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PubMed1991

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.

Adult↗
PubMed1994

Controlled exposure to mite allergen for a dose-finding of dimethindene maleate (DMM).

The aim of the study was to develop a laboratory system to challenge mite allergic patients with physiological concentrations of Der p I in order to evaluate the efficacy of antiallergic drugs in mite allergic patients. A double-blind, placebo-controlled, cross-over study was designed with three consecutive sessions. Twelve patients with proven sensitivity to dust mite were treated with a single dose of dimethindene maleate in a FOAD formulation (4 and 8 mg vs. placebo) 12 h before a long-term challenge with mite allergen Der p I in the Vienna challenge chamber. Challenge was performed with a constant concentration of 40 ng Der p I per cubic meter of air for 4 h. Nasal parameters were recorded at 15 min intervals during long-term challenge. In comparison to placebo, dimethindene leads to a statistically significant reduction (p < 0.05) of the nasal response at both concentrations tested. The house-dust mite model in the Vienna challenge chamber thus proved to be a useful tool for drug investigations in mite allergies.

Adult↗
PubMed2006

Comparison of capillary zone electrophoresis and isotachophoresis determination of dimethindene enantiomers in pharmaceuticals using charged carboxyethyl-beta-cyclodextrin as a chiral selector.

Charged cyclodextrin-mediated capillary electrophoretic methods (capillary zone electrophoresis [CZE] and isotachophoresis [ITP]) in a hydrodynamically closed separation system with suppressed electroosmotic flow and UV absorbance photometric detection (for CZE) or conductivity detection (for ITP) were developed for a highly effective separation and quantitation of dimethindene enantiomers in various pharmaceutical formulations (solution, gel, capsules). Optimized electrolyte systems were based on low-mobility buffer constituents (epsilon-aminocaproic acid, beta-alanine, potassium acetate, acetic acid), negatively charged (at pH > 4.5) carboxyethyl-beta-cyclodextrin (CE-beta-CD), serving as chiral selector, and methylhydroxyethylcellulose, serving as an electroosmotic flow suppressor. Complete enantioseparations of dimethindene in the presence of low concentrations of CE-beta-CD (2.5 mg/ml in CZE, 6.0 mg/ml in ITP) clearly indicated a role of charge of this chiral selector in enantioresolution. It also outlined the potential of charged CD-derivatives as chiral selectors for various CE techniques. The proposed methods were successfully validated, appraising parameters of sensitivity, linearity, precision, accuracy/recovery, and robustness, and then, they were applied to pharmaceutical samples. Consistent results obtained by both CE methods indicate their usefulness for routine use.

Dimethindene↗
PubMed1991

[Dimethindene maleate administered via intramuscular route in man: local and systemic tolerance].

Local and systemic tolerance of dimethindene maleate was studied in 10 healthy volunteers by the intramuscular route (4 mg in 4 ml solvent). Subjective perception of pain and other reported side effects were registered and objective signs at the injection site were assessed repeatedly. Hematologic and biochemical tests were performed before and after completion of the study. Two volunteers complained about local pain immediately and one hour after the injection. An other volunteer developed a small hematoma within 48 hours after injection. No other side effects or adverse reactions were noted. Good tolerance of dimethindene maleate after intramuscular application could thus be established.

Adult↗
PubMed1996

Effects of dimethindene maleate on psychomotor performance in the oculodynamic test compared with placebo and loratadine.

The effects of dimethindene maleate (CAS 3614-69-5) on the central nervous system-as sustained release pellets (Fenistil OAD; OAD = once a day) and sustained release tablets (Fenistil retard) with an immediate release fraction-were investigated by means of the oculodynamic test (ODT) and visual analogue scales and compared to loratadine (CAS 79794-75-5) and placebo. In the confirmatory part of the study 18 healthy volunteers were included in a single-blind, randomised, 3-way change-over design with Fenistil OAD, loratadine, and placebo. An additional, fourth exploratory arm with Fenistil retard was run in 6 (out of the 18) subjects after completing the main part of the study. The ODT includes electro-oculography, choice reaction task, and cardiologic parameters under workload. Visual analogue scales were used for subjective ratings on well-being and drug effects concerning wakefulness (sedation), excitation, dizziness, performance, effort, and dry mouth. The results show no relevant differences between either of the active drugs and placebo. Therefore it can be stated that after a single dose there is no sedating effect of dimethindene maleate compared to loratadine or placebo.

Adult↗
PubMed1996

Efficacy of intranasally applied dimethindene maleate solution as spray in adult volunteers with symptoms of seasonal allergic rhinitis in the Vienna challenge chamber.

Twelve asymptomatic subjects (4 female, 8 male), being allergic to grass pollen proved by positive anamnesis, positive Prick-test and positive nasal provocation test, were challenged under controlled conditions with purified airborne grass pollen of Dactylis glomerata in the Vienna Challenge Chamber (VCC), located at the Universitätsklinik für Hals-Nasen-Ohrenheilkunde, Allgemeines Krankenhaus (AKH), der Stadt Wien, Vienna (Austria) by means of a double-blind, randomised, cross-over design, with 2 weeks wash-out periods between. Efficacy and safety of 2 concentrations of dimethindene (dimethindene maleate; DMM, CAS 3614-69-5, Fenistil resp. Foristal) 0.025% DMM, 0.1% DMM) were tested vs placebo as negative control and vs 0.1% azelastine as positive control, as topical nasal sprays. The tested nasal sprays were applied as single doses in the morning (2 puffs = 0.28 ml of the respective solution) to each nostril 15 min before the start of the 4 h lasting provocation procedure in the VCC, thus representing a total daily dose of 0.14 mg resp. 0.56 mg DMM and 0.56 mg azelastine, respectively. Compared to placebo, the objective variables nasal flow (150 Pa., measured by active anterior rhinomanometry) and nasal secretion (g), showed similar onset of antiobstructive and antisecretory effects in the nose after 0.1% DMM and 0.1% azelastine, respectively. The same applied for the subjective nasal symptom complex and for nasal symptom scores, evaluated by Visual Analog Scale (VAS): Time curves showed statistically significant and clinically relevant superiority of 0.1% DMM and 0.1% azelastine vs placebo, during the 4 h lasting provocation period. 0.025% DMM was not significantly different from placebo. No systemic adverse events were reported after the 4 tested preparations. Only a total of 3 subjects reported very slight local irritations (1 subject after placebo, 1 subject after 0.025% DMM and 1 subject after 0.1% azelastine). However, after 0.1% DMM no local adverse events were reported. It is concluded from this study that 0.1% DMM as nasal spray, is an efficient and safe galenical formulation for nasal spray application for patients suffering from seasonal allergic rhinitis (SAR).

Administration, Intranasal↗
PubMed1997

Dimethindene maleate in the treatment of pruritus caused by varizella zoster virus infection in children.

The efficacy and tolerability of dimethindene maleate (CAS 3614-69-5, DMM, Fenistil) as drops in the treatment of pruritus in children suffering from chicken-pox were investigated in a study with two different doses of dimethindene maleate and placebo. 128 children, 1 to 6 years of age, were included in a double blind, randomized, placebo controlled, multi-center clinical trial. Patients received either a dosage of DMM of 0.1 mg/kg x d, or 0.05 mg/kg x d, or placebo, respectively. All patients received a commercially available astringent lotion for topical treatment of skin lesions. The primary efficacy criterion which was the change in the itching severity score from baseline to the end of the treatment assessed as area under the baseline (AUB) showed for both treatments with DMM a statistically significant superiority versus placebo in reducing the severity of itching. There was no statistically proven difference between the two verum groups.

Appetite↗
PubMed1991

Investigation of the antihistaminic action of dimethindene maleate (Fenistil) and its optical isomers.

Dimethindene maleate (DM) (= Fenistil) is a potent antihistamine with a prolonged duration of action. On the histamine-stimulated guinea-pig ileum DM has a pA2 of 9.3 but produces a very marked depression of the maximum response at 10(-8) M. DM has no effect on H2 receptors nor on H3 receptors, and is not a calcium channel blocker. Muscarinic receptors (carbachol-stimulated ileum) were only influenced (competitively) at 10(-7) M or above, suggesting that the non-competitive effects described above could be due to a specific reaction with the histamine H1 receptor. As non-specific effects, such as membrane-stabilisation, would normally be seen with both isomers equally, we studied the effects of the optical isomers of DM. The (-) isomer had a profile identical to that of DM, but was slightly more potent. The (+) isomer was some 30 times less potent (results confirmed by binding studies). However in contrast to DM and the (-) isomer, the (+) isomer showed a "classical" antagonism, pA2 = 7.7, with no evidence of non-competitive effects. Thus the more active (-) isomer of DM has a potent, non-competitive H1 histamine antagonist effect. The relevance of these findings to DM's clinical profile is discussed.

Animals↗
PubMed1987

Blockage of the fast sodium current by dimethindene in frog auricular fibres.

The effect of dimethindene (DMI) on action potential and fast inward Na current (INa) of frog atrial fibres was studied using double sucrose gap voltage-clamp technique. DMI reduced the amplitude and maximum rate of rise of the action potentials without altering the resting membrane potential. The drug inhibited the fast Na conductance in a concentration-dependent manner, without changing the reversal potential. The shape of the current-voltage curve along the voltage axis remained unchanged in the presence of DMI. The time to peak of the INa was not significantly altered by the drug whereas the rate of the INa inactivation (tau h) was slowed. DMI shifted the steady-state inactivation curve of INa (h infinity) to more negative potentials, and increased the reactivation time constant of the sodium system (tau r). The inhibition of INa was use-dependent. The results suggest that DMI interacts with the inactivation mechanism of the sodium channel of the frog myocardium, and explain its favourable antiarrhythmic activity.

Action Potentials↗
PubMed1994

Influences of dimethindene maleate in a new formulation on oculo and psychomotor performance using the oculodynamic test (ODT) in volunteers.

Most antihistamines are assumed to possess a more or less pronounced sedative potential in addition to their antihistaminic properties. Therefore, a single-blind three-way crossover study was designed to assess the influence of single-dose dimethindene maleate (new "once a day formulation") on vigilance and performance vs. loratadine as reference and vs. placebo. Drug effects on performance were tested in 18 healthy volunteers by the oculodynamic test [ODT, i.e. choice reaction task (CRT), combined with recording of electrooculography (EOG) and cardiovascular parameters] and effects on subjective well-being by visual analogue scales (VAS). Main target parameters for evaluation of CNS-effects are latency and subjective perception of sedation (VAS). Neither statistically significant nor clinically relevant differences in all objective and subjective target variables (ODT and VAS) between active drugs and placebo, after single-dose administration were found. The same holds for accessory EOG, CRT and vital parameters under workload.

Adult↗
PubMed1983

Action of dimethindene on the electrophysiological and mechanical properties of atrial and ventricular myocardium of guinea-pig.

The effect of dimethindene (DMI) on transmembrane potentials and contractile force was studied in atrial and ventricular myocardium of guinea-pigs. DMI reduced the maximum rate of depolarization (Vmax) without changing the resting potential in both preparations. In ventricular myocardium, DMI shortened the action potential duration and exerted a negative inotropic effect. In atrial muscle, the drug prolonged the action potential duration and induced a positive inotropic effect which could be antagonized with neither the alpha-blocker phentolamine, nor the beta-blocker pindolol, H1-blocker mepyramine and H2-blocker cimetidine. DMI had no effect on the slow action potentials induced by caffeine in K+-depolarized myocardial preparations. The drug consistently shifted the sodium inactivation curve to more negative membrane potentials. The results suggest that DMI has a quinidine-like membrane-stabilizing property, which may be due to its fast Na+ channel blocking activity. The differential inotropic action of the drug in atrial and ventricular myocardium is discussed.

Action Potentials↗
PubMed2000

Mechanistic study of opposite migration order of dimethindene enantiomers in capillary electrophoresis in the presence of native beta-cyclodextrin and heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin.

The possible mechanisms of the opposite affinity pattern of the enantiomers of dimethindene [(R,S)-N,N-dimethyl-3[1(2-pyridyl)ethyl]indene-2-ethylamine] (DIM) towards native beta-cyclodextrin (beta-CD) and heptakis(2,3,6-tri-O-methyl-)-beta-CD (TM-beta-CD) were studied using capillary electrophoresis (CE), NMR spectrometry, electrospray ionization mass spectrometry (ESI-MS) and X-ray crystallography. NMR spectrometry allowed to estimate the stoichiometry of the complex and to determine the binding constants. As found using ESI-MS, together with more abundant 1:1 complex, a complex with 1:2 stoichiometry may also be present in a rather small amount in a solution of DIM and beta-CD. One-dimensional ROESY experiments indicated that the geometry of the complexes of DIM with native beta-CD depends on the ratio of the components in the solution. In the 1:1 solution of DIM and beta-CD the complex may be formed by inclusion of the indene moiety of DIM into the cavity of beta-CD on the primary side and into the cavity of TM-beta-CD into the secondary side. The most likely structural reason for lower affinity of the enantiomers of DIM towards the cavity of TM-beta-CD compared to native beta-CD could be elucidated. The indene moiety does not enter the cavity of TM-beta-CD as deeply as the cavity of beta-CD. This may be the most likely explanation of significantly higher affinity constants of DIM enantiomers towards the latter CD compared to the former one. The marked difference between the structure of the complexes may also be responsible for the opposite affinity pattern of the DIM enantiomers towards beta-CD and TM-beta-CD.

Cyclodextrins↗
PubMed1999

Dimethindene maleate in the treatment of sunburn. A double-blind, placebo-controlled pilot study.

The efficacy of topical dimethindene maleate (DMM, CAS 31614-69-5, Fenistil Gel) in the treatment of sunburn was evaluated in a placebo-controlled, 1-period crossover trial in 24 healthy volunteers. An UV-erythema (sunburn) of a well-defined intensity and extent was experimentally induced on three different skin test-areas by means of UV-A/B irradiation with three times the minimal erythema dose (MED). About 24 h after irradiation, one skin test-area was subjected to a 1-h occlusive treatment with DMM gel, the second test area was subjected to treatment with a placebo gel and the third one remained untreated. As objective-quantitative indicators of tenderness, a key symptom of sunburn, sensory and pain thresholds to CO2-Laser stimulation and laser somatosensory evoked potentials (SEPs) in Vertex-EEG were assessed about 1.5 h postdose. The reaction times (RTs) to painless and painful CO2-laser stimulation (sensory and pain threshold level, respectively) on the DMM-treated area were significantly longer than RTs to stimulation on the placebo-treated area. Thresholds in terms of laser energy showed no differences between the treatments. The SEP N1-amplitude on the DMM-area was markedly decreased in comparison to placebo. With regard to subjective sensations of pain, itching and tenderness assessed by means of visual analogue scales (VAS), no clinically relevant differences between treatments were observed after sole UV-irradiation. After additional laser stimulation tenderness was--objectively but not subjectively--decreased on the DMM-area versus placebo. Both gel preparations were well tolerated.

Adult↗
PubMed2003

Effects of dimethindene maleate nasal spray on the quality of life in seasonal allergic rhinitis.

OBJECTIVE: To determine if the H1-receptor antagonist dimethindene maleate (DMM), topically applied, is able to improve the quality of life (QoL) in patients with seasonal allergic rhinitis better than placebo. METHODS: The study was a multi-centre, randomised, placebo-controlled, double-blinded phase III trial including 157 patients. Two parallel groups received either DMM nasal spray or placebo for 2 weeks. Patients answered 5 QoL questionnaires (Rhinoconjunctivitis QoL Questionnaire (LQ-AR), Munich Life Dimension List (MLDL), Profile of Mood States (POMS), 2 Visual Analogue Scales (VAS-QoL, VAS-GES)) on days 1, 4, 8, and 15. RESULTS: QoL improved significantly in all scales and groups. Statistically significant differences between groups were achieved in the sub-scales LQ-AR Eye Symptoms and Daily Activities, MLDL Total, POMS Depression and Energy, VAS-QoL and VAS-General Health. All differences favoured the DMM group and were present initially but disappeared in visit 4, except MLDL Total and POMS Energy. Almost all other scores had a better tendency of DMM. CONCLUSION: A significant improvement of QoL was found in both groups. Only weak differences between groups (in favour of DMM) were found. There are several reasons explaining this outcome, mainly the rainy weather during the study period (mean weather index 10-20% less sunny than in previous seasons).

Administration, Intranasal↗
PubMed2004

[Prescription and safety of dimethindene maleate micropellet capsules in Hungary].

INTRODUCTION: Dimethindene maleate, the active substance of the extended-release Fenistil 24 capsule, is a first-generation histamine receptor antagonist, which is marketed in 10 European countries. In Hungary approximately 200,000 boxes are sold yearly from this product, which is mainly used for treatment of symptoms associated with allergic diseases (urticaria, itch, hay fever) The aim of the present study was to gather information with the help of medical doctors about the indications, efficacy and primarily the safety of use, observed side effects and frequency of adverse events associated with this product. METHOD: During the study 4574 questionnaires were evaluated out of the 5578 filled by 249 doctors. Responses were included into the evaluation only if the address and type of polyclinic of the doctor filling the questionnaire, indication of the use of the product could be precisely identified and the patient returned for control visit at least once. RESULTS: Based on the study results in Hungary in most cases the product is prescribed according to the indications and dosing schedule given in the SPC. In this study participating doctors found the drug to be effective in 95% of cases. Unexpected, new adverse events were not observed during the study. Approximately 22% of patients reported adverse events, tiredness and sleepiness being the most frequent ones. Occurrence of sedative adverse events was more frequent among those who were prone to tiredness (51 vs. 17%). The adverse events most frequently were reported 10-12 hours after intake. The average length of treatment was 4 weeks or less. The medicine is taken usually at night, before going to sleep. CONCLUSIONS: In Hungary in most cases the product is prescribed according to the indications and dosing schedule given in the current approved Summary of Product Characteristics.

Adolescent↗