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PubMed1991

Onset of action of astemizole.

Astemizole has been described to have a slow onset of action and this has to a large extent been attributed to its unusual pharmacokinetic profile. Yet, pharmacokinetically, there are no reasons why astemizole should not act within the first hours after intake, since plasma levels of unchanged astemizole are maximal within 40 min and there is fast tissue distribution. Animal pharmacology data show effective antihistamine activity with astemizole within 1 h after intake. Clinical data referring to the onset of action of astemizole with regard to symptom relief were available from 27 studies on over 7000 patients. These studies showed astemizole to provide symptom relief within 4 to 6 h of intake in 16-85% of patients, and within 24 h in 42-90% of patients; these figures are comparable to those reported for other new antihistamines. Comparative studies between astemizole and other new antihistamines (terfenadine, loratadine and cetirizine) indicated no or only minor differences in onset of clinical effect. Two recent studies compared astemizole to both terfenadine and loratadine under well-controlled circumstances. One was a pollen challenge study showing all three drugs to be able to reverse the challenge-induced effects within 1-3 h after intake. In the other, the mean time to relief of at least one rhinitis symptom was assessed as 18 min for astemizole, 24 min for terfenadine and 36 min for loratadine. Compared with the systemic decongestant pseudoephedrine, time to first relief of symptoms was similar for astemizole (4 h) and pseudoephedrine (3.5 h). Controlled clinical trials thus show astemizole to provide fast symptom relief. This was confirmed in patient surveys in Canada and Switzerland: over 80% of patients were very satisfied with astemizole and experienced onset of action within hours. In conclusion, astemizole results in symptom relief within hours after its administration. Its onset of action is not different from that of other nonsedating antihistamines and is also similar to that of pseudoephedrine.

Animals↗

PubMed1987

Uptake, subcellular distribution and biotransformation of 3H-labelled astemizole in cultured rat hepatocytes.

When incubated with 3H-astemizole, a potent antagonist of H1 receptor, cultured rat hepatocytes, which do not express specific receptors for this ligand, avidly take up 3H-label proportionally to the drug concentration. HPLC analysis indicates that at 10 ng 3H-astemizole/ml, cells almost entirely deplete the culture medium of the drug within 4 hr of incubation. At 37 degrees, astemizole is metabolized and released into the culture medium mainly under the form of glucuronoconjugated metabolites. Differential centrifugation of homogenates from hepatocytes incubated with 3H-astemizole indicates that astemizole and unconjugated metabolites are found in the particulate fraction, whereas astemizole and conjugated metabolites are present in the cytosol. Isopycnic centrifugation on sucrose gradient shows that the major part of the 3H-label in the particulate fraction distributes like phospholipids and NADPH cytochrome c reductase, suggesting an association with membranes and, in particular, with the endoplasmic reticulum. Chloroquine, a drug accumulating within lysosomes and acidic endosomes, decreases the uptake of 3H-astemizole by hepatocytes and induces, during isopycnic centrifugation of a particulate fraction, a shift of the 3H-label towards lower densities where it closely accompanies cathepsin B. This suggests that a minor part of astemizole accumulated in the hepatocytes could be trapped within lysosomes. These results could support the hypothesis that aspecific binding of astemizole to cellular membranes and, to a lesser extent, trapping in lysosomes could play a role in the pharmacokinetics of the drug.

Animals↗

PubMed1992

Pharmacokinetics of astemizole in children.

Astemizole is often administered to children in the treatment of rhinoconjunctivitis and urticaria with good efficacy and few side effects. Both astemizole and its major metabolite desmethylastemizole (DMA) are clinically effective without annoying side effects such as sedation. The pharmacokinetics in adults is well known. In three different studies we have investigated the pharmacokinetical properties of the drug in children. Study I (absorption): Thirty-eight children 8-16 years old (mean 12.6 years) and weighing 25-80 kg (mean 45 kg), with rhinoconjunctivitis due to birch pollinosis, were pretreated with either astemizole 5 mg daily or placebo for two weeks. Then, all children were treated with astemizole in doses increasing every week, i.e. 5, 10, 20 and 40 mg per day. There was a good correlation between the given dose per kg body weight and the plasma concentration of astemizole plus hydroxylated metabolites, indicating that astemizole is completely absorbed. Study II (time to reach steady state): A group of 21 children 7-18 years old (mean 13.9 years), plus 2 younger children, 2 and 5 years old, with allergy against birch- or grass pollen were treated with astemizole 10 mg daily for 12 weeks. Astemizole had reached steady-state plasma levels when the first sample was taken after 1 week, DMA reached steady state within 4 weeks. Study III (elimination half-life [t1/2 beta]): In 10 of the children from study II, t1/2 beta for astemizole plus DMA could be calculated (two samples) and was 10.8 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1986

The treatment of mild to severe chronic idiopathic urticaria with astemizole: double-blind and open trials.

Astemizole is a new H1 histamine-receptor antagonist that has a long elimination half-life and high H1-receptor affinity. This double-blind study evaluated the safety and efficacy of astemizole in the treatment of chronic idiopathic urticaria (more than or equal to 3 months). Seventeen male and 34 female adult patients with chronic idiopathic urticaria entered the 2-month study. After a 48- to 72-hour washout, half the subjects were prerandomized to receive astemizole (10 mg), and the other half received placebo. Placebo-treated patients who were unable to complete the full 8 weeks because of uncontrolled chronic urticaria symptoms were entered into a 2-month open astemizole trial. Treatment with astemizole, as measured at the end point of each patient's treatment and compared to placebo, resulted in significant improvement of pruritus, erythema, number of wheals, frequency of urticarial attacks, and control of urticaria (p less than or equal to 0.03). The overall response to astemizole was significantly better than for placebo, according to both the investigator's and the patient's global evaluations (p less than 0.01) and as indicated by dropouts caused by treatment failure with placebo (p = 0.005). Six of 26 (24%) of the placebo-treated patients in the double-blind study had good to excellent results on the basis of global assessments. Thirteen of 16 patients with placebo-treatment failures who received astemizole in the open trial improved significantly from baseline symptoms of pruritus, erythema, and number of wheals (p less than or equal to 0.05). No significant side effects were reported except mild sedation in three astemizole-treated subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1990

Antiallergic effects of astemizole on immediate type hypersensitivity reactions.

Astemizole (0.5-5 mg/kg, p.o.) dose-dependently inhibited heterologous and homologous PCA reactions in rats at ID50 values of 1.48 mg/kg and 2.37 mg/kg, respectively. The inhibitory effect of astemizole on heterologous PCA was most remarkable when this compound was given p.o. 2 h prior to antigen challenge. Astemizole (0.1-5 mg/kg, p.o.) dose-dependently inhibited experimentally-induced asthma in guinea pigs at an ID50 of 0.86 mg/kg. Ex vivo, astemizole (0.5-5 mg/kg, p.o.) inhibited antigen-induced histamine release from lung pieces of sensitized guinea pigs. In in vitro experiments, the drug dose-dependently inhibited antigen-induced histamine and SRS-A releases from guinea pig lung pieces at concentrations of 0.05-10 microM. Furthermore, astemizole (0.1-10 microM) inhibited the histamine release induced by compound 48/80 and antigen-antibody reaction from rat peritoneal mast cells, and at 0.1-500 nM inhibited both leukotriene C4- and platelet-activating factor (PAF)-induced contraction of isolated guinea pig trachea at submicromolar concentrations. Astemizole not only inhibited 45Ca uptake into rat mast cells but also prevented the Ca2+ release from the intracellular Ca store induced by compound 48/80, although this compound did not affect the histamine release from permeabilized mast cells induced by Ca2+. Our results suggest that one of the antiallergic mechanisms of astemizole may be an inhibition of signal transduction from the mast cell membrane to the intracellular systems.

Airway Resistance↗

PubMed1985

Astemizole--a new, non-sedating antihistamine for hayfever.

Astemizole, a new histamine H1 receptor blocker, was compared with placebo in an eight week, double-blind trial in the treatment of seasonal allergic rhinitis. Sixty-five patients of either sex were randomized to either astemizole (32 patients: 10 mg t.i.d. on day 1, 10 mg b.i.d. on day 2, 10 mg o.d. for the remainder of the study) or placebo (33 patients). Patients were seen bi-weekly and maintained a daily diary record of symptoms throughout the study. Significantly more patients in the placebo group (12) compared to the astemizole group (2) dropped out of the study due to treatment failure (p less than 0.05). Astemizole significantly reduced the frequency and severity of allergic symptoms. In subjective evaluations of each treatment by both the investigator and the patients, astemizole was judged good to excellent by 68% compared to 30% for placebo (p less than 0.05). One patient in each group experienced drowsiness. The only significant side effect of astemizole was weight gain (20 patients compared to 1 in the placebo group), although only one patient discontinued astemizole for this reason.

Adolescent↗

PubMed1988

[General review of a non-sedative antihistaminic, astemizole (Hismanal), a H1 receptor antagonist].

The non-sedating antihistamine Astemizole seems to approach all the major characteristics of the ideal histamine H1 antagonist, according to a comprehensive review of 54 clinical trials and clinical use in over 6,500,000 patients worldwide. The following statements concerning Astemizole can now be made: Astemizole is more potent than any other known antihistamine, following Astemizole therapy, H1 blockade is complete in the main target tissues, such as nasal and ocular mucosa, this blockade is also specific, since all histamine-mediated signs and symptoms respond to the drug, this blockade is maintained, since tolerance does not appear during long-term treatment. Astemizole is a non-sedative and non-toxic drug, even during chronic use. Astemizole is very effective in patients with chronic urticaria. Astemizole has well-documented beneficial protective effects on histamine-induced bronchoconstriction.

Astemizole↗

PubMed1985

Astemizole and other H1-antihistaminic drug treatment of asthma.

The disparity between the activation of mast cells in the airways of patients with allergic asthma and the lack of efficacy of H1-antihistamines in asthma therapy has been difficult to reconcile. Histamine causes bronchoconstriction when inhaled by subjects with asthma and is released in detectable amounts into the circulation after bronchial provocation with an antigen. However, it is only weakly antagonized at bronchial H1-receptors by conventional antihistamines such as chlorpheniramine and clemastine, achieving dose ratios of 2 to 4 at maximally tolerated doses. Astemizole and terfenadine are two new H1-histamine antagonists with greatly increased potency and no sedative and anticholinergic side effects. Astemizole has a delayed onset of maximal activity but induces prolonged H1-blockade that extends 15 to 30 days after the end of treatment, whereas terfenadine has a rapid onset of action with a much shorter duration of effect. With therapeutic doses (10 mg/day), astemizole is at least four times more potent in antagonizing histamine-induced bronchoconstriction than the previously available H1-antihistamines and also effectively antagonizes antigen-induced bronchoconstriction in asthma. Astemizole has been shown to be highly effective in the symptomatic treatment of seasonal allergic rhinoconjunctivitis, with the exception of nasal obstruction. With continued treatment, astemizole also offers useful protection from the symptoms of seasonal asthma. Thus the role of histamine in the pathogenesis of asthma should be reappraised. Potent H1-histamine antagonists such as astemizole and terfenadine may offer some benefit in asthma therapy, but the precise clinical indications for their use will require critical evaluation.

Astemizole↗

PubMed1989

Comparison of beclomethasone dipropionate aqueous nasal spray, astemizole, and the combination in the prophylactic treatment of ragweed pollen-induced rhinoconjunctivitis.

The clinical efficacy and side effect of (1) beclomethasone dipropionate aqueous nasal spray, 400 micrograms daily, (2) astemizole, 10 mg daily, and (3) beclomethasone, 400 micrograms, plus astemizole, 10 mg daily, were compared in a double-blind, randomized, parallel-group trial. Ninety adults were matched into groups of three according to sensitivity to ragweed pollen. One of each of the three subjects was assigned to nasal spray alone, one was assigned to astemizole alone, and one subject was assigned to both medications. Medications were started 1 week before and continued daily until 1 week after the ragweed-pollen season (6 weeks). If rhinoconjunctivitis was inadequately controlled with the trial medications, pressurized steroid nasal spray and/or antihistamine-decongestant eye drops were used in the minimum dose that would ensure relief. Nose and eye symptoms and concomitant medication use were recorded daily in a diary. Sneezing, nasal obstruction, and rhinorrhea were significantly better, and less additional nasal spray was used in subjects taking beclomethasone alone than in subjects taking astemizole alone. Beclomethasone plus astemizole provided no better control of rhinitis than beclomethasone alone. Eye symptoms and eye drop use tended to be less in subjects taking astemizole alone than in subjects taking beclomethasone alone, but the best control of eye symptoms was recorded in the subjects taking both trial medications. Side effects were mild or transient.

Administration, Intranasal↗

PubMed1991

Detection and determination of free and plasma protein-bound astemizole by thin-layer chromatography: a useful technique for bioavailability studies.

A thin-layer chromatographic (TLC) procedure has been developed for the determination of astemizole in plasma as the free and as protein-bound substance. The detection and quantification were performed without using internal standards. In earlier described methods for the estimation of astemizole by high-performance liquid chromatography and radioimmunoassay, only free levels in plasma were quantified, at 3.3% of the total astemizole, with the remaining 96.7% bound to plasma protein and tissue. Our method employs proteolysis of plasma proteins by incubating plasma for 2 h in pepsin. After proteolysis the astemizole is extracted, and a known amount of the extract is spotted on precoated silica gel F 254 plates. Astemizole was quantified using a Shimadzu CS-930 dual-wavelength TLC scanner. The method provides a direct estimate of total astemizole present in the plasma.

Animals↗

PubMed1986

Comparison of the suppressive effect of astemizole, terfenadine, and hydroxyzine on histamine-induced wheals and flares in humans.

Thirty-two healthy volunteers completed a 14-day, double-blind, noncrossover study comparing the efficacy and adverse effects of astemizole, terfenadine, and hydroxyzine. The subjects received either astemizole (load), 30 mg once daily for 1 week and then 10 mg once daily for 1 week, or astemizole (no load), 10 mg once daily for 2 weeks, or terfenadine, 60 mg twice daily for 2 weeks, or hydroxyzine, 50 mg once daily for 2 weeks. Before and on days 7 and 14 of treatment, five intradermal tests with various amounts of histamine phosphate (range 0.3 to 40 micrograms) were performed. Wheal-and-flare responses were traced, and the areas were computed by use of a graphics tablet. All four H1-receptor antagonist treatment regimens were equally effective in reducing the flare response to histamine. Astemizole (load) and hydroxyzine were significantly more effective than terfenadine and astemizole (no load) in reducing wheal size. The incidence of adverse effects, including sedation, was low overall and lowest in the astemizole (no load) and terfenadine groups, although this difference was not statistically significant.

Adult↗

PubMed1985

A comparison of astemizole and chlorpheniramine in dermographic urticaria.

The effects of the H I receptor antagonists astemizole and chlorpheniramine on dermographism were compared in a double-blind study in sixteen patients. Both drugs resulted in a parallel and significant depression of the dermographic force-response curve and an elevation of the weal-force threshold, but the changes were greater in the patients receiving astemizole (a maximal potency shift of 74% for astemizole and 37% for chlorpheniramine). Subjective itch (10 cm line) and frequency of dermographic episodes were also reduced more by astemizole than by chlorpheniramine. The effect of astemizole was greater at 4 weeks than at 2 weeks, whereas the effect of chlorpheniramine had decreased at 4 weeks. The effect of astemizole but not chlorpheniramine was still apparent 4 weeks after treatment had been stopped. Since the degree of residual dermographism was comparable despite great differences in histamine weal inhibition a vasoactive mechanism in addition to that mediated by histamine must be involved in dermographic urticaria.

Adolescent↗

PubMed1991

Antiallergic effects of major metabolites of astemizole in rats and guinea pigs.

Antiallergic effects of astemizole (CAS 68844-77-9) and its metabolites were studied using rats and guinea pigs. All the metabolites of astemizole tested i.e., desmethylastemizole, 6-hydroxydesmethylastemizole and norastemizole, were more active than astemizole in inhibiting the contraction of the ileum as well as the bronchoconstriction induced by histamine in guinea pigs. Desmethylastemizole was about the same as the parent compound in inhibiting the 3H-mepyramine binding in guinea pig cerebellum. In heterologous passive cutaneous anaphylaxis (PCA) and homologous PCA, the metabolites caused almost equipotent inhibition to that seen in astemizole. On the other hand, in the studies of histamine release from rat peritoneal mast cells induced by compound 48/80 or from lung fragments in actively sensitized guinea pigs, desmethylastemizole, 6-hydroxydesmethylastemizole and norastemizole were much less potent than was astemizole. No H2-antagonistic activity was observed with either astemizole or desmethylastemizole.

Animals↗

PubMed1985

[Pharmacology of astemizole (Hismanal) a non-sedating H1 antihistaminic].

In the compound 48/80 lethality test in rats, which is based on the specific activation of mast cells, astemizole was found to be a potent, long-acting and orally very effective inhibitor of anaphylactoid shock. In comparison to other histamine-H1 antagonists, astemizole was remarkably free of interactions with muscarine, serotonin, dopamine, noradrenaline and opiate receptors, and devoid of effects on normal body functions. No evidence of central effects was found, and astemizole did not change the intensity of action of several centrally acting drugs. Toxicity studies have shown astemizole to be a very safe drug. Astemizole is a very effective inhibitor of allergic reactions in rats and dogs. The low oral therapeutic doses of astemizole are expected to provide a pronounced and long-lasting inhibition of allergic reactions in the absence of side effects.

Administration, Oral↗

PubMed1987

Inhibition by astemizole of activity from the isolated semicircular canal.

Since astemizole does not readily pass the blood-brain barrier, it was surprising that it was found useful in patients with chronic vertigo. We therefore speculated that the drug may reach the inner ear and act directly on the sensory cell-afferent nerve synapse. Mice, injected with tritiated astemizole and killed 17 hours later, showed the presence of the drug in the vestibular tissues. Nerve recordings were made from the isolated posterior semicircular canal of the frog. Both spontaneous and stimulated firing rates were obtained with artificial perilymph containing astemizole bathing the isolated canal preparation. Results showed that astemizole has a significant inhibitory effect on vestibular nerve activity at concentrations of 10(-7) mol/L and higher. The exact site of astemizole's inhibitory action is undetermined but is most likely at the hair cell-afferent nerve synapse.

Animals↗

PubMed1985

Effect of the nonsedative H1-receptor antagonist astemizole in perennial allergic and nonallergic rhinitis.

We studied the efficacy and side effects of the H1-antihistamine astemizole in perennial rhinitis. We also defined subgroups of responders and examined the added effect of a steroid spray. Fifty-five adults completed a 10- to 14-week controlled trial. Astemizole reduced the number of sneezes to 41% (p less than 0.001) and the number of nose blowings to 55% (p less than 0.001) of the placebo values. The added use of beclomethasone dipropionate caused a further reduction to 14% (p less than 0.001) and 37% (p less than 0.05), respectively. Nasal blockage was only marginally affected by the antihistamine, but it was reduced to 64% by the steroid spray (p less than 0.001). "Sneezers" responded better to the antihistamine than "blockers," with "nose blowers" in an intermediate position. The effect was equal in allergic and nonallergic patients. Astemizole was completely nonsedative but increased appetite and body weight. An open 1-year study of 17 patients demonstrated that astemizole maintained its efficacy and that further weight gain did not occur. It is concluded that astemizole is a highly effective nonsedative H1-antihistamine suitable for continuous therapy of perennial rhinitis.

Adolescent↗

PubMed1988

Efficacy of continuous treatment with astemizole (Hismanal) and terfenadine (Seldane) in ragweed pollen-induced rhinoconjunctivitis.

Astemizole (Hismanal; Janssen Pharmaceutica Inc., Mississauga, Ontario, Canada) and terfenadine (Seldane; Merrell Dow Pharmaceuticals [Canada], Inc., Concord, Ontario, Canada) were compared for clinical efficacy in a double-blind randomized trial during the ragweed pollen season. Sixty adults, with a history of ragweed-induced rhinoconjunctivitis, were matched according to sensitivity to ragweed pollen. Half took astemizole, 10 mg/day, and the rest took terfenadine, 60 mg twice daily. Medications were started 1 week before and continued daily until 1 week after the ragweed pollen season (7 weeks). If the trial medication was insufficient to keep symptoms well controlled, a steroid nasal spray and/or eye drops were used in the minimum dose that would ensure symptoms were not troublesome. Subjects completed a diary of nocturnal and daytime nasal and eye symptoms and recorded the amount of concomitant medications used. Astemizole showed greater efficacy than terfenadine in controlling rhinorrhea; in addition, the astemizole group used less nasal spray. Other nasal symptoms, eye symptoms, and use of eye drops were similar in the two groups. Skin test sensitivity to serial dilutions of histamine and ragweed extract was determined 1 and 7 weeks after the start of the trial medication. More tachyphylaxis to histamine was shown by the subjects taking terfenadine, as demonstrated by a larger increase in skin sensitivity over the study period. However, a similar change was not observed for ragweed skin sensitivity. These results suggest that when the medication is started before and continued daily throughout the pollen season, astemizole is more efficacious than terfenadine in controlling nasal symptoms, but there is little difference for eye symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMedDate not supplied

Astemizole reduces blood-retinal barrier leakage in experimental diabetes.

We examined the potential of astemizole, a histamine H1-receptor antagonist that does not cross the blood-brain barrier, to reverse blood-retinal barrier leakage to albumin in streptozotocin diabetic rats. Four groups of nondiabetic and four groups of diabetic rats received vehicle or astemizole at dosages of 5, 10, or 20 mg/kg body weight for days 22-28 of a 28-day holding period. There were no significant differences in nondiabetic plasma-vitreous albumin ratios between animals receiving vehicle or any of the three astemizole dosages. Only diabetic rats receiving vehicle showed a significant (p < 0.05) 100% increase in the plasma-vitreous albumin ratio over their nondiabetic counterparts. Diabetic rats receiving either 5, 10, or 20 mg/kg astemizole exhibited total normalization of vitreous albumin accumulation, despite persistence of diabetes. These data indicate that astemizole, an H1-receptor antagonist that does not cross the blood-retinal barrier, is effective in reversing blood-retinal barrier leakage of albumin in experimental diabetes.

Animals↗