15 results on '"Bianzano, A."'
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2. Efficacy and safety of the ghrelin-O-acyltransferase inhibitor BI 1356225 in overweight/obesity: Data from two Phase I, randomised, placebo-controlled studies
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Bianzano, Susanna, Henrich, Andrea, Herich, Lena, Kalsch, Brigitte, Sarubbi, Donald, Seitz, Friedeborg, and Forst, Thomas
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- 2023
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3. Pharmacogenomics of GLP-1 receptor agonists: a genome-wide analysis of observational data and large randomised controlled trials
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't Hart, L.M., Abdalla, M., Adam, J., Adamski, J., Adragni, K., Allin, K.H., Arumugam, M., Atabaki Pasdar, N., Baltauss, T., Banasik, K.B., Baum, P., Bell, J.D., Bergstrom, M., Beulens, J.W., Bianzano, S., Bizzotto, R., Bonneford, A., Brorsson, C.A.B., Brown, A.A., Brunak, S.B., Cabrelli, L., Caiazzo, R., Canouil, M., Dale, M., Davtian, D., Dawed, A.Y., De Masi, F.M., de Preville, N., Dekkers, K.F., Dermitzakis, E.T., Deshmukh, H.A., Dings, C., Donnelly, L., Dutta, A., Ehrhardt, B., Elders, P.J.M., Engel Thomas, C.E.T., Engelbrechtsen, L., Eriksen, R.G., Eriksen, R.E., Fan, Y., Fernandez, J., Ferrer, J., Fitipaldi, H., Forgie, I.M., Forman, A., Franks, P.W., Frau, F., Fritsche, A., Froguel, P., Frost, G., Gassenhuber, J., Giordano, G.N., Giorgino, T., Gough, S., Graefe-Mody, U., Grallert, H., Grempler, R., Groeneveld, L., Groop, L., Gudmundsdóttir, V.G., Gupta, R.G., Haid, M., Hansen, T., Hansen, T.H., Hattersley, A.T., Haussler, R.S., Heggie, A.J., Hennige, A.M., Hill, A.V., Holl, R.W., Hong, M.-G., Hudson, M., Jablonka, B., Jennison, C., Jiao, J., Johansen, J.J., Jones, A.G., Jonsson, A., Karaderi, T.K., Kaye, J., Klintenberg, M., Koivula, R.W., Kokkola, T., Koopman, A.D.M., Kurbasic, A, Kuulasmaa, T., Laakso, M., Lehr, T., Loftus, H., Lundbye Allesøe, R.L.A, Mahajan, A., Mari, A., Mazzoni, G.M., McCarthy, M.I., McDonald, T.J., McEvoy, D., McRobert, N., McVittie, I., Mourby, M., Musholt, P., Mutie, P, Nice, R., Nicolay, C., Nielsen, A.M.N., Nilsson, B.N., Palmer, C.N., Pattou, F., Pavo, I., Pearson, E.R., Pedersen, O., Pedersen, H.K.P., Perry, M.H., Pomares-Millan, H., Ramisch, A., Rasmussen, S.R., Raverdi, V., Ridderstrale, M., Robertson, N., Roderick, R.C., Rodriquez, M., Ruetten, H., Rutters, F., Sackett, W., Scherer, N., Schwenk, J.M., Shah, N., Sharma, S., Sihinevich, I., Sondertoft, N.B., Staerfeldt, H., Steckel-Hamann, B., Teare, H., Thomas, M.K., Thomas, E.L., Thomsen, H.S., Thorand, B., Thorne, C.E., Tillner, J., Troen Lundgaard, A.T.L., Troll, M., Tsirigos, K.D.T., Tura, A., Uhlen, M., van Leeuwen, N., van Oort, S., Verkindt, H., Vestergaard, H., Viñuela, A., Vogt, J.K, Wad Sackett, P.W.S, Wake, D., Walker, M., Wesolowska-Andersen, A., Whitcher, B., White, M.W., Wu, H., Dawed, Adem Y, Mari, Andrea, Brown, Andrew, McDonald, Timothy J, Li, Lin, Wang, Shuaicheng, Hong, Mun-Gwan, Sharma, Sapna, Robertson, Neil R, Mahajan, Anubha, Wang, Xuan, Walker, Mark, Gough, Stephen, Hart, Leen M ‘t, Zhou, Kaixin, Forgie, Ian, Ruetten, Hartmut, Pavo, Imre, Bhatnagar, Pallav, Jones, Angus G, and Pearson, Ewan R
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- 2023
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4. Safety, tolerability, pharmacokinetics and pharmacodynamics of single oral doses of BI 187004, an inhibitor of 11beta-hydroxysteroid dehydrogenase-1, in healthy male volunteers with overweight or obesity
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Susanna Bianzano, Tim Heise, Arvid Jungnik, Cornelia Schepers, Corinna Schölch, and Ulrike Gräfe-Mody
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11beta-Hydroxysteroid dehydrogynase-1 inhibitor ,Single rising dose ,Pharmacokinetics ,Pharmacodynamics ,Type 2 diabetes ,BI 187004 ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Abstract Background The study characterizes safety, tolerability, pharmacokinetic and pharmacodynamic profiles of single rising doses of the 11beta-hydroxysteroid dehydrogenase-1 (11beta-HSD1) inhibitor BI 187004 in healthy men with overweight or obesity. Methods This was a randomized, double-blind, parallel group, placebo-controlled study with administration of 2.5–360 mg BI 187004 or placebo once daily as single dose in 72 healthy male volunteers with overweight or obesity. Assessments included 11beta-HSD1 inhibition in the liver (assessed indirectly by urinary tetrahydrocortisol/tetrahydrocortisone ratio) and in subcutaneous adipose tissue ex vivo and determination of hypothalamus–pituitary–adrenal axis hormones. Results BI 187004 was well tolerated and safe in all tested dose groups. The incidence of drug-related adverse events was 16.7% (n = 9) for all 9 BI 187004 dose groups and 5.9% (n = 1) for placebo. All treatment groups were similar concerning kind and intensity of adverse events. No clinically relevant deviations in clinical laboratory or ECG parameters were reported. Exposure of BI 187004 increased non-proportionally over the entire dose range tested. The geometric mean apparent terminal half-life decreased from 33.5 h (5 mg) to 14.5 h (160 mg) remaining stable up to 360 mg. Renal excretion of BI 187004 was low (3–5%). Urinary tetrahydrocortisol/tetrahydrocortisone ratio decreased, indicating liver 11beta-HSD1 inhibition. Median inhibition of 11beta-HSD1 in subcutaneous adipose tissue biopsies following single dosing ranged from 86.8% (10 mg) to 99.5% (360 mg) after 10 h and from 59.4% (10 mg) to 98.6% (360 mg) after 24 h. Conclusions BI 187004 as single dose was safe and well tolerated and is suitable for once daily dosing. There was significant, sustained 11beta-HSD1 inhibition in liver and adipose tissue. Trial registration ClinicalTrials.gov, NCT01587417 , registered on 26-Apr-2012.
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- 2021
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5. MRI in LARS1 deficiency—Spectrum, patterns, and correlation with acute neurological deterioration.
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Hammann, Nicole, Lenz, Dominic, Bianzano, Alyssa, Husain, Ralf A., Forman, Eva, Bernstein, Jonathan A., Dattner, Tal, Engelen, Marc, Hanson‐Kahn, Andrea K., Isidor, Bertrand, Kotzaeridou, Urania, Tietze, Anna, Trollmann, Regina, Weiß, Claudia, Wolffenbuttel, Bruce H. R., Kölker, Stefan, Hoffmann, Georg F., Crushell, Ellen, Staufner, Christian, and Mohr, Alexander
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Leucine aminoacyl tRNA‐synthetase 1 (LARS1)‐deficiency (infantile liver failure syndrome type 1 (ILFS1)) has a multisystemic phenotype including fever‐associated acute liver failure (ALF), chronic neurologic abnormalities, and encephalopathic episodes. In order to better characterize encephalopathic episodes and MRI changes, 35 cranial MRIs from 13 individuals with LARS1 deficiency were systematically assessed and neurological phenotype was analyzed. All individuals had developmental delay and 10/13 had seizures. Encephalopathic episodes in 8/13 were typically associated with infections, presented with seizures and reduced consciousness, mostly accompanied by hepatic dysfunction, and recovery in 17/19 episodes. Encephalopathy without hepatic dysfunction occurred in one individual after liver transplantation. On MRI, 5/7 individuals with MRI during acute encephalopathy had deep gray matter and brainstem changes. Supratentorial cortex involvement (6/13) and cerebellar watershed injury (4/13) occurred with seizures and/or encephalopathy. Abnormal brainstem contour on sagittal images (8/13), atrophy (8/13), and myelination delay (8/13) were not clearly associated with encephalopathy. The pattern of deep gray matter and brainstem changes are apparently characteristic of encephalopathy in LARS1‐deficiency, differing from patterns of hepatic encephalopathy or metabolic stroke in organic acidurias and mitochondrial diseases. While the pathomechanism remains unclear, fever and energy deficit during infections might be causative; thus, sufficient glucose and protein intake along with pro‐active fever management is suggested. As severe episodes were observed during influenza infections, we strongly recommend seasonal vaccination. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Genotypic diversity and phenotypic spectrum of infantile liver failure syndrome type 1 due to variants in LARS1
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Lenz, Dominic, Smith, Desirée E.C., Crushell, Ellen, Husain, Ralf A., Salomons, Gajja S., Alhaddad, Bader, Bernstein, Jonathan A., Bianzano, Alyssa, Biskup, Saskia, Brennenstuhl, Heiko, Caldari, Dominique, Dikow, Nicola, Haack, Tobias B., Hanson-Kahn, Andrea, Harting, Inga, Horn, Denise, Hughes, Joanne, Huijberts, Maya, Isidor, Bertrand, Kathemann, Simone, Kopajtich, Robert, Kotzaeridou, Urania, Küry, Sébastien, Lainka, Elke, Laugwitz, Lucia, Lupski, James R., Posey, Jennifer E., Reynolds, Claire, Rosenfeld, Jill A., Schröter, Julian, Vansenne, Fleur, Wagner, Matias, Weiß, Claudia, Wolffenbuttel, Bruce H.R., Wortmann, Saskia B., Kölker, Stefan, Hoffmann, Georg F., Prokisch, Holger, Mendes, Marisa I., and Staufner, Christian
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- 2020
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7. Safety, tolerability, pharmacokinetics and pharmacodynamics of single oral doses of BI 187004, an inhibitor of 11beta-hydroxysteroid dehydrogenase-1, in healthy male volunteers with overweight or obesity
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Bianzano, Susanna, Heise, Tim, Jungnik, Arvid, Schepers, Cornelia, Schölch, Corinna, and Gräfe-Mody, Ulrike
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- 2021
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8. Genetic landscape of pediatric acute liver failure of indeterminate origin.
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Lenz, Dominic, Schlieben, Lea D., Masaru Shimura, Bianzano, Alyssa, Smirnov, Dmitrii, Kopajtich, Robert, Berutti, Riccardo, Adam, Rüdiger, Aldrian, Denise, Baric, Ivo, Baumann, Ulrich, Bozbulut, Neslihan E., Brugger, Melanie, Brunet, Theresa, Bufler, Philip, Burnytė, Birutė, Calvo, Pier L., Crushell, Ellen, Dalgıç, Buket, and Das, Anibh M.
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- 2024
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9. Discovery of drug–omics associations in type 2 diabetes with generative deep-learning models
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Allesøe, Rosa Lundbye, Lundgaard, Agnete Troen, Hernández Medina, Ricardo, Aguayo-Orozco, Alejandro, Johansen, Joachim, Nissen, Jakob Nybo, Brorsson, Caroline, Mazzoni, Gianluca, Niu, Lili, Biel, Jorge Hernansanz, Brasas, Valentas, Webel, Henry, Benros, Michael Eriksen, Pedersen, Anders Gorm, Chmura, Piotr Jaroslaw, Jacobsen, Ulrik Plesner, Mari, Andrea, Koivula, Robert, Mahajan, Anubha, Vinuela, Ana, Tajes, Juan Fernandez, Sharma, Sapna, Haid, Mark, Hong, Mun-Gwan, Musholt, Petra B., de Masi, Federico, Vogt, Josef, Pedersen, Helle Krogh, Gudmundsdottir, Valborg, Jones, Angus, Kennedy, Gwen, Bell, Jimmy, Thomas, E. Louise, Frost, Gary, Thomsen, Henrik, Hansen, Elizaveta, Hansen, Tue Haldor, Vestergaard, Henrik, Muilwijk, Mirthe, Blom, Marieke T., ‘t Hart, Leen M., Pattou, Francois, Raverdy, Violeta, Brage, Soren, Kokkola, Tarja, Heggie, Alison, McEvoy, Donna, Mourby, Miranda, Kaye, Jane, Hattersley, Andrew, McDonald, Timothy, Ridderstråle, Martin, Walker, Mark, Forgie, Ian, Giordano, Giuseppe N., Pavo, Imre, Ruetten, Hartmut, Pedersen, Oluf, Hansen, Torben, Dermitzakis, Emmanouil, Franks, Paul W., Schwenk, Jochen M., Adamski, Jerzy, McCarthy, Mark I., Pearson, Ewan, Banasik, Karina, Rasmussen, Simon, Brunak, S. ren, Froguel, Philippe, Thomas, Cecilia Engel, Haussler, Ragna, Beulens, Joline, Rutters, Femke, Nijpels, Giel, van Oort, Sabine, Groeneveld, Lenka, Elders, Petra, Giorgino, Toni, Rodriquez, Marianne, Nice, Rachel, Perry, Mandy, Bianzano, Susanna, Graefe-Mody, Ulrike, Hennige, Anita, Grempler, Rolf, Baum, Patrick, Stærfeldt, Hans-Henrik, Shah, Nisha, Teare, Harriet, Ehrhardt, Beate, Tillner, Joachim, Dings, Christiane, Lehr, Thorsten, Scherer, Nina, Sihinevich, Iryna, Cabrelli, Louise, Loftus, Heather, Bizzotto, Roberto, Tura, Andrea, Dekkers, Koen, van Leeuwen, Nienke, Groop, Leif, Slieker, Roderick, Ramisch, Anna, Jennison, Christopher, McVittie, Ian, Frau, Francesca, Steckel-Hamann, Birgit, Adragni, Kofi, Thomas, Melissa, Pasdar, Naeimeh Atabaki, Fitipaldi, Hugo, Kurbasic, Azra, Mutie, Pascal, Pomares-Millan, Hugo, Bonnefond, Amelie, Canouil, Mickael, Caiazzo, Robert, Verkindt, Helene, Holl, Reinhard, Kuulasmaa, Teemu, Deshmukh, Harshal, Cederberg, Henna, Laakso, Markku, Vangipurapu, Jagadish, Dale, Matilda, Thorand, Barbara, Nicolay, Claudia, Fritsche, Andreas, Hill, Anita, Hudson, Michelle, Thorne, Claire, Allin, Kristine, Arumugam, Manimozhiyan, Jonsson, Anna, Engelbrechtsen, Line, Forman, Annemette, Dutta, Avirup, Sondertoft, Nadja, Fan, Yong, Gough, Stephen, Robertson, Neil, McRobert, Nicky, Wesolowska-Andersen, Agata, Brown, Andrew, Davtian, David, Dawed, Adem, Donnelly, Louise, Palmer, Colin, White, Margaret, Ferrer, Jorge, Whitcher, Brandon, Artati, Anna, Prehn, Cornelia, Adam, Jonathan, Grallert, Harald, Gupta, Ramneek, Sackett, Peter Wad, Nilsson, Birgitte, Tsirigos, Konstantinos, Eriksen, Rebeca, Jablonka, Bernd, Uhlen, Mathias, Gassenhuber, Johann, Baltauss, Tania, de Preville, Nathalie, Klintenberg, Maria, Abdalla, Moustafa, Lundgaard, Agnete Troen [0000-0001-7447-6560], Hernández Medina, Ricardo [0000-0001-6373-2362], Johansen, Joachim [0000-0001-7052-1870], Niu, Lili [0000-0003-4571-4368], Biel, Jorge Hernansanz [0000-0002-3125-2951], Benros, Michael Eriksen [0000-0003-4939-9465], Pedersen, Anders Gorm [0000-0001-9650-8965], Jacobsen, Ulrik Plesner [0000-0001-9181-6854], Koivula, Robert [0000-0002-1646-4163], Vinuela, Ana [0000-0003-3771-8537], Haid, Mark [0000-0001-6118-1333], Hong, Mun-Gwan [0000-0001-8603-8293], Kennedy, Gwen [0000-0002-9856-3236], Thomas, E Louise [0000-0003-4235-4694], Frost, Gary [0000-0003-0529-6325], Hansen, Tue Haldor [0000-0001-5948-8993], Kaye, Jane [0000-0002-7311-4725], Hattersley, Andrew [0000-0001-5620-473X], Ridderstråle, Martin [0000-0002-3270-9167], Pedersen, Oluf [0000-0002-3321-3972], Hansen, Torben [0000-0001-8748-3831], Schwenk, Jochen M [0000-0001-8141-8449], Rasmussen, Simon [0000-0001-6323-9041], Brunak, Søren [0000-0003-0316-5866], Apollo - University of Cambridge Repository, Epidemiology and Data Science, ACS - Diabetes & metabolism, APH - Health Behaviors & Chronic Diseases, General practice, ACS - Heart failure & arrhythmias, APH - Aging & Later Life, Graduate School, and APH - Methodology
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Biomedical Engineering ,Type 2 diabetes ,Bioengineering ,Applied Microbiology and Biotechnology ,Deep Learning ,SDG 3 - Good Health and Well-being ,Diabetes Mellitus, Type 2 ,Machine learning ,Molecular Medicine ,Humans ,Data integration ,IMI DIRECT Consortium ,Systems biology ,Algorithms ,Biotechnology - Abstract
The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug–omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug–drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.
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- 2023
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10. Pharmacogenomics of GLP-1 receptor agonists : a genome-wide analysis of observational data and large randomised controlled trials
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Adem Y Dawed, Andrea Mari, Andrew Brown, Timothy J McDonald, Lin Li, Shuaicheng Wang, Mun-Gwan Hong, Sapna Sharma, Neil R Robertson, Anubha Mahajan, Xuan Wang, Mark Walker, Stephen Gough, Leen M ‘t Hart, Kaixin Zhou, Ian Forgie, Hartmut Ruetten, Imre Pavo, Pallav Bhatnagar, Angus G Jones, Ewan R Pearson, L.M. 't Hart, M. Abdalla, J. Adam, J. Adamski, K. Adragni, K.H. Allin, M. Arumugam, N. Atabaki Pasdar, T. Baltauss, K.B. Banasik, P. Baum, J.D. Bell, M. Bergstrom, J.W. Beulens, S. Bianzano, R. Bizzotto, A. Bonneford, C.A.B. Brorsson, A.A. Brown, S.B. Brunak, L. Cabrelli, R. Caiazzo, M. Canouil, M. Dale, D. Davtian, A.Y. Dawed, F.M. De Masi, N. de Preville, K.F. Dekkers, E.T. Dermitzakis, H.A. Deshmukh, C. Dings, L. Donnelly, A. Dutta, B. Ehrhardt, P.J.M. Elders, C.E.T. Engel Thomas, L. Engelbrechtsen, R.G. Eriksen, R.E. Eriksen, Y. Fan, J. Fernandez, J. Ferrer, H. Fitipaldi, I.M. Forgie, A. Forman, P.W. Franks, F. Frau, A. Fritsche, P. Froguel, G. Frost, J. Gassenhuber, G.N. Giordano, T. Giorgino, S. Gough, U. Graefe-Mody, H. Grallert, R. Grempler, L. Groeneveld, L. Groop, V.G. Gudmundsdóttir, R.G. Gupta, M. Haid, T. Hansen, T.H. Hansen, A.T. Hattersley, R.S. Haussler, A.J. Heggie, A.M. Hennige, A.V. Hill, R.W. Holl, M.-G. Hong, M. Hudson, B. Jablonka, C. Jennison, J. Jiao, J.J. Johansen, A.G. Jones, A. Jonsson, T.K. Karaderi, J. Kaye, M. Klintenberg, R.W. Koivula, T. Kokkola, A.D.M. Koopman, A Kurbasic, T. Kuulasmaa, M. Laakso, T. Lehr, H. Loftus, R.L.A Lundbye Allesøe, A. Mahajan, A. Mari, G.M. Mazzoni, M.I. McCarthy, T.J. McDonald, D. McEvoy, N. McRobert, I. McVittie, M. Mourby, P. Musholt, P Mutie, R. Nice, C. Nicolay, A.M.N. Nielsen, B.N. Nilsson, C.N. Palmer, F. Pattou, I. Pavo, E.R. Pearson, O. Pedersen, H.K.P. Pedersen, M.H. Perry, H. Pomares-Millan, A. Ramisch, S.R. Rasmussen, V. Raverdi, M. Ridderstrale, N. Robertson, R.C. Roderick, M. Rodriquez, H. Ruetten, F. Rutters, W. Sackett, N. Scherer, J.M. Schwenk, N. Shah, S. Sharma, I. Sihinevich, N.B. Sondertoft, H. Staerfeldt, B. Steckel-Hamann, H. Teare, M.K. Thomas, E.L. Thomas, H.S. Thomsen, B. Thorand, C.E. Thorne, J. Tillner, A.T.L. Troen Lundgaard, M. Troll, K.D.T. Tsirigos, A. Tura, M. Uhlen, N. van Leeuwen, S. van Oort, H. Verkindt, H. Vestergaard, A. Viñuela, J.K Vogt, P.W.S Wad Sackett, D. Wake, M. Walker, A. Wesolowska-Andersen, B. Whitcher, M.W. White, H. Wu, Epidemiology and Data Science, ACS - Diabetes & metabolism, ACS - Heart failure & arrhythmias, APH - Health Behaviors & Chronic Diseases, General practice, and APH - Aging & Later Life
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Adult ,Male ,Blood Glucose ,Adolescent ,Endocrinology, Diabetes and Metabolism ,Endocrinology and Diabetes ,Glucagon-Like Peptide-1 Receptor ,Endocrinology ,Treatment Outcome ,Diabetes Mellitus, Type 2 ,Pharmacogenetics ,Endokrinologi och diabetes ,Internal Medicine ,Humans ,Hypoglycemic Agents ,Female ,Genome-Wide Association Study ,Randomized Controlled Trials as Topic - Abstract
Background: In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1 receptor agonists vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insight into drug action and provide biomarkers to inform clinical decision making. We therefore aimed to identify genetic variants associated with glycaemic response to GLP-1 receptor agonist treatment. Methods: In this genome-wide analysis we included adults (aged ≥18 years) with type 2 diabetes treated with GLP-1 receptor agonists with baseline HbA 1c of 7% or more (53 mmol/mol) from four prospective observational cohorts (DIRECT, PRIBA, PROMASTER, and GoDARTS) and two randomised clinical trials (HARMONY phase 3 and AWARD). The primary endpoint was HbA 1c reduction at 6 months after starting GLP-1 receptor agonists. We evaluated variants in GLP1R, then did a genome-wide association study and gene-based burden tests. Findings: 4571 adults were included in our analysis, of these, 3339 (73%) were White European, 449 (10%) Hispanic, 312 (7%) American Indian or Alaskan Native, and 471 (10%) were other, and around 2140 (47%) of the participants were women. Variation in HbA 1c reduction with GLP-1 receptor agonists treatment was associated with rs6923761G→A (Gly168Ser) in the GLP1R (0·08% [95% CI 0·04–0·12] or 0·9 mmol/mol lower reduction in HbA 1c per serine, p=6·0 × 10 −5) and low frequency variants in ARRB1 (optimal sequence kernel association test p=6·7 × 10 −8), largely driven by rs140226575G→A (Thr370Met; 0·25% [SE 0·06] or 2·7 mmol/mol [SE 0·7] greater HbA 1c reduction per methionine, p=5·2 × 10 −6). A similar effect size for the ARRB1 Thr370Met was seen in Hispanic and American Indian or Alaska Native populations who have a higher frequency of this variant (6–11%) than in White European populations. Combining these two genes identified 4% of the population who had a 30% greater reduction in HbA 1c than the 9% of the population with the worse response. Interpretation: This genome-wide pharmacogenomic study of GLP-1 receptor agonists provides novel biological and clinical insights. Clinically, when genotype is routinely available at the point of prescribing, individuals with ARRB1 variants might benefit from earlier initiation of GLP-1 receptor agonists.
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- 2023
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11. Genotypic diversity and phenotypic spectrum of infantile liver failure syndrome type 1 due to variants inLARS1
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Nicola Dikow, Alyssa Bianzano, Robert Kopajtich, James R. Lupski, Gajja S. Salomons, Jennifer E. Posey, Saskia Biskup, Jill A. Rosenfeld, Bruce H. R. Wolffenbuttel, Dominic Lenz, Saskia B. Wortmann, Denise Horn, Urania Kotzaeridou, Joanne Hughes, Maya Huijberts, Simone Kathemann, Tobias B. Haack, Stefan Kölker, Elke Lainka, Ralf A. Husain, Fleur Vansenne, Sébastien Küry, Andrea Hanson-Kahn, Bertrand Isidor, Matias Wagner, Ellen Crushell, Inga Harting, Jonathan A. Bernstein, Lucia Laugwitz, Dominique Caldari, Desirée E.C. Smith, Marisa I. Mendes, Christian Staufner, Julian Schröter, Claire Reynolds, Heiko Brennenstuhl, Claudia Weiß, Bader Alhaddad, Holger Prokisch, Georg F. Hoffmann, Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Laboratory Genetic Metabolic Diseases, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Laboratory Medicine, AGEM - Endocrinology, metabolism and nutrition, AGEM - Inborn errors of metabolism, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Amsterdam Gastroenterology Endocrinology Metabolism, and Amsterdam Reproduction & Development (AR&D)
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medicine.medical_specialty ,HOMEOSTASIS ,Microcytic anemia ,Medizin ,Disease ,Gastroenterology ,DISEASE ,MECHANISMS ,TRANSFER-RNA SYNTHETASES ,Seizures ,Internal medicine ,Genotype ,medicine ,Humans ,Stroke ,Genetics (clinical) ,RECESSIVE MUTATIONS ,medicine.diagnostic_test ,Muscular hypotonia ,business.industry ,infantile liver failure syndrome type 1 ,Magnetic resonance imaging ,LARS1 ,acute liver failure ,medicine.disease ,Phenotype ,aminoacyl-tRNA synthetase deficiency ,Mutation ,ONSET ,Muscle Hypotonia ,business ,Lars1 ,Infantile Liver Failure Syndrome Type 1 ,Acute Liver Failure ,Aminoacyl-trna Synthetase Deficiency ,Metabolic Stroke ,metabolic stroke ,Liver Failure ,Homeostasis - Abstract
Purpose: Biallelic variants in LARS1, coding for the cytosolic leucyl-tRNA synthetase, cause infantile liver failure syndrome 1 (ILFS1). Since its description in 2012, there has been no systematic analysis of the clinical spectrum and genetic findings. Methods: Individuals with biallelic variants in LARS1 were included through an international, multicenter collaboration including novel and previously published patients. Clinical variables were analyzed and functional studies were performed in patient-derived fibroblasts. Results: Twenty-five individuals from 15 families were ascertained including 12 novel patients with eight previously unreported variants. The most prominent clinical findings are recurrent elevation of liver transaminases up to liver failure and encephalopathic episodes, both triggered by febrile illness. Magnetic resonance image (MRI) changes during an encephalopathic episode can be consistent with metabolic stroke. Furthermore, growth retardation, microcytic anemia, neurodevelopmental delay, muscular hypotonia, and infection-related seizures are prevalent. Aminoacylation activity is significantly decreased in all patient cells studied upon temperature elevation in vitro. Conclusion: ILFS1 is characterized by recurrent elevation of liver transaminases up to liver failure in conjunction with abnormalities of growth, blood, nervous system, and musculature. Encephalopathic episodes with seizures can occur independently from liver crises and may present with metabolic stroke.
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- 2020
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12. Safety, tolerability, pharmacodynamics and pharmacokinetics following once‐daily doses of BI 187004, an inhibitor of 11 beta‐hydroxysteroid dehydrogenase‐1, over 28 days in patients with type 2 diabetes mellitus and overweight or obesity
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Bianzano, Susanna, Nordaby, Matias, Plum‐Mörschel, Leona, Peil, Barbara, and Heise, Tim
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TYPE 2 diabetes , *BLOOD sugar , *BODY mass index , *PHARMACOKINETICS , *PHARMACODYNAMICS , *CHILDHOOD obesity - Abstract
Aims: To study the oral 11 beta‐hydroxysteroid dehydrogenase‐1 (11β‐HSD1) inhibitor BI 187004 (NCT02150824), as monotherapy and in combination with metformin, versus placebo in patients with type 2 diabetes mellitus (T2DM) affected by overweight or obesity. Materials and Methods: This Phase II, randomized controlled trial investigated multiple rising doses of BI 187004 as monotherapy (Arm 1: 20, 80 or 240 mg) and in combination with metformin (Arm 2: 240 mg), in adults with T2DM and a body mass index of 28–40 kg/m2. Results: In total, 103 patients (Arm 1: n = 62, Arm 2: n = 41) were included in this study. BI 187004 was rapidly absorbed and exposure increased approximately dose‐dependently. Target engagement of 11β‐HSD1 was observed with near‐full inhibition of 11β‐HSD1 in the liver [decreased (5α‐tetrahydrocortisol + 5β‐tetrahydrocortisol)/tetrahydrocortisone ratio]; hypothalamic–pituitary–adrenal axis activation was also seen (increased total urinary corticosteroids). No clinically relevant changes from baseline with BI 187004 treatment were observed for bodyweight or meal tolerance test parameters, or in most efficacy endpoints testing glucose and lipid metabolism; a significant increase was observed in weighted mean plasma glucose (p <.05 for 80 and 240 mg BI 187004) but not fasting plasma glucose. Drug‐related adverse events were reported for 14 patients (22.6%) in Arm 1 and 10 patients (24.4%) in Arm 2, most frequently headache, diarrhoea, flushing and dizziness. A dose‐dependent increase in heart rate was seen with BI 187004 treatment. Conclusions: BI 187004 was generally well tolerated in patients with T2DM. Despite complete 11β‐HSD1 inhibition, no clinically relevant effects were observed with BI 187004. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
13. Selective Inhibition of 11beta-Hydroxysteroiddehydrogenase-1 with BI 187004 in Patients with Type 2 Diabetes and Overweight or Obesity: Safety, Pharmacokinetics, and Pharmacodynamics After Multiple Dosing Over 14 Days.
- Author
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Bianzano, Susanna, Schepers, Cornelia, Wolff, Michael, Heise, Tim, and Plum-Moerschel, Leona
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TYPE 2 diabetes , *SUPRAVENTRICULAR tachycardia , *PATIENTS , *OBESITY , *PHARMACOKINETICS , *ADIPOSE tissues - Abstract
Objective To assess safety, tolerability, pharmacokinetics, and pharmacodynamics of treatment with the selective 11beta-hydroxysteroid dehydrogenase-1 (11beta-HSD1) inhibitor BI 187004 in male and female patients with type 2 diabetes and overweight or obesity. Methods Randomized, double-blind, parallel-group, placebo-controlled multiple rising dose study, with 10–360 mg BI 187004 once daily over 14 days in 71 patients. Assessments included 11beta-HSD1 inhibition in the liver and subcutaneous adipose tissue ex vivo (clinical trial registry number NCT01874483). Results BI 187004 was well tolerated and safe in all tested dose groups. The incidence of drug-related adverse events was 51.8% (n=29) for BI 187004 and 35.7% (n=5) for placebo. There were no clinically relevant deviations in laboratory or electrocardiogram parameters besides one patient on 360 mg discontinuing treatment due to moderate supraventricular tachycardia. BI 187004 was rapidly absorbed within 2 h; exposure increased non-proportionally. The oral clearance was low, apparent volume of distribution was moderate to large, and terminal half-life with 106–124 h was rather long. Urinary tetrahydrocortisol/tetrahydrocortisone ratio decreased, indicating liver 11beta-HSD1 inhibition. Median inhibition of 11beta-HSD1 in subcutaneous adipose tissue biopsies was 87.9–99.4% immediately after the second dose and 73.8–97.5% 24 h after the last dose of BI 187004. Conclusions BI 187004 was safe and well tolerated over 14 days and could be dosed once daily. Targeted 11beta-HSD1 enzyme inhibition of≥80% could be shown for BI 187004 doses≥40 mg. This dose should be targeted in further studies to test blood glucose lowering in patients with type 2 diabetes and overweight or obesity. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
14. Genetic landscape of paediatric acute liver failure.
- Author
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Lenz, D., D Schlieben, L., Shimura, M., Bianzano, A., Garbade, S., Smirnov, D., Kopajtich, R., Adam, R., Aldrian, D., Baric, I., Baumann, U., Bozbulut, N. E., Bufler, P., Burnyte, B., Calvo, P. L., Crushell, E., Dalgıç, B., Das, A., Dezsofi, A., and Dick, A.
- Published
- 2022
- Full Text
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15. Polarization profiling of the surface region of PVDF and P(VDF-TrFE).
- Author
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Ploss, B. and Bianzano, O.
- Published
- 1994
- Full Text
- View/download PDF
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