Laboratory of Clinical Pharmacology Copenhagen

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Research

Clinical pharmacology is the science of therapeutics. The full potential of clinical pharmacology will be achieved only by research.

Advances made over the past decade, a description of diseases in molecular terms, improves the ways in which human diseases are detected, classified, monitored, and treated. Diseases such as heart disease, diabetes, and cancer.

Our aim is to incorporate (or 'translate') our laboratory research into the clinical pratice so clinical pharmacologists can advise other professionals on these matters.  

The projects of our lab are right now:

  • Dr. Laura Kofoed Kj√¶r: Type 2 diabetes is a multi-organ disease, which affects both large and small vessels. In particular, the eyes, kidneys, nerves, feet, and heart. We need more than one marker in order to fine-tune the treatment. Some can provide a specific condition report on the various organs; others can provide a whole-body measurement. Our method covers all cells, and the urine analysis gives a kind of condition report for the entire body, including the risk of death. Read more: ScienceNordic   Read this article in Danish at ForskerZonen, part of Videnskab.dk
  • MSc Helle Kirstine M√łrup Bergholdt: My project concerns obese patients, who undergo weight-loss surgery (bariatric surgery). Obese patients have a changed metabolism. However, following bariatric surgery, we see an immediate normalization of the patients' metabolism, even in patients with diabetes. In diabetics, the altered metabolism results in an increased production of reactive oxygen-metabolites. The damage to the RNA caused by these reactive oxygen-metabolites is predictive of survival. We are investigating whether the RNA damage caused by oxidative stress might be reversed following bariatric surgery.
  • Dr. Laura Kofoed Kj√¶r: My PhD study concerns oxidative stress, measured by 8-oxodG and 8-oxoGuo, as a biomarker in the late complications of type 2 diabetes with special focus on antidiabetic medicine.
  • Emil List Larsen: The overall aim of my study is to identify an intervention that reduces oxidative stress measured by 8-oxoGuo in patients with type 2 diabetes. Due to [Oelze, M. et al., PLoS ONE, 2014] among others we hypothesize empagliflozin has this ability. We conduct a double-blinded, placebo controlled trial, where 34 participants are randomized to either two weeks 25 mg empagliflozin or placebo treatment. Hereby, we are evaluating the effect of empagliflozin on oxidative stress measured by urinary excretion of 8-oxoGuo and 8-oxodG as a measurement of RNA and DNA oxidation, respectively. For more information about this study: Clinicaltrials.gov (NCT02890745)
  • Arendse L√¶rke Torp-Pedersen: My project concerns the use of drugs during pregnancy. I examine two drugs: mebendazole and pyrvinium. WHO estimates that 2 billion people, more than 30 percent of the world's population, are infected with worms. The vast majority of these infections occur in third world countries and may eventually lead to death. Only limited data is available and my project will contribute to more knowledge. I am using the extensive Danish Register Database to examine if there is a link between use of mebendazole and pyrvinium and birth defects, premature birth, and spontaneous abortion.
  • Dr. Kasper Br√łdb√¶k Epidemiological studies suggest that type 2 diabetes is associated with increased risks of several cancer types, including cancers of the liver, pancreas, breast, endometrium, kidney, bladder, and colorectum. Although diabetes may influence carcinogenesis by several mechanisms, e.g., hyperinsulinaemia, hyperglycaemia, or chronic inflammation, any exact mechanisms underlying the association between type 2 diabetes and cancer remain to be established. The mutagenic properties of oxidatively damaged DNA and the fact that diabetes is associated with increased urinary excretion of the DNA oxidation marker 8-oxo-7,8-dihydro-2‚Ä≤-deoxyguanosine (8-oxodG) suggest that DNA oxidation could be one possible biological link between diabetes and cancer risk, and that urinary 8-oxodG may predict development of cancer in diabetes patients. No previous studies have explored the relationship between 8-oxodG excretion and cancer incidence in type 2 diabetes patients
  • Dr. Kasper Meidahl Petersen: The past decade has provided exciting insights into the role of oxidative stress in the development of diabetes-related complications. We aim to contribute to the understanding of oxidative stress-induced damage to DNA and RNA in type 2 diabetes by measuring the urinary biomarkers 8-oxodG and 8-oxoGuo. These biomarkers could potentially be used in risk stratification in type 2 diabetes.
  • RNA oxidation  -  Dr. Vanja Cejvanovic is investigating associations between RNA oxidation and iron overload. It has previously been shown that RNA oxidation is increased in patients with hereditary hemochromatosis, which is a condition with severe iron overload. In her PhD study she will focus on associations between RNA oxidation, iron overload, diabetes and abdominal obesity. Furthermore, she is investigating the effects of iron overload on mitochondrial function.
  • We have investigated the relationship between taking SSRI antidepressants during pregnancy, and foetal heart abnormalities. The results show that children of mothers who have taken antidepressants during the first trimester do have twice the risk of heart abnormalities, but this is not merely due to the medication. We've demonstrated that the higher incidence of heart abnormalities cannot be attributed to the SSRI medication with certainty, so we have to find another explanation for the fact that, for one reason or another, the abnormalities are linked to the mother's depression," said Dr. Espen Jimenez-Solem from the Clinical Pharmacology Laboratory at Rigshospitalet, who is leading the study.
  • New approach to managing diabetes treatment
    Urinary excretion of RNA oxidation marker 8-oxoGuo measured shortly after diagnosis of type 2 diabetes predicts long-term mortality. This finding suggests that 8-oxoGuo could serve as a new clinical biomarker for diabetes. This newly discovered disease marker can lead to better management of diabetes treatment - with potentially fewer cases of deaths. This method can also be used to give us a better understanding of other diseases such as Alzheimer's disease and heart failure.
  • Impact of genetic polymorphisms on heart failure prognosis. Recent progress in genomic applications have led to a better understanding of the relationship between genetic background and cardiovascular diseases such as heart failure.
  • Oncopharmacogenetic predictive markers associated with fluoropyrimidine based adjuvant chemotherapeutic treatment of colorectal cancer
  • MicroRNA - Cancer and future treatment. How do microRNAs affect gene expression. This could provide a new drug target for cancer therapies. MicroRNAs (miRNAs) are small noncoding RNA molecules found in eukaryotes and regulates gene expression at the level of translation. They are small regulatory RNAs that are emerging as important regulators of cell differentiation and human cancer genes. Genes that control cell differentiation and development, and they are frequently mutated in human cancer. The Laboratory is investigating the miRNA - cancer connection

  • Role of oxidative stress in development of late complications in diabetes
  • Dr. Jon Tr√¶rup Andersen, Ph.D. :Development of a Danish electronic record surveillance system for drugs in Denmark for cooperation with other EU countries with initial focus on the first two years after marketing. To quantitate the frequency of exposure in pregnancy to drugs associated with fetal malformations
  • Dr. Jon Tr√¶rup Andersen, Ph.D. :The use of trimethoprim in first trimester may be associated with abortion. There is performed a nationwide cohort study of all women in Denmark with a registered pregnancy between 1997 and 2005. Our results suggest that trimethoprim exposure in the first trimester is associated with a doubling of the risk of miscarriage.
  • Ability of Metoprolol to alter the exercise induced elevation of catecholamines (Mexicho). The purpose of this study is to investigate the effect of Selo-Zok ÔŅĹ (metoprolol) on the blood concentration of epinephrine and norepinephrine. This is done by creating a stress condition for the body, while doing blood samples to determine the concentration of catecholamines. It is determined through blood samples whether there are small changes in DNA in the form of point mutations also called single nucleotide polymorphisms, since these changes can affect how we respond to metoprolol treatment. Our aim is to incorporate the research into the clinical pratice.
  • Study of the ability of Clarithromycin to induce oxidative stress (CLAROX) in healthy subjects. This is done by measuring the content of a particular substance in the urine sample, which is released when the body is exposed to oxidative stress. In addition, there has also be taken blood samples, which were analysed for another substance that is indicative of oxidative stress.
  • Genetic variation in the hTAS2R38 taste receptor and brassica vegetable intake. The human TAS2R38 receptor is believed to be partly responsible for the ability to taste phenylthiocarbamide (PTC), a bitter compound very similar to the bitter glucosinolates found in brassica vegetables. These vegetables and their active compounds have chemo-protective properties. This study investigated the relationship between genetic variation in the h TAS2R38 receptor and the actual consumption of brassica vegetables with the hypothesis that taster status was associated with intake of these vegetables.

Former projects of our lab:

Adding plenty of olive oil to a diet

We looked at 182 healthy men aged between 20 and 60 from five European countries. We added either virgin, common or refined olive oil to their diets over two weeks. At the end of study, we measured levels of the substance which indicates oxidative damage to cells, called 8oxodG, in the men's urine.

Oxidative damage is a process whereby the metabolic balance of a cell is disrupted by exposure to substances that result in the accumulation of free-radicals, which can then damage the cell.

The men were found to have around 13% less 8oxodG compared with their levels at the beginning of the study. At the beginning of the study, men from northern Europe had higher levels of 8oxodG than those from southern Europe, supporting the idea that olive oil had a reductive effect.

North-south difference

Olive oil contains a number of compounds, called phenols, which are believed to act as powerful antioxidants.

But we said the men in the study used the three different oils, which had different levels of phenols, so that was unlikely to explain the protective effect. We saw that the monounsaturated fats in olive oil were probably behind the effect.

Professor Henrik Poulsen, wrote in the FASEB journal: "These data provide evidence that olive oil consumption explains the difference in cancer incidence between north and southern Europe."

The study is in the Federation American Societies for Experimental Biology.

Cancer risk and oxidative DNA damage in man 

In living cells reactive oxygen species (ROS) are formed continuously as a consequence of metabolic and other biochemical reactions as well as external factors. Antioxidant defense systems cannot provide complete protection from noxious effects of ROS. These include oxidative damage to DNA, which experimental studies in animals and in vitro have suggested are an important factor in carcinogenesis. Despite extensive repair oxidatively modified DNA is abundant in human tissues, in particular in tumors, i.e., in terms of 1-200 modified nucleosides per 105 intact nucleosides. 

The biomarkers reflect the rate of damage and the balance between the damage and repair rate, respectively. By means of biomarkers a number of important factors have been studied in humans. Ionizing radiation, a carcinogenic and pure source of ROS, induced both urinary and leukocyte biomarkers of oxidative DNA damage. Tobacco smoking, another carcinogenic source of ROS, increased the oxidative DNA damage rate by 35-50%  estimated from the urinary excretion of 8-oxodG, and the level of 8-oxodG in leukocytes by 20-50%. The main endogenous source of ROS, the oxygen consumption, showed a close correlation with the 8-oxodG excretion rate although moderate exercise appeared to have no immediate effect. So far, cross-sectional study of diet composition and intervention studies, including energy restriction and antioxidant supplements, have generally failed to show an influence on the oxidative DNA modification. However, a diet rich of Brussels sprouts reduced the oxidative DNA damage rate, estimated by the urinary excretion of 8-oxodG, and the intake of vitamin C was a determinant for the level of 8-oxodG in sperm DNA. A low-fat diet reduced another marker of oxidative DNA damage in leukocytes. In patients with diseases associated with a mechanistically based increased risk of cancer, including Fanconi anemia, chronic hepatitis, cystic fibrosis, and various autoimmune diseases, the biomarker studies indicate an increased rate of oxidative DNA damage or in some instances deficient repair. Human studies support the experimentally based notion of oxidative DNA damage as an important mutagenic and apparently carcinogenic factor. However, the proof of a causal relationship in humans is still lacking. This could possibly be supported by demonstration of the rate of oxidative DNA damage as an independent risk factor for cancer in a prospective study of biobank material using a nested case control design. In addition, oxidative damage may be important for the aging process, particularly with respect to mitochondrial DNA and the pathogenesis of inflammatory diseases. J Mol Med 1997 Jan;75(1):67-8, Acta Biochim Pol. 1998;45(1):133-44 J Toxicol Environ Health. 1993 Oct-Nov;40(2-3):391-404. Carcinogenesis. 1998 Feb;19(2):347-51, J Toxicol Environ Health.

Oxidative DNA modifications

Poulsen HE. Exp Toxicol Pathol. 2005 Jul;57 Suppl 1:161-9.

Oxidative DNA modifications are frequent in mammalian DNA and have been suggested an important mechanism in carcinogenesis, diabetes and ageing. The foundations for this suggestion are: Evidence for the importance of oxidative DNA modifications in cancer development is: high levels of oxidative lesions in cancer tissue; highly conserved and specific DNA repair systems targeting oxidative lesions; high levels of oxidative DNA lesions in oxidative DNA repair knock-out animals; defective repair of oxidative lesions in cancer-prone progeria syndromes; reduced cancer incidence in populations with high dietary antioxidant intake; and increased oxidative stress to DNA in tobacco smokers. Conflicting evidence for a relation between oxidative stress to DNA and cancer is: disagreement about the true levels and occurrence of the oxidative lesions in vivo; failure to identify the localization of oxidative lesions in important genes, e.g. tumor suppressor and oncogenes; lack of evidence that the oxidative lesions induce mutations in vivo; no cancer development in animals knocked-out for specific DNA repair enzymes in spite of high tissue levels of oxidative lesions; and unchanged cancer rates after antioxidant interventions in large clinical controlled and randomized trials. The rate of DNA oxidation has been estimated from urinary excretion of repair products and it is evident that if these lesions were not repaired, a large part of DNA would be oxidized to a degree not compatible with living. The methodologies by which oxidative DNA modifications are measured cover a wide and different range, advantages and disadvantages will be presented. One particular problem is artificial oxidation, and methods to prevent such artifacts will be presented together with results from a large interlaboratory standardization program. The methodology by which the lesions can be measured is complicated and prone to artifacts during DNA isolation, digestion, derivatization and maybe even during the separation procedure proper prior to detection. A large effort from 20+ laboratories supported by a grant from the EU has reduced artifacts considerably and work towards interlaboratory standardization of the methodology is in progress. The presently agreed "normal" levels of the most frequent known lesion 8-oxodG is about 5 per million dG's in DNA. A comprehensive evaluation of the evidence, from chemistry to clinical and epidemiological trials, linking oxidative modifications to cancer will be given. Finally, an estimate of the quantitative role oxidative DNA modifications play among the multiplicity of other insults is given. While there is no question that all of these oxidative mechanisms do exist, quantitative data on their importance for the human situation do not exist. Prospective human studies that can provide such quantitative data on different mechanisms are underway.

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