Treatment of hay fever with loratadine - a new non-sedating antihistamine

The efficacy and safety of loratadine, a new orally active specific H1-receptor blocking antihistamine with poor penetration into the CNS, was evaluated in a double blind comparative study. One hundred and seven hay fever patients, sensitive to birch pollen, were randomized into three parallel groups receiving loratadine 40 mg once daily, clemastine 1 mg twice daily, or placebo during the birch pollen season. Both active treatments showed reduction of symptoms in comparison with placebo, but the results were more pronounced with loratadine treatment, which significantly reduced the overall allergic condition as well as all separate allergic rhino-conjunctivitis symptoms except nasal stuffiness. Compared with placebo the sedation rate was significantly higher with clemastine treatment (P less than 0.05) but not with loratadine. Loratadine was thus concluded to be efficacious in hay fever treatment with a sedation rate not differing from placebo.     

Cardiovascular profile of loratadine

The extremely low reporting rate of cardiovascular adverse events for loratadine, the possible preferential use of loratadine in patients with pre-existing cardiovascular disorders, and the impressive lack of cardiovascular effects at extremely high concentrations in clinical and preclinical studies demonstrate the very safe cardiovascular profile of loratadine.     

Clinical investigation of terfenadine, a non-sedating antihistamine

Terfenadine was evaluated for the relief of symptoms in patients with allergic pollinosis on a double-blind basis. Terfenadine 20 mg tid was as effective as Chlorpheniramine maleate 4 mg tid. Chlorpheniramine consistently showed a higher incidence of sedation than placebo. None of the terfenadein dosage schedules up to 200 mg tid caused sedation significantly different from that of placebo. Terfenadine appears to be the first antihistamine to lack significant central nervous system effects.     

Efficacy and safety of loratadine suspension in the treatment of children with allergic rhinitis

The safety and efficacy of loratadine was compared with that of dexchlorpheniramine in children with allergic rhinitis. Twenty-one children received loratadine 0.11-0.24 mg/kg ideal body weight once daily and 19 dexchlorpheniramine 0.10-0.23 mg/kg every 8 h (0.30-0.69 mg/24 h) for 14 consecutive days. Both loratadine and dexchlorpheniramine were effective in reducing nasal and ocular symptoms in allergic children. Substantial improvement in allergy symptoms was observed at the first evaluation (day 3 of treatment) and was maintained for the study duration. No significant trend of abnormality in laboratory parameters was observed. Drowsiness was present only in the dexchlorpheniramine-treated group. Loratadine appears to be a simple, effective and safe therapy for seasonal allergic rhinitis.     

Safety and efficacy of loratadine (Sch-29851): a new non-sedating antihistamine in seasonal allergic rhinitis

Loratadine, a new antihistamine in the non-sedating class, was evaluated for efficacy and safety in treatment of allergic rhinitis in a multicentered study. Loratadine was found to be both safe and efficacious. When administered to patients with seasonal allergic rhinitis, a single daily oral dose of 10 mg is comparable in efficacy to clemastine, 1 mg, given twice daily. The incidence of sedation with loratadine is comparable to placebo and significantly lower than with clemastine. The incidence of anticholinergic side effects with loratadine is low and in this study was comparable to placebo and clemastine.     

Effect of cetirizine, a new H1 antihistamine, on the early and late allergic reactions in a bronchial provocation test with allergen

Background: Cetirizine is a highly sensitive H₁ antihistamine with particular antiallergic properties, which has been shown to be effective in the treatment of allergic rhinitis, urticaria, and hay-fever-associated asthma.Methods: To assess the effect of cetirizine on the late allergic reaction to a specific bronchial provocation test (BPT) with allergen, we selected 25 patients with allergic asthma as determined by history, skin tests, and specific IgE levels. They were challenged with increasing doses of a cat or mite extract until a 20% drop in forced expiratory volume in 1 second (FEV₁) was recorded. Sixteen patients (11 men and 5 women with a mean age of 22 years; range, 18 to 48 years) exhibited a dual response (early and late allergic reactions). These 16 patients underwent a second BPT 2 weeks later, and each again showed a dual response. They were then randomized to receive either a placebo (8 patients) or cetirizine, 15 mg twice daily (8 patients) in a double-blind fashion. After 7 days of treatment, they underwent a third BPT with the same allergen dose as given in the second BPT.Results: The intensity and duration of early allergic reaction were not affected by cetirizine, whereas all parameters of late allergic reaction were statistically significantly improved in the cetirizine group when compared with those of the placebo group (maximum FEV₁ decrease, p = 0.046; FEV₁ [area above the curve], p = 0.027; maximum airway resistance increase, p = 0.021; airway resistance [area under the curve], p = 0.036).Conclusions: Cetirizine produced a significant protective effect against an allergen-induced late allergic reaction in a BPT. Cetirizine might therefore be effective in the treatment of asthma.     

Effects of loratadine on anti-IgE-induced inflammation, histamine release, and leukocyte recruitment in skin of atopics

The aim of this study was to assess the ability of the H¹-receptor antagonist loratadine to modify anti-IgE-induced cutaneous wheal-and-flare and late-phase reactions (WFR and LPR), as well as histamine release and leukocyte accumulation in skin chambers. For this purpose, 10 atopics with allergic rhinitis were entered into a double-blind crossover study in which they received either placebo or loratadine (20 mg/day orally) for 8 days separated by a 7-day washout period. Blisters were induced on both forearms on day 7 of each treatment period, and were unroofed on day 8 and covered with plastic skin chambers. Chamber fluids were collected during 7 h after 1-h incubation with anti-IgE or control IgG. Intradermal challenge with histamine and anti-IgE was performed at the same occasion. As compared to placebo treatment, loratadine inhibited the immediate WFRs to anti-IgE by 35% (wheal) and 65% (flare), respectively (P < 0.01), and corresponding reactions to histamine challenge by 50% and 70% (P<0.001), respectively. Moreover, the initial phase (0-2 h) of the LPR induced by anti-IgE was attenuated by up to ～60% (P < 0.001) during loratadine treatment. Thereafter, no inhibition of the LPR was observed. The magnitude and time course of histamine release into skin chambers was virtually the same after loratadine and placebo treatment, with a peak during 0-1 h and a progressive decline during the following 2 h. Accumulation of α2-macroglobulin, reflecting extravasation of large plasma proteins, also peaked during the first hour and was unaffected by loratadine during the 8-h observation period. Moreover, loratadine did not reduce the anti-IgE-induced recruitment of eosinophils or other subtypes of leukocytes. Altogether, loratadine inhibited both the WFRs to histamine and anti-IgE and the initial phase of the IgE-mediated LPR. However, loratadine did not express anti-inflammatory activity with respect to mast-cell mediator release or leukocyte recruitment. The latter findings are in contrast to the action of loratadine in allergic rhinitis and conjunctivitis, suggesting that the actions of loratadine may be organ specific and that the effects of loratadine cannot always be extrapolated from one tissue to another.     

Onset of action in the nasal antihistaminic effect of cetirizine and loratadine in patients with allergic rhinitis

Several studies have compared the cutaneous efficacy of cetirizine and loratadine and their onset of action. We assessed the nasal effect of these two antihistamines in a randomized, double-blind, crossover, placebo-controlled trial in order to compare objectively their efficacy and onset of action in the noses of patients with allergic rhinitis. Nasal challenge was performed by nebulization of increasing doubling doses of histamine (0, 0.04-1.28 mg/nostril) in 12 patients (eight men, four women, aged 22-39 years). Nasal airway resistance (NAR) was measured by posterior rhinomanometry either 1.5 h or 4 h after intake of cetirizine (10 mg), loratadine (10 mg), or placebo. Baseline NAR was identical between all study days (2.60-2.88 cmH₂O·1⁻¹·s). One and a half hours after intake, the increase in NAR induced by histamine was significantly reduced by both cetirizine and loratadine in contrast to placebo. However, with cetirizine the nasal obstruction was significantly lower than with loratadine ( P <0.05). Four hours after intake, a similar inhibition of the nasal obstruction caused by histamine was observed with both cetirizine and loratadine ( P <0.05). In conclusion, this study found cetirizine and loratadine to have similar nasal efficacy at therapeutic dosage 4 h after intake, whereas cetirizine was more effective than loratadine 1.5 h after intake. In agreement with the results observed in the skin, our study suggests a more rapid onset of action of cetirizine in the nose in allergic rhinitis.     

Recombinant human alpha-2a interferon promotes an atypical process of mast cell secretion with ultrastructural features suggestive for piecemeal degranulation

Purified mast cells (MC), isolated from the rat peritoneum, were stimulated in vitro with recombinant human IFN-alpha 2a (rhIFN-alpha 2a) and studied ultrastructurally. Quantitative determination of histamine release was also performed. The following ultrastructural features were observed: (1) dilation of single granules, leading to the formation of cytoplasmic cavities filled with dissolved or eroded matrices; (2) induction of partially empty, nonfused granule containers close to unaltered resting granules, a process very suggestive of piecemeal degranulation; (3) focal exocytosis, characterized by opening of single granules to the cell exterior and/or fusion of a few granules into small secretory channels. Histamine release was slightly increased in rhIFN-alpha 2a-treated MC, although not to significant levels. These results indicate that rhIFN-alpha 2a induces a characteristic pattern of degranulation in rat peritoneal MC and that a small proportion of rhIFN-alpha 2a-stimulated MC shows ultrastructural features suggestive for piecemeal degranulation.     

Evaluation of the CNS properties of SCH 29851, a potential non-sedating antihistamine

SCH 29851 [8-chloro[6,11-dihydro-11-(1-carboethoxy-4-piperidylidene)-5-H-benzo[5,6]cyclohepta[1,2-b]-pyridine] was discovered as part of a search for a new antihistamine without effects on the central nervous system (CHS). Antihistaminc potency and duration of action of SCH 29851 and other antihistamines were assessed by inhibition of histamine-induced lethality in guinea pigs and histamine-induced paw edema in mice. Evaluation of possible CNS effects included gross observation of mice, rats, dogs and monkeys, prevention of electroshock-induced convulsions, acetic acid-induced writhing and physostigmine-induced lethality in mice and biochemical measures related to sedative liability such as displacement ofin vivo ³H-mepyramine binding in mouse brain andin vitro ³H-WB 4101 binding in guinea pig cortex. Comparisons were made to several antihistamines considered to be sedative to varying degrees, including diphenhydramine, promethazine, chlorpheniramine and azatadine and to the newer antihistamines terfenadine and astemizole which are reported to be non-sedating in man at doses that antagonize the effects of histamine peripherally.SCH 29851 had antihistamine activity in the tests used with a potency at least comparable to most standards and was devoid of activity in all the functional and biochemical models used as indices of CNS activity. It is expected that SCH 29851 should be an effective, long acting, antihistamine in man without sedative effects at therapeutic doses.     

Evaluation of the CNS properties of SCH 29851, a potential non-sedating antihistamine

SCH 29851 [8-chloro[6,11-dihydro-11-(1-carboethoxy-4-piperidylidene)-5-H-benzo[5,6]cyclohepta[1,2-b]-pyridine] was discovered as part of a search for a new antihistamine without effects on the central nervous system (CHS). Antihistaminic potency and duration of action of SCH 29851 and other antihistamines were assessed by inhibition of histamine-induced lethality in guinea pigs and histamine-induced paw edema in mice. Evaluation of possible CNS effects included gross observation of mice, rats, dogs and monkeys, prevention of electroshock-induced convulsions, acetic acid-induced writhing and physostigmine-induced lethality in mice and biochemical measures related to sedative liability such as displacement ofin vivo ³H-mepyramine binding in mouse brain andin vitro ³H-WB 4101 binding in guinea pig cortex. Comparisons were made to several antihistamines considered to be sedative to varying degrees, including diphenhydramine, promethazine, chlorpheniramine and azatadine and to the newer antihistamines terfenadine and astemizole which are reported to be non-sedating in man at doses that antagonize the effects of histamine peripherally.SCH 29851 had antihistamine activity in the tests used with a potency at least comparable to most standards and was devoid of activity in all the functional and biochemical models used as indices of CNS activity. It is expected that SCH 29851 should be an effective, long acting, antihistamine in man without sedative effects at therapeutic doses.     

A comparison of once daily fexofenadine versus the combination of montelukast plus loratadine on domiciliary nasal peak flow and symptoms in seasonal allergic rhinitis

BACKGROUND: The combination of montelukast (ML) and loratadine (LT) has previously been shown to be superior to either drug alone in managing seasonal allergic rhinitis (SAR), whilst fexofenadine (FEX) has been shown to be better than LT as monotherapy. OBJECTIVES: We wished to compare ML + LT vs. FEX alone for effects on daily measurements (am/pm) of peak inspiratory flow (PIF) and symptoms. METHODS: Thirty-seven patients with SAR (skin prick positive to grass pollen) were randomised into a single-blind, double-dummy placebo (PL)-controlled cross-over study during the grass pollen season, comparing 2 weeks of once daily treatment with (a) 120mg FEX or (b) 10mg ML + 10mg LT. There was a 7-10 day placebo run-in and washout prior to each randomised treatment. The average of am/pm PIF (the primary outcome variable) was analysed. Patients recorded their symptom scores (from 0 to 3) twice daily, for nasal blockage, discharge, itching and sneezing with; total eye symptoms, ocular cromoglycate use, and daily activity. The total nasal symptom score was calculated as a composite (out of 24). RESULTS: There were no significant differences between baselines after the run-in and washout placebos for any variables. There were significant (P < 0.05, Bonferroni) improvements in all symptoms and PIF compared to pooled placebo with both treatments for all end-points, but no differences between the two treatment regimes (as means and within-treatment 95% confidence intervals): PIF: PL 102 (98-107), FEX 111 (107-116), ML+LT 113 (109-118); total nasal symptoms: PL 7.4 (6.7-2.0), FEX 5.0 (4.3-5.7), ML + LT 4.0 (3.3-4.7). CONCLUSIONS: Once daily FEX as monotherapy was equally effective as the combination of once daily ML + LT in improving nasal peak flow and controlling symptoms in SAR. Further studies are indicated to assess whether ML confers additional benefits to FEX in SAR.     

Desloratadine prevents compound 48/80-induced mast cell degranulation: visualization using a vital fluorescent dye technique

BACKGROUND: Desloratadine is a selective H1-antihistamine used in the treatment of allergic rhinitis and chronic idiopathic urticaria. Desloratadine inhibits the release of allergic inflammatory mediators in vitro. We studied the impact of desloratadine on mast cell degranulation due to activation and re-activation by the secretagogue, compound 48/80. METHODS: Rat peritoneal eluate containing 5-6% mast cells were activated by a low concentration of compound 48/80 in a medium containing the vital fluorescent dye, Sulforhodamine-B (SFRM-B, 200 microg/ml), which is engulfed by activated mast cells. The fluorescent image of activated mast cells was captured digitally and the total fluorescent area was analyzed when desloratadine was applied before or after compound 48/80. RESULTS: Mast cells were not activated by desloratadine (10(-4) M), SFRM-B (200 microg/ml), or diluent alone. A low concentration of compound 48/80 (0.125 microg/ml) induced fluorescence, while mast cells lost fluorescent images due to further degranulation on re-exposure to compound 48/80. Desloratadine (10(-8)-10(-4) M), inhibited compound 48/80-induced mast cell degranulation in a concentration-dependent manner. Desloratadine also reduced the loss of fluorescent images due to re-exposure to compound 48/80. CONCLUSIONS: Desloratadine may have a mast cell stabilizing effect at low concentrations in response to repeated mast cell activation in vitro.     

Studies on the Specific Degranulation of Mast Cell Sensitized by Several Allergens in vitro

Food allergy is a major health issue worldwide. Mast cells play a very important role in the immediate hypersensitivity for which mast cell degranulation needs to be studied extensively. In this study, an approach was taken to study the characteristics of sensitized mast cell degranulation in vitro, which associated with the study of mast cells and animal models. BALB/c mice were immunized respectively by several food allergens, then blood and peritoneal mast cells were collected at different time points. A dynamic determination was carried out between mast cells and serumal IgE. Comparative analysis on sequential time points showed that there was a close coincidence between mast cell degranulation and IgE antibody titers in sensitized BALB/c mice. Furthermore, it is interesting that sensitized mast cells could implement specific degranulation against the challenges in vitro, but the closely tropomyosins induced mast cell degranulation displayed cross reactions. This is very similar to IgE resisting the allergens in vivo. The study disclosed some characteristics on mast cells, coming from sensitized BALB/c mice, degranulation in vitro.     

Efficacy of mizolastine, a new antihistamine, compared with placebo in the treatment of chronic idiopathic urticaria

A two-centre, double-blind, randomized, placebo (P)-controlled, parallel-group study was conducted in the UK to examine the efficacy and safety of mizolastine (M), a new H₁-receptor antagonist, as a once-daily 10-mg dose in chronic idiopathic urticaria. Fifty-six outpatients (M: n = 28; P: n = 28) with a mean age of 38 ± 15 years, a duration of disease of more than 3 years, and symptoms of urticaria at least twice a week in the absence of treatment were recruited. After a single-blind placebo run-in period, patients were allocated to one of two treatment groups and were evaluated after 7 and 28 days. The main characteristics (age, duration of disease, number of urticarial episodes, and total score) of the two groups were comparable at inclusion. Mizolastine was shown to improve the urticaria symptoms: at the end of the study, mizolastine produced a significantly greater decrease in the global symptom score comprising itch, wheals, and erythema (M: 2.1 ± 2.1 vs P: 0.4 ± 2.0; P = 0.002). The patient-rated global discomfort from symptoms measured by visual analog scale was significantly improved with mizolastine (M: 31.4 ± 36.7) compared to placebo (P: 5.4 ± 27.6; P = 0.003), with respectively more M responders (74.1%) than P responders (28.6%, P = 0.001), a responder being a patient with a ≥50% decrease in VAS. Premature dropouts due to lack of efficacy and loss to follow-up mainly occurred at the first evaluation (day 7) and were more often observed in patients in the placebo group ( n = 17) than in the mizolastine group ( n = 8) ( P = 0.031). No serious adverse events were recorded. Somnolence was reported in two mizolastine patients, one of whom discontinued the study. Thus, mizolastine may be considered a new treatment option for the symptoms of chronic urticaria.     

Assessment of urticaria and angio-oedema

There are many types of urticaria and the principal form of assessment is by clinical history and examination. Urticarial weal formation involves acute, reversible vasodilatation and increased vascular permeability. If the process is deeper the more diffuse swelling is termed angio-oedema. The major types of urticaria include allergic, physical and idiopathic forms. In allergic urticaria, IgE-mediated degranulation of mast cells results in weals of short duration which typically respond well to antihistamines. Physical urticarias are induced by physical insults including pressure, scratch, cold, etc. The distribution and duration of individual weals may suggest the causal factor. Chronic idiopathic urticaria can be very variable, with individual weals lasting between 90 min and 24 hours. Longer-lasting weals are less responsive to anti-histamines and clearly involve other mediators. When long-lasting weals fade leaving a bruised appearance urticarial vasculitis is present which may only respond to systemic corticosteroids. In a proportion of individuals with chronic idiopathic urticaria, auto-antibodies are present with specificity for the high affinity receptor for IgE or sometimes, for IgE itself. In general laboratory tests for allergic factors or other assessments of general health are completely unhelpful.     

Comparative Analysis of Bone Marrow-derived Mast Cell Differentiation in C57BL/6 and BALB/c Mice

Allergic diseases have increased in the last three decades. Mast cells play a critical role in allergic diseases along with allergen-specific immunoglobulin E (IgE). Following mast cell degranulation elicited by ligation of the IgE-FcεRI receptor complex with allergen, allergic reactions are followed by various symptoms such as vascular hyperpermeability, mucous secretion, itching, sneezing, wheezing, rashes, fever, and anaphylactic shock. Susceptibility or inclination to allergy varies depending on individual genetic traits and living environment, and it has long been believed that such an inclination is determined by an immunologic balance of T helper cell types.

Mouse strains also have different susceptibilities to allergy. Similar to T helper cells and macrophages, it is not known whether mast cells can also be divided into two different types between mouse strains. In this study, we prepared bone marrow-derived mast cells from BALB/c and C57BL/6 mice and examined their cellular properties. Cellular response to IL-3 and the process of mast cell differentiation from bone marrow cells were different on the basis of cell surface marker molecules. BALB/c-derived cells more efficiently exhibited degranulation than did C57BL/6-derived cells following both calcium ionophore and receptor crosslinking.

These functional differences persisted even after a longer cell culture for 8 weeks, suggesting a difference in cell-autonomous characteristics. These results support the concept that mast cells also have different cell types dependent on their genetic background.

Abbreviations: Ab: antibody; BMMC: bone marrow-derived mast cell; DNP: dinitrophenyl; FACS: fluorescence-activated cell sorter; FCS: fetal calf serum; FITC: fluorescein isothiocyanate; FSC: forward scatter; HRP: horseradish peroxidase; HSA: human serum albumin; Ig: immunoglobulin; IL: interleukin; MIP-2: macrophage inflammatory protein-2; MCP: mast cell protease; PE: phycoerythrin; PerCP: Peridinin chlorophyll protein complex; SNP: single nucleotide polymorphisms; SSC: side scatter; Th: T helper; TNF-α: tumor necrosis factor alpha