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  • 1
    Electronic Resource
    Electronic Resource
    Duration of the antihistaminic effect after discontinuation
of ebastine (2001)
    Copenhagen : Munksgaard International Publishers
    Allergy 56 (2001), S. 0 
    Details
    ISSN: 1398-9995
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background: The inhibitory effect of antihistamines on allergen-induced skin reactions can impair the results of allergen skin testing, which are necessary for the diagnosis of atopic diseases. This study was designed to determine the time period required for the inhibitory effect of ebastine on allergen-induced skin reactivity to disappear completely. Methods: This was a double-blind, placebo-controlled, parallel-group study including 23 out of 27 randomized patients. They received either ebastine 20 mg or placebo once daily for 7 days. At the end of treatment, allergen challenge was performed daily for 7 days. Histamine challenge was performed on day 1 (6 and 24 h) and day 5 after treatment. The wheal and flare surface areas were measured and analyzed. Results: Highly significant inhibition of the wheal and flare response induced by allergen was observed after ebastine treatment on days 1 and 2 as compared with placebo (P〈0.01 for both). The inhibition was reduced, although still significant, by day 3 (P〈0.05). No significant difference was observed by day 4 between the ebastine and the placebo groups. The effects of histamine challenge were significantly reduced in the ebastine compared with the placebo group at day 1 (6 and 24 h), and were similar at day 5 after treatment. Conclusions: Our results show that the wheal and flare response to allergen after ebastine discontinuation returns to placebo values after 4 days. Therefore, patients using ebastine need to be antihistamine-free for 4 days before the skin prick test. This is valuable information for the allergologist seeking to diagnose allergen sensitivity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1034/j.1398-9995.2001.056006553.x
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  • 2
    Electronic Resource
    Electronic Resource
    Laboratory screening method for selection of healthy volunteers (1990)
    Springer
    European journal of clinical pharmacology 39 (1990), S. 475-479 
    Details
    ISSN: 1432-1041
    Keywords: volunteer selection ; Phase I trial ; health screening ; Bayesian probability ; laboratory screening
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The aim of laboratory screening in Phase I is to exclude subjects with subclinical illness, who might be at increased risk in the study, and who might also adversely influence interpretation of the results. A new method for laboratory screening, based on Bayesian probability theory, is proposed, which consists of: 1. Drawing up a list of diseases to be excluded. 2. Defining for each disease, the maximum acceptable risk that an included subject could be affected by it. 3. Identifying one test for each disease. 4. Using a contingency table to calculate the specificity of the test and integrating the estimated prevalence of the disease from epidemiological data. 5. Applying the percentage obtained by the calculation of specificity to the previously determined distribution of values in the volunteer population to identify the threshold value for inclusion. Use of this deductive method in screening volunteers for Phase I trials affords increased security of selection, while reducing the number of non-pertinent exclusions because of laboratory findings.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00280939
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  • 3
    Electronic Resource
    Electronic Resource
    Adverse events in phase-I studies: a report in 1015 healthy volunteers (1998)
    Springer
    European journal of clinical pharmacology 54 (1998), S. 13-20 
    Details
    ISSN: 1432-1041
    Keywords: Key words Adverse events ; phase-I studies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: This report describes all clinical, laboratory and electrocardiographical adverse events detected in healthy volunteers in a phase-I centre over a 10-year period: 54 phase-I studies are involved, including 1015 healthy young volunteers (993 males) who received 1538 treatments (23 different active drugs or placebo) corresponding to 12143 days of follow-up. This updates a similar report published previously in the European Journal ofClinical Pharmacology. Methods: Adverse events were defined as all events noted in case-report forms. Incidence of adverse events was defined as the ratio between the number of adverse events and the number of follow-up days. Severity was rated as death, life-threatening, severe or minor. Incidences or occurrence rates were compared using the Chi-squared test with Yates' correction. Results: The overall incidence of adverse events was 12.8% with a significant difference between active-drug (13.7%) and placebo (7.9%) treatments. There were 1558 adverse events of 110 distinct kinds. Only for three (headache, diarrhoea and dyspepsia) was the incidence superior to 10‰. Most of these adverse events were also observed with placebo. Ninety-seven percentage of adverse events were of minor intensity; forty three (3%) were rated as severe, including nine worrying cases – six malaises with loss of consciousness, one atrial fibrillation, one hyperthyroidism and one bicytopenia. Some of the adverse events were not related to the tested drugs, but to a vagal reaction or to study conditions. There was no death or life-threatening event. The global rate of occurrence was one adverse event per treatment, one and a half per subject and one out of eight follow-up days. No difference in the overall incidence with placebo was observed between the two successive 5-year periods. Conclusions: This report confirms that adverse events in phase I studies are very common, usually of minor intensity and rarely severe; even though exceptional, life-threatening adverse events are possible. Adverse events occuring in phase I are rarely published, leading to lack of information. Thus, authors invite clinical research organization (CROs) and phase-I centres to regularly publicise at least severe adverse events; they also suggest that the life-threatening adverse events reported to health authorities should be publicised, for example by the World Health Organization (WHO).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050413
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  • 4
    Electronic Resource
    Electronic Resource
    Laboratory data in healthy volunteers: reference values, reference changes, screening and laboratory adverse event limits in Phase I clinical trials (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 13-19 
    Details
    ISSN: 1432-1041
    Keywords: Key words Reference values ; Reference changes ; Phase I clinical trials
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Laboratory data are key evaluation procedures for Phase I clinical pharmacology for two reasons. Firstly, laboratory data are used within the screening process to exclude subjects with asymptomatic diseases, which could result in increased danger to themselves or confuse interpretation of the study results. Secondly, during study implementation, safety evaluation and in particular maximum tolerated dose determination have to be done by a case-by-case analysis, sometimes using laboratory adverse events (LAEs). Thus, relevant limits are needed to discriminate between a usual common variation and a significant abnormality, which is considered to be a LAE. This report presents laboratory data distribution, reference values and reference changes and, based on previously published new methods, suggests inclusion limits at screening and laboratory adverse event limits for analysis during study implementation. Subjects and methods: Nine hundred and twenty-seven young healthy male volunteers were recruited in one centre (Association de Recherche Thérapeutique). A standard screening process was carried out. Protocols were approved by the local ethics committee. Blood sampling was performed in the same conditions. Reference values (at screening and at baseline) were determined by a non-parametric procedure selecting 2.5% and 97.5% of the distribution of data. Reference changes were also defined as the 2.5–97.5% interval of distribution of the variations between the end of treatment and baseline. Inclusion limit and LAE limit methods of determination used had been specified in previous articles. Results: Detailed results of laboratory data distribution, reference values at screening and at baseline, reference changes, inclusion limits and LAE limits are presented in tables with number of subjects, mean, median, standard deviation, minimal and maximal values and the 2.5–97.5% interval for each laboratory parameter. Conclusion: The key aims of this paper are to provide clinical pharmacologists with data, reference values or changes obtained in the real conditions of Phase I study implementation, and to propose relevant limits, either for screening as inclusion limits, or during studies as LAE limits. Thus, these data, reference values and specific limits improve the capacity to screen healthy volunteers and to analyse LAEs during Phase I studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050586
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  • 5
    Electronic Resource
    Electronic Resource
    Upper limit of plasma alanine amino transferase during Phase I studies (1995)
    Springer
    European journal of clinical pharmacology 47 (1995), S. 417-421 
    Details
    ISSN: 1432-1041
    Keywords: Phase I trials ; Alanine amino transferase ; healthy volunteers ; adverse experience ; normal range ; liver function test
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract In Phase I clinical studies, the maximum tolerated dose has to be determined by a case by case analysis sometimes using a laboratory adverse effect, e.g. an increase in alanine amino transferase (ALT). For this reason a threshold to discriminate between significant or non significant adverse changes in ALT is required particularly in Phase I studies, in order to deal with the very common “close to the limit values”. Previous methods (limit of normal range or normal range plus an arbitrary margin) do not solve this problem. The authors propose a new method taking into account the threshold used as inclusion criteria for ALT (R) and the range of spontaneous variations measured under identical Phase I study conditions (V). The (R) and (V) thresholds, respectively, are defined as 50 IU·1−1 and a 50% increase, from baseline. Thus an ALT value is recognized as a “significant adverse experience” if it exceeds 50 IU·1−1 above an increase from baseline exceeding 50% of the baseline value. To highlight the value of the method, it was implemented in a one year period including 8 studies and 134 subjects. The sensitivity, specificity and positive predictive value of various methods were compared. The results showed the following: Six out of 134 subjects had significant adverse changes in ALT (4%); and all these 6 subjects were detected by the proposed new method without error. Eight subjects including two false positives, were detected by an use of the normal range limit, and only 4 were detected using, the 10% margin. Thus, use of the new method showed 1. keeping the normal range limit as the detection threshold led to preserved sensitivity; 2. it reduced the background noise of false positive results related to chance variation around the upper limit, mainly in subjects with a baseline value close to the limit; 3. it allowed better judgment of the significance of a value which lay just beyond the limit when variation from the baseline exceeding the normal range. The new method produced the best combination of sensitivity, specificity and positive predictive value. Given the small number of subjects in the study, further evaluation with a larger population is required. Finally, the proposed new method seems to be a tool easy to use determining the significance of adverse changes in ALT when the values are close to the limit that is common in Phase I studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00196855
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