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Giorgio Cocconi – One of the best experts on this subject based on the ideXlab platform.

  • First generation aromatase inhibitors — Aminoglutethimide and testololactone
    Breast cancer research and treatment, 1994
    Co-Authors: Giorgio Cocconi
    Abstract:

    Aminoglutethimide and testololactone may be considered the first generation aromatase inhiinhibitors for the endocrine treatment of breast carcinoma. Initially, both of these agents were designed and used clinically based on different concepts of their mechanisms of action. Only later were they both demonstrated to inhibit aromatase. Curiously, testololactone was earlier and more widely used than Aminoglutethimide in treating advanced breast carcinoma. The discovery of the peripheral aromatase inhibition as the proper mechanism of action was delayed for both the agents but was relatively more timely for Aminoglutethimide. Paradoxically, the clinical use of testololactone has become already obsolete since its true mechanism of action was discovered. Aminoglutethimide is still the most widely used aromatase inhibitor in treating advanced breast carcinoma. Due to the initial misinterpretation of its mechanism of action, Aminoglutethimide was used for a long time at a relative high daily dose, always combined with hydrocortisone. Subsequent phase II and then randomized phase III studies demonstrated an equivalent efficacy using half (500 mg) of the previous conventional daily dose (1000 mg), with hydrocortisone. Very recently, a randomized clinical trial demonstrated that administering this lower dose without hydrocortisone did not significantly decrease the clinical efficacy. By decreasing the dose of Aminoglutethimide, the incidence of side effects has been reduced. So, the last paradoxical aspect of the Aminoglutethimide story is that this agent seemed initially very toxic but finally, with the new schedules, shows a very low toxicity profile, especially after the first few weeks of treatment.

  • first generation aromatase inhibitors Aminoglutethimide and testololactone
    Breast Cancer Research and Treatment, 1994
    Co-Authors: Giorgio Cocconi
    Abstract:

    Aminoglutethimide and testololactone may be considered the first generation aromatase inhiinhibitors for the endocrine treatment of breast carcinoma. Initially, both of these agents were designed and used clinically based on different concepts of their mechanisms of action. Only later were they both demonstrated to inhibit aromatase. Curiously, testololactone was earlier and more widely used than Aminoglutethimide in treating advanced breast carcinoma. The discovery of the peripheral aromatase inhibition as the proper mechanism of action was delayed for both the agents but was relatively more timely for Aminoglutethimide. Paradoxically, the clinical use of testololactone has become already obsolete since its true mechanism of action was discovered. Aminoglutethimide is still the most widely used aromatase inhibitor in treating advanced breast carcinoma. Due to the initial misinterpretation of its mechanism of action, Aminoglutethimide was used for a long time at a relative high daily dose, always combined with hydrocortisone. Subsequent phase II and then randomized phase III studies demonstrated an equivalent efficacy using half (500 mg) of the previous conventional daily dose (1000 mg), with hydrocortisone. Very recently, a randomized clinical trial demonstrated that administering this lower dose without hydrocortisone did not significantly decrease the clinical efficacy. By decreasing the dose of Aminoglutethimide, the incidence of side effects has been reduced. So, the last paradoxical aspect of the Aminoglutethimide story is that this agent seemed initially very toxic but finally, with the new schedules, shows a very low toxicity profile, especially after the first few weeks of treatment.

Samuel Cos – One of the best experts on this subject based on the ideXlab platform.

  • Melatonin enhances the inhibitory effect of Aminoglutethimide on aromatase activity in MCF-7 human breast cancer cells
    Breast cancer research and treatment, 2005
    Co-Authors: Carlos Martínez-campa, Alicia González, M. D. Mediavilla, Carolina Alonso-gonzález, Emilio J. Sánchez-barceló, Samuel Cos
    Abstract:

    The inhibition of the aromatase-induced intratumoral estrogen synthesis is one of the main anticancer pharmacological strategies. The aim of this paper was to study if a melatonin pretreatment prior to Aminoglutethimide increases the efficiency of the aromatase inhibitor used in treating breast cancer. Aminoglutethimide (100 microM) and melatonin (1 nM) significantly decreased cellular aromatase activity in unpretreated MCF-7 cells. A sequential regimen of melatonin (1 nM) followed 24 h later by Aminoglutethimide (100 microM) induced a significantly higher decrease in MCF-7 cell aromatase activity to below the values obtained in unpretreated cells. Melatonin treatment inhibited aromatase mRNA expression in unpretreated cells and a sequential treatment of cells with melatonin followed by Aminoglutethimide induced a significant inhibition in the aromatase mRNA expression as compared to cells exposed to the same doses of Aminoglutethimide, but without melatonin pretreatment. The present study demonstrates that a treatment with melatonin followed by Aminoglutethimide is the most effective way of reducing the aromatase activity in the MCF-7 cell line. The Aminoglutethimide inhibitory effect is more potent when MCF-7 cells are pre-exposed to melatonin. Our results suggest that melatonin pretreatment increases the reduction of the aromatase activity of cells exposed to Aminoglutethimide as a result of the decrease in the aromatase mRNA expression. The findings presented here point to melatonin pretreatment as a novel and interesting means to increase the efficacy of competitive aromatase inhiinhibitors used in treating breast cancer.

  • melatonin enhances the inhibitory effect of Aminoglutethimide on aromatase activity in mcf 7 human breast cancer cells
    Breast Cancer Research and Treatment, 2005
    Co-Authors: Carlos Martinezcampa, Alicia González, M. D. Mediavilla, Carolina Alonsogonzalez, Emilio J Sanchezbarcelo, Samuel Cos
    Abstract:

    The inhibition of the aromatase-induced intratumoral estrogen synthesis is one of the main anticancer pharmacological strategies. The aim of this paper was to study if a melatonin pretreatment prior to Aminoglutethimide increases the efficiency of the aromatase inhibitor used in treating breast cancer. Aminoglutethimide (100 μM) and melatonin (1 nM) significantly decreased cellular aromatase activity in unpretreated MCF−7 cells. A sequential regimen of melatonin (1 nM) followed 24 h later by Aminoglutethimide (100 μM) induced a significantly higher decrease in MCF-7 cell aromatase activity to below the values obtained in unpretreated cells. Melatonin treatment inhibited aromatase mRNA expression in unpretreated cells and a sequential treatment of cells with melatonin followed by Aminoglutethimide induced a significant inhibition in the aromatase mRNA expression as compared to cells exposed to the same doses of Aminoglutethimide, but without melatonin pretreatment.

Wilhelm Schänzer – One of the best experts on this subject based on the ideXlab platform.

  • identification of the aromatase inhibitor Aminoglutethimide in urine by gas chromatography mass spectrometry
    Rapid Communications in Mass Spectrometry, 2002
    Co-Authors: Ute Mareck, Gerd Sigmund, Georg Opfermann, Hans Geyer, Wilhelm Schänzer
    Abstract:

    Aminoglutethimide is used therapeutically as an aromatase inhibitor in the treatment of metastatic breast cancer in post-menopausal women. For doping purposes, Aminoglutethimide may be used for treatment of adverse effects of an extensive abuse of anabolic androgenic steroids (gynaecomastia) and to increase the testosterone concentration and stimulation of testosterone biosynthesis. The use of aromatase inhiinhibitors has been prohibited for male athletes since September 1, 2001. The purpose of this study was to develop methods for the identification of the parent compound or its main metabolite and the inclusion of this information into established screening procedures in doping analysis. An excretion study was conducted using oral application of one single therapeutic dose (500 mg) of Orimeten®. The analysis was performed by gas chromatography/mass spectrometry (GC/MS). Aminoglutethimide is excreted almost totally as unconjugated parent compound and is detectable by different screening procedures for up to 165 h. Most suitable for the detection of Aminoglutethimide is the screening procedure for heavy volatile nitrogen-containing drugs (‘Screening 2’). However, since only competition samples are analysed in that screening procedure, the additional inclusion of Aminoglutethimide in the screening procedure for anabolic androgenic agents (‘Screening 4’) is recommended. Full mass spectra and diagnostic ions for the analysis of Aminoglutethimide are presented. Copyright © 2002 John Wiley & Sons, Ltd.

  • Identification of the aromatase inhibitor Aminoglutethimide in urine by gas chromatography/mass spectrometry
    Rapid communications in mass spectrometry : RCM, 2002
    Co-Authors: Ute Mareck, Gerd Sigmund, Georg Opfermann, Hans Geyer, Wilhelm Schänzer
    Abstract:

    Aminoglutethimide is used therapeutically as an aromatase inhibitor in the treatment of metastatic breast cancer in post-menopausal women. For doping purposes, Aminoglutethimide may be used for treatment of adverse effects of an extensive abuse of anabolic androgenic steroids (gynaecomastia) and to increase the testosterone concentration and stimulation of testosterone biosynthesis. The use of aromatase inhiinhibitors has been prohibited for male athletes since September 1, 2001. The purpose of this study was to develop methods for the identification of the parent compound or its main metabolite and the inclusion of this information into established screening procedures in doping analysis. An excretion study was conducted using oral application of one single therapeutic dose (500 mg) of Orimeten®. The analysis was performed by gas chromatography/mass spectrometry (GC/MS). Aminoglutethimide is excreted almost totally as unconjugated parent compound and is detectable by different screening procedures for up to 165 h. Most suitable for the detection of Aminoglutethimide is the screening procedure for heavy volatile nitrogen-containing drugs (‘Screening 2’). However, since only competition samples are analysed in that screening procedure, the additional inclusion of Aminoglutethimide in the screening procedure for anabolic androgenic agents (‘Screening 4’) is recommended. Full mass spectra and diagnostic ions for the analysis of Aminoglutethimide are presented. Copyright © 2002 John Wiley & Sons, Ltd.

Paul J. Nicholls – One of the best experts on this subject based on the ideXlab platform.

  • Aminoglutethimide-induced leucopenia in a mouse model:effects of metabolic and structural determinates
    Environmental toxicology and pharmacology, 2003
    Co-Authors: Michael D. Coleman, Laila F. Khalaf, Paul J. Nicholls
    Abstract:

    A model of human leucopenia has been developed further in the female mouse. Following daily administration to female mice of 50 mg/kg of the aromatase inhibitor Aminoglutethimide, significant falls in platelet and white cell counts occurred after 2 and 3 weeks. At week 4, drug dosage was stopped and the cell counts recovered at the end of that week, although on rechallenge at the beginning of week 5, both platelet and white cell counts fell rapidly. Administration to the mice of structural analogues of Aminoglutethimide, such as WSP-3, glutethimide and 4-nitroglutethimide, showed no reductions in platelet and white cell counts. The haemotoxicity of Aminoglutethimide over 21 days was unaffected by the presence of either the P-450 inhibitor SKF-525A or the hepatic P-450 inducer phenobarbitone. However, the co-administration of cimetidine abolished the haemotoxicity of Aminoglutethimide in terms of platelet and white cell levels. In in vitro studies, both Aminoglutethimide and WSP-3 were oxidised to cytotoxic species, although Aminoglutethimide was significantly more cytotoxic than WSP-3. The NADPH-dependent covalent binding of 14C Aminoglutethimide to mouse microsomes in vitro was significantly reduced by the presence of cimetidine. The activation of the compound to reactive species in vitro, the inhibitory effects of cimetidine in vivo and in vitro, as well as the rapid fall in the in vivo white cell count on rechallenge with Aminoglutethimide suggest that this model illustrates a form of leucopenia which may be related to hapten formation and subsequent immune-mediated platelet and white cell lysis. © 2003 Elsevier B.V. All rights reserved.

Rolf W Hartmann – One of the best experts on this subject based on the ideXlab platform.

  • Pyridyl-substituierte Tetralonderivate : Eine neue Klasse nichtsteroidaler Aromatase-Inhibitoren
    Archiv der Pharmazie, 2010
    Co-Authors: Herbert Bayer, Rolf W Hartmann
    Abstract:

    Ausgehend von Flavon und Flavanon, zwei Naturstoffen mit schwacher Aromatase-inhibitorischer Wirkung, wurden die Verbindungen 1-7 synthetisiert und auf ihre Hemmaktivitat gegenuber Aromatase und Desmolase unlersucht. Mit Ausnahme von Verbindung 2 zeigen alle Derivate eine starkere Aromatase-Hemmung als die Ausgangsverbindungen und erweisen sich auch als potentere Aromatase-Inhibitoren als Aminoglutethimid (AG), der einzige im Handel befindliche Wirkstoff. Im Gegensatz zu AG zeigen die Verbindungen 1 und 3-7 keine Hemmung der Desmolase, die bei AG zu unerwunschten Nebenwirkungen fuhrt. Pyridyl-substituted Tetralone Derivatives: A New Class of Nonsteroidal Aromatase InhiInhibitors Structural modification of flavone and flavanone, two weak inhibitors of aromatase, led to the new compounds 1-7, the syntheses of which are described as well as the evaluation of their aromatase and desmolase inhibitory potency. With the exception of 2 all compounds show a stronger inhibition of aromatase than the parent compounds and are more effective inhibitors than Aminoglutethimide (AG), the only commercially available compound. In contrast to AG compounds 1 and 3-7 exhibit no desmolase inhibitory activity. In case of AG this effect leads to undesirable side effects.

  • Neue Hemmstoffe der Aromatase: Synthese und biologische Aktivität pyridyl-substituierter Phenanthrenonderivate
    Archiv der Pharmazie, 1991
    Co-Authors: Herbert Bayer, Rolf W Hartmann
    Abstract:

    Die Phenanthrenonderivate 3–6 wurden synthetisiert und auf ihre Aromatase- und Desmolase-hemmende Wirkung untersucht. Sie weisen zum Teil eine deutlich starkere Aromatase-Hemmung auf als Aminoglutethimid (Verb. 5 und 6), ohne allerdings die Aktivitaten der Ausgangsverbindungen 1 und 2 zu ubertreffen. Die Verbindungen 4 und 5 zeigen keine Hemmung der Desmolase. New Inhibitors of Aromatase: Syntheses and Biological Activity of Pyridyl-substituted Phenanthrenone Derivatives The phenanthrenone derivatives 3–6 were synthesized and tested for their aromatase and desmolase inhibitory potency. Compounds 5 and 6 show a stronger inhibition of aromatase than Aminoglutethimide not exceeding, however, the activity of the parent compounds 1 and 2. Compounds 4 and 5 do not inhibit desmolase.