Characterization of novel selective H1-antihistamines for clinical evaluation in the treatment of insomnia.

Analogues of the known H(1)-antihistamine R-dimethindene were profiled as potential agents for the treatment of insomnia. Several highly selective compounds were efficacious in rodent sleep models. On the basis of overall profile, indene 1d and benzothiophene 2a had pharmacokinetic properties suitable for evaluation in night time dosing. Compound 2a did not show an in vivo cardiovascular effect from weak hERG channel inhibition.

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.

Metabolism of dimetindene in rats.

The preparative separation of dimetindene (CAS 5636-83-9) enantiomers was achieved by fractionated crystallization of the diastereomeric tartrate salts. HPLC on alpha-AGP (alpha 1-acid glycoprotein) was used for confirmation of the enantiomeric purity. After administration of the enantiomers to rats the AUC and Cmax of S(+) dimetindene and (-)N-demethyldimetindene were slightly increased. In agreement with the serum concentration data significantly more (-)N-demethyldimethindene was excreted into urine after administration of the individual enantiomers. S(+) dimetindene was metabolised to a lesser extent in vivo (see above) as well as in vitro in rat liver homogenate. After prior enzyme induction conversion of the enantioselectivity with respect to unmetabolised dimetindene occurred. 6-Methoxydimetindene, 6-hydroxydimetindene and 6-hydroxy-N-demethyldimetindene were synthesized. 6-Methoxydimetindene is likely to be a metabolite since the retention times of synthetic compound and the substance extracted from serum and urine are identical. The formation of 6-hydroxy-N-demethyldimetindene was proved for the first time by comparison of the mass spectra of metabolite isolated from in vitro incubations and synthetic compound after derivatisation with acetic anhydride.

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.

Pharmacodynamic dose finding of dimetindene in a sustained release formulation.

A sustained release form of dimetindene (dimethindene maleate, Fenistil, CAS 3614-69-5) was developed based on a micropellet technique. Aim of the study was to evaluate the efficacy and duration of two doses of dimetindene in a sustained release pellet formulation with a standardised grass pollen provacation model (Vienna Challenge Chamber; VCC). The study with 12 grass pollen allergic volunteers--verified by case history, skin prick test (SPT), and radio allergo sorbent test (RAST)--was carried out in a placebo controlled, double blind, cross-over design. 12 h before a 4-h-lasting continuous challenge with permanent 1000 dactylis grass pollen in the VCC, administration of dimetindene (Fenistil R Pellets) in doses of 4 mg, 8 mg or identically appearing placebo was scheduled 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, dimetindene leads to a statistically significant reduction (p < 0.05) of nasal response and clinical symptoms for at least 16 h after treatment. The efficacy of 8 mg dimetindene was pronounced over 4 mg, however, the differences between both active treatments were not statistically significant. Therefore 4 mg dimetindene once a day is the adequate treatment for usual pollinotic disease conditions.

Effect time-course of the inhibition of histamine induced skin reactions by orally applied dimethindene maleate.

We have investigated the time-course of the 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 orally applied, followed by intracutaneous histamine provocations (-1, 2, 5, 14, 17, 20, 23, 26, 29 h). The two cross-over periods were separated by a wash-out phase of 17 h. Flare areas were documented 5, 10, 20 and 30 min after provocation with histamine. A strong inhibition of the development of flares was observed. With regard to the time-course of the inhibiting effect, its maximum was observed at a provocation time of 5 h. The mean residence time of the inhibiting effect was calculated to be ca. 13 h. This is different from the mean residence time of ca. 8 h obtained from blood level data. Blood- and effect-levels are not linearly related under oral treatment conditions.

Pharmacokinetics of dimetindene after intravenous and oral administration to healthy volunteers.

The pharmacokinetics of dimetindene (dimethindene maleate, Fenistil, CAS 3614-69-5) were studied after its intravenous and oral administration to 8 healthy male volunteers. Serum concentrations were measured for 48 h using an enzyme-linked immunosorbent assay. Pharmacokinetic parameters (AUC, t1/2, CLs, Vd and F) were calculated using the clearance approach.

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.

Time course of the effect of intravenous dimetindene maleate.

In order to evaluate the time course of its effects, dimetindene maleate has been investigated in a histamine provocation model in man. Eight healthy male volunteers were treated i.v. with 4 mg dimetindene maleate or sodium chloride solution in a double blind, cross over study. Intracutaneous histamine injections were given at -1, 2, 5, 14, 17, 20, 23, 26, and 29 h following drug administration and the areas of flares and wheals were measured after 5, 10, 20, and 30 min. There was strong inhibition of the development both of flares and wheals, which was more pronounced for the former. Baseline adjusted areas under the curve differed significantly following drug and placebo treatment. The maximum effect was observed at 2 h. The mean residence time of the inhibitory effect was calculated to be approximately 13 h compared to the mean residence time of dimetindene in blood of approximately 5 h, which indicates a non-linear relationship between blood level and effect.

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.