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:

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.