed1997

Enantioselective biotransformation of the chiral antihistaminic drug dimethindene in humans and rats.

The biotransformation of dimethindene (CAS 5636-83-9, dimethindene maleate, CAS 3614-69-5) after oral administration was determined in urine using an HPLC gradient method. Besides the phase I metabolites the conjugates of the hydroxylated metabolites with glucuronic and/or sulfuric acid were quantitatively determined after enzymatic deconjugation. The cumulative excretion of 6-hydroxydimethindene and 6-hydroxy-N-demethyldimethindene in human urine after hydrolysis of the conjugates ranged from 18 to 23% of the administered dose, independent of the amount of the dose applied. The results indicate that conjugated 6-hydroxydimethindene is the main metabolite of dimethindene. Increasing doses of 5 to 20 mg dimethindene maleate did not affect the relative amount of the excreted metabolites but changed the ratio of 6-hydroxydimethindene to 6-hydroxy-N-demethyldimethindene from 3:1 to 1:1. In rats about 4 to 8% of the administered dose of dimethindene was excreted as dimethindene-N-oxide which is the main metabolite in rat urine. After administration of R-(-)-dimethindene the elimination of all metabolites was 2 to 3 fold higher compared to the administration of the S-(+)-enantiomer. By chiral HPLC, in 10 human volunteers a stereoselective elimination of N-demethyl-dimethindene after oral administration of racemic dimethindene with the predominant excretion of the R-(-)-enantiomer was observed.

Adult↗

PubMedDate not supplied

Comparative effect of dimethindene maleate and chlorpheniramine maleate on histamine-induced weal and flare.

Antihistaminic activity of 3 or 6 mg dimethindene maleate was compared with that of placebo and 12 mg chlorpheniramine maleate in 60 healthy volunteers in a randomized, crossover study. Activity of each drug was assessed by measuring 2 micrograms histamine-induced weal and flare areas. Compared with placebo, both doses of dimethindene and chlorpheniramine significantly (P less than 0.001) reduced weal area. Both doses of dimethindene (P less than 0.001) and chlorpheniramine (P less than 0.05) also significantly reduced flare area. Dimethindene (6 mg) brought about the maximum reduction in weal area (28.8%) and flare area (39.1%). Dimethindene (6 mg) also reduced weal area significantly (P less than 0.01) compared with chlorpheniramine and reduced flare area significantly (P less than 0.05) compared with 3 mg dimethindene. Using a 100 mm visual analogue scale for assessment of weal and flare intensities, 6 mg dimethindene again produced the maximum response. The study confirmed that the antihistamine activity of dimethindene was better than that of chlorpheniramine.

Adult↗

PubMed2003

Structure-activity relationships of dimethindene derivatives as new M2-selective muscarinic receptor antagonists.

A series of 2,3-disubstituted indenes, which are analogues of the widely used histamine H(1) receptor antagonist dimethindene, have been synthesized and studied as muscarinic and histamine receptor antagonists. The affinities of these compounds for the five human muscarinic receptor subtypes (M(1)-M(5)) and for human histamine H(1) receptors were determined in radioligand binding studies using membranes from transfected Chinese hamster ovary (CHO) cells and [(3)H]N-methylscopolamine ([(3)H]NMS). The results demonstrate that the diisopropyl analogue 19 has a similar high affinity as (S)-dimethindene at M(2) receptors ((S)-dimethindene: pK(i) = 7.52; (-)-19: pK(i) = 7.37) with an improved selectivity pattern ((S)-dimethindene: M(2)/M(1) = 6-fold, M(2)/M(3) = 5-fold, M(2)/M(4) = 10-fold, M(2)/M(5) = 25-fold; (-)-19: M(2)/M(1) = 36-fold, M(2)/M(3) = 96-fold, M(2)/M(4) = 42-fold, M(2)/M(5) = 275-fold). In addition, compound (-)-19 showed 35-fold lower affinity at histamine H(1) receptors (pK(i) = 5.61) than (S)-dimethindene (pK(i) = 7.16). Another interesting compound is the fluoroethyl derivative 20 (pK(i)/M(2) = 7.49), which also exhibits a higher M(2) selectivity (M(2)/M(1) = 19-fold; M(2)/M(3) = 22-fold; M(2)/M(4) = 13-fold; M(2)/M(5) = 62-fold) than (S)-dimethindene. Unfortunately, compound 20 also shows a high affinity for histamine H(1) receptors (pK(i) = 8.14). The compound with the highest affinity for M(2) receptors (pK(i) = 7.91), the dimethylaminomethylene analogue 31, displayed only a small preference for M(2) receptors. In conclusion, compound (-)-19 might be useful to test the hypothesis that blockade of muscarinic M(2) receptors in the brain is a viable mechanism by which to produce improved cognition. This second-generation dimethindene analogue might also be the starting point for the development of M(2)-selective muscarinic antagonists useful for quantifying M(2) receptors in the central nervous system with positron emission tomography imaging.

Animals↗

PubMed1995

Transdermal absorption of dimethindene in man.

Dimethindene and its metabolite N-demethyldimethindene were determined in human urine after dermal administration of dimethindene. The HPLC-method used was previously described. Data of 8 volunteers are presented. After 32 h an average of 0.023% of the administered dose of dimethindene and 0.022% of N-demethyldimethindene were excreted into urine. Since also after oral administration of dimethindene only about 1% of unmetabolised dimethindene is found in urine it can be concluded that a certain amount of dimethindene is absorbed through the skin after dermal administration.

Administration, Cutaneous↗

PubMed1997

Studies of the metabolism of the antihistaminic drug dimethindene by high-performance liquid chromatography and capillary electrophoresis including enantioselective aspects.

A reversed-phase high-performance liquid chromatography method for the determination of dimethindene and its main metabolites N-demethyldimethindene, 6-hydroxydimethindene and 6-hydroxy-N-demethyldimethindene in human urine was developed. The assay was also applied to the quantification of dimethindene-N-oxide in rat urine. Conjugates of the hydroxylated metabolites were determined after enzymatic deconjugation. Moreover the direct determination of dimethindene and its metabolites without prior extraction from urine was performed by capillary electrophoresis. The direct simultaneous determination of the enantiomers of dimethindene and N-demethyldimethindene was achieved on a Chiralcel OD column. Urinary data after oral administration of dimethindene are presented. The assays were used to study dimethindene and it metabolites in urine upon oral administration of the drug to rats and human volunteers.

Adult↗

PubMed1994

Dose-related control of allergic rhinitis symptoms by a H1-receptor antagonist. Finding the proper doses [correction of dosis] of dimethindene maleate in patients with allergic rhinitis.

The aim of the study was to evaluate the efficacy and duration of two doses of dimethindene, in a sustained release pellet formulation, with a standardized grass pollen provocation model (Vienna Challenge Chamber, VCC). The study of 12 grass pollen-allergic volunteers (verified by case history, skin prick test and RAST) was carried out in a placebo-controlled, double-blind, cross-over design. 12 h before a 4-hour continuous challenge with permanent 1,000 Dactylis grass pollen/m3 of air in the VCC, 4 or 8 mg of dimethindene (Fenistil pellets) or an identically appearing placebo was administered in three sessions. Nasal flow and resistance, nasal secretion and subjective symptoms were recorded at 15-min intervals during this long-term challenge under reproducible conditions. In comparison to placebo, dimethindene leads to a statistically significant reduction (p < 0.05) in nasal response and clinical symptoms for at least 16 h after treatment. The efficacy of 8 mg dimethindene was superior to that of 4 mg dimethindene; however, the differences between both active treatments were not statistically significant. Therefore 4 mg dimethindene once a day is adequate for usual pollinotic disease conditions.

Adult↗

PubMed1995

The (S)-(+)-enantiomer of dimethindene: a novel M2-selective muscarinic receptor antagonist.

The present study was designed to determine to determine the in vitro affinity profile of (R)-(-)-dimethindene and (S)-(+)-dimethindene at muscarinic receptor subtypes using both functional and binding assays. In addition, the racemate was investigated in functional studies. The functional muscarinic receptors studied were putative M1 receptors in rabbit vas deferens and rat duodenum, M2 receptors in guinea-pig left atria and rabbit vas deferens, as well as M3 receptors in guinea-pig ileum and trachea. Furthermore, the histamine H1 antagonism by (R)-(-)- and (S)-(+)-dimethindene has been examined in guinea-pig ileum. Muscarinic binding selectivity was assessed in homogenates from human neuroblastoma NB-OF 1 cells (M1), rat heart (M2), pancreas (3) and striatum (M4). The results demonstrate that (S)-(+)-dimethindene is a potent M2-selective muscarinic receptor antagonist (pA2 = 7.86/7.74; pKi = 7.78) with lower affinities for the muscarinic M1 (pA2 = 6.83/6.36; pKi = 7.08), the M3 (pA2 = 6.92/6.96; pKi = 6.70) and the M4 receptors (pKi = 7.00), respectively. The (S)-(+)-enantiomer was more potent (up to 41-fold) than the (R)-(-)-enantiomer in all muscarinic assays. In contrast, the stereoselectivity was inverse at histamine H1 receptors, the (R)-(-)-enantiomer being the eutomer (pA2 = 9.42; pA2/(S)-isomer = 7.48). In conclusion, (S)-(+)-dimethindene is a useful tool to investigate muscarinic receptor heterogeneity. In addition, this lipophilic compound might become the starting point for the development of M2-selective muscarinic receptor antagonists useful as diagnostic tools for quantifying muscarinic M2 receptors in the central nervous system with positron emission tomography imaging, and to test the hypothesis that muscarinic M2 receptor antagonists show beneficial effects in the treatment of cognitive disorders.

Animals↗

PubMed1993

Quantification of dimethindene in plasma by gas chromatography-mass fragmentography using ammonia chemical ionization.

A gas chromatographic-mass fragmentographic method using ammonia chemical ionization for the determination of dimethindene in human plasma is described. The drug was isolated from plasma by liquid-liquid extraction with hexane-2-methylbutanol. Plasma components were separated on a capillary column coated with chemically bonded methyl silicone. For detection of dimethindene, its quasi-molecular ion (M + H+) was mass fragmentographically monitored after chemical ionization with ammonia as reagent gas. Dimethindene was quantified using methaqualone as the internal standard: the quantification limit in plasma was 0.2 ng/ml, the within-run precision was 8.0% and the inter-run precision 5.6%. The plasma concentration-time profile was established after a single dose of 4 mg of dimethindene with an average maximum concentration of 5.5 ng/ml, detectable up to 48 h post application.

Ammonia↗

PubMed1990

Effect-kinetic characterization of dimethindene maleate following oral administration (Fenistil, Tropfen).

Dimethindene maleate is a well known H1-receptor antagonist with strong affinity to the H1-receptor. In order to evaluate the time course of its activity, dimethindene maleate was investigated in a histamine provocation model in man. Eight healthy male volunteers were treated either with 4 mg dimethindene maleate using a commercially available solution (Fenistile, Tropfen) or an identically appearing placebo solution (po) following a double-blind, crossover study design. Intracutaneous histamine injections were administered at -1, 2, 5, 14, 17, 20, 23, 26 and 29 h following drug administration. Areas of flares and weals were measured 5, 10, 20, and 30 min following histamine provocation. A strong inhibition of the development of flares and weals was observed to be more pronounced in flares than in weals. Baseline adjusted areas under the curve differ statistically significantly following verum and placebo treatment conditions (P = 0.0028). According to the time schedule of the study maximal effects were observed at time point 5 h. The mean residence times of the inhibitory effects were calculated to be congruent to 13 h compared to the mean residence times of dimethindene blood levels of approximately 8 h indicating a non-linear relationship between blood level and effect.

Administration, Oral↗

PubMed1991

Sedation and histamine H1-receptor antagonism: studies in man with the enantiomers of chlorpheniramine and dimethindene.

1. The effects of 10 mg (+)- and (-)-chlorpheniramine and 5 mg (+)- and (-)-dimethindene on daytime sleep latencies, digit symbol substitution and subjective assessments of mood and well-being were studied in 6 healthy young adult humans. Each subject also took 5 mg triprolidine hydrochloride as an active control and two placebos. 2. Daytime sleep latencies were reduced with triprolidine, (+)-chlorpheniramine and (-)-dimethindene, and subjects also reported that they felt more sleepy after (+)-chlorpheniramine and (-)-dimethindene. Performance on digit symbol substitution was impaired with (+)-chlorpheniramine. 3. Changes in measures with (-)-chlorpheniramine and (+)-dimethindene were not different from changes with placebo. 4. In the present study, changes in measures of drowsiness and performance were limited to the enantiomers with high affinity for the histamine H1-receptor. These findings strongly suggest that sedation can arise from H1-receptor antagonism alone, and provide further support for the belief that the histaminergic system is concerned with the regulation of alertness in man.

Adult↗

PubMed1999

Stereoselectivity of the phase-II-metabolism of the H1 antihistaminic drug dimethindene investigated by capillary electrophoresis.

Two capillary electrophoretic (CE) methods for the determination of conjugated metabolites of the antihistaminic drug dimethindene were developed. These methods allow the determination of the diastereomeric ratios of both Phase II glucuronides, 6-hydroxy dimethindene glucuronide (5) and 6-hydroxy-N-demethyl dimethindene glucuronide (6). Furthermore, after enzymatic deconjugation of both glucuronides, enantiomeric ratios of the hydroxylated Phase I metabolites 3 and 4 were determined. For comparison, glucuronides 5 and 6 were prepared by enzymatic synthesis and identified by MALDI-TOF mass spectrometry and deconjugation with beta-glucuronidase to the corresponding phenols 3 and 4. The assay of the glucuronides in rat urine and serum was performed by a combination of liquid/liquid extraction followed by solid phase extraction. After a high dose treatment with racemic dimethindene the diastereomeric glucuronides 5 and 6 could be directly determined in the urine of a guinea pig by CE without prior extraction or preconcentration of the urine sample. In all cases, stereoselectivities of the formation of Phase I as well as Phase II metabolites were observed.

Animals↗

PubMed1992

Dialysability of dimethindene maleate (Fenistil) from blood after intravenous injection.

Dimethindene, an antihistaminic drug, is the treatment of choice in dialysis patients suffering from skin itching. During hemodialysis procedures not only toxic metabolites, but also drugs are extracted from plasma. To answer the question if dimethindene is dialyzable from plasma, three healthy male volunteers received 4 mg of dimethindene solution intravenously. Ten minutes later 100 ml cubital vein blood was taken and 25,000 I.E. Liquemine was added. Plasma was separated and pumped through a cuprophan hollow fiber dialyzing module with an effective surface of 35 cm2. In periods of ten minutes samples of plasma and dialysate were taken to analyze their dimetindene concentrations. A mean clearance of 38 ml/min*m2, SD 10.2 and coefficient of variation [%] 26.8 was found. This is comparable to the well known clearance of theophylline, so it can be considered that dimethindene is eliminated from plasma during hemodialysis procedures.

Algorithms↗

PubMed1998

Determination of dimethindene in human tears by high-performance liquid chromatography.

A high-performance liquid chromatographic method is described for the determination of dimethindene in human tears. The tear samples were diluted in a 0.01 M hydrochloric acid-n-propanol mixture to prevent the irreversible adsorption of dimethindene. The diluted samples were directly injected into the chromatographic system to avoid sample pretreatment. The validation data demonstrate that the method is specific, precise and accurate within the calibration range of 12 to 1000 ng/ml dimethindene free base.

Anti-Allergic Agents↗

PubMed1987

The effect of topical dimethindene maleate on weal reactions.

The topical effect of the histamine H1-receptor antagonist dimethindene maleate on the wealing response to intradermal histamine, compound 48/80 and house dust mite antigen was studied in 16 subjects using a double-blind procedure. The mean reduction in weal area +/- s.e. mean was 44% +/- 13%, 43% +/- 13% and 31% +/- 13% for histamine, 48/80 and antigen respectively. We conclude that dimethindene maleate is a moderately potent H1-receptor antagonist, and that the inhibition of the 48/80 and house dust mite induced weals is accounted for by the antihistaminic effect of dimethindene maleate.

Adult↗

PubMed2005

[Dimethindene determination in various dosage forms by means of capillary isotachophoresis].

Capillary isotachophoresis was employed to determine dimethindene in various dosage forms. Several electrolyte systems of varying compositions and varying pH were tested. For validation of the method and the determination of dimethindene in real samples (gel, drops, capsules), two electrolyte systems were selected. Precision, correctness, linearity, robustness, and selectivity of the ITP method were evaluated for both electrolyte systems. The pre-treatment of the sample prior to analysis consisted in dissolving and diluting the pertinent dosage form containing dimethindene with demineralized water to the required concentration. The sample adjusted in this way was directly dosed into the apparatus.

Dimethindene↗

PubMed1990

Effect-time-relation of the H1-receptor antagonist dimethindene maleate following intravenous injection.

We have investigated the time-course of the weal and flare inhibiting activity of dimethindene maleate in man and compared the resulting effect-kinetic data with those from pharmacokinetic investigations. The study was carried out in a double blind, placebo controlled cross-over design with randomly assigned healthy volunteers. Dimethindene maleate (4 mg) was intravenously injected, followed by intracutaneous histamine provocations (-1, 2, 5, 14, 17, 20, 23, 26, and 29 h). The two cross-over periods were separated by a wash-out phase of 17 h. Flare and weal areas were documented 5, 10, 20, and 30 min after provocation with histamine. A strong inhibition of the development of flares and weals was observed and was more pronounced in flares than in weals. With regard to the time course of the inhibiting effect, its maxima both for flares and weals were observed at a provocation time of 2 h. The mean residence time of the inhibiting effect was calculated to be ca. 13 h for flares and ca. 15 h for weals. These values are nearly 2-3 times as high as the mean residence time of 6 h calculated from blood level data. Blood- and effect-levels are thus non-linearly related.

Adult↗