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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↗
PubMed1982

In vitro and in vivo binding characteristics of a new long-acting histamine H1 antagonist, astemizole.

Binding characteristics of astemizole were studied in vitro in various receptor binding models and in vivo by determining the occupancy of histamine H1 receptors in guinea pig lung and cerebellum. In vitro, astemizole was found to have a high affinity for histamine H1 receptors, but great difficulties were encountered in proving this because of its high affinity for nonspecific binding sites. Since the equilibrium conditions were not reached in vitro, the real affinity of astemizole remains unclear and its receptor profile must be interpreted with caution. Nevertheless, the drug is certainly much more potent on histamine H1 receptors than on serotonin S2 and adrenergic alpha 1-receptors. Moreover, it was found to be devoid of antimuscarinic and antidopaminergic properties. The most striking property of this drug is its extremely slow dissociation rate from H1 receptors when assayed in vitro using [3H]-pyrilamine. Ex vivo experiments were performed in guinea pigs; astemizole was given orally to the animals, and the occupancy of H1 receptors in the lung and the cerebellum was determined in vitro by the [3H]-pyrilamine binding assay. Astemizole was found to occupy H1 receptors in lung at very low doses. Here again the most striking receptor binding property was its very long duration. The occupancy of H1 receptors in lung began to decline only 4-6 days after administration of the drug. However, there was a marked difference between the occupancy of peripheral and central receptors; indeed, in contrast to pyrilamine, astemizole at pharmacological doses did not reach the H1 receptors in the cerebellum, presumably because the drug does not readily cross the blood-brain barrier.

Animals↗
PubMed1996

Astemizole in combination with pseudoephedrine in the treatment of seasonal allergic rhinitis.

The efficacy and side effects of once-daily astemizole-D, a combination of 10 mg astemizole and 240 mg pseudoephedrine, were compared with those of twice-daily brompheniramine-D, a combination of 12 mg brompheniramine and 50 mg phenylpropanolamine (Lunerin), in 64 patients with seasonal allergic rhinitis caused by birch pollen. Efficacy was monitored by patient's diary scores, investigator assessments of nasal and eye symptoms and need of rescue medication during the 4-week study period. Both astemizole-D and brompheniramine-D reduced nasal and eye symptoms of allergy. There were no significant differences between the treatment groups regarding obstruction, but brompheniramine-D alleviated symptoms of rhinorrhoea and itchy eyes significantly more than astemizole-D. On the other hand, the patients in the brompheniramine-D group reported dry mouth, tiredness and drowsiness more often than those in the astemizole-D group. The results indicate that the two drugs are effective in the treatment of seasonal allergic rhinitis, but astemizole-D is better tolerated than brompheniramine-D.

Adolescent↗
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↗
PubMed1983

The effects of astemizole on histamine-induced weal and flare.

The effect of astemizole on the weal and flare response to intradermal histamine has been studied in normal volunteers after single dosing, and in patients with urticaria and pruritus after chronic dosing with the drug. Single doses of astemizole (40 mg) in normal volunteers significantly reduced histamine weal and flare at 24 and 48 h (p less than 0.001). Before treatment, there was a significantly greater response to intradermal histamine in patients with urticaria than pruritus (p less than 0.05). Chronic dosing with astemizole produced significant reduction in histamine-induced weal and flare in both patient groups which did not show evidence of tachyphalaxis over the period of the study. The effect of astemizole on histamine-induced weal and flare was accompanied by a significant increase in the rate of weal and flare disappearance in both patients (weal p less than 0.002, flare p less than 0.05) and volunteers (weal p less than 0.02, flare p less than 0.005); but there was no change in the rate of weal formation. The effects of astemizole on weal and flare kinetics may be a function of its high level of H1 antagonist activity.

Adult↗
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↗
PubMed1998

Dual effect of the anti-allergic astemizole on Ca2+ fluxes in rat basophilic leukemia (RBL-2H3) cells: release of Ca2+ from intracellular stores and inhibition of Ca2+ release-activated Ca2+ influx.

The antiallergic drugs astemizole and norastemizole inhibit exocytosis in mast cells, which might be relevant for their therapeutic action. From previous studies, it appeared that the drugs inhibited 45Ca2+ influx. Here, we present a more detailed study on the effects of astemizole and norastemizole on Ca2+ fluxes. Fura-2-loaded rat basophilic leukemia (RBL-2H3) cells were activated through the high-affinity receptor for IgE (FcepsilonRI) with antigen or by the endoplasmatic reticulum ATPase inhibitor thapsigargin, bypassing direct FcepsilonRI-related events. It appeared that astemizole (>15 microM), in contrast to norastemizole, showed a dual effect on intracellular calcium concentration ([Ca2+]i): a rise in intracellular calcium concentration was induced, which originated in the release of intracellular Ca2+ stores, whereas Ca2+ influx via store-operated Ca2+ (SOC) channels was inhibited. Ca2+ influx was further characterized using Ba2+ influx, whereas processes in the absence of Ca2+ influx were studied using Ni2+ or EGTA. It was concluded that the drugs most likely affect the store-operated Ca2+ channels in RBL cells directly. The two effects of astemizole on Ca2+ fluxes had opposing influences on exocytosis, thereby accounting for the biphasic effect of increasing astemizole concentration on mediator release in RBL cells.

Animals↗
PubMed1994

Torsades de pointes ventricular tachycardia associated with overdose of astemizole.

An overdose of astemizole predisposes the myocardium to ventricular dysrhythmias, including torsades de pointes. Herein we describe a case of astemizole-induced torsades de pointes ventricular tachycardia and also review previous case reports in the literature. All the patients were young, and dysrhythmias developed only in those with corrected QT intervals greater than 500 ms. Although several mechanisms have been postulated, no clear explanation has been provided for why astemizole promotes myocardial dysrhythmias. Treatment of astemizole-induced torsades de pointes includes discontinuing use of astemizole, intravenous administration of magnesium sulfate and isoproterenol, temporary cardiac pacing, and, when necessary, direct current cardioversion. A cardiac cause of syncope or convulsions must not be overlooked, especially in patients taking H1 antagonists because they often have these symptoms before hospitalization or detection of torsades de pointes (or both).

Adult↗
PubMed2006

An extension of the Early Treatment Diabetic Retinopathy Study (ETDRS) system for grading of diabetic macular edema in the Astemizole Retinopathy Trial.

PURPOSE: To compare the effects of astemizole, an antihistamine, versus placebo on the 1-year course of diabetic macular edema (DME) and to illustrate use of a modified ETDRS system for grading areas of retinal thickening and hard exudates that may be useful in clinical trials of treatments for this disorder. METHODS: Between June 1994 and September 1997, at 2 clinics, 63 patients who had, in at least one eye (the study eye), DME that had not previously been treated with macular photocoagulation, and for which photocoagulation was not currently recommended by the investigator, were enrolled and randomly assigned to astemizole or placebo. Fifty-four of the 63 patients (86%, 26 in Clinic 1 and 28 in Clinic 2) completed 1 year of followup and had adequate 7-field stereoscopic film-based color fundus photographs of the study eye at the baseline and 1-year visits. DME was > 0.33 disc diameters (DD) from the center of the macula in 48% of study eyes and involved the center in 13%. Photographs were graded using the ETDRS protocol modified to allow estimates of areas of retinal thickening (RT) and hard exudate (HE) to be made on continuous scales in disc area (DA) units. Principal outcome measures were mean change in the square root of RT area (the average diameter of the area in DD), mean change in area of HE, and change in the degree to which RT involved or threatened the center of the macula. RESULTS: At baseline, RT area in the 54 study eyes ranged from 0.09 to 4.0 DA (median 1.1). At the 1-year visit the square root of RT area (RTdd) had decreased by > or= 0.3 DD in 10 eyes, increased by >or = 0.3 DD in 19 and was about the same in 25. Mean change at 1 year was +0.09 DD (SD 0.57) for astemizole versus +0.19 DD (SD 0.48) for placebo, for a difference of -0.10 DD (95% CI -0.38, +0.19; p = 0.51). Adjustments for baseline and time-dependent risk factors did not change this result appreciably, although there was a trend towards a difference in favor of astemizole in the subgroup of patients with more severe retinopathy. Other morphologic outcomes paralleled change in RTdd. Change in RTdd did vary by clinic: -0.03 DD in Clinic 2, versus + 0.32 DD in Clinic 1, for a difference of -0.35 DD (95% CI -0.62, -0.07; p = 0.014). Clinic 1 is a tertiary retinal referral center in Pennsylvania and Clinic 2 a retinal clinic closely affiliated with a large diabetes clinic in Copenhagen. The unexpected clinic difference in outcome provided an opportunity for further analyses using the modified ETDRS system. In comparison to Clinic 1, Clinic 2 patients were more often male, were younger at diagnosis of diabetes, and had less severe retinopathy and better visual acuity, but these differences did not appear to explain the trend for lesser increase in RTdd. CONCLUSION: No effect of astemizole was found, but the confidence interval for the principal outcome, mean change in RTdd, included both a modest beneficial effect and a small harmful effect. This outcome measure did demonstrate a small difference in outcome by clinic, which could not be explained by baseline characteristics but may reflect differences in access to and/or continuity of care or other unmeasured differences associated with different referral patterns. Although optical coherence tomography may supplant photography as a measure of central RT, photographic assessments of change in RT and HE areas analyzed with the methods described herein may be useful outcomes in trials assessing treatment of early stages of DME. Application of these methods to other data sets is needed to confirm this conclusion.

Adult↗
PubMed1983

The acute and chronic effects of H1 receptor blockade with astemizole on indocyanine green clearance.

The effects of acute and chronic (3 months) dosing with astemizole on indocyanine green kinetics have been investigated in normal volunteers and patients. A single dose of astemizole 40 mg produced significant reduction in indocyanine green clearance (P less than 0.02) and volume of distribution (P less than 0.02) when assessed at 48 h, but not at 24 h. In six volunteers who did not receive astemizole there was no significant change in indocyanine green kinetics over a 48 h period. In seven patients on chronic treatment with astemizole there was no significant change in indocyanine green kinetics when these were measured at 1 month and 3 months and compared to pre-treatment values. The change in indocyanine green clearance and volume of distribution following acute astemizole treatment did not correlate with H1-receptor antagonism. Change in indocyanine green clearance following acute drug administration may not be due to changes in liver blood flow and should therefore be interpreted with caution.

Adult↗
PubMed1992

Comparison of the effects of loratadine and astemizole in the treatment of children with seasonal allergic rhinoconjunctivitis.

The efficacy and safety of a once-daily dose of loratadine 10 mg (5 mg in patients whose body weight was less than or equal to 30 kg) and astemizole 2 mg/10 kg body weight o.d. were compared in a 14-day third-party blind study. Forty-one children (30 boys and 11 girls, aged 6-14 years) with seasonal allergic rhinoconjunctivitis entered the study. The pollen count was monitored throughout the study. A significant improvement (p less than 0.01) in allergy symptoms was observed from the third day for both drugs; there was no significant difference between drugs, although loratadine led to a greater reduction in symptoms. In the astemizole group, the apparently rapid onset of drug action might by explained by reduced pollen exposure. Therapeutic response was excellent/good in 83.3% and 58.8% of the loratadine and astemizole groups, respectively. The results reported by the patients/parents were similar. Nine of the children on astemizole and four children on loratadine complained of side effects; three patients in the astemizole group were withdrawn from treatment because of adverse effects. No abnormal changes in lab values were observed in either group.

Adolescent↗
PubMedDate not supplied

Astemizole-D causes less sleep impairment than loratadine-D.

This randomized, double-blind, double-dummy, parallel-group trial was initiated to evaluate and compare the tolerability of once-daily astemizole-D capsules (10 mg astemizole/240 mg pseudoephedrine) and twice-daily loratadine-D tablets (5 mg loratadine/120 mg pseudoephedrine), with particular reference to the impact of treatment on quality of sleep. A total of 240 healthy volunteers participated in this study with a treatment duration of 3 days. Astemizole-D consistently produced less sleep impairment than loratadine-D with statistically significant differences in favour of astemizole-D reported for night-time waking on days 4 and 5 (P = 0.004 and P = 0.006, respectively), as well as for night-time restlessness on day 4 and the total score for all sleep parameters on day 4 (P < 0.05). Global evaluations of overall sleep quality at the end of the trial also revealed some statistically significant differences in favour of astemizole-D. Both drugs were well tolerated and there were no differences in the incidence and type of adverse events reported in the two treatment groups. Slight changes in heart rate and blood-pressure were observed in both treatment groups, but these were small and were not considered to be of clinical significance. In conclusion, once-daily astemizole-D is well tolerated and appears to cause less sleep impairment than twice-daily loratadine-D.

Adolescent↗
PubMed1987

Astemizole: a long-acting, nonsedating antihistamine.

Astemizole is a long-acting, highly selective histamine1-receptor antagonist with minimal central and anticholinergic effects. Comparison studies have shown astemizole to be equal or superior to currently available antihistamines, beclomethasone nasal spray, and cromolyn sodium in relieving allergic symptoms of seasonal and perennial allergic rhinitis. Other uses include treatment of allergic conjunctivitis and chronic urticaria. Astemizole is not as effective for treatment of acute allergic symptoms because of its delayed onset of action. Astemizole and its active metabolite, desmethylastemizole, have long elimination half-lives permitting once-daily dosing. The incidence of sedation is lower than with conventional antihistamines, but increased appetite and weight gain do occur. Astemizole should be useful for both maintenance and prophylactic therapy in patients with chronic allergic conditions who cannot tolerate the sedative or anticholinergic effects of conventional antihistamines.

Animals↗
PubMedDate not supplied

Lack of weight gain associated with short-term astemizole treatment.

The effect of treatment with astemizole for three weeks on weight was assessed in 44 patients with seasonal allergic rhinitis who participated in a randomized, double-blind, placebo-controlled clinical trial. Astemizole 10-mg tablets and identical placebo tablets were used. Compared with baseline, weight increased significantly in astemizole-treated patients (1.07 +/- 1.39 kg; p = 0.0004); however, the mean change in weight in astemizole-treated patients was not statistically significantly different than that seen in placebo-treated patients (0.85 +/- 1.68 kg). No relationship was found between changes in weight and age, sex, initial weight, percentage of obesity, and plasma astemizole concentrations.

Adult↗
PubMed2000

Reversal of acquired resistance to doxorubicin in K562 human leukemia cells by astemizole.

This study demonstrates that astemizole, a non-sedating anti-histaminergic drug with low toxicity in vivo, greatly potentiates the growth-inhibitory activity of doxorubicin in doxorubicin-resistant human leukemia cells (K562/DXR). Astemizole synergistically potentiated the cytotoxicity of doxorubicin for K562/DXR cells at a concentration of 0.1-3 microM in a dose-dependent manner, whereas they showed hardly any synthergistic effect in the parental cell line (K562) at the same concentration. Since doxorubicin resistance in these cells is associated with the expression of high levels of P-glycoprotein, we evaluated the effect of astemizole on P-glycoprotein activity in cytofluorographic efflux experiments with doxorubicin. Our results indicate that astemizole inhibits the P-glycoprotein pump-efflux activity in a dose-related manner. Moreover, it also inhibits the photolabeling of P-glycoprotein by [3H]azidopine in a dose-dependent manner. These findings provide a biological basis for the potential therapeutic application of astemizole as an anticancer drug either alone or in combination with doxorubicin to multidrug-resistant leukemic cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

[Efficacy and safety of astemizole in the treatment of allergic rhinitis and urticaria: a systematic review with meta-analysis].

OBJECTIVE: To compare astemizole with other first or second generation antihistaminics in the treatment of allergic rhinitis or urticaria. DESIGN: Systematic revision of clinical, controlled and randomized tests. MATERIAL AND METHODS: 36 controlled, randomized, clinical, double or simple blind tests were made in 6,446 patients; 4,513 of them were assigned to astemizole and 1,933 to other first or second generation antihistaminics. Analyzed outcomes: Rate of global success; global scoring improvement of rhinitis; ocular, nasal or pharingeal pruritus; watering; nasal obstruction; sneeze; urticaria; cutaneous response to histamine; time to get a satisfactory improvent; frequency of sedation and headache. RESULTS: In connection to global success there were significant differences in favor of astemizole (OR 6.72, CI95% 5.36 to 8.41, p 0.0001); alike global scoring improvement of rhinitis (SMD -0.82, CI95% -1.70 to 0.06, p 0.04); rhinorrhea (SMD of -0.70, CI95% -1.47 to -0.03, p 0.02); nasal, pharingeal or ocular pruritus (SMD -0.64, CI95% -1.63 to 0.35, p 0.03); urticaria (SMD of -3.53, CI95% -4.11 to -2.94, p 0.0001), and reduction of cutaneous response to histamine (SMD -2.02, CI95% -2.47 to -1.57, p 0.0001). Differences for watering, nasal obstruction or sneeze were not observed. Finally, the safety area was analyzed considering the existence of sedation and headache; it was demonstrated less sedation (OR 0.23, CI95% 0.18 to 0.30, p 0.0001) and less headache (OR 0.58, CI95% 0.40 to 0.85, p 0.005) in the group treated with astemizole. CONCLUSIONS: The available evidence shows a therapeutic superiority of astemizole versus other antihistaminics in relation to the percentage of global success and the global scoring improvement of rhinitis, rhinorrhea, pruritus in general, urticaria symptoms and of the reduction of response to histamine, with a smaller frequency of headache or sedation.

Adult↗