bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lack of behavioural toxicity of mizolastine: a review of the clinical pharmacology studies
Authors: Rosenzweig P. , Patat A. 
Published: March 2003

First‐generation H1 antihistamines were associated with major sedative side‐effects which were heavily disruptive to young active and aged patients when performing everyday activities. Mizolastine is a potent and selective H1‐receptor antagonist which slowly penetrates into the brain and thus lacks the sedative effects of earlier antihistamines.In this paper we present an overview of five clinical pharmacology studies which were carried out with a view to assessing mizolastine effects on psychomotor and skilled performances, and on cognitive functions in young and aged subjects.The studies were all randomized, double‐blind, placebo and (with the exception of one) active‐drug controlled, cross‐over studies. A total of 76 young and 15 aged subjects were enrolled. Two studies evaluated mizolastine over a range of doses (5–45 mg), and three involved a single or multiple administrations of the therapeutic dose (10 mg/day). Comparators were first generation (clemastine, tripolidine) and second generation (terfenadine, cetirizine) antihistamines. Drug effects were evaluated through standardized psychometric and memory tests, and subjective self‐ratings (visual analogue scales). In two studies, driving performance was assessed using an actual driving test. Two studies investigated drug interaction with depressants of the central nervous system such as alcohol and lorazepam.The results of the five reported studies were consistent in that mizolastine showed to be free from sedative effects when administered at the therapeutic dose. As with other newly developed antihistamines, some changes occurred at higher dose levels. At the therapeutic dose mizolastine did not alter driving performance and did not potentiate the depressant effects of alcohol and lorazepam.Mizolastine was shown to be free from sedative effects that could affect the safe performance of everyday life activities in young and aged patients when administered at the therapeutic dose.
Sensory neuropeptides induce histamine release from bronchoalveolar lavage cells in both nonasthmatic coughers and cough variant asthmatics
Authors: Forsythe  , Mcgarvey  , Heaney  , Macmahon  , Ennis  
Published: March 2003

BackgroundSensory neuropeptides have been suggested to play a role in the pathogenesis of a number of respiratory diseases including asthma and chronic non‐productive cough.ObjectivesTo investigate the action of sensory neuropeptides on airway mast cells obtained by bronchoalveolar lavage (BAL).MethodsBAL was performed on 23 nonasthmatic patients with cough (NAC), 11 patients with cough variant asthma (CVA) and 10 nonatopic controls. Washed lavage cells were stimulated (20 min, 37 °C) with calcitonin gene‐related peptide (CGRP), neurokinin A (NKA) and substance P (25 and 50 μmol/L).ResultsThe neuropeptides tested induced histamine release in all groups studied. Only CGRP (50 μmol/L) induced significantly more histamine release from both NAC and CVA patients compared with control subjects (P = 0.038 and 0.045, respectively).ConclusionRegardless of aetiology, mast cells from patients with chronic cough appear to have an increased responsiveness to CGRP compared with controls. The results of the present study suggest that the role of CGRP in chronic cough should be further investigated.
Functional effects of the inhibition of the cysteine protease activity of the major house dust mite allergen Der p 1 by a novel peptide‐based inhibitor
Authors: John  , Rusznak  , Ramjee  , Lamont  , Abrahamson  , Hewitt  
Published: March 2003

BackgroundThe house dust mite (HDM) Dermatophagoides pteronyssinus is an important source of allergens, which can cause allergic conditions. The cysteine protease activity of Der p 1 may enhance the potency of this major mite allergen through cleavage of CD23 and CD25 from the surface of immune cells, IgE independent mast cell activation, increases in epithelial cell permeability and inactivation of an endogenous serine protease inhibitor. Inhibition of the enzymatic activity of Der p 1 may therefore be of therapeutic benefit.ObjectiveTo examine the activity of PTL11028, a newly developed Der p 1 inhibitor, in a range of assays that directly or indirectly measure Der p 1 protease activity and to compare its activity to endogenous cysteine protease inhibitors.MethodsThe proteolytic activities of purified Der p 1 or HDM extract and inhibitory properties of PTL11028 were examined through cleavage of an artificial peptidyl substrate, cleavage of CD23 from human B cells and permeability studies on primary human bronchial epithelial cells.ResultsPTL11028 is a highly potent and specific Der p 1 inhibitor, being effective against both purified protease and Der p 1 within HDM extract. PTL11028 can completely inhibit Der p 1‐mediated CD23 cleavage from human B cells and also reduces HDM‐induced human bronchial epithelial cell permeability by 50%. Der p 1 is potently inhibited by cystatin A and to a lesser extent by cystatins C and E/M.ConclusionPTL11028 is a highly potent and selective irreversible inhibitor of the cysteine protease activity of Der p 1, an activity that may be modulated in vivo by some human cystatins. PTL11028 prevents the Der p 1‐mediated cleavage of CD23 from human B cells and significantly reduces HDM‐induced permeabilization of the epithelial barrier. PTL11028 is an important tool to examine the biological effects of Der p 1 in a range of in vitro and in vivo model systems.
Validation of the ISAAC video questionnaire (AVQ3.0) in adolescents from a mixed ethnic background
Authors: Gibson  , Henry  , Shah  , Toneguzzi  , Francis  , Norzila  , Davies  
Published: March 2003

BackgroundThe International Study of Asthma and Allergies in Childhood (ISAAC) has developed an international version of the asthma video questionnaire (AVQ3.0) to measure asthma prevalence. This questionnaire has not been validated in adolescents from a mixed ethnic background.ObjectiveThe aims of this study were to compare the video questionnaire with a written questionnaire in the detection of airway hyperresponsiveness to hypertonic saline in a population of adolescents from a mixed ethnic background, and to establish the repeatability and psychometric properties of the asthma video questionnaire.MethodsThe study was conducted in four secondary schools in Sydney, an area with a high proportion of people from a non‐English speaking background. Four hundred and seventy‐five students from schools 1 and 2 completed the video questionnaire and a subgroup of these students (n = 170) completed the written questionnaire and a hypertonic saline inhalation challenge. Reproducibility of the questionnaire was evaluated by administering the questionnaire to a subsample of students 2 weeks later. The psychometric properties of the video questionnaire were examined in 852 students at two other schools (schools 3 and 4).ResultsOne hundred and sixty‐nine students aged 13.5 (sd 1.3) years completed both written and video questionnaires, and the hypertonic saline challenge. The students had widely different cultural backgrounds including Asian, South Pacific, Middle Eastern, European and African countries. There was good agreement between the questionnaires for wheeze (kappa 0.42). Questions on the video questionnaire concerning wheezing had good sensitivity (90%) and specificity (68%) for airway hyperresponsiveness to hypertonic saline. The video questionnaire was reproducible (kappa 0.82), had good internal consistency (Cronbach's alpha 0.81) and each question pertained to a single construct explaining 58% of the variance in total score.ConclusionThis study has validated the international version of the ISAAC video questionnaire against airway hyperresponsiveness to hypertonic saline in adolescents from a mixed ethnic background, and identified that the questionnaire has good psychometric properties. The ISAAC video has proved to be a valuable tool for the assessment of asthma prevalence in populations of ethnic diversity.
Anaphylaxis to chlorhexidine. Case report. Implication of immunoglobulin E antibodies and identification of an allergenic determinant
Authors: Pham  , Weiner  , Reisner  , Baldo  
Published: March 2003

BackgroundThere are many reports of allergic reactions, including anaphylaxis, following exposure to chlorhexidine. Reactions may occur via contact with the skin and mucous membranes or from catheters treated with the antibacterial agent. Apart from implicating chlorguanide in immunoglobulin (Ig) E antibody‐binding studies on serum from an anaphylactic patient, little work has been done on the molecular basis of recognition of the agent in sensitive subjects.ObjectivesThe molecular basis of IgE‐binding to chlorhexidine was closely examined with the view of defining its fine structural recognition features by antibodies from a subject who experienced anaphylaxis following contact with the antiseptic.MethodsTryptase determinations, different drug‐solid phases, immunoassays and quantitative hapten inhibition studies with chlorhexidine and selected structural analogues were employed together with serum from the anaphylactic patient. Results were analysed to define the complete drug allergenic determinant and to identify the important structural features complementary to the IgE antibody combining sites.ResultsThe subject's serum tryptase levels sampled after the reaction were elevated and employment of a chlorhexidine‐EA Sepharose solid phase showed the presence of serum IgE antibodies to the drug. Lack of inhibition by 4‐chlorophenol and other selected substituted phenyl compounds showed that the terminal groups at each end of the chlorhexidine molecule, alone, did not account for antibody recognition of the antibacterial agent. Although chlorguanide and alexidine, the structures of which each comprise part of the chlorhexidine molecule, showed significant inhibition of the binding of IgE antibodies to chlorhexidine, neither compound was as potent an inhibitor as chlorhexidine itself. Two molecules of chlorguanide make up the symmetrical molecule of chlorhexidine while the interior structure of alexidine (that is excluding the terminal 2‐ethylhexyl groups) is identical to part of the chlorhexidine molecule.ConclusionsTaken together, for this patient, these results lead to the conclusion that the whole chlorhexidine molecule is complementary to the IgE antibody combining sites and that the 4‐chlorophenol, biguanide and hexamethylene structures together comprise the allergenic determinant. Hence, like one of the trimethoprim determinants identified, but unlike most drug allergenic determinants identified so far, the chlorhexidine allergenic determinant identified here encompasses the entire molecule.
The association of sensitization to inhalant allergens with allergy symptoms: the influence of bronchial hyperresponsiveness and blood eosinophil count
Authors: Kerkhof M. , Schouten J. P. , De Monchy J. G. R. 
Published: March 2003

BackgroundWe investigated whether the association of allergy symptoms with sensitization to inhalant allergens depends on bronchial hyperresponsiveness, blood eosinophil count, or the degree and nature of sensitization.MethodsData on asthma and rhino‐conjunctivitis symptoms were obtained from 1904 subjects from a random sample of the Dutch population, aged 20–70 years by the ECRHS questionnaire. Total IgE and specific IgE to four inhalant allergens were measured using CAP System. Bronchial hyperresponsiveness (BHR) was defined as PD20≤ 2 mg methacholine and ‘high eosinophil count’ as an eosinophil count in the highest quartile.ResultsForty‐three percent of the subjects with specific IgE to inhalant allergens was asymptomatic. These subjects had a lower degree of sensitization than symptomatic sensitized subjects and had ‘normal’ prevalences of BHR and ‘high eosinophil count’. Logistic regression showed that the presence of BHR increased the risk of having symptoms for subjects who were sensitized to indoor allergens. Low levels of specific IgE to indoor allergens were only associated with symptoms when BHR was present. Sensitization to outdoor allergens was associated with symptoms at all levels of specific IgE, independently of BHR or eosinophils.ConclusionOur epidemiological data suggest that whether low levels of specific IgE to indoor allergens lead to allergic symptoms is probably determined by the concurrent existence of inflammation of the airways.
Intranasal capsaicin is lacking therapeutic effect in perennial allergic rhinitis to house dust mite. A placebo‐controlled study
Authors: Gerth Van Wijk R. , Terreehorst I. T. , Mulder P. G. H. , Garrelds I. M. , Blom H. M. , Popering S. 
Published: March 2003

In a recent placebo‐controlled study we demonstrated that capsaicin is an efficacious substance in the treatment of non‐allergic non‐infectious rhinitis. In this study the therapeutic effect lasted more than 9 months. This effect was not based on modulation of inflammation.To evaluate the effect of repeated application of capsaicin to patients with a nasal allergy to house dust mites (HDM), using the same treatment protocol as recently introduced in the treatment of non‐allergic patients.Twenty‐six patients with rhinitis, 15 females and 11 males (range: 20–46 years; mean 30.5), allergic to HDM were treated with either capsaicin or placebo in a double‐blind, placebo‐controlled, parallel group design. Nasal reactivity to HDM expressed as nasal symptoms, albumin and leukotriene levels in nasal lavage fluid and responsiveness to histamine, assessed as symptoms before and 6 weeks after treatment, were used to compare both treatment groups. In addition, visual analogue scales and rhinitis quality of life (RQL) assessment before, 6 weeks after and 3 months after treatment were used as outcome variables.No significant effect of capsaicin on nasal challenge tests with HDM (nasal symptoms, albumin and leukotriene levels), on VAS or RQL outcome 6 weeks or 3 month's after treatment, was demonstrated. Capsaicin did have a small effect on the area of the curve (AUC) of histamine dose response curves (P = 0.03).Desensitization with capsaicin in doses sufficient to control symptoms in patients with severe non‐allergic rhinitis is lacking therapeutic effect in perennial allergic rhinitis.
The lymphoproliferative response to enzymatically digested gelatin in subjects with gelatin hypersensitivity
Authors: Kumagai T. , Nakayama T. , Kamada M. , Igarashi C. , Yuri K. , Furukawa H. , Wagatuma K. , Tsutsumi H. , Chiba S. , Kojima H. , Saito A. , Okui T. , Yano S. 
Published: March 2003

BackgroundThis study was designed to evaluate the immunogenic characteristics of enzymatically digested gelatin, ‘FreAlagin’, employing the lymphoproliferative response in subjects with gelatin hypersensitivity. Our purpose was to assess the response of primed lymphocytes to the newly developed FreAlagin and compare it to the response to conventional gelatin.MethodsA gelatin‐specific lymphocyte proliferation test (LPT) was performed in 110 children with adverse reactions to gelatin‐containing vaccines, who showed positive gelatin‐specific cell‐mediated immunity and were thus diagnosed as having gelatin hypersensitivity. Gelatin‐specific IgE was measured in all subjects. The antigenic activity of FreAlagin to lymphocytes was compared with that of conventional bovine gelatin. Positive and negative control specimens were obtained from the patients with anaphylaxis and from subjects inoculated with gelatin‐free vaccine who showed no adverse reactions in order to establish the fluorometric ELISA system to determine IgE antibody to gelatin and LPT.ResultsThe lymphocyte activity against FreAlagin was much less than that to Wako gelatin and more than half of the subjects who reacted positively to Wako gelatin had a negative LPT to FreAlagin. Although 47% of the subjects had positive LPTs to FreAlagin, all but two still had lower SIs to FreAlagin compared with Wako gelatin.ConclusionWe conclude that the antigenic activity of FreAlagin as measured by the cell‐mediated immune response is significantly less than that of conventional bovine gelatin. However, it is still necessary to perform clinical trials to show a reduced or absent clinical reactivity to FreAlagin in sensitized patients to conventional gelatin.
Differential mediator release from basophils of allergic and non‐allergic asthmatic patients after stimulation with anti‐IgE and C5a
Authors: Abrahamsen O. , Haas H. , Schreiber J. , Schlaak M. 
Published: March 2003

The differentiation between allergic and non‐allergic asthma is a common and important challenge for the clinician. Until now, no in vitro diagnostic characteristics have been described to distinguish between these types.To examine the diagnostic value of a basophil stimulation test, we compared anti‐IgE‐ and C5a‐induced mediator release from peripheral blood leucocytes in different types of bronchial asthma.Peripheral blood leucocytes (PBL) from 10 aspirin‐sensitive asthmatics (ASA), 12 non‐allergic asthmatics without aspirin intolerance (NAA), seven allergic asthmatics (AA), and nine healthy controls were prepared by dextran sedimentation. After priming with interleukin‐3 (IL‐3) PBL were stimulated with anti‐IgE and C5a, and the release of histamine (HR) and sulfidoleukotrienes (LTR) in the supernatant was compared. Additionally, purified leucocyte fractions were studied to determine the cellular source of mediator release.Upon stimulation with anti‐IgE LTR was slightly, but not significantly, lower in ASA and NAA compared to AA and controls. In contrast, C5a‐triggered LTR was significantly higher in ASA (14.4 ± 12.88 pg/105 cells) and NAA (22.9 ± 22.61 pg/105 cells) than in AA (9.6 ± 3.29 pg/105 cells) and controls (7.5 ± 7.19 pg/105 cells) (P < 0.05). This difference between ASA and NAA vs. AA and controls was even more pronounced when determining the quotient C5a‐/anti‐IgE‐induced LTR (P < 0.001). At an optimal cut‐off point of 1.0, calculated by relative operating characteristics (ROC) analysis, the positive predictive value for a donor to belong to ASA or NAA was 0.94. No significant differences could be found in HR between the asthmatic patient groups and healthy controls in either condition. As cellular source of LTR and HR the basophil could be determined.Determination of anti‐IgE‐ and C5a‐induced LTR from basophils allows us to discriminate between allergic and non‐allergic asthmatic patients. For diagnostic purposes the quotient C5a‐/anti‐IgE‐induced LTR is more significant than considering a single parameter. ASA cannot be distinguished from NAA.
The NK‐2 receptor antagonist SR 48968C does not improve adenosine hyperresponsiveness and airway obstruction in allergic asthma
Authors: Kraan J. , Vink‐Klooster H. , Postma D. S. 
Published: March 2003

When stimulated, excitatory nonadrenergic noncholinergic (e‐NANC) nerves locally release tachykinins like Neurokinin (NK) A and Substance P, causing neurogenic inflammation and airway obstruction via activation of specific NK‐1 and NK‐2 receptors. The recently developed nonpeptide NK‐2 receptor antagonist SR 48968C has a high affinity for the NK‐2 receptor, and is a strong and selective antagonist of NK‐2 receptor mediated airway obstruction.In a placebo‐controlled cross‐over study, we investigated the effect of SR 48968C, administrated orally once‐daily in a dosage of 100 mg during 9 days, on airway responsiveness to adenosine 5′‐monophosphate (AMP) in 12 allergic asthmatic patients. Furthermore, we assessed its effect on airway obstruction, by measuring FEV1 on the first and last day of each treatment period and by peak flow registration at home throughout the study period.SR 48968C had no significant effect on PC20AMP or on FEV1 measured on day 1 and 9, and morning and evening peakflow measured at home on day 2–8. Thus, although SR 48968C was administrated in a dosage that might cause a demonstrable blocking effect on airway NK‐2 receptors in asthma, it did not have a significant bronchodilatory or bronchoprotective effect against adenosine hyperresponsiveness in this study. Further studies are needed to assess the value of SR 48968C and other NK receptor antagonists in the treatment of asthma
Pharmacokinetics of an allergen and a monomeric allergoid for oromucosal immunotherapy in allergic volunteers
Authors: Bagnasco M. , Passalacqua G. , Villa G. , Augeri C. , Flamigni G. , Borini E. , Falagiani P. , Mistrello G. , Canonica G.W. , Mariani G. 
Published: March 2003

Little is known about the pharmacokinetics of allergens for local immunotherapy. Thus, we studied the pharmacokinetics in allergic volunteers of a commercial allergenic vaccine in orosoluble tablets (LAIS®, Lofarma S.p.A).The carbamylated monomeric allergoid derived from Parietaria judaica major allergen (Par j 1), characterized by maintenance of the original molecular size, and the native allergen, were radiolabelled with 123I, then incorporated into the commercial soluble tablets and administered to allergic subjects. Early sequential and late static scintigraphic acquisitions were performed, and plasma radioactivity was measured at different time intervals.No difference in local pharmacokinetics was observed between the allergen and the allergoid: part of the tracer was retained in the mouth for at least 2 h after swallowing. No direct absorption through the oral mucosa could be detected, as plasma radioactivity increased only after swallowing and peaked at 2 h. However, the plasma peak attained with the allergoid in tablets was significantly higher with respect to the native allergen. Finally, some undegraded allergoid, but not the allergen, could be constantly detected in the bloodstream at plasma peak.The results showed a similar behaviour of the allergoid and the allergen in tablets as far as their local kinetics are concerned, whereas plasma peak was higher with the allergoid than with the allergen. Therefore we conclude that the chemical modification of the allergen may affect its pharmacokinetics, by making it less susceptible to enzymatic degradation.
Allergen‐induced bronchial inflammation is associated with decreased levels of surfactant proteins A and D in a murine model of asthma
Authors: Wang J. Y. , Shieh C. C. , Yu C. K. , Lei H. Y. 
Published: March 2003

Background Increasing evidence suggests that pulmonary surfactant protein A (SP‐A) and D (SP‐D) participate in the lung defence against pathogens. However, the role of surfactant proteins in the pathogenesis of allergen‐induced airway inflammation has not been elucidated. In this study we examined the levels and distributions of SP‐A and SP‐D in a dust mite (Dermatophagoides pteronyssinus, Der p) allergen‐induced murine model of asthma.Methods The concentration of SP‐A and SP‐D in the bronchoalveolar lavage fluid (BALF) and the distribution of surfactant proteins in the lung were assayed by ELISA and immunohistochemistry methods, respectively. The effect of surfactant proteins on allergen‐induced pulmonary lymphocyte proliferation was also studied.Results We demonstrated that there were marked reductions of SP‐A and SP‐D levels in the BALF of Der p‐sensitized BALB/c mice at 48–72 h after allergen challenge (AC). Both purified SP‐A and SP‐D were able to suppress, in a dose dependent manner, Der p‐stimulated intrapulmonary lymphocyte proliferation of naïve mice with saline or allergen challenge, or of Der p‐sensitized mice with saline challenge. On the contrary, this suppressive effect was mild (< 9%) on lymphocytes from sensitized mice after AC.Conclusion These results indicated the involvement of pulmonary surfactant proteins in the allergic bronchial inflammation of sensitized mice.