E.K.J. Pauwels

Leiden University Medical Centre, Leyden, South Holland, Netherlands

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Publications (343)1053.55 Total impact

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  • C.M.F. Gomes · A.J. Abrunhosa · E.K.J. Pauwels
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    ABSTRACT: The phase 0 microdosing concept was introduced recently by the FDA in order to shorten the timeline for drug development and to reduce the overall cost of the process. The aim of this approach is to provide drug pharmacokinetic and pharmacodynamic data using subpharmacological doses of prospective drug candidates in a small number of human volunteers at the earliest stages of drug development. A microdose is defined as 1/100th of the pharmacological dose or a maximum of 100 μg, which requires ultrasensitive analytical methods for measuring such a small amount of drug. Molecular imaging plays a fundamental role in this process. Radionuclide-based imaging modalities such as single-photon emission computed tomography (SPECT) and positron emission tomography (PET) allow the noninvasive visualization and quantitative assessment of physiological and biochemical processes occurring at cellular and subcellular levels within the human body. Due to the high sensitivity of such techniques it is possible to evaluate in vivo the biodistribution and pharmacokinetics of drug candidates in the nano- to picomolar concentration range. This information obtained in the earlier phases of drug development might have a tremendous impact on the success rate of agents entering clinical trials and on the overall efficiency of the process. In this article we provide an overview of the basic principles of molecular imaging with SPECT and PET and explain how these techniques can be implemented in exploratory IND studies and used to accelerate new drug approvals. Copyright © 2011 Prous Science, S.A.U. or its licensors. All rights reserved.
    No preview · Article · Jan 2011 · Drugs of the Future
  • AP Jekunen · E K J Pauwels · K J A Kairemo
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    ABSTRACT: Microdosing provides a tool to enhance drug development by initiating human studies prior to Phase I studies. The purpose is to assist in the go versus no-go decision-making process and to eliminate early ineffective compounds from the drug pipeline. Selection of multiple potential leads can be performed at the clinical stage instead of in preclinical studies. The microdosing approach can be easily used for a molecularly targeted potential drug compound with a known mechanism of action. It provides useful data regarding accessibility and biodistribution that can be used in many estimations benefiting the development of the molecule. In addition, steady state and genetic investigations are becoming possible. Microdosing has a sparing effect on timelines and costs, however, the real importance is not yet known because, although it is known to be widely performed, only a few original reports have been published.
    No preview · Article · Mar 2010 · Bioanalysis
  • E.K.J. Pauwels · M. Kostkiewicz
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    ABSTRACT: The rapidly increasing worldwide prevalence of obesity is currently considered a serious health problem that increases the risk for several comorbidities, such as diabetes, cardiovascular disease, hypertension, cancer, osteoarthritis and neuropathological disease. Increasing carbohydrate and/or fat consumption has been established to lead to obesity, and dietary approaches have been suggested to control this epidemic. Epidemiological studies suggest that the Mediterranean diet, rich in vegetal ingredients, fish and olive oil, may reduce the risk for obesity. This diet is an ample source of unsaturated fats and fibers and has a low energy density. Studies have provided evidence that the main component of olive oil (the monounsaturated fatty acid oleic acid) may promote weight loss by biochemical mechanisms, including enhanced β-oxidation and increased channeling of saturated fatty acids into triglyceride pools. By contrast, in the absence of oleic acid, dietary saturated fatty acids give rise to fat storage. This review analyzes the literature that has been published in this field and summarizes experimental and human studies on obesity prevention. Copyright © 2010 Prous Science, S.A.U. or its licensors. All rights reserved.
    No preview · Article · Feb 2010 · Drugs of the Future
  • E.K.J. Pauwels · M. Kostkiewicz
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    ABSTRACT: The Western-type diet, rich in saturated fats and low in fish and vegetables, has been associated with a high incidence of cardiovascular disease due to its proinflammatory, pro-oxidative and prothrombotic properties. In contrast, a Mediterranean-type diet (less meat, more fish, nuts, fruits, olive oil and red wine) has been linked to a better health status, including a reduced risk for cardiovascular disease. Wine contains many oxidizable phenolic compounds, and in red wine the concentration of these antioxidants is especially high. These compounds may exert anti-inflammatory activity and confer favorable effects on lipoprotein oxidation, platelet aggregation and vasodilatation. Cardioprotective effects have been demonstrated in numerous experimental and human studies, but controversy still exists on the type of alcohol-containing drink and on the specific role of alcohol and wine antioxidants. This review examines the scientific evidence underlying the prevention of cardiovascular disease by red wine. Copyright © 2009 Prous Science, S.A.U. or its licensors. All rights reserved.
    No preview · Article · Jul 2009 · Drugs of the Future
  • E. K. J. Pauwels · M. I. Covas
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    ABSTRACT: For good scientific reasons it has been argued that the Mediterranean diet has beneficial anticarcinogenic effects, evidenced by a relatively long cancer-free survival. Olive oil plays an important culinary role in the different regions of the Mediterranean basin, providing a legitimate reason to hypothesize that its constituents could exert a beneficial effect in cancer prevention. Indeed, many experimental studies have shown that both the monounsaturated oleic acid, the major lipid in olive oil, and minor olive oil components exert an anticancer effect, particularly on breast cancer and colon cancer cells. A recent meta-analysis by Sofi et al. (2008) provided solid evidence that adherence to the Mediterranean diet is positively correlated with a diminished cancer risk and there is a growing understanding that olive oil components act in an integrated manner with other molecules present in the diet. Data from epidemiological studies consistently show a beneficial effect of olive oil consumption on reducing breast cancer, but -up until now-not for colon cancer. Olive oil and olive oil phenolics have been positively associated with reduced oxidative DNA damage in humans. These encouraging findings need further confirmation in human interventional trials or large cohort studies in order to determine how this translates into decreased cancer incidence. Copyright © 2009 Prous Science, S.A.U. or its licensors. All rights reserved.
    No preview · Article · Apr 2009 · Drugs of the Future
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    ABSTRACT: Purpose: Multidrug resistance (MDR) is a significant obstacle to successful chemotherapy and a major prognostic factor in osteosarcoma (OS). We have previously observed that the chemosensitivity of OS cell lines to doxorubicin depends on P-glycoprotein (Pgp) and can be predicted based on functional assays using 99mTc-Sestamibi (MIBI). These results prompted us to develop an orthotopic model of OS for in vivo imaging of MDR and pharmacological inhibition with MIBI. Methods: Sensitive (143B) and resistant (MNNG) OS cell lines expressing different levels of Pgp and carrying a luciferase reporter gene were inoculated into the tibia of nude mice. Local tumor growth was monitored weekly by bioluminescence imaging and X-ray. After primary tumor growth, the animals were imaged with MIBI during 60 min. A group of animals were pre-treated with a Pgp inhibitor (PSC833). Images were analyzed for calculation of MIBI washout half-life (t1/2) and T/NT uptake ratios. Results: A progressively increasing bioluminescent signal was detected at 1-2 weeks after cells inoculation. The t1/2 of MIBI in drug resistant MNNG-tumors (t1/2 = 87.3±15.7 min) was significantly (pt1/2 = 161.0±47.4 min). Administration of PSC833 increased significantly the retention of MIBI in MNNG-tumors (t1/2 = 173.0±24.5 min) and had no significant effects in 143Btumors. The T/NT ratio was significantly (p
    Full-text · Article · Jan 2009 · IFMBE proceedings
  • E. K. J. Pauwels · M. Kostkiweicz
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    ABSTRACT: Cardiovascular disease is the major cause of death worldwide. Apart from the traditional risk factors of smoking, hypertension and diabetes, high homocysteine plasma concentrations have also been suggested as a factor causing atherosclerosis. It has been shown that this amino acid is able to activate the immune system in such a way that monocyte chemotaxis to the injured vessel wall (a major feature of atherosclerosis) is enhanced. In addition, high homocysteine levels may induce highly reactive oxygen species that inactivate nitric oxide (NO), an important vascular relaxing factor. High homocysteine levels have also been associated with altered lipid metabolism and increased uptake of modified low-density lipoprotein (LDL) by macrophages in the vessel wall. Numerous observational studies have demonstrated high homocysteine levels in patients with atherosclerotic disease, including myocardial infarction and cerebral stroke. However, over the past two decades, various highly powered, large, randomized, controlled and population-based studies have failed to show a relationship between homocysteine levels and the risk of vascular diseases, with the exception of stroke, calling into question whether high homocysteine levels represent a risk factor or merely a risk indicator. Furthermore, folic acid treatment alters the methylation potential, which may induce carcinogenesis. A number of well-designed epidemiological studies are still under way and at present it seems best to adhere to a wait-and-see policy. Copyright 2008 Prous Science, S.A.U. or its licensors. All rights reserved.
    No preview · Article · May 2008 · Drugs of the Future
  • E. K. J. Pauwels
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    ABSTRACT: Tetrahydrofolate is derived from folate and serves as a backbone for single-carbon transfer reactions. The donation of one-carbon units, such as methyl and methylene, is crucial for nucleotide synthesis and consequently for proper DNA formation and gene regulation. The biochemical pathways of dietary methionine produce S-adenosylmethionine, which is the universal methyl donor and a precursor for homocysteine. To save methionine for the body, homocysteine can be converted to methionine. This bioreaction shares the reaction process with the folate bioreaction cycle. Thus, dietary folate and methionine are biochemically linked and folate intake may reduce homocysteine levels. This explains why homocysteine is a sensitive marker for folate deficiency and reduced biomethylation. The results of various epidemiological studies suggest a link between low folate intake and an increased risk of various malignancies, such as cancer of the breast, ovary, esophagus, pancreas, lung, cervix and, notably, colorectal cancer. There is ample preclinical evidence that folate depletion induces hypomethylation in essential coding regions, which may result in dysfunctional tumor suppressor genes and DNA repair mechanisms. In addition to hypomethylation, hypermethylation is also frequently associated with cancer, which suggests that aberrant methylation creates suitable conditions for malignant cells to proliferate. This brings about a valid concern that both folate deficiency and excessive use of folic acid supplementation may increase the risk of cancer. This article reviews the present knowledge on the relationship between folate intake and the risk of cancer.
    No preview · Article · Apr 2008 · Drugs of the Future
  • T A F El-Maghraby · H M Moustafa · E K J Pauwels
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    ABSTRACT: Skeletal infection continues to be a common and difficult condition in clinical practice and early accurate diagnosis is very challenging. Clinical and laboratory features of skeletal infections are not always present, may be confusing, and are nonspecific for bone infection in its early stages, therefore, several imaging modalities are used for early detection of osteomyelitis. Plain films should always be the first step in the imaging assessment of osteomyelitis, however, the sensitivity for X-ray radiography has been reported to range from 43% to 75%, and the specificity from 75% to 83%. Over years, scintigraphic procedures have become an essential part of the diagnostic procedure for osteomyelitis. The standard approach for bone scintigraphy with tech 99mTc labeled methylene diphosphonate to assess for osteomyelitis is to perform a three-phase procedure. The positive uptake on all three phases is highly sensitive for osteomyelitis (sensitivity 73% to 100%). 67Ga citrate gained more attention for the more specific diagnosis of osteomyelitis due to its known capacity to localize in cases of active infection and pus. The reported specificity for 67Ga scintigraphy in osteomyelitis is around 67-70% and the specificity is much higher (92%) when 67Ga single photon emission tomography was obtained. Labeled white blood cell (WBC) imaging has become the procedure of choice to diagnose most cases of skeletal infections except for those of the spine. Labeling of leucocytes can be done either by 111In or 99mTc labeled hexamethylpropylene amineoxime. The sensitivity and specificity for labeled WBCs are in the high range of 80% to 90%. [18F]fluorodeoxyglucose positron emission tomography (PET) has been found to accumulate non-specifically at sites of infection and inflammation. Investigational studies showed that PET is particularly valuable in the evaluation of chronic osteomyelitis and infected prostheses. Other imaging modalities include sonography, computed tomography (CT) and magnetic resonance imaging (MRI). The sensitivity and specificity of CT for the diagnosis of osteomyelitis has not been established clearly and are in the range of 65% to 75%. The sensitivity of MRI for osteomyelitis has been generally reported as being between 82% and 100%, and specificity between 75% and 96%. Cases of osteomyelitis commonly referred to diagnostic imaging departments include chronic osteomyelitis, diabetic foot infections, vertebral osteomyelitis, joint prostheses and patients with suspected reinfection. These specific entities need special attention and careful selection of the correct tracer or combination of imaging modalities that is best suited for the proper therapeutic management protocols.
    No preview · Article · Oct 2006 · The quarterly journal of nuclear medicine and molecular imaging: official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of...
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    A Lupetti · M M Welling · E K J Pauwels · P H Nibbering
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    ABSTRACT: The outcome of antifungal therapy depends on the progression of the infection at the start of therapy. Unfortunately, most patients are diagnosed once the fungal infection has progressed considerably as a result of the non-specific clinical signs of fungal infections in immunocompromised patients and the poor sensitivity of current mycological diagnostic tests. This review will highlight current fungal diagnostic techniques and will focus on scintigraphic methods for the specific detection of fungal infections in mice. For this purpose, antifungal components (e.g. fluconazole and antifungal peptides) are radiolabeled e.g. with technetium-99m ((99m)Tc) and their in vivo distribution is monitored in infected mice. It has been demonstrated that (99m)Tc-fluconazole is an excellent tracer to detect Candida albicans infections in mice as it distinguishes these infections from bacterial infections and sterile inflammations. However, this radiopharmaceutical only poorly detects infections with Aspergillus fumigatus in mice. (99m)Tc-peptides derived from antifungal peptides/proteins, such as human ubiquicidin and lactoferrin, can distinguish C. albicans and A. fumigatus infections from sterile inflammations, but not from bacterial infections, in mice. Furthermore, the efficacy of fluconazole in C. albicans-infected mice could be successfully monitored using (99m)Tc-ubiquicidin. In conclusion, neither (99m)Tc-fluconazole nor the (99m)Tc-peptides tested are optimal tracers for fungal infections. Nonetheless, since early initiation of antifungal therapy for candidemia reduces its high mortality rate, a positive result with (99m)Tc-fluconazole scintigraphy is of clinical relevance. Finally, the possibility that other (radiolabeled) antifungal agents, e.g. voriconazole, caspofungin, antifungal plant or insect defensins, can be useful for detection of fungal infections should be considered.
    Full-text · Article · Jan 2006 · Current Drug Targets
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    ABSTRACT: Glomerular function of all long-term survivors who underwent hemopoietic stem cell transplantation (HSCT) from 1991 to 1998 (study I, n=121) was studied retrospectively. In addition, we prospectively analyzed glomerular and tubular function of all long-term surviving children who received an HSCT between 1998 and 2000 (study II, n=41). We found a lower prevalence of children with chronic renal failure (CRF) post-HSCT in our more recent cohort (study II: 10%) as compared to the older cohort (study I: 24%) 5.0 (0.7 s.d.) and 7.6 (2.4 s.d.) year's post-HSCT, respectively. Furthermore, it seems that renal function may stabilize after 1-year post-HSCT. None of the patients required dialysis or antihypertensive medication at long-term follow-up. The sole predictor of CRF in our study was high serum creatinine pre-HSCT (P=0.007), while acute renal failure within 3 months after HSCT (P=0.08) only showed a trend towards predicting CRF. We could not confirm a relation of conditioning with irradiation with CRF post-HSCT, as was shown in several other pediatric and adult studies. Proximal and distal tubular dysfunction only occurred in a minority of long-time survivors of HSCT (3-12 and 9-13%, respectively) and had no clinical consequences.
    Full-text · Article · Nov 2005 · Bone Marrow Transplantation
  • E. K. J. Pauwels · H. Arkies
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    ABSTRACT: Technetium-99m (Tc-99m) is the radionuclide of choice for nuclear medicine imaging. However, some radiotracers are still labeled with radioiodine, which has various detrimental characteristics. Among these agents is the radioiodine-labeled guanethidine analogue MIBG (metaiodobenzylguanidine), which is used for the study of cardiac innervation. This scintigraphic depiction of the innervation patterns is of clinical importance to evaluate the function of the cardiac sympathetic nervous system. This paper reviews the possibilities of developing a Tc-99m-labeled radiotracer that has adrenergic specificity. This search has resulted in four agents which, with some effort, can be labeled with 99mTc and have the potential to be used for diagnostic purposes: epinephrine, metahydroxyepinephrine, desipramine and atomoxetine. In order to avoid pharmacological effects, the final product after labeling should be (nearly) carrier-free.
    No preview · Article · Oct 2005 · Drugs of the Future
  • E. K. J. Pauwels

    No preview · Article · Jul 2005 · European journal of nuclear medicine and molecular imaging
  • E. K. J. Pauwels

    No preview · Article · Jul 2005 · European journal of nuclear medicine and molecular imaging

Publication Stats

5k Citations
1,053.55 Total Impact Points

Institutions

  • 1977-2011
    • Leiden University Medical Centre
      • • Department of Radiology
      • • Department of Pediatrics
      • • Department of Cardiology
      • • Department of Rheumatology
      • • Department of Clinical Oncology
      • • Department of Nephrology
      Leyden, South Holland, Netherlands
  • 2009-2010
    • Università di Pisa
      Pisa, Tuscany, Italy
  • 1976-2010
    • Leiden University
      • • Leiden Amsterdam Center for Drug Research
      • • Molecular Cell Biology Group
      Leyden, South Holland, Netherlands
  • 2008
    • Jagiellonian University
      Cracovia, Lesser Poland Voivodeship, Poland
  • 2004
    • Curium-LUMC
      Leyden, South Holland, Netherlands
  • 2001
    • Eskisehir Osmangazi University
      • Department of Nuclear Medicine
      Eskişehir, Eskisehir, Turkey
  • 1998
    • Martini Ziekenhuis
      Groningen, Groningen, Netherlands
  • 1990-1997
    • St. Antonius Ziekenhuis
      • Department of Cardiology
      Nieuwegein, Provincie Utrecht, Netherlands
  • 1995
    • University of Groningen
      Groningen, Groningen, Netherlands
  • 1993
    • Canisius-Wilhelmina Ziekenhuis
      Nymegen, Gelderland, Netherlands
  • 1992
    • Academisch Medisch Centrum Universiteit van Amsterdam
      Amsterdamo, North Holland, Netherlands