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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 52 (1997), S. 81-86 
    ISSN: 1432-1041
    Keywords: Key words Phase I study ; Adverse events; critical limits ; drug developments
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The first goal of phase I drug development is the determination of maximal tolerated dose, which must be established by case-by-case analysis, sometimes using a laboratory adverse event. Since no accurate rule defining lab adverse events, has been validated yet, we propose a new “combined method” based on combination of two thresholds: inclusion values and magnitude of variation. Using this combined method, the label “lab adverse event” is applied if any lab value exceeds the inclusion threshold and is associated with a variation from baseline exceeding the variation threshold defined from reference change limit. Thus, this study aimed to test this combined method on a large healthy volunteer population, studied in 19 phase I centres worldwide, and on five lab parameters: alanine amino transferase, aspartate amino transferase, alkaline phosphatases, creatinine and polymorphonuclear leukocytes. Methods: The inclusion threshold from each center was used. Reference change limits were defined from volunteers previously included in comparable studies and were expressed as absolute values: increases of 10 IU · l−1 for alanine amino transferase or aspartate amino transferase, 15 IU · l−1 for alkaline phosphatases, 15 μmol · l−1 for creatinine and a 0.34 109 · l−1 decrease for polymorphonuclear leukocytes. Comparison between the “combined method” and a normal range method was made using positive predictive value and a ratio between relevant and irrelevant results. This application was implemented in all young healthy volunteers (1134) included in 38 phase I studies sponsored by Rhône Poulenc Rorer from 1991 to 1993. Results: Seventy seven subjects (6.7%) were indicated in final study reports as having a lab adverse event (reference group). Of 179 subjects with lab abnormalities defined by the normal range method, 77 belonged to the reference group, inducing a poor 0.43 positive predictive value. Of ninety subjects with lab adverse events defined by the “combined method”, seventy-five belonged to the reference group, inducing a two-fold higher 0.83 positive predictive value. The combined method produced a high ratio of relevant/irrelevant results ( ) compared with the low ratio ( ) achieved using the normal range method. Conclusion: This new “combined method”, leading to a better definition of lab adverse event, seems an accurate and useful tool for routine case-by-case analysis within phase I drug development studies.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 47 (1995), S. 417-421 
    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
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  • 3
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy Section 43 (1987), S. 489-496 
    ISSN: 0584-8539
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy Section 41 (1985), S. 435-450 
    ISSN: 0584-8539
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1365-2222
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Eosinophils, mast cells and T lymphocytes are important cells in the allergic inflammatory process. These cells produce and are regulated by cytokines such as interleukin-3 (IL-3), interleukin-5 (IL-5) and granulocyte macrophage-colony stimulating factor (GM-CSF). We initiated this study to evaluate pathological abnormalities and to detect IL-5 in the duodenal mucosa from patients with food allergy.〈section xml:id="abs1-2"〉〈title type="main"〉MethodsEndoscopy duodenal biopsy specimens were obtained from seven food-allergic patients, six atopic healthy controls and six nonatopic healthy controls. IL-5 protein was evaluated by immunohistochemistry. Electron microscopy as well as double immunofluorescent staining were used to identify the labelled cells and to localize IL-5. IL-5 mRNA expression was evaluated by qualitative polymerase chain reaction.〈section xml:id="abs1-3"〉〈title type="main"〉ResultsA significantly increased number of lymphocytes, mast cells and eosinophils was detected in the lamina propria in food-allergic patients and, in lower number, in atopic controls. Immunostaining for IL-5 was markedly positive in food-allergic patients, slightly increased in atopic controls and negative in nonatopic controls. Ultrastructurally, in food-allergic patients and in atopic controls, IL-5 was localized in eosinophil granules, in the matrix of intact granules and at the periphery of altered granules. Double immunofluorescent staining was performed in food-allergic patients and showed that 86.7% of IL-5+ cells were eosinophils, and that IL-5 was expressed by 24% of eosinophils. IL-5 mRNA was expressed in food-allergic patients but was not detected in atopic and nonatopic controls.〈section xml:id="abs1-4"〉〈title type="main"〉ConclusionActivated eosinophils are involved in gut atopic reactions occurring in food allergy and are probably in part upregulated by their own local production of IL-5.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    British journal of dermatology 134 (1996), S. 0 
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Summary Hyperpigmentation is a well-recognized feature of cutaneous graft-versus-host disease (GVHU). and is usually restricted to sites where lichenoid or sclerodermiform lesions have occurred. Since 1975, two of 745 patients treated by allogeneic bone marrow transplantation in our institution have developed diffuse melanoderma which differed considerably from the classic presentations. They both developed acute GVHD. then lichen planus-like chronic lesions and diffuse melanoderma. Histology of biopsies of the pigmented skin showed intense pigment deposition in the basal and suprabasal layers, and in dermal macrophages. On split-dopa, melanocyte counts were 98 and 93 per Held, respectively. Electron microscopy showed melanocytes protruding into the dermis, and dark melanosomes in all epidermal layers and in macrophages. These findings were suggestive of post-inflammatory hyperpigmentation. In bone marrow recipients, de nova melanoderma is a rare event which could represent a feature of cutaneous GVHD in pigmented subjects.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Keratoderma with scleroatrophy of the extremities, also referred to as Huriez syndrome, is a rare, autosomal dominant condition, first described in 42 of 132 members of two families from northern France. The term clerotylosis was proposed because of the pseudosclerodermatous appearance of the hands and digits. The distinctive feature of this syndrome is the risk of the development of squamous cell carcinoma on affected skin. Since the initial description of this disease, three other families, and possibly a fourth, have been reported. In the present study, we reassessed the clinical, pathological and genetic data in 114 members of one of the two original families, of whom 27 were affected by this syndrome.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    British journal of dermatology 132 (1995), S. 0 
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background Psoriasis involving sensitive skin areas remains difficult to treat because of the side-effects of topical corticosteroids and the irritancy potential of vitamin D3 derivatives. Several clinical trials have demonstrated that calcitriol, the naturally occurring and hormonally active form of vitamin D3, is effective and safe at the dose of 3 µg g−1 for the treatment of psoriasis affecting the trunk and limbs. Methods We compared the safety and efficacy of calcitriol 3 µg g−1 ointment and calcipotriol 50 µg g−1 ointment in a multicentre, randomized, investigator-blinded, left–right comparison in mild to moderate chronic plaque psoriasis affecting sensitive areas, defined as being the face, hairline, retroauricular and flexural areas. One pair of symmetrical and bilateral target lesions was selected from each area and assessed for perilesional erythema, oedema, and stinging/burning. Global assessment of local tolerability and global improvement were rated by the investigator, and the subjects were asked to evaluate the tolerability and efficacy of each product and to express their global preference. Results In the 75 subjects, calcitriol and calcipotriol both led to clearing of at least one target lesion in 21 (28%) of the subjects each. Perilesional erythema (P 〈 0·001), perilesional oedema (P 〈 0·02) and stinging/burning (P 〈 0·001) were all significantly less severe with calcitriol than with calcipotriol. The subjects' evaluation of local tolerability was significantly (P 〈 0·0001) in favour of calcitriol. Ten treatment-related dermatological events occurred in eight subjects, including one subject who experienced skin discomfort on both sides. All other events occurred only on the calcipotriol-treated side (irritant dermatitis, six subjects; contact dermatitis, one subject). Global assessment of improvement from baseline by the investigators was significantly greater for the calcitriol-treated lesions (P 〈 0·02). The subjects' global preference was significantly in favour of calcitriol (P 〈 0·02). Conclusions In the present study, calcitriol ointment was found to be better tolerated and would appear to be more effective than calcipotriol ointment in the treatment of psoriasis in sensitive areas.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 0022-2860
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
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