96 results on '"Van Dyck K"'
Search Results
2. Bioavailability of silicon from food and food supplements
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Van Dyck, K., Van Cauwenbergh, R., Robberecht, Harry, and Deelstra, Hendrik
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- 1999
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3. Effect of the Cathepsin K Inhibitor Odanacatib on Bone Resorption Biomarkers in Healthy Postmenopausal Women: Two Double-Blind, Randomized, Placebo-Controlled Phase I Studies
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Stoch, S A, Zajic, S, Stone, J, Miller, D L, Van Dyck, K, Gutierrez, M J, De Decker, M, Liu, L, Liu, Q, Scott, B B, Panebianco, D, Jin, B, Duong, L T, Gottesdiener, K, and Wagner, J A
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- 2009
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4. Staphylococcus aureusPathogenicity in Cystic Fibrosis Patients-Results from an Observational Prospective Multicenter Study Concerning Virulence Genes, Phylogeny, and Gene Plasticity
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Lange, JF, Heidenreich, K, Higelin, K, Van Dyck, K, Marx, V, Reichel, C, van Wamel, Willem, Reijer, Martijn, Gorlich, D, Kahl, B C, and Medical Microbiology & Infectious Diseases
- Published
- 2020
5. Multiple-Dose Pharmacodynamics and Pharmacokinetics of Anacetrapib, a Potent Cholesteryl Ester Transfer Protein (CETP) Inhibitor, in Healthy Subjects
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Krishna, R, Bergman, A J, Jin, B, Fallon, M, Cote, J, Van Hoydonck, P, Laethem, T, Gendrano, I N, III, Van Dyck, K, Hilliard, D, Laterza, O, Snyder, K, Chavez-Eng, C, Lutz, R, Chen, J, Bloomfield, D M, De Smet, M, Van Bortel, L M, Gutierrez, M, Al-Huniti, N, Dykstra, K, Gottesdiener, K M, and Wagner, J A
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- 2008
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6. Optimizing dose selection using population PK/FD modeling and simulation for the cholesteryl ester transfer protein (CETP) inhibitor MK-0859 in healthy subjects: 8
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Bergman, A., Dykstra, K., Al-Huniti, N., Fallon, M., Lute, R., Chavez-Eng, C., Jin, B., Hartford, A., Cote, J., Hilliard, D., Laethem, T., Van Hoydonck, P., Snyder, K., Van Dyck, K., Stone, J., Lasseter, K. C., Van Bortel, L., Wagner, J., and Krishna, R.
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- 2008
7. Serum Silicon Concentration of Healthy Persons in the Antwerp Region (Belgium)
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Van Dyck, K., primary, Robberecht, H., additional, Van Cauwenbergh, R., additional, and Deelstra, H., additional
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- 2002
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8. Daily dietary silicon intake in Belgium using duplicate portion sampling
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Van Dyck, K., Robberecht, H., Van Cauwenbergh, R., and Deelstra, H.
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- 1999
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9. Symmetry breaking and vortex precession in low-swirling annular jets
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Vanierschot, M., primary, Van Dyck, K., additional, Sas, P., additional, and Van den Bulck, E., additional
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- 2014
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10. Adherence to guidelines for antiretroviral therapy and for preventing opportunistic infections in HIV-infected adults and adolescents in Ryan White-funded facilities in the United States
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Soto-Torres L, Greaves Ja, van Dyck K, Ellis B, Parham Dl, Amandus He, Rauch K, and Jonathan E. Kaplan
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,National Health Programs ,Opportunistic infection ,Anti-HIV Agents ,Tuberculin ,Antibodies, Protozoan ,Acquired immunodeficiency syndrome (AIDS) ,Internal medicine ,Health care ,Medicine ,Animals ,Humans ,Pharmacology (medical) ,Medical prescription ,Sida ,Preventive healthcare ,Mycobacterium avium-intracellulare Infection ,Vaginal Smears ,biology ,AIDS-Related Opportunistic Infections ,business.industry ,Tuberculin Test ,Pneumonia, Pneumocystis ,Middle Aged ,Pneumonia, Pneumococcal ,biology.organism_classification ,medicine.disease ,United States ,Infectious Diseases ,Immunology ,Bacterial Vaccines ,Practice Guidelines as Topic ,RNA, Viral ,Female ,Viral disease ,Guideline Adherence ,Health Facilities ,business ,Toxoplasma ,Papanicolaou Test - Abstract
To determine adherence by health care providers to guidelines for antiretroviral therapy and for prevention of opportunistic infections (OIs) in adults with HIV infection in federally funded facilities in the United States, we reviewed records of HIV-infected adults (13 years) in 11 Ryan White Title III facilities in four states for information on eight standard-of-care recommendations during November 1996 through September 1997. Eligibility required a visit to the facility within 6 months before record abstraction and a lowest CD4+ lymphocyte count500 cells/microl. Reviews were completed for 148 patients in Maryland, 355 in New York, 370 in Georgia, and 538 in Illinois. Adherence to prevention measures by health care providers was85% for HIV plasma RNA testing, prescription of antiretroviral therapy, Pneumocystis carinii pneumonia (PCP) prophylaxis, anti-Toxoplasma antibody testing, and obtaining Papanicolaou (Pap) smears but lower (69%-80%) for Mycobacterium avium complex (MAC) prophylaxis, tuberculin skin testing (TST), and pneumococcal vaccination. Adherence was similar by patient age, gender, racial/ethnic group, urban versus rural, and hospital versus clinic setting but was generally lower for injecting drug users (IDUs) than for patients with other HIV exposures (p.05 by multivariate analysis for TST, anti-Toxoplasma antibody testing, Pap smear, and measurement of HIV plasma RNA). Adherence by health care providers to guidelines for preventing OIs in these federally funded facilities is generally high but could be improved for some prevention measures, for instance, MAC prophylaxis, TST, and pneumococcal vaccination, especially for IDUs.
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- 1999
11. 913 USING SHORT-TERM MONOTHERAPY AND IN VITRO DATA TO MAKE EARLY PREDICTIONS OF CLINICAL HCV RESPONSE: EXAMPLES FROM MK-5172, A SECOND GENERATION HCV NS3/4A PROTEASE INHIBITOR
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Nachbar, R.B., primary, Stone, J.A., additional, Petry, A., additional, Poland, B., additional, Caro, L., additional, Wenning, L.A., additional, Khan, A., additional, Palcza, J., additional, Van Dyck, K., additional, Fraser, I., additional, Mobashery, N., additional, and O'Mara, E., additional
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- 2012
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12. The effects of TPA023, a GABAAα2,3 subtype-selective partial agonist, on essential tremor in comparison to alcohol
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de Haas, SL, primary, Zoethout, RWM, additional, Van Dyck, K, additional, De Smet, M, additional, Rosen, LB, additional, Murphy, MG, additional, Gottesdiener, KM, additional, Schoemaker, RC, additional, Cohen, AF, additional, and van Gerven, JMA, additional
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- 2011
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13. The effects of a novel histamine-3 receptor inverse agonist on essential tremor in comparison to stable levels of alcohol
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Zoethout, RWM, primary, Iannone, R, additional, Bloem, BR, additional, Palcza, J, additional, Murphy, G, additional, Chodakewitz, J, additional, Buntinx, A, additional, Gottesdiener, K, additional, Marsilio, S, additional, Rosen, L, additional, van Dyck, K, additional, Louis, ED, additional, Cohen, AF, additional, Schoemaker, RC, additional, Tokita, S, additional, Sato, N, additional, Koblan, KS, additional, Hargreaves, RH, additional, Renger, JJ, additional, and van Gerven, JMA, additional
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- 2011
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14. Evaluation of Two Sputum Processing Methods Applying Sensitive Detection Techniques in Allergic Asthmatics.
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Diamant, Z, primary, Boot, JD, additional, Zuiker, R, additional, van Dyck, K, additional, Cohen, AF, additional, Pica-Mendez, A, additional, and Tanen, M, additional
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- 2009
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15. Pharmacodynamic and pharmacokinetic effects of MK-0343, a GABAA α2,3 subtype selective agonist, compared to lorazepam and placebo in healthy male volunteers
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de Haas, S.L., primary, de Visser, S.J., additional, van der Post, J.P., additional, Schoemaker, R.C., additional, van Dyck, K., additional, Murphy, M.G., additional, de Smet, M., additional, Vessey, L.K., additional, Ramakrishnan, R., additional, Xue, L., additional, Cohen, A.F., additional, and van Gerven, J.M.A., additional
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- 2007
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16. PPAR gamma activation rapidly increases ACRP30 in non‐diabetic subjects
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Wagner, J. A., primary, Flynn, M. E., additional, Knops, A., additional, Hartford, A. H., additional, Dallob, A. L., additional, Tanaka, W. K., additional, DeSmet, M., additional, Van Dyck, K., additional, Stevens, C., additional, Scherer, P. E., additional, and Gottesdiener, K. M., additional
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- 2003
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17. Determination of silicon in organic matrices with grazing-emission X-ray fluorescence spectrometry
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Claes, M., primary, Van Dyck, K., additional, Deelstra, H., additional, and Van Grieken, R., additional
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- 1999
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18. IN VITRO BIOAVAILABILITY OF IRON AND ZINC FROM HUMAN MILK, AND INFANT FORMULAE WITH AND WITHOUT THICKENING AGENTS
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Bosscher, D., primary, Van Dyck, K., additional, Van Caillie-Bertrand, M., additional, Robberecht, H., additional, and Deelstra, H., additional
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- 1999
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19. Role of Hyperventilation in Panic Attacks: A Lot of Hot Air?
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Garssen, B., primary, Buikhuisen, M., additional, and van Dyck, K., additional
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- 1996
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20. A comparison of the natriuretic and kaliuretic effects of cicletanine and hydrochlorothiazide in prehypertensive and hypertensive humans.
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Wagner F, Malice MP, Wiegert E, McGrath HE, Gildea J, Mitta S, Van Dyck K, De Lepeleire I, Johnson-Levonas AO, Sisk CM, Fernandez R, Greenwalt DM, Beals C, Carey RM, and Nunes I
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- 2012
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21. The effects of TPA023, a GABAA[alpha]2,3 subtype-selective partial agonist, on essential tremor in comparison to alcohol.
- Author
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de Haas S, Zoethout R, Van Dyck K, De Smet M, Rosen L, Murphy M, Gottesdiener K, Schoemaker R, Cohen A, and van Gerven J
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- 2012
22. The effects of a novel histamine-3 receptor inverse agonist on essential tremor in comparison to stable levels of alcohol.
- Author
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Zoethout R, Iannone R, Bloem B, Palcza J, Murphy G, Chodakewitz J, Buntinx A, Gottesdiener K, Marsilio S, Rosen L, van Dyck K, Louis E, Cohen A, Schoemaker R, Tokita S, Sato N, Koblan K, Hargreaves R, Renger J, and van Gerven J
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- 2012
23. Pharmacodynamic and pharmacokinetic effects of MK-0343, a GABA α2,3 subtype selective agonist, compared to lorazepam and placebo in healthy male volunteers.
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De Haas, S. L., De Visser, S. J., Van Der Post, J. P., Schoemaker, R. C., Van Dyck, K., Murphy, M. G., De Smet, M., Vessey, L. K., Ramakrishnan, R., Xue, L., Cohen, A. F., and Van Gerven, J. M. A.
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GABA agonists ,ANXIETY ,LORAZEPAM ,PLACEBOS ,TRANQUILIZING drugs ,MEMORY ,SACCADIC eye movements - Abstract
The use of non-selective γ-aminobutydc acid (GABA) enhancers, such as benzodiazepines in the treatment of anxiety disorders is still widespread but hampered by unfavourable side effects. Some of these may be associated with binding properties to certain subtypes of the GABA
A receptor that are unnecessary for therapeutic effects. MK-0343 was designed to be a less sedating anxiolytic, based on reduced efficacy at the α1 subtype and significant efficacy at α2 and α3 subtypes of the GABAA receptor. This paper is a double-blind, four-way cross-over (n = 12) study to investigate the effects of MK-0343 (0.25 and 0.75 rag) in comparison to placebo and an anxiolytic dose (2 mg) of the non-selective agonist lorazepam. Effects were measured by eye movements, body sway, Visual Analogue Scales (VAS) and memory tests. Lorazepam impaired saccadic peak velocity (SPV), VAS alertness scores, postural stability and memory and increased saccadic latency and inaccuracy. MK-0343 0.75 mg was equipotent with lorazepam as indicated by SPV (-42.4 deg/s), saccadic latency (0.02 s) and VAS alertness scores (1.50 ln mm), while effects on memory and postural stability were smaller. MK-0343 0.25 mg only affected postural stability to a similar extent as MK-0343 0.75 mg. The effect profile of MK-0343 0.75 mg is different from the full agonist lorazepam, which could reflect the selective actions of this compound. Although less effect on VAS alertness was expected, diminished effects on memory and postural stability were present. Clinical studies in anxiety patients should show whether this dose of MK-0343 is therapeutically effective with a different side-effect profile. [ABSTRACT FROM AUTHOR]- Published
- 2008
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24. In vitro availability of calcium, iron, and zinc from first-age infant formulae and human milk.
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Bosscher, Douwina, Van Caillie-Bertrand, Micheline, Robberecht, Harry, Van Dyck, Kristien, Van Cauwenbergh, Rudy, Deelstra, Hendrik, Bosscher, D, Van Caillie-Bertrand, M, Robberecht, H, Van Dyck, K, Van Cauwenbergh, R, and Deelstra, H
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- 2001
25. Thickening infant formula with digestible and indigestible carbohydrate: availability of calcium, iron, and zinc in vitro.
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Bosscher, Douwina, Van Caillie-Bertrand, Micheline, Van Dyck, Kristien, Robberecht, Harry, Van Cauwenbergh, Rudy, Deelstra, Hendrik, Bosscher, D, Van Caillie-Bertrand, M, Van Dyck, K, Robberecht, H, Van Cauwenbergh, R, and Deelstra, H
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- 2000
26. Antiviral Activity, Safety, and Tolerability of Multiple Ascending Doses of Elbasvir or Grazoprevir in Participants Infected With Hepatitis C Virus Genotype-1 or -3
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Yeh W.W., Fraser I.P., Jumes P., Petry A., Lepeleire I.D., Robberechts M., Reitmann C., Huang X., Guo Z., Panebianco D., Nachbar R.B., O'Mara E., Wagner J.A., Butterton J.R., Dutko F.J., Moiseev V., Kobalava Z., Hüser A., Visan S., Schwabe C., Gane E., Popa S., Ghicavii N., Uhle M., Wagner F., Van Dyck K., Yeh W.W., Fraser I.P., Jumes P., Petry A., Lepeleire I.D., Robberechts M., Reitmann C., Huang X., Guo Z., Panebianco D., Nachbar R.B., O'Mara E., Wagner J.A., Butterton J.R., Dutko F.J., Moiseev V., Kobalava Z., Hüser A., Visan S., Schwabe C., Gane E., Popa S., Ghicavii N., Uhle M., Wagner F., and Van Dyck K.
- Abstract
Purpose: Elbasvir (MK-8742) and grazoprevir (MK-5172; Merck & Co, Inc, Kenilworth, New Jersey) are hepatitis C virus (HCV)-specific inhibitors of the nonstructural protein 5A phosphoprotein and the nonstructural protein 3/4A protease, respectively. The aims of these studies were to evaluate the antiviral activity and safety of different doses of elbasvir or grazoprevir each administered as monotherapy to participants infected with either HCV genotype (GT) 1 or GT3. Methods: These 2 double-blind, randomized, placebo-controlled, sequential-panel, multiple ascending dose studies were conducted to assess the safety and pharmacodynamics of 5 days of once-daily elbasvir or 7 days of once-daily grazoprevir in adult male participants chronically infected with either HCV GT1 or GT3. Findings: Oral administration of elbasvir or grazoprevir once daily exhibited potent antiviral activity in participants with chronic GT1 or GT3 HCV infections. HCV RNA levels declined rapidly (within 1 day for elbasvir and 2 days for grazoprevir). At 50 mg of elbasvir once daily, the mean maximum reductions in HCV RNA from baseline were 5.21, 4.17, and 3.12 log10 IU/mL for GT1b-, GT1a-, and GT3-infected participants, respectively. At 100 mg of grazoprevir once daily, the mean maximum reductions in HCV RNA from baseline were 4.74 and 2.64 log10 IU/mL for GT1- and GT3-infected participants. Implications: The results in the elbasvir monotherapy study showed that 10 to 50 mg of elbasvir was associated with a rapid decline in HCV viral load; the results in the grazoprevir monotherapy study suggest that doses of 50 mg of grazoprevir and higher are on the maximum response plateau of the dose–response curve for GT1-infected participants. The results of these proof-of-concept studies provided preliminary data for the selection of the dosages of elbasvir and grazoprevir to test in Phase II and III clinical studies. ClinicalTrials.gov identifiers: NCT00998985 (Protocol 5172-004) and NCT01532973 (Protoco
27. Magnetic resonance and computed tomography imaging of a carotid body tumor in a dog
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Kromhout Kaatje, Gielen Ingrid, De Cock Hilde EV, Van Dyck Kristof, and van Bree Henri
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CT ,MRI ,Carotid body tumor ,Paraganglioma ,Chemodectoma ,Veterinary medicine ,SF600-1100 - Abstract
Abstract A 5-year-old castrated male Labrador Retriever was presented to a referring veterinarian for a swelling in the neck region. Based on the results of histopathology, a carotid body tumor, was diagnosed. The dog was referred to a medical imaging unit for further staging and follow up. This report describes the magnetic resonance (MR) and computed tomographic (CT) appearance of a carotid body tumor.
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- 2012
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28. STUDY OF THE BIOAVAILABILITY OF CALCIUM, IRON AND ZINC FROM HUMAN MILK AND INFANT FORMULAE IN VITRO
- Author
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Bosscher, D., Van Dyck, K., Van Caillie‐Bertrand, M., Robberecht, H., and Deelstra, H.
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- 1999
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29. 40(th) EASD Annual Meeting of the European Association for the Study of Diabetes : Munich, Germany, 5-9 September 2004
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S. Artigas, A V Dreval, Mark I. McCarthy, C Watson, Peter H. Bennett, M Quint, Y Ikeda, E Alpert, F Schiele, H Sekihara, Erik Gylfe, P Lowe, J Kuhlmann, Alain Golay, V Longo, Shahidul Alam Khan Akm., L G Mantovani, M Zawodniak-Szalapska, G Winkler, T Harrity, L Virág, U Johne, Kuo S-W., Linda C Tapsell, J Rodriguez, Michel Komajda, K Kankova, Carole A. Cull, M Sporna, E Estilles, U Ribel, M C Spruce, E Buzzigoli, T Prazak, J K McLaughlin, M K Lingohr, M Lim, F Calara, A Siebenhofer, G Meregalli, Roberto Anichini, A D Baron, R Kurashvili, P C Butler, G I Fantus, T. E. De Gooyer, Park Y-M., R. Walther, S Heinrich, Agnieszka Zawiejska, S Mukherjee, Nikolaos Papanas, G Wong, Ian D. Caterson, David M. Maahs, Shuichi Kaneko, Alexandra E. Butler, Francisco Javier Ampudia-Blasco, O N Kong, Attali J-R., C A Hedman, K Oshinyemi, Nicolle Müller, I C Cranston, N Okumus, M V Vlaiculescu, Balasubramanian Ravikumar, W W Cheatham, K Mukasa, K B Biswas, Annunziata Lapolla, Phil McEwan, G Mader, Gilles Chassot, Dragi Anevski, Werner A. Scherbaum, M Donath, C Hesselmann, R A Gandhi, David E. Moller, Ezio Bonifacio, C Garcia, V Ifandi, P Hornnes, Nieuwenhoven Fav., C Puech, S Pérez-Del-Pulgar, Kim S-R., G Hines, C Rubio Terrés, Michael Gaster, N. Hosszufalusi, A Scholze, Andrew A. Young, Stavros Liatis, F Hariri, S Tan, Paul Valensi, Allan E. Karlsen, J Kim, E. Moberg, J Kaiser, L Berman, G Nelson, A Altkrüger, P Kothare, D B Cook, S Doran, G. van Dijk, Shahnaz Shahinfar, Kim C-S., P Stahl, M Manousaki, S Sigrist, S K Lim, M. P. Stern, A Guberti, C Rezzani, J McKenney, Karl Thomaseth, Sofia Carlsson, M Julia, R Brillante, I Rubesova, T Darkow, E Matsumoto, Wendy M. Macfarlane, M Di Martino, G Bardini, Rossella Menghini, D Duhot, E Farcasiu, Annalisa Natalicchio, I Lindner, J Buvat, Christian L. Brand, Harry Dorchy, Iwona Pietrzak, Z T Luo, P Home, M Ekelund, Jesper Gromada, Kristine Færch, F Piarulli, H Kim, R Mentel, Zsuzsanna K. Zsengellér, Dullaart Rpf., Anton Luger, Thomas A. Pearson, V Manicardi, P Rösen, Feng Y-M., R Morganti, Lars Hansen, Demuth H-U., Haruo Kasai, A Shostak, Rudi Steffensen, G Taylor, Markolf Hanefeld, C Santini, E Hamaguchi, Roberto Miccoli, F Storms, M Cooper, Y Lee, Allison E. Aiello, P Smith, T Suehiro, K Treece, M Waluś, Timothy A Welborn, Simone Baltrusch, E Kontela, S Chai, J Crean, H Yokoyama, Johan G. Eriksson, Rafael Hernández Hernández, J Rodríguez-Saldaña, M P Tornero, G Formoso, D. Lovell, E Bingham, A Mylonakis, M Manteghetti, D Fedele, Antonio Martín-Duce, Ralph A. DeFronzo, D Salcedo, Kurt Højlund, Antonio Petrone, Sheu Whh., C Gutierrez, Flavia Pricci, S Kurita, Z G Abbas, M M Benedetti, Philippe A. Halban, Daniel J. Cox, O Ljungkvist, Justine Davies, J Palsgaard, Lars Sjöström, E Bosi, L Janin-Manificat, W. F. Kelly, M. Fernandez, E Colak, O V Mulyarchik, B Kronshage, F Lang, M Erfurth, Takashi Kadowaki, N Jendrike, U Walter, J Wishart, Y. Neye, D Kim, N Furuhashi, M Barsotti, D Florow, L Ke, L Borgquist, N C Jackson, Ffolliott M. Fisher, V Baskar, K Yoshioka, Bryan A. Wolf, G Chabrier, R Skoumal, Livio Luzi, H Kose, I Pharisien, B. Klein, H Winiarska, M C Johnson, L Griffiths, Nonna Kravchun, C Combe, Baptist Gallwitz, J Zdychova, L Skorda, Jorma Ilonen, W Gao, I N Steen, A Terrinoni, P D Ambery, W Kern, C M Kusminski, Cho M-H., Paolo Pozzilli, Louise G. Grunnet, E Schönle, David R Matthews, Robert W. Taylor, Y Cohen, Kim H-S., M P Eccles, N B Tutuncu, D McDowell, Richard M. Bergenstal, K Takamatsu, T Steiner, Jaan Palgi, Valdemar Grill, N Niculescu, G Federici, S Lehto, P. M. McKeigue, M Barone, Michael E. Trautmann, S Smirnov, J Mannion, M Eto, C Rousseau, M Conti, C S Ernest, Antonio Ceriello, D H Schweitzer, Jung E-D., Andreas Festa, Avijit Lahiri, A Shepelkevich, A Murro, A Kollmann, Jonathan R.S. Arch, R Landgraf, Son H-Y., I Engelsberger, E Agardh, S Rodríguez-Mulero, P J Kraml, K Lee, D. F. Du Toit, E Kim, G Fadini, Williams Ajk., Philip Home, M B Antcieferov, C Perlemoine, D Perrea, Song X-L., D Ruggieri, Krister Bokvist, Heidi Sørensen, Bilbao, G Yoshino, J P Taylor, Shen H-M., S M Furier, R Urquhart, J Wohlgelernter, Jianping Weng, T. Baba, Q Hong, C Silva, Castaigne J-P., M Felaco, X X Zhang, M Jaroň, Milla Rosengård-Bärlund, J G Papp, Toshio Miyata, Lervang H-H., Park M-K., I Kinalska, A Long, Oomen Phn., N Kogawa, Ippolita Patrizia Patera, S. Karadeniz, Dinesh Selvarajah, D S Chung, A Wensaas, Richard Imrich, M Recasens, J Ruxer, O Buchea, E Wilpart, S P Stepanenko, Le Ttd., H Ohgawara, Mariaconsuelo Valentini, A Mondok, M Peltonen, Marianne O. Larsen, K Chatzianagnostou, Agneta Ståhle, A L Ferrari, L Bordier, F Maingrette, A Matsuda, G Vukomanovic, Jakob D. Wikstrom, T Yamakita, E Gorostiaga, J Jin, B Gopalan, Heinz Drexel, S Hewitt, Rury R. Holman, C Dieterle, T L Ruchti, N Asatiani, M Sidira, A Iezzi, A J Sommerfield, D Châtenet, M L Olsen, R Bergemann, C Koehler, T L Kuraeva, B Balas, Christian Berne, E Santos-Mazo, G Smith, A Siejka, R Kožnarová, A Mattina, S Sheikh, A Adomeit, M Rasmussen, J. Fagerudd, N Busciantella Ricci, Nuria Vilarrasa, E Hammar, T L Thoms, L Aydın, Ron G. Rosenfeld, A Nikolajuk, R Gos, C L Morgan, H L Yu, D Dheelchand, S Ramrath, N Boudriga, Jerome I. Rotter, C Jahannault, W M Weston, Folke Lindgärde, M Hertlova, D Knight, A Monroy-Mayorga, E Pardini, A Chamson-Reig, B Franke, Janie McCluskey, Joseph Bryan, C Nikolopoulou, Christie M. Ballantyne, Fausto Santeusanio, L Pegoraro, M Lee, A Klimenko, S Jaiveer, K. Pettersson-Fernholm, Michael A. Nauck, A Ekbom-Schnell, G Deferrari, Riccardo Schiaffini, S. Pampanelli, Khan Aka., David Hopkins, Maija Wessman, M Kamarinos, Noh J-H., O Ebisui, K McCarroll, Jeppe Sturis, Peter Nowotny, N Gorbenko, Åke Sjöholm, David G. Maggs, A E Halseth, B Cresci, A A Ortiz-Gress, A Korakovouni, O Matejkova, C E Mogensen, C J Lin, Ramon Gomis, H Seaman, C Granier, Yang C-H., F Assah, O Sanchez, Fausto Machicao, Peter G. Morris, Alberto Ortiz, A Giardinelli, D Bracaglia, A Gonzalo, S Pavlatos, Andreas Lechner, F Canovic, L Sjolind, Allan Vaag, Birgitte Bruun Nielsen, David A. Ziegler, Vito Lampasona, R Gershoni-Baruch, A. Dei Cas, H Renz, E Mena, Matthew Waltham, Kim D-M., H Levanen, D D Mick, Valentina Alexandrovna Peterkova, E Meskhishvili, Sarah Nutland, R Bustani, John R. 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Paulin, S, Marcu, S, Tauveron, I, Zimmermann, C, Schiele, F, Seronde, M, Vautrin, P, Lusson, J, Thieblot, P, Bernard, Y, Mistry, A, Pye, M, Peovska, I, Maksimovic Pavlovic, J, Vavlukis, M, Pop Gorceva, D, Bosevski, M, Scognamiglio, R, Negut, C, De Kreutzenberg, S, Madonna, R, De Caterina, R, Willerson, J, Geng, Y, Vahsen, S, Ledwig, D, Ramrath, S, Frantz, S, Schmidt, I, Calvillo, L, Dienesch, C, Elbing, I, Bischoff, H, Ertl, G, Bauersachs, J, Davydov, A, Mkrtum'Yan, A, Baranova, L, Ikeda, Y, Suehiro, T, Osaki, F, Ota, K, Arii, K, Kumon, Y, Hashimoto, K, Doney, A, Morris, A, Palmer, C, Byun, S, Doo, H, Pagnin, E, Calo, L, Fadini, G, Kubaszek, A, Chai, S, Chai, Q, Rasmussen, L, Ledet, T, Wogensen, L, Lengyel, C, Varró, A, Virág, L, Magyar, J, Bíró, T, Jost, N, Skoumal, R, Nánási, P, Tóth, M, Horkay, F, Papp, J, Zacharopoulou, O, Athanaselis, S, Tsokos, N, Doupis, J, Psallas, M, Cokkinos, D, Pavlatos, S, Liatis, S, Akhobadze, T, Dzneladze, L, Samarguliani, I, Taskiran, M, Rasmussen, V, Jensen, G, Fisher, A, Petrovsky, N, Srikusalanukul, W, Budge, M, Trifunovic zamaklar, D, Zivkovic, M, Jelic, V, Vukomanovic, G, Ristic, A, Seferovic, P, Costa, J, Duarte, S, Manley, S, Sailesh, S, Venkataraman, A, Haider, Y, Groza, I, Oprean, M, Ardelean, A, Morosanu, A, Darkow, T, Vanderplas, A, Mamas, M, Mcelduff, P, Burns, J, Edwards, R, Fitchet, A, Young, R, Gibson, J, Lichiardopol, R, Niculescu, N, Totora, A, Pencea, C, Tomescu, I, Cinteza, M, Manicardi, V, Coscelli, C, Navazio, A, Catellani, E, Michelini, M, Dall'Asta, D, Guberti, A, Piazza, A, Gasparini, E, Pantaleoni, M, Guiducci, U, Manari, A, Sejil, S, Janand delenne, B, Avierinos, J, Habib, G, Labastie, N, Vague, P, Lassmann vague, V, Luźniak, P, Tatoń, J, Wojciechowska Luźniak, A, Zairis, M, Lyras, A, Patsourakos, N, Tsirimbis, V, Foussas, S, Lupón, J, Urrutia, A, Herreros, J, González, B, Coll, R, Altimir, S, Prats, M, Valle, V, Abreu padí, C, Rábago, G, Ivanova, L, Brasacchio, D, Harno, E, Keenan, A, Li, H, Lu, Z, Ke, L, Liu, H, Jeong, I, Chae, M, Choi, M, Yoo, H, Kim, C, Yun, M, Na, M, Kang, Y, Kong, O, Son, S, Kim, I, Tanaka, N, Hosoi, M, Matsuyama, Y, Fukumoto, M, Yamakita, T, Yoshioka, K, Ishii, T, Sato, T, Fujii, S, Aoki, T, Shibata, T, Mizutani, N, Suzuki, J, Fowelin, J, Samuelsson, P, Brandrup wogsen, G, Okumura, K, Tokmakova, A, Staroverova, D, Antcieferov, M, Shutichina, I, Kuntchevich, G, Vriesendorp, T, Morélis, Q, Legemate, D, Schaper, F, Mainas, E, Gkioulmpasanis, I, Panagiotou, I, Vassilikos, G, Skorda, L, Sidira, M, Christoforidou, M, Alaveras, A, Artikis, V, Evdemon, E, Lechleitner, M, Koch, T, Ebenbichler, C, Sturm, W, Moretti, L, Moruzzo, D, Boldrini, E, Pandolfo, C, Kameyama, M, Iwasa, R, Cho, M, Nam, J, Huh, K, Kaplar, M, Paragh, G, Erdei, A, Csongradi, E, Garai, I, Varga, J, Galuska, L, Udvardy, M, Higa, M, Kaneko, Y, Hiroi, N, Koziarska, D, Nowacki, P, Majkowska, L, Luzniak, P, Wojciechowska luźniak, A, Tushuizen, M, Nieuwland, R, Snoeck, D, Sturk, A, Diamant, M, Aguiar, L, Bahia, L, Villela, N, Laflor, C, Conde, C, Bottino, D, Dorigo, D, Bouskela, E, Pu, S, Luo, Z, Lam, K, Dan, Q, Xu, A, Shen, J, Cheng, K, Xu, J, Thamer, C, Stefan, N, Haap, M, Heller, E, Tschritter, O, De Prado, A, Ortiz, A, Ybarra, J, Gich, I, Pou, J, Ehren, M, Roggenland, D, Reinsen, B, Klein, H, Rittig, K, Stock, J, Kocher, B, Balletshofer, B, Shon, H, Chung, D, Nakatani, Y, Matsuhisa, M, Kaneto, H, Hatazaki, M, Yoshiuchi, K, Katakami, N, Kawamori, D, Ohtoshi, K, Sakamoto, K, Matsuoka, T, Ozawa, K, Ogawa, S, Hori, M, Yamasaki, Y, Zitouni, K, Harry, D, Nourooz zadeh, J, Earle, K, Olesen, P, Franco, L, Corvaja, C, Semplicini, A, Ceylan işık, A, Arı, N, Rösen, P, Lee, I, Park, K, Jung, E, Shin, D, Jo, S, Obuobie, K, Prakash, P, Hanna, F, Lazarus, J, Varadhan, L, Gurushankar, J, James, D, Sheikh, S, Gaede, P, Zou, D, Vilarrasa, N, Perez maraver, M, Mena, E, Perez, D, Setti, G, Buckingham, R, Urbančič, V, Stefanovska, A, Bernjak, A, Ažman juvan, K, Kocijančič, A, Glowania, A, Filters, T, Fosmark, D, Torjesen, P, Kilhovd, B, Berg, T, Sandvik, L, Hanssen, K, Mentink, C, Donchenko, G, Stepanenko, S, Maingrette, F, Deng, H, Lindenmair, A, Freudenthaler, A, Baumgartner parzer, S, Nizheradze, K, Khoruzhenko, A, Tronko, N, Sheu, W, Ou, H, Shen, H, Lin, T, Wu, H, Yang, C, Mogylnytska, L, Schmoelzer, I, Davies, J, Band, M, Struthers, A, Prázný, M, Škrha, J, Kasalová, Z, Neelotpol, S, Jahan, P, Kauschke, S, Harrop, C, Schäfer, A, Widder, J, Eigenthaler, M, Walter, U, Uchimura, I, Ikebukuro, M, Kaibara, M, Hirata, M, Helal, R, Pervin, F, Yang, X, Jansson, P, Nagaev, I, Jack, M, Carvalho, E, Sunnerhagen, K, Cam, M, Cushman, S, Smith, U, Creely, S, Farmer, J, Gustafson, B, Kusminski, C, Krusinova, E, Wohl, P, Klementova, M, Lanska, V, Mcdougall, C, Kelly, I, Abbas, Z, Lutale, J, Archibald, L, Karunajeewa, H, Stingemore, N, Stuccio, G, Mcgechie, D, Muller, L, Hak, E, Goudzwaard, W, Montorsi, F, Homering, M, Sprenger, K, Goldstein, I, Asnaghi, V, Ferrari, G, Rastaldi, M, Gabellini, D, Dell'Antonio, G, Maestroni, A, Ruggieri, D, Luzi, L, Piemonti, L, Zerbini, G, Anafaroglu, I, Tutuncu, N, Sultana, M, Siddiqua, N, Iwasaki, T, Nakajima, A, Yoneda, M, Mukasa, K, Tanaka, S, and Sekihara, H
- Subjects
0303 health sciences ,medicine.medical_specialty ,business.industry ,EASD ,Endocrinology, Diabetes and Metabolism ,Human physiology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Diabetes mellitus ,Family medicine ,Internal Medicine ,Medicine ,business ,030217 neurology & neurosurgery ,030304 developmental biology - Published
- 2004
30. A randomized phase 1 study of safety, tolerability, and pharmacokinetics of MK-1088, a novel dual adenosine receptor antagonist, in healthy adult participants.
- Author
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Gupta P, Chatterjee M, Kim Y, Deschamps K, Lemoine L, Van Dyck K, Matthews CZ, Rottey S, Stoch A, and Lai E
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- Humans, Male, Adult, Female, Young Adult, Food-Drug Interactions, Double-Blind Method, Middle Aged, Dose-Response Relationship, Drug, Purinergic P1 Receptor Antagonists pharmacokinetics, Purinergic P1 Receptor Antagonists administration & dosage, Purinergic P1 Receptor Antagonists adverse effects, Pyrimidines, Triazoles, Healthy Volunteers
- Abstract
This phase 1 first-in-human study evaluated the safety, tolerability, and pharmacokinetics of MK-1088, a novel, small-molecule dual inhibitor of adenosine A
2A and A2B receptors. Healthy adult participants were enrolled in two panels (n = 8 each) and randomly assigned to receive MK-1088 (n = 6) or placebo (n = 2) orally in each of five treatment periods. Participants in panel A received single ascending doses of MK-1088 at 1, 10, 50, and 150 mg or placebo in a fasted or fed (50 mg only) state. Participants in panel B received MK-1088 at 3, 25, 100, and 224 mg or placebo in a fasted state. Primary objectives were to evaluate safety, tolerability, and plasma pharmacokinetics following a single dose of MK-1088. The secondary objective was to evaluate the effects of a high-fat meal on pharmacokinetics. All participants (n = 16) completed the study (median age: 33 years [range: 20-43]; all were male). Treatment-related adverse events (AEs) occurred in 1 of 6 (17%), 4 of 6 (67%), 4 of 6 (67%), and 2 of 6 (33%) participants after receiving MK-1088 at 3, 25, 100, and 224 mg, respectively. No serious AEs or deaths due to any cause occurred. MK-1088 was rapidly absorbed after a single dose; half-life was ~ 11 h in the 100-224 mg dose range. The target concentration at 12 h (> 0.3 µM) was exceeded at the 50-mg dose level. MK-1088 plasma pharmacokinetics increased dose proportionately. A high-fat meal did not significantly affect pharmacokinetics at the 50-mg dose. MK-1088 was well tolerated and demonstrated dose-proportional pharmacokinetic properties that were not affected by a high-fat meal., Competing Interests: Declarations. Ethical approval: The study protocol and all amendments were approved by the institutional review board or ethics committee at each participating institution (Medical Ethics Committee UZ Ghent). The study was conducted in accordance with the protocol, its amendments, the ethical principles originating from the Declaration of Helsinki, and Good Clinical Practice guidelines. Consent to participate: Written informed consent was provided by all patients before enrollment. Competing interests: PG, MC, YK, KD, LL, KVD, CZM, AS, and EL are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and may hold stock in Merck & Co., Inc., Rahway, NJ, USA.SR reports grants or contracts during the conduct of the trial for which they received payment; speaker fees to their institution from BMS, MSD, Pfizer, and Roche; travel support for Astellas, MSD, and Sanofi; served on an advisory board for Ipsen, J&J, and MSD; serving as a member of a Data Safety Monitoring Board for all industry-driven phase 1 trials in the department (>20/year); and replacing a member of the CTG (commission for reimbursement of drugs in Belgium) every time a COI is requested per voting., (© 2024. The Author(s).)- Published
- 2024
- Full Text
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31. Orally Bioavailable Macrocyclic Peptide That Inhibits Binding of PCSK9 to the Low Density Lipoprotein Receptor.
- Author
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Johns DG, Campeau LC, Banka P, Bautmans A, Bueters T, Bianchi E, Branca D, Bulger PG, Crevecoeur I, Ding FX, Garbaccio RM, Guetschow ED, Guo Y, Ha SN, Johnston JM, Josien H, Kauh EA, Koeplinger KA, Kuethe JT, Lai E, Lanning CL, Lee AYH, Li L, Nair AG, O'Neill EA, Stoch SA, Thaisrivongs DA, Tucker TJ, Vachal P, van Dyck K, Vanhoutte FP, Volckaert B, Wolford DG, Xu A, Zhao T, Zhou D, Zhou S, Zhu X, Zokian HJ, Walji AM, and Wood HB
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- Adult, Humans, Cholesterol, Cholesterol, LDL, Peptides therapeutic use, Proprotein Convertase 9 genetics, Proprotein Convertase 9 metabolism, Receptors, LDL genetics, Receptors, LDL metabolism, Anticholesteremic Agents adverse effects, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Hypercholesterolemia
- Abstract
Background: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9)-low density lipoprotein receptor interaction with injectable monoclonal antibodies or small interfering RNA lowers plasma low density lipoprotein-cholesterol, but despite nearly 2 decades of effort, an oral inhibitor of PCSK9 is not available. Macrocyclic peptides represent a novel approach to target proteins traditionally considered intractable to small-molecule drug design., Methods: Novel mRNA display screening technology was used to identify lead chemical matter, which was then optimized by applying structure-based drug design enabled by novel synthetic chemistry to identify macrocyclic peptide (MK-0616) with exquisite potency and selectivity for PCSK9. Following completion of nonclinical safety studies, MK-0616 was administered to healthy adult participants in a single rising-dose Phase 1 clinical trial designed to evaluate its safety, pharmacokinetics, and pharmacodynamics. In a multiple-dose trial in participants taking statins, MK-0616 was administered once daily for 14 days to characterize the safety, pharmacokinetics, and pharmacodynamics (change in low density lipoprotein cholesterol)., Results: MK-0616 displayed high affinity ( K
i = 5pM) for PCSK9 in vitro and sufficient safety and oral bioavailability preclinically to enable advancement into the clinic. In Phase 1 clinical studies in healthy adults, single oral doses of MK-0616 were associated with >93% geometric mean reduction (95% CI, 84-103) of free, unbound plasma PCSK9; in participants on statin therapy, multiple-oral-dose regimens provided a maximum 61% geometric mean reduction (95% CI, 43-85) in low density lipoprotein cholesterol from baseline after 14 days of once-daily dosing of 20 mg MK-0616., Conclusions: This work validates the use of mRNA display technology for identification of novel oral therapeutic agents, exemplified by the identification of an oral PCSK9 inhibitor, which has the potential to be a highly effective cholesterol lowering therapy for patients in need., Competing Interests: Disclosures D.G.J., L.-C.C., P.B., A.B., T.B., P.G.B., I.C., F.-X.D., R.M.G., E.D.G., Y.G., S.N.H., J.M.J., H.J., E.A.K., K.A.K., J.T.K., E.L., C.L.L., A.Y.H.L., L.L., A.G.N., E.A.O., S.A.S., D.A.T., T.J.T., P.V., K.v.D., D.G.W., A.X., T.Z., D.Z., S.Z., X.Z., H.J.Z., A.M.W., and H.B.W. are current or former employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ and may own stock/stock options in Merck & Co., Inc., Rahway, NJ. The other authors have no conflicts of interest.- Published
- 2023
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32. Microbial Interkingdom Biofilms and the Quest for Novel Therapeutic Strategies.
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Van Dyck K, Pinto RM, Pully D, and Van Dijck P
- Abstract
Fungal and bacterial species interact with each other within polymicrobial biofilm communities in various niches of the human body. Interactions between these species can greatly affect human health and disease. Diseases caused by polymicrobial biofilms pose a major challenge in clinical settings because of their enhanced virulence and increased drug tolerance. Therefore, different approaches are being explored to treat fungal-bacterial biofilm infections. This review focuses on the main mechanisms involved in polymicrobial drug tolerance and the implications of the polymicrobial nature for the therapeutic treatment by highlighting clinically relevant fungal-bacterial interactions. Furthermore, innovative treatment strategies which specifically target polymicrobial biofilms are discussed.
- Published
- 2021
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33. Adhesion of Staphylococcus aureus to Candida albicans During Co-Infection Promotes Bacterial Dissemination Through the Host Immune Response.
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Van Dyck K, Viela F, Mathelié-Guinlet M, Demuyser L, Hauben E, Jabra-Rizk MA, Vande Velde G, Dufrêne YF, Krom BP, and Van Dijck P
- Subjects
- Biofilms, Candida albicans, Humans, Immunity, Staphylococcus aureus, Coinfection, Staphylococcal Infections
- Abstract
Interspecies interactions greatly influence the virulence, drug tolerance and ultimately the outcome of polymicrobial biofilm infections. A synergistic interaction is observed between the fungus Candida albicans and the bacterium Staphylococcus aureus . These species are both normal commensals of most healthy humans and co-exist in several niches of the host. However, under certain circumstances, they can cause hospital-acquired infections with high morbidity and mortality rates. Using a mouse model of oral co-infection, we previously showed that an oral infection with C. albicans predisposes to a secondary systemic infection with S. aureus . Here, we unraveled this intriguing mechanism of bacterial dissemination. Using static and dynamic adhesion assays in combination with single-cell force spectroscopy, we identified C. albicans Als1 and Als3 adhesins as the molecular players involved in the interaction with S. aureus and in subsequent bacterial dissemination. Remarkably, we identified the host immune response as a key element required for bacterial dissemination. We found that the level of immunosuppression of the host plays a critical yet paradoxical role in this process. In addition, secretion of candidalysin, the C. albicans peptide responsible for immune activation and cell damage, is required for C. albicans colonization and subsequent bacterial dissemination. The physical interaction with C. albicans enhances bacterial uptake by phagocytic immune cells, thereby enabling an opportunity to disseminate., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Van Dyck, Viela, Mathelié-Guinlet, Demuyser, Hauben, Jabra-Rizk, Vande Velde, Dufrêne, Krom and Van Dijck.)
- Published
- 2021
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34. Fine-Needle Aspiration for the Evaluation of Hepatic Pharmacokinetics of Vaniprevir: A Randomized Trial in Patients With Hepatitis C Virus Infection.
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Gao W, Webber AL, Maxwell J, Anderson M, Caro L, Chung C, Miltenburg AMM, Popa S, Van Dyck K, Wenning L, Mangin E, Fandozzi C, Railkar R, Shire NJ, Fraser I, Howell B, Talal AH, and Stoch SA
- Subjects
- Adult, Antiviral Agents administration & dosage, Cyclopropanes administration & dosage, Female, Genotype, Hepacivirus genetics, Hepacivirus isolation & purification, Hepatitis C, Chronic virology, Humans, Isoindoles administration & dosage, Lactams, Macrocyclic administration & dosage, Leucine administration & dosage, Leucine pharmacokinetics, Liver virology, Male, Middle Aged, Proline administration & dosage, Proline pharmacokinetics, Sulfonamides administration & dosage, Tissue Distribution, Young Adult, Antiviral Agents pharmacokinetics, Biopsy, Fine-Needle methods, Cyclopropanes pharmacokinetics, Hepatitis C, Chronic drug therapy, Isoindoles pharmacokinetics, Lactams, Macrocyclic pharmacokinetics, Leucine analogs & derivatives, Liver metabolism, Proline analogs & derivatives, Sulfonamides pharmacokinetics
- Abstract
Fine-needle aspiration (FNA) for serial hepatic sampling may be an efficient and less invasive alternative to core needle biopsy (CNB), the current standard for liver tissue sampling. In this randomized, open-label trial in 31 participants with hepatitis C virus genotype 1 infection (NCT01678131/Merck protocol PN048), we evaluated the feasibility of using FNA to obtain human liver tissue samples appropriate for measuring hepatic pharmacokinetics (PK), using vaniprevir as a tool compound. The primary end point was successful retrieval of liver tissue specimens with measurable vaniprevir concentrations at two of three specified FNA time points. Twenty-nine patients met the primary end point and, therefore, were included in the PK analyses. Hepatic vaniprevir concentrations obtained with FNA were consistent with known vaniprevir PK properties. The shape of liver FNA and CNB concentration-time profiles were comparable. In conclusion, FNA may be effective for serial tissue sampling to assess hepatic drug exposure in patients with liver disease., (© 2019 Merck Sharp & Dohme Corp. Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)
- Published
- 2020
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35. Let's shine a light on fungal infections: A noninvasive imaging toolbox.
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Van Dyck K, Rogiers O, Vande Velde G, and Van Dijck P
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- Animals, Fungi genetics, Humans, Mycoses diagnosis, Mycoses microbiology, Fungi physiology, Molecular Imaging methods, Mycoses diagnostic imaging
- Abstract
Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2020
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36. Bioluminescence Imaging to Study Mature Biofilm Formation by Candida spp. and Antifungal Activity In Vitro and In Vivo.
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Van Dyck K, Van Dijck P, and Vande Velde G
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- Animals, Candida genetics, Candida metabolism, Candidiasis drug therapy, Female, Gene Expression, Genes, Reporter, Mice, Rats, Antifungal Agents pharmacology, Biofilms drug effects, Candida drug effects, Candidiasis microbiology, Luminescent Measurements methods, Optical Imaging methods
- Abstract
The widespread use of indwelling medical devices has increased the number of device-related infections in hospitalized patients. These infections are often associated with the formation of biofilms on the medical implants that are difficult to treat because of their resistance to the classical antifungal drugs. The most common fungi isolated from catheters and other medical devices are Candida species. The Candida genus contains multiple species of which C. albicans and C. glabrata are the two most common pathogenic yeasts in humans. A limited number of animal models is available for investigating host-pathogen interactions and testing novel antifungal drugs in vivo against these species. Fungal load in biofilms in these models is traditionally analyzed postmortem, requiring host sacrifice and enumeration of microorganisms from individual biofilms in order to evaluate the amount of colony forming units and the efficacy of antifungal treatment. Bioluminescence imaging (BLI) made compatible with small animal models for in vivo biofilm formation is a valuable tool to follow biofilm development and its treatment longitudinally. Due to the noninvasive nature of BLI, the imaging procedure can be repeated in the same animal, allowing for follow-up of the biofilm growth in vivo without removing the implanted device or detaching the biofilm from its substrate. Although detecting a quantifiable in vivo BLI signal from biofilms formed on the inside of implanted catheters is challenging, BLI proved to be a practical tool in the study of fungal biofilms. This method describes the use of BLI for in vitro and in vivo follow-up of device-related fungal biofilm formation in mice and rats and antifungal activity testing against both C. albicans and C. glabrata device-associated biofilms. It can further be applied for efficient in vivo screening for interesting genes of the pathogen and the host involved in biofilm formation.
- Published
- 2020
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37. Candida albicans and Staphylococcus Species: A Threatening Twosome.
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Carolus H, Van Dyck K, and Van Dijck P
- Abstract
Candida albicans and Staphylococcus species are, respectively, the most common fungal and bacterial agents isolated from bloodstream infections, worldwide. Moreover, it has been shown that 20% of all C. albicans bloodstream infections are polymicrobial in nature, with Staphylococcus epidermidis and Staphylococcus aureus being the first and third most common co-isolated organisms, respectively. These species are part of the commensal microbial flora but can cause hospital-acquired infections with an extreme ability to inhabit diverse host niches, especially in immunocompromised patients. They are well known for their ability to form persistent biofilms in the host or on abiotic surfaces such as indwelling medical devices. Interactions within these biofilm communities can lead to increased virulence, drug tolerance, and immune evasion. This can ultimately impact morbidity and infection outcome, often leading to an increased mortality. Therefore, characterizing the interactions between these species could lead to the development of novel therapeutic approaches that target polymicrobial infections. In this mini review, we briefly highlight the current knowledge and most recent insights into the complex interspecies interactions of C. albicans with Staphylococcus bacteria., (Copyright © 2019 Carolus, Van Dyck and Van Dijck.)
- Published
- 2019
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38. Inhibition of Vesicular Transport Influences Fungal Susceptibility to Fluconazole.
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Demuyser L, Van Dyck K, Timmermans B, and Van Dijck P
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- Candida albicans drug effects, Candida glabrata drug effects, Drug Resistance, Fungal, Fungal Proteins genetics, Fungal Proteins metabolism, Microbial Sensitivity Tests, Antifungal Agents pharmacology, Fluconazole pharmacology, Saccharomyces cerevisiae drug effects
- Abstract
Fungal infections pose a substantial threat to the human population. They can cause either mild and relatively harmless infections or invasive and often lethal diseases in patients with a weakened immune system. The majority of these human fungal infections are caused by Candida species. The limited amount of available therapies, together with the development of resistance against these drugs, strongly emphasizes the need for novel therapeutic strategies. As it is quite time-consuming to introduce completely new drugs to the market, potentiating the efficacy of existing drugs would be a better strategy. Therefore, it is important to identify cellular pathways involved in the development of drug resistance. We found that vesicular transport is involved in fungal susceptibility to the most widely used antifungal drug, fluconazole. We identified specific complexes in the vesicular transport pathway which contribute to fluconazole resistance or tolerance in the model organism Saccharomyces cerevisiae Furthermore, we confirmed our findings in the clinically relevant fungi Candida albicans and Candida glabrata Finally, we show that the combination of fluconazole with a specific inhibitor of the vesicular transport pathway increases the susceptibility of Candida species, indicating the potential of using vesicular transport as a target in combination therapy., (Copyright © 2019 American Society for Microbiology.)
- Published
- 2019
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39. Antiviral Activity, Safety, and Tolerability of Multiple Ascending Doses of Elbasvir or Grazoprevir in Participants Infected With Hepatitis C Virus Genotype-1 or -3.
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Yeh WW, Fraser IP, Jumes P, Petry A, Lepeleire I, Robberechts M, Reitmann C, Van Dyck K, Huang X, Guo Z, Panebianco D, Nachbar RB, O'Mara E, Wagner JA, Butterton JR, Dutko FJ, Moiseev V, Kobalava Z, Hüser A, Visan S, Schwabe C, Gane E, Popa S, Ghicavii N, Uhle M, and Wagner F
- Subjects
- Adult, Amides, Carbamates, Cyclopropanes, Double-Blind Method, Genotype, Hepacivirus genetics, Humans, Male, Middle Aged, RNA, Viral, Sulfonamides, Antiviral Agents therapeutic use, Benzofurans therapeutic use, Hepatitis C, Chronic drug therapy, Imidazoles therapeutic use, Quinoxalines therapeutic use
- Abstract
Purpose: Elbasvir (MK-8742) and grazoprevir (MK-5172; Merck & Co, Inc, Kenilworth, New Jersey) are hepatitis C virus (HCV)-specific inhibitors of the nonstructural protein 5A phosphoprotein and the nonstructural protein 3/4A protease, respectively. The aims of these studies were to evaluate the antiviral activity and safety of different doses of elbasvir or grazoprevir each administered as monotherapy to participants infected with either HCV genotype (GT) 1 or GT3., Methods: These 2 double-blind, randomized, placebo-controlled, sequential-panel, multiple ascending dose studies were conducted to assess the safety and pharmacodynamics of 5 days of once-daily elbasvir or 7 days of once-daily grazoprevir in adult male participants chronically infected with either HCV GT1 or GT3., Findings: Oral administration of elbasvir or grazoprevir once daily exhibited potent antiviral activity in participants with chronic GT1 or GT3 HCV infections. HCV RNA levels declined rapidly (within 1 day for elbasvir and 2 days for grazoprevir). At 50 mg of elbasvir once daily, the mean maximum reductions in HCV RNA from baseline were 5.21, 4.17, and 3.12 log
10 IU/mL for GT1b-, GT1a-, and GT3-infected participants, respectively. At 100 mg of grazoprevir once daily, the mean maximum reductions in HCV RNA from baseline were 4.74 and 2.64 log10 IU/mL for GT1- and GT3-infected participants., Implications: The results in the elbasvir monotherapy study showed that 10 to 50 mg of elbasvir was associated with a rapid decline in HCV viral load; the results in the grazoprevir monotherapy study suggest that doses of 50 mg of grazoprevir and higher are on the maximum response plateau of the dose-response curve for GT1-infected participants. The results of these proof-of-concept studies provided preliminary data for the selection of the dosages of elbasvir and grazoprevir to test in Phase II and III clinical studies. ClinicalTrials.gov identifiers: NCT00998985 (Protocol 5172-004) and NCT01532973 (Protocol 8742-002)., (Copyright © 2018 Elsevier HS Journals, Inc. All rights reserved.)- Published
- 2018
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40. Essential oils and their components are a class of antifungals with potent vapour-phase-mediated anti-Candida activity.
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Feyaerts AF, Mathé L, Luyten W, De Graeve S, Van Dyck K, Broekx L, and Van Dijck P
- Subjects
- Gas Chromatography-Mass Spectrometry methods, Microbial Sensitivity Tests, Oils, Volatile chemistry, Proof of Concept Study, Solid Phase Microextraction methods, Volatilization, Antifungal Agents pharmacology, Candida albicans drug effects, Candida glabrata drug effects, Gases, Oils, Volatile pharmacology
- Abstract
Multi-resistant microorganisms continue to challenge medicine and fuel the search for new antimicrobials. Here we show that essential oils and their components are a promising class of antifungals that can have specific anti-Candida activity via their vapour-phase. We quantify the vapour-phase-mediated antimicrobial activity (VMAA) of 175 essential oils and 37 essential oil components, representing more than a 1,000 unique molecules, against C. albicans and C. glabrata in a novel vapour-phase-mediated susceptibility assay. Approximately half of the tested essential oils and their components show growth-inhibitory VMAA. Moreover, an average greater activity was observed against the intrinsically more resistant C. glabrata, with essential oil component citronellal having a highly significant differential VMAA. In contrast, representatives of each class of antifungals currently used in clinical practice showed no VMAA. The vapour-phase-mediated susceptibility assay presented here thus allows for the simple detection of VMAA and can advance the search for novel (applications of existing) antimicrobials. This study represents the first comprehensive characterisation of essential oils and their components as a unique class of antifungals with antimicrobial properties that differentiate them from existing antifungal classes.
- Published
- 2018
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41. Sputum RNA signature in allergic asthmatics following allergen bronchoprovocation test.
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Zuiker RG, Tribouley C, Diamant Z, Boot JD, Cohen AF, Van Dyck K, De Lepeleire I, Rivas VM, Malkov VA, Burggraaf J, and Ruddy MK
- Abstract
Background: Inhaled allergen challenge is a validated disease model of allergic asthma offering useful pharmacodynamic assessment of pharmacotherapeutic effects in a limited number of subjects., Objectives: To evaluate whether an RNA signature can be identified from induced sputum following an inhaled allergen challenge, whether a RNA signature could be modulated by limited doses of inhaled fluticasone, and whether these gene expression profiles would correlate with the clinical endpoints measured in this study., Methods: Thirteen non-smoking, allergic subjects with mild-to-moderate asthma participated in a randomised, placebo-controlled, 2-period cross-over study following a single-blind placebo run-in period. Each period consisted of three consecutive days, separated by a wash-out period of at least 3 weeks. Subjects randomly received inhaled fluticasone ((FP) MDI; 500 mcg BID×5 doses in total) or placebo. On day 2, house dust mite extract was inhaled and airway response was measured by FEV1 at predefined time points until 7 h post-allergen. Sputum was induced by NaCl 4.5%, processed and analysed at 24 h pre-allergen and 7 and 24 h post-allergen. RNA was isolated from eligible sputum cell pellets (<80% squamous of 500 cells), amplified according to NuGEN technology, and profiled on Affymetrix arrays. Gene expression changes from baseline and fluticasone treatment effects were evaluated using a mixed effects ANCOVA model at 7 and at 24 h post-allergen challenge., Results: Inhaled allergen-induced statistically significant gene expression changes in sputum, which were effectively blunted by fluticasone (adjusted p<0.025). Forty-seven RNA signatures were selected from these responses for correlation analyses and further validation. This included Th2 mRNA levels for cytokines, chemokines, high-affinity IgE receptor FCER1A, histamine receptor HRH4, and enzymes and receptors in the arachidonic pathway. Individual messengers from the 47 RNA signatures correlated significantly with lung function and sputum eosinophil counts., Conclusion: Our RNA extraction and profiling protocols allowed reproducible assessments of inflammatory signatures in sputum including quantification of drug effects on this response in allergic asthmatics. This approach offers novel possibilities for the development of pharmacodynamic (PD) biomarkers in asthma.
- Published
- 2016
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42. Kinetics of TH2 biomarkers in sputum of asthmatics following inhaled allergen.
- Author
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Zuiker RG, Ruddy MK, Morelli N, Mogg R, Rivas VM, van Dyck K, De Lepeleire I, Tanen MR, Boot JD, Kamerling IM, and Diamant Z
- Abstract
Background: Allergen-induced late airway response offers important pharmacodynamic targets, including T helper 2 (TH2) biomarkers. However, detection of inflammatory markers has been limited in dithiothreitol-processed sputum., Objectives: To test whether allergen-induced TH2 inflammatory markers can be reproducibly quantified by sensitive detection techniques in ultracentrifuged sputum and the effect of fluticasone (FP) on these endpoints., Methods: Thirteen allergic asthmatics with dual allergen-induced airway responses, documented during a single-blind placebo run-in period, participated in a double-blind, two-period crossover study. Each period consisted of three consecutive days, separated by ≥3 weeks. Following randomization, subjects inhaled FP (500 µg bid, five doses total) or placebo. On Day 2 in each study period, allergen challenge was performed and airway response measured by forced expiratory volume in 1 sec (FEV1) until 7 h post-challenge. Sputum was induced 24 h pre-allergen and 7 and 24 h post-allergen. Sputum samples were split into two portions: TH2 biomarkers were quantified by Meso Scale multiplex platform following ultracentrifugation, and cell differentials were counted on Giemsa-May-Grünwald-stained cytospins. Allergen-induced changes in inflammatory endpoints were compared between FP and placebo using a mixed model ANCOVA., Results: Inhaled allergen induced dual airway responses in all subjects during both placebo periods with reproducible late asthmatic response (LAR) and increased sputum inflammatory biomarkers (IL-2, IL-4, IL-13, and eotaxin-1) and eosinophil counts. FP effectively blunted both the LAR and the inflammatory biomarkers., Conclusions: Combining novel, sensitive quantification methods with ultracentrifugation allows reproducible quantification of sputum biomarkers following allergen challenge, reversed by FP. This approach allows non-invasive identification of pharmacodynamic targets for anti-asthma therapies.
- Published
- 2015
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43. Characterizing the PK/PD relationship for inhibition of capsaicin-induced dermal vasodilatation by MK-3207, an oral calcitonin gene related peptide receptor antagonist.
- Author
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Li CC, Vermeersch S, Denney WS, Kennedy WP, Palcza J, Gipson A, Han TH, Blanchard R, De Lepeleire I, Depré M, Murphy MG, Van Dyck K, and de Hoon JN
- Subjects
- Administration, Oral, Adolescent, Adult, Cross-Over Studies, Dose-Response Relationship, Drug, Double-Blind Method, Healthy Volunteers, Humans, Male, Predictive Value of Tests, TRPV Cation Channels antagonists & inhibitors, Young Adult, Bridged Bicyclo Compounds, Heterocyclic administration & dosage, Bridged Bicyclo Compounds, Heterocyclic pharmacokinetics, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Calcitonin Gene-Related Peptide Receptor Antagonists, Capsaicin pharmacology, Models, Biological, Skin blood supply, Spiro Compounds administration & dosage, Spiro Compounds pharmacokinetics, Spiro Compounds pharmacology, Vasodilation drug effects
- Abstract
Aims: Calcitonin gene related peptide (CGRP) receptor antagonists are effective acute migraine treatments. A capsaicin-induced dermal vasodilatation (CIDV) model has been developed to provide target-engagement information in healthy volunteers. In the model, CGRP release is provoked after dermal capsaicin application, by activating transient receptor potential vanilloid-type-1 (TRPV1) receptors at peripheral sensory nerves. Laser Doppler imaging is used to quantify CIDV and subsequent inhibition by CGRP receptor antagonists. We sought to evaluate a CGRP receptor antagonist, MK-3207, in the biomarker model and to assess the predictability of the CIDV response to migraine clinical efficacy., Methods: An integrated population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the exposure-response relationship for CIDV inhibition by CGRP and TRPV1 receptor antagonists. MK-3207 dose-response predictions were made based on estimated potency from the PK/PD model and mean plasma concentrations observed at the doses investigated., Results: The results suggested that a 20 mg dose of MK-3207 (EC50 of 1.59 nm) would be required to attain the peripheral CIDV response at a target level that was shown previously to correlate with 2 h clinical efficacy based on phase 3 telcagepant clinical data, and that a plateau of the dose-response would be reached around 40-100 mg. These predictions provided a quantitative rationale for dose selection in a phase 2 clinical trial of MK-3207 and helped with interpretation of the efficacy results from the trial., Conclusions: The integrated CIDV PK/PD model provides a useful platform for characterization of PK/PD relationships and predictions of dose-response relationships to aid in future development of CGRP and TRPV1 receptor antagonists., (© 2014 The British Pharmacological Society.)
- Published
- 2015
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44. Placebo- and amitriptyline-controlled evaluation of central nervous system effects of the NK1 receptor antagonist aprepitant and intravenous alcohol infusion at pseudo-steady state.
- Author
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te Beek ET, Tatosian D, Majumdar A, Selverian D, Klaassen ES, Petty KJ, Gargano C, van Dyck K, McCrea J, Murphy G, and van Gerven JM
- Subjects
- Adolescent, Adult, Amitriptyline, Aprepitant, Central Nervous System drug effects, Cognition drug effects, Cross-Over Studies, Double-Blind Method, Drug Interactions, Female, Humans, Infusions, Intravenous, Male, Middle Aged, Morpholines blood, Morpholines pharmacokinetics, Neurokinin-1 Receptor Antagonists blood, Neurokinin-1 Receptor Antagonists pharmacokinetics, Psychomotor Performance drug effects, Young Adult, Ethanol administration & dosage, Morpholines administration & dosage, Neurokinin-1 Receptor Antagonists administration & dosage
- Abstract
Recent interest in NK1 receptor antagonists has focused on a potential role in the treatment of drug addiction and substance abuse. In the present study, the potential for interactions between the NK1 receptor antagonist aprepitant and alcohol, given as an infusion at a target level of 0.65 g/L, was evaluated. Amitriptyline was included as positive control to provide an impression of the profile of central nervous system (CNS) effects. In a double-blind, randomized, placebo- and amitriptyline-controlled study, the pharmacokinetics and CNS effects of aprepitant and alcohol were investigated in 16 healthy volunteers. Cognitive and psychomotor function tests included the visual verbal learning test (VVLT), Bond and Lader visual analogue scales (VAS), digit symbol substitution test (DSST), visual pattern recognition, binary choice reaction time, critical flicker fusion (CFF), body sway, finger tapping, and adaptive tracking. Alcohol impaired finger tapping and body sway. Amitriptyline impaired DSST performance, VAS alertness, CFF, body sway, finger tapping, and adaptive tracking. No impairments were found after administration of aprepitant. Co-administration of aprepitant with alcohol was generally well tolerated and did not cause significant additive CNS effects, compared with alcohol alone. Therefore, our study found no indications for clinically relevant interactions between aprepitant and alcohol., (© The Author(s) 2013.)
- Published
- 2013
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45. Prednisone affects inflammation, glucose tolerance, and bone turnover within hours of treatment in healthy individuals.
- Author
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Kauh E, Mixson L, Malice MP, Mesens S, Ramael S, Burke J, Reynders T, Van Dyck K, Beals C, Rosenberg E, and Ruddy M
- Subjects
- Adolescent, Adult, Biomarkers metabolism, Double-Blind Method, Female, Glucose Tolerance Test methods, Humans, Inflammation drug therapy, Inflammation metabolism, Inflammation pathology, Inflammation Mediators therapeutic use, Male, Middle Aged, Prednisone therapeutic use, Time Factors, Treatment Outcome, Young Adult, Blood Glucose metabolism, Bone Remodeling drug effects, Bone Remodeling physiology, Inflammation Mediators administration & dosage, Prednisone administration & dosage
- Abstract
Objective: Use of glucocorticoids for anti-inflammatory efficacy is limited by their side effects. This study examined, in the same individuals, prednisone's acute, dose-dependent effects on inflammation as well as biomarkers of glucose regulation and bone homeostasis., Design: In this randomized, double-blind, parallel-design trial of healthy adults demonstrating cutaneous allergen-induced hypersensitivity, patients received placebo or prednisone 10, 25 or 60 mg daily for 7 days., Methods: Effects on peripheral white blood cell (WBC) count, ex vivo whole blood lipopolysaccharide (LPS)-stimulated TNF-α release and response to cutaneous allergen challenge were assessed concurrently with biomarkers for glucose tolerance and bone turnover., Results: Differential peripheral WBC counts changed significantly within hours of prednisone administration. Ex vivo, LPS-stimulated TNF-α was significantly reduced by all prednisone doses on days 1 and 7. The late phase cutaneous allergen reaction was significantly reduced with prednisone 60 mg vs placebo on days 1 and 7. Oral glucose tolerance tests revealed significant increases in glycaemic excursion on days 1 and 7, whereas increases in insulin and C-peptide excursions were more notable on day 7 with all doses of prednisone. The bone formation markers osteocalcin, and procollagen I N- and C-terminal peptides decreased significantly on days 1 and 7 vs placebo., Conclusions: In healthy young adults after single doses as low as 10 mg, prednisone treatment has significant effects on glucose tolerance and bone formation markers within hours of treatment, in parallel with anti-inflammatory effects.
- Published
- 2012
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46. A randomized clinical trial comparing point-of-care platelet function assays and bleeding time in healthy subjects treated with aspirin or clopidogrel.
- Author
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Chen F, Maridakis V, O'neill EA, Beals C, Radziszewski W, de Lepeleire I, Van Dyck K, Depré M, Bolognese JA, de Hoon J, and Jacquemin M
- Subjects
- Adult, Aryl Hydrocarbon Hydroxylases genetics, Clopidogrel, Cross-Over Studies, Cytochrome P-450 CYP2C19, Female, Genotype, Humans, Male, Middle Aged, Platelet Aggregation drug effects, Ticlopidine administration & dosage, Young Adult, Aspirin administration & dosage, Bleeding Time, Platelet Aggregation Inhibitors administration & dosage, Platelet Function Tests, Point-of-Care Systems, Ticlopidine analogs & derivatives
- Abstract
Traditional assays of the coagulation status of patients, bleeding time assessment (BT) and light transmission aggregometry (LTA), are useful in clinical drug development. However, these assays are both labor intensive and expensive. BT results can be operator dependent and by its nature can inhibit subject enrollment in a clinical trial. The preparation of platelet-rich plasma necessary for LTA requires specialized training and laboratory support. Alternatives to these methods are desirable. The goal of this study was identification of a quantitative, easy-to-use, point-of-care device with minimal technical variables that could facilitate assessment of platelet aggregation in clinical drug development. This was a double-blind, placebo-controlled, randomized, three-period cross-over study in healthy volunteers designed to compare the abilities of BT, LTA, and three point-of-care devices, Multiplate®, Platelet Function Analyzer-100®, and VerifyNow® to quantitate the effects on platelet function of 3 days of treatment with aspirin, clopidogrel, or placebo. The effect size (difference in treatment means divided by the pooled standard deviations [SD]) of the three point-of-care devices was greater than or similar to BT and LTA for all treatment comparisons examined. VerifyNow® had the highest effect size comparing ASA to placebo. Multiplate® had the highest effect size comparing clopidogrel to placebo. From this study, we conclude that any one of the three simple-to-use point-of-care devices can reliably assess the treatment effect of ASA and CLP on platelet function in comparison with BT or LTA at the study population level
- Published
- 2012
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47. Effect of diltiazem, a moderate CYP3A inhibitor, on the pharmacokinetics of anacetrapib, a potent cholesteryl ester transfer protein inhibitor, in healthy subjects.
- Author
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Garg A, Maes A, Corr C, Jin B, Wadhwa T, Handa N, Van Dyck K, De Lepeleire I, Shah J, Wagner JA, and Krishna R
- Subjects
- Adolescent, Adult, Delayed-Action Preparations, Diltiazem administration & dosage, Diltiazem adverse effects, Drug Interactions, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors adverse effects, Female, Half-Life, Humans, Hyperlipidemias drug therapy, Linear Models, Male, Middle Aged, Oxazolidinones adverse effects, Oxazolidinones blood, Young Adult, Cholesterol Ester Transfer Proteins antagonists & inhibitors, Cytochrome P-450 CYP3A Inhibitors, Diltiazem pharmacology, Enzyme Inhibitors pharmacology, Oxazolidinones pharmacokinetics
- Published
- 2011
- Full Text
- View/download PDF
48. A single supratherapeutic dose of vorinostat does not prolong the QTc interval in patients with advanced cancer.
- Author
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Munster PN, Rubin EH, Van Belle S, Friedman E, Patterson JK, Van Dyck K, Li X, Comisar W, Chodakewitz JA, Wagner JA, and Iwamoto M
- Subjects
- Adult, Aged, Area Under Curve, Cross-Over Studies, Female, Humans, Male, Middle Aged, Placebos, Risk, Treatment Outcome, Vorinostat, Antineoplastic Agents adverse effects, Electrocardiography methods, Hydroxamic Acids adverse effects, Neoplasms complications, Neoplasms drug therapy
- Abstract
Purpose: This dedicated QTc phase I study, conducted in advanced-stage cancer patients, assessed the effect of a single supratherapeutic dose (800 mg) of vorinostat on the QTc interval., Experimental Design: A randomized, partially blind, placebo-controlled, two-period, crossover study was conducted. Patients (n = 25) received single doses of 800 mg vorinostat and placebo in the fasted state. Holter electrocardiogram monitoring was done before each treatment and for 24 h postdose. Blood samples for vorinostat concentration were collected through 24 h postdose following vorinostat treatment only. Prescribed electrocardiogram and blood sampling times were designed to capture the expected C(max) of vorinostat., Results: Twenty-four of the 25 patients enrolled in the study were included in the QTc analysis. The upper bound of the two-sided 90% confidence interval for the QTcF interval for the placebo-adjusted mean change from baseline of vorinostat was <10 ms at every time point. No patient had a QTcF change from baseline value >30 ms. One patient had QTcF values >450 ms (seen after both vorinostat and placebo administration) and none had values >480 ms. Mean AUC(0-infinity) and C(max) values attained were on the order of approximately 1.93- and approximately 1.41-fold higher, respectively, compared with the 400 mg clinical dose. Based on assessment of clinical and laboratory adverse experiences, single doses of 800 mg vorinostat were generally well tolerated., Conclusions: Administration of a single supratherapeutic dose of the histone deacetylase inhibitor vorinostat is not associated with prolongation of the QTc interval. A dedicated QTc study in advanced cancer patients is a robust means for assessing risk for ventricular repolarization prolongation.
- Published
- 2009
- Full Text
- View/download PDF
49. Single-dose pharmacokinetics and pharmacodynamics of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects.
- Author
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Krishna R, Garg A, Panebianco D, Cote J, Bergman AJ, Van Hoydonck P, Laethem T, Van Dyck K, Chen J, Chavez-Eng C, Archer L, Lutz R, Hilliard D, Snyder K, Jin B, Van Bortel L, Lasseter KC, Al-Huniti N, Dykstra K, Gottesdiener K, and Wagner JA
- Subjects
- Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Cross-Over Studies, Double-Blind Method, Fasting, Female, Humans, Male, Middle Aged, Obesity, Oxazolidinones administration & dosage, Oxazolidinones pharmacology, Sex Factors, Treatment Outcome, Young Adult, Cholesterol Ester Transfer Proteins antagonists & inhibitors, Dyslipidemias drug therapy, Oxazolidinones pharmacokinetics
- Abstract
Aims: Anacetrapib is an orally active and potent inhibitor of CETP in development for the treatment of dyslipidaemia. These studies endeavoured to establish the safety, tolerability, pharmacokinetics and pharmacodynamics of rising single doses of anacetrapib, administered in fasted or fed conditions, and to preliminarily assess the effect of food, age, gender and obesity on the single-dose pharmacokinetics and pharmacodynamics of anacetrapib., Methods: Safety, tolerability, anacetrapib concentrations and CETP activity were evaluated., Results: Anacetrapib was rapidly absorbed, with peak concentrations occurring at approximately 4 h post-dose and an apparent terminal half-life ranging from approximately 9 to 62 h in the fasted state and from approximately 42 to approximately 83 h in the fed state. Plasma AUC and C(max) appeared to increase in a less than approximately dose-dependent manner in the fasted state, with an apparent plateau in absorption at higher doses. Single doses of anacetrapib markedly and dose-dependently inhibited serum CETP activity with peak effects of approximately 90% inhibition at t(max) and approximately 58% inhibition at 24 h post-dose. An E(max) model best described the plasma anacetrapib concentration vs CETP activity relationship with an EC(50) of approximately 22 nm. Food increased exposure to anacetrapib; up to approximately two-three-fold with a low-fat meal and by up to approximately six-eight fold with a high-fat meal. Anacetrapib pharmacokinetics and pharmacodynamics were similar in elderly vs young adults, women vs men, and obese vs non-obese young adults. Anacetrapib was well tolerated and was not associated with any meaningful increase in blood pressure., Conclusions: Whereas food increased exposure to anacetrapib significantly, age, gender and obese status did not meaningfully influence anacetrapib pharmacokinetics and pharmacodynamics.
- Published
- 2009
- Full Text
- View/download PDF
50. Lack of erectogenic activity of a novel selective melanocortin-4 receptor agonist in a clinical experimental model.
- Author
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Krishna R, Wong P, Stevens C, De Lepeleire I, Van Dyck K, Rosen RC, Gendrano IN 3rd, Peeters M, Wagner JA, and Herman GA
- Subjects
- Adult, Cross-Over Studies, Dose-Response Relationship, Drug, Double-Blind Method, Humans, Male, Middle Aged, Piperazines pharmacology, Purines pharmacology, Sildenafil Citrate, Sulfones pharmacology, Vasodilator Agents pharmacology, Erectile Dysfunction drug therapy, Receptor, Melanocortin, Type 4 antagonists & inhibitors
- Published
- 2008
- Full Text
- View/download PDF
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