Adequate clinical trials of immunotherapy.
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Biomedical subjects
Publications and source records attributed to K Aas.
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A new, low dose sustained-release tablet of theophylline has been developed in order to facilitate a correct dose regimen in asthmatic children treated with theophylline. The formulation (Euphyllin retard mite w/groove) contains 128 mg of theophylline, and can easily be divided. The extent of bioavailability in adults is 0.91, and the peak serum concentration is reached after 8.7 h. 25 children treated with plain theophylline tablets were followed when changing to the sustained-release tablets. Compared to the plain tablets, the serum theophylline concentration before the morning dose was 29 mumol/l higher (range 12-51) when the same daily dose was given as a sustained-release preparation. The serum concentration fluctuations during one dosing interval were reduced with 13 mumol/l (0-26). Mild gastrointestinal side effects reported by the children when using the plain theophylline tablets all disappeared on changing to the sustained-release tablets.
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A solid phase synthesis (SPPS) hexadecapeptide corresponding to residues 49-64 of allergen M from cod was found to bind specifically IgE antibodies from sera of cod-allergic individuals. The SPPS peptide was similarly reactive in IgG-mediated reactions; it could interfere with Allergen M line precipitate in rocket-line immunoelectrophoresis, giving a distinct deflection. It is the only reported synthetic polypeptide imposing allergenic and antigenic reactivity. The hexadecapeptide is composed of two homologous tetrapeptides located at its terminai, tentatively concluded to be mutually critical for the immunological specificity. The data obtained confirmed the predicted reactivity of the Ca2+-binding CD loop of the intact Allergen M.
Most extracts used in hyposensitization (immunotherapy) are complex and ill-defined mixtures of a large number of non-antigenic and antigenic components, only a few of the latter being of significance for allergy and allergen specific immunotherapy. A new purified and well-characterized allergen preparation from timothy pollen is now available, and it has been shown to be superior to the corresponding crude aqueous extract in the diagnosis of IgE-mediated human allergy to timothy pollen. This paper describes the results of hyposensitization for 2 years, with the purified preparation and the crude extract compared. The changes in in vivo and in vitro tests following this treatment in 40 patients with allergic rhinitis due to grass pollen are reported. Both patient groups showed a significant decrease in clinical symptom scores when compared with a control group during the grass pollen season. For all groups the symptom scores correlated well with atmospheric pollen counts. Nasal challenge tests showed a significant increase in nasal tolerance to timothy pollen after 2 years of treatment, but nasal tolerance was unchanged in the control group. Nasal function as a criterion for evaluating the effect of specific hyposensitization is discussed. Serum concentrations of timothy pollen-specific IgE antibodies showed a significant decrease for the group treated with the purified preparation and a slighter and non-significant reduction for the other treated group. There was no significant change in total serum IgE levels. The results indicate that the purified preparation is preferable to the crude aqueous extract in hyposensitization.
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Extracts of five common atmospheric moulds (Alternaria, Aspergillus, Cladosporium, Mucor and Penicillium) obtained from different manufacturers were compared by means of skin prick testing and, partly, with the radioallergosorbent test. Considerable differences were found between the extracts with respect to positive tests found in mould-allergic individuals and controls. A purified allergen preparation of Cladosporium herbarum was superior to the crude allergen extracts. The results suggest that the allergen contents of the extract differed both with respect to total allergenic potency and to allergenic composition.
Six reported cases of anaphylactic reactions due to measles vaccinations of children were investigated. The reactions appeared to be immediate hypersensitivity reactions most probably due to allergy. Trace amounts of calf serum proteins were demonstrated in the measles vaccine by means of crossed immunoelectrophoresis whereas egg antigens could not be detected by this method. The reason for the untoward reactions was not identified. Atopic traits were not reported in any of the patients but were found in first degree family members of three of them. Skin prick testing with measles vaccine was positive in one of the patients only, whereas skin prick testing with egg yolk, egg white, cow's milk and calf serum were negative in all cases. RAST was performed with allergosorbents containing different material used during the vaccine production, but was negative in all cases. The results with control individuals were in accord with previous reports that patients with allergy to hen's egg tolerate the injection of measles vaccine. Immediate hypersensitivity reactions to measles vaccine may occur independent of allergy to egg and even in children without any known allergy or atopic heredity.
Passive transfer (PK) tests were performed with a reaginic serum on a recipient reacting with an immediate and a more prolonged reaction when specificity challenged. Both reactions are thought to be mediated by IgE immunology. Ketotifen, a cycloheptathiophene derivative, and clemastine, given to the recipient in maximal clinical doses for 3 days, inhibited the immediate reaction. Ketotifen had a very slight effect also on the prolonged reaction. The results indicate that the in vivo effects of ketotifen in the human system are due not so much to mast cell inhibitory mechanisms, but more to post-release antihistaminic and some anti-inflammatory properties.
Serum concentrations of theophylline following intravenous and oral administration of aminophylline were studied in asthmatic children, 2--17 years of age. The biological half-life (t 1/2 beta) of theophylline varied between 165 and 495 min. The results revealed that an intravenous loading dose of 6 mg of aminophylline per kg body weight was necessary in order to obtain therapeutic concentrations in children who had not received the drug for the last 6 to 8 hours. The maintenance dose should be determined and controlled by use of serum concentration determinations. In a group of children receiving 5 mg of aminophylline per kg body weight 3 times a day orally, none had concentrations within the therapeutic range in the morning, and only 39% reached therapeutic levels 2 h after the morning dose. No correlation was found between the serum concentration of theophylline and the amount of drug given per kg body weight. The results show that theophylline concentration analysis is necessary to obtain adequate therapeutic levels in children without risking toxic effects.
The diagnostic reliability in food allergy of skin prick tests (SPT) and the radio-allergosorbent test (RAST) was investigated in paediatric patients with respiratory and skin allergies. SPT and RAST were found to be reliable for the diagnosis of allergy to codfish, peas, nuts, peanuts and egg white. Positive SPT and RAST to cereals were common, but were most often without clinical significance or were correlated with respiratory allergy to the inhalation of flour dust. SPT and RAST were only partly reliable with regard to allergy to cow's milk, and were mostly reliable when used together and showing corresponding results. Experimental allergosorbents for RAST with soy beans and white beans were not reliable. The study shows the need to improve the diagnostic materials and to establish the diagnostic reliability of the material and tests used for each food item in question.
The major allergen from codfish (DS 22) was used to study specific and non-specific radiostaining in crossed radioimmunoelectrophoresis (CRIE). Various modifications of CRIE experiments were performed including experiments where immunoprecipitates in agarose were transferred to test tubes and the radioactivity was measured in a gammacounter. The degree of non-specific binding of IgE and 125 I-anti-IgE to the percipitates was low. A linear relation was found between the amount of human serum IgE antibody used in CRIE and the degree of radiostaining obtained. Increasing the amount of DS 22 in the precipitates from 0.31 to 2.5 microgram resulted in a moderate increase in the uptake of 125 I-anti-IgE, whereas further increase of the amount of DS 22 (5--10 microgram) resulted in reduced uptake of isotope. Serum from a patient containing IgE antibodies to rabbit serum gave rise to radiostaining over the entire antibody-containing gel area, and it is suggested that such human sera be avoided when using CRIE.
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