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  • 1.
    Ahlin, Gustav
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Karlsson, Johan
    Pedersen, Jenny M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Gustavsson, Lena
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Matsson, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Norinder, Ulf
    Bergström, Christel A S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Structural requirements for drug inhibition of the liver specific human organic cation transport protein 12008In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 51, no 19, p. 5932-5942Article in journal (Refereed)
    Abstract [en]

    The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.

  • 2.
    Alenius, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Dahl, Marja-Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Hartvig, Per
    Lindström, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting2008In: Journal of Psychiatric Research, ISSN 0022-3956, E-ISSN 1879-1379, Vol. 42, no 11, p. 884-893Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Many patients with psychotic symptoms respond poorly to treatment. Factors possibly affecting treatment response include the presence of polymorphisms in genes coding for various receptor populations, drug-metabolizing enzymes or transport proteins. OBJECTIVES: To investigate whether genetic polymorphisms could be indicators of treatment response to antipsychotic drugs. The genes of interest were the dopamine D2 receptor gene (DRD2), the serotonin 2A and 2C receptor genes (HTR2A and HTR2C), the P-glycoprotein gene (ABCB1 or MDR1) and the drug-metabolizing cytochrome P450 2D6 gene (CYP2D6). MATERIAL AND METHODS: Data for this naturalistic, cross-sectional study of patients requiring antipsychotic drugs and attending the Psychosis Outpatient Care clinic in Jönköping, Sweden were obtained from patient interviews, blood samples and information from patient files. Blood samples were genotyped for DRD2 Taq1 A, Ins/Del and Ser311Cys, HTR2A T102C, HTR2C Cys23Ser, ABCB1 1236C>T, 2677G>T/A, 3435C>T and genetic variants of CYP2D6. The patients (n=116) were grouped according to the CANSEPT method regarding significant social and clinical needs and significant side effects. RESULTS: Patients on olanzapine homozygous for ABCB1 3435T, had more significant social and clinical needs than others. Patients with one or two DRD2 Taq1 A1 alleles had a greater risk of significant side effects, particularly if they were male, Caucasian, had a schizophrenic or delusional disorder or were taking strong dopamine D2-receptor antagonistic drugs. CONCLUSION: If these results are confirmed, patients carrying the DRD2 Taq1 A1 allele would benefit from using drugs without strong dopamine D2 receptor antagonistic properties.

  • 3.
    Alvarsson, Jonathan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andersson, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Spjuth, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wikberg, Jarl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brunn: an open source laboratory information system for microplates with a graphical plate layout design process2011In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 12, no 1, article id 179Article in journal (Refereed)
    Abstract [en]

    Background:

    Compound profiling and drug screening generates large amounts of data and is generally based on microplate assays. Current information systems used for handling this are mainly commercial, closed source, expensive, and heavyweight and there is a need for a flexible lightweight open system for handling plate design, and validation and preparation of data.

    Results:

    A Bioclipse plugin consisting of a client part and a relational database was constructed. A multiple-step plate layout point-and-click interface was implemented inside Bioclipse. The system contains a data validation step, where outliers can be removed, and finally a plate report with all relevant calculated data, including dose-response curves.

    Conclusions:

    Brunn is capable of handling the data from microplate assays. It can create dose-response curves and calculate IC50 values. Using a system of this sort facilitates work in the laboratory. Being able to reuse already constructed plates and plate layouts by starting out from an earlier step in the plate layout design process saves time and cuts down on error sources.

  • 4.
    Andersson, Claes R.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rickardson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Gustafsson, Mats G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Signals and Systems Group.
    In vitro drug sensitivity-gene expression correlations involve a tissue of origin dependency2007In: Journal of chemical information and modeling, ISSN 1549-9596, Vol. 47, no 1, p. 239-248Article in journal (Refereed)
    Abstract [en]

    A major concern of chemogenomics is to associate drug activity with biological variables. Several reports have clustered cell line drug activity profiles as well as drug activity-gene expression correlation profiles and noted that the resulting groupings differ but still reflect mechanism of action. The present paper shows that these discrepancies can be viewed as a weighting of drug-drug distances, the weights depending on which cell lines the two drugs differ in.

  • 5.
    Andersson, Claes R.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Hvidsten, Torgeir R.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gustafsson, Mats G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Signals and Systems Group.
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Revealing cell cycle control by combining model-based detection of periodic expression with novel cis-regulatory descriptors2007In: BMC Systems Biology, ISSN 1752-0509, Vol. 1, p. 45-Article in journal (Refereed)
    Abstract [en]

    Background: We address the issue of explaining the presence or absence of phase-specific transcription in budding yeast cultures under different conditions. To this end we use a model-based detector of gene expression periodicity to divide genes into classes depending on their behavior in experiments using different synchronization methods. While computational inference of gene regulatory circuits typically relies on expression similarity (clustering) in order to find classes of potentially co-regulated genes, this method instead takes advantage of known time profile signatures related to the studied process. Results: We explain the regulatory mechanisms of the inferred periodic classes with cis-regulatory descriptors that combine upstream sequence motifs with experimentally determined binding of transcription factors. By systematic statistical analysis we show that periodic classes are best explained by combinations of descriptors rather than single descriptors, and that different combinations correspond to periodic expression in different classes. We also find evidence for additive regulation in that the combinations of cis-regulatory descriptors associated with genes periodically expressed in fewer conditions are frequently subsets of combinations associated with genes periodically expression in more conditions. Finally, we demonstrate that our approach retrieves combinations that are more specific towards known cell-cycle related regulators than the frequently used clustering approach. Conclusion: The results illustrate how a model-based approach to expression analysis may be particularly well suited to detect biologically relevant mechanisms. Our new approach makes it possible to provide more refined hypotheses about regulatory mechanisms of the cell cycle and it can easily be adjusted to reveal regulation of other, non-periodic, cellular processes.

  • 6. Aomori, Tohru
    et al.
    Yamamoto, Koujirou
    Oguchi-Katayama, Atsuko
    Kawai, Yuki
    Ishidao, Takefumi
    Mitani, Yasumasa
    Kogo, Yasushi
    Lezhava, Alexander
    Fujita, Yukiyoshi
    Obayashi, Kyoko
    Nakamura, Katsunori
    Kohnke, Hugo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Ekström, Lena
    Skogastierna, Cristine
    Rane, Anders
    Kurabayashi, Masahiko
    Murakami, Masami
    Cizdziel, Paul E.
    Hayashizaki, Yoshihide
    Horiuchi, Ryuya
    Rapid Single-Nucleotide Polymorphism Detection of Cytochrome P450 (CYP2C9) and Vitamin K Epoxide Reductase (VKORC1) Genes for the Warfarin Dose Adjustment by the SMart-Amplification Process Version 22009In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 55, no 4, p. 804-812Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Polymorphisms of the CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) gene (CYP2C9*2, CYP2C9*3) and the VKORC1 (vitamin K epoxide reductase complex, subunit 1) gene (-1639G>A) greatly impact the maintenance dose for the drug warfarin. Prescreening patients for their genotypes before prescribing the drug facilitates a faster individualized determination of the proper maintenance dose, minimizing the risk for adverse reaction and reoccurrence of thromboembolic episodes. With current methodologies, therapy can be delayed by several hours to 1 day if genotyping is to determine the loading dose. A simpler and more rapid genotyping method is required. METHODS: We developed a single-nucleotide polymorphism (SNP)-detection assay based on the SMart Amplification Process version 2 (SMAP 2) to analyze CYP2C9*2, CYP2C9*3, and VKORC1 -1639G>A polymorphisms. Blood from consenting participants was used directly in a closed-tube real-time assay without DNA purification to obtain results within 1 h of blood collection. RESULTS: We analyzed 125 blood samples by both SMAP 2 and PCR-RFLP methods. The results showed perfect concordance. CONCLUSIONS: The results validate the accuracy of the SMAP 2 for determination of SNPs critical to personalized warfarin therapy. SMAP 2 offers speed, simplicity of sample preparation, the convenience of isothermal amplification, and assay-design flexibility, which are significant advantages over conventional genotyping technologies. In this example and other clinical scenarios in which genetic testing is required for immediate and better-informed therapeutic decisions, SMAP 2-based diagnostics have key advantages.

  • 7. Avery, P. J.
    et al.
    Jorgensen, A.
    Hamberg, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Pirmohamed, M.
    Kamali, F.
    A Proposal for an Individualized Pharmacogenetics-Based Warfarin Initiation Dose Regimen for Patients Commencing Anticoagulation Therapy2011In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 90, no 5, p. 701-706Article in journal (Refereed)
    Abstract [en]

    A significant proportion of the interindividual variability in warfarin dose requirements can be explained on the basis of CYP2C9 and VKORC1 genotypes. We report the development of a novel pharmacogenetics-based 3-day warfarin initiation dose (ID) algorithm based on the International Warfarin Pharmacogenetics Consortium (IWPC) maintenance dose algorithm and the CYP2C9 genotype-based variance in warfarin half-life. The predictive value of the pharmacogenetics-based ID was assessed in a large cohort of 671 newly diagnosed patients with thromboembolic disorders who were about to commence anticoagulation therapy in accordance with standard induction regimens. In patients with mean international normalized ratio (INR)(days 4-7)>4.0 (n = 63) after warfarin initiation, the pharmacogenetics-based ID algorithm predicted a markedly lower dose requirement (median reduction = 4.2 mg), whereas in those with mean INR(days 4-7) < 2.0 (n = 145), the predicted dose requirement was very similar to that in the standard regimen. The use of a pharmacogenetics-based ID may avoid overshooting of INR in warfarin-sensitive patients without unduly affecting the time taken to reach target range in the majority of patients.

  • 8. Bergendal, Annica
    et al.
    Adami, Johanna
    Bahmanyar, Shahram
    Hedenmalm, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Larfars, Gerd
    Persson, Ingemar
    Sundstrom, Anders
    Kieler, Helle
    Non-steroidal anti-inflammatory drugs and venous thromboembolism in women2013In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 22, no 6, p. 658-666Article in journal (Refereed)
    Abstract [en]

    Background Non-steroidal anti-inflammatory drugs (NSAIDs) might increase the risk of venous thromboembolism (VTE), and risks might differ by type of NSAID. Compared with men, women have a higher incidence of VTE at younger age, and they more often use NSAIDs. Objectives To assess risks of VTE in young and middle-aged women in association with use of NSAIDs. Patients/Methods In a nationwide case-control study (Thrombo Embolism Hormone Study) performed in Sweden 2003-2009, we included as cases 1433 women, 18 to 64years of age with a first time VTE. Controls were 1402 randomly selected women, frequency matched by age. Information was obtained by telephone interviews and DNA analyses of blood samples. We calculated adjusted odds ratios (ORs) with 95% confidence intervals (CIs) adjusting for degree of immobilization, chronic disease, smoking, body mass index, use of hormonal contraception, hormone therapy or other NSAIDs. Results Use of NSAIDs was not associated with increased risks of VTE (OR=0.98, 95% CI 0.80-1.19). The OR was 0.88 for propionic acid derivatives (95% CI 0.72-1.10), 1.18 for acetic acid derivatives (95% CI 0.82-1.70) and 1.76 for coxibs (95% CI 0.73-4.27). For users of acetic acid derivatives and coxibs, the ORs increased by cumulative dose. Carriership of the prothrombin gene mutation or factor V Leiden had only minor effects on the results. Conclusions We found no increased risks of VTE in association with use of NSAIDs. Users of high cumulative doses of acetic acid derivatives and coxibs had the highest risks, suggesting a relationship with cyclooxygenase selectivity and dose.

  • 9.
    Berglund, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Thunberg, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Fridberg, Marie
    Wingren, Anette Gjörloff
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Leuchowius, Karl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lagercrantz, Svetlana
    Horvat, Andrea
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Establishment of a cell line from a chemotherapy resistant diffuse large B-cell lymphoma2007In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 48, no 5, p. 1038-1041Article in journal (Refereed)
  • 10.
    Berndtsson, Maria
    et al.
    Karolinska Institutet.
    Beaujouin, Melanie
    Rickardson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Havelka, Aleksandra Mandic
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Westman, Jacob
    Liaudet-Coopman, Emmanuelle
    Linder, Stig
    Karolinska Institutet.
    Induction of the lysosomal apoptosis pathway by inhibitors of the ubiquitin-proteasome system2009In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 124, no 6, p. 1463-1469Article in journal (Refereed)
    Abstract [en]

    The lysosomal apoptosis pathway is a potentially interesting therapeutic target. Since apoptosis involving the lysosomal pathway has been described to involve cathepsins, we screened a drug library for agents that induce cathepsin-dependent apoptosis. Using pharmacological inhibitors and siRNA, we identified 2 structurally related agents (NSC687852 and NSC638646) that induced cathepsin D-dependent caspase-cleavage activity in human breast cancer cells. Both agents were found to induce the mitochondrial apoptosis pathway. NSC687852 and NSC638646 were found to inhibit the activity of ubiquitin isopeptidases and to induce the accumulation of high-molecular-mass ubiquitins in cells. We show that 3 other inhibitors of the proteasome degradation pathway induce lysosomal membrane permeabilization (LMP) and that cathepsin-D siRNA inhibits apoptosis induced by these agents. We conclude that a screen for cathepsin-dependent apoptosis-inducing agents resulted in the identification of ubiquitin isopeptidase inhibitors and that proteasome inhibitors with different mechanisms of action induce LMP and cathepsin D-dependent apoptosis.

  • 11.
    Björklund, Peyman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Cupisti, Kenko
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Willenberg, H. S.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Stathmin as a Marker for Malignancy in Pheochromocytomas2010In: Experimental and clinical endocrinology & diabetes, ISSN 0947-7349, E-ISSN 1439-3646, Vol. 118, no 1, p. 27-30Article in journal (Refereed)
    Abstract [en]

    Pheochromocytomas of the adrenal medulla may be life-threatening catecholamine-producing tumors which are malignant in about 10% of cases. Differential diagnosis between malignant and benign tumors is dependent on the development of metastasis or extensive local invasion. A number of genetic aberrations have been described in pheochromocytomas, but no marker associated to malignancy has been reported. We applied an expression microarray containing 7770 cDNA clones and analysed the expression profiles in eleven tumors compared to normal adrenal medulla. Stathmin (STMN1, Op18) was most conspiciously overexpressed among the differentially expressed genes. RT-PCR analysis further confirmed mRNA overexpression, 6 to 8-fold for benign and malignant tumors, and 16-fold for metastases. Stathmin protein overexpression was observed by immunohistochemistry, and distinct differential protein expression between benign and malignant/metastasis specimens was confirmed by Western blot analysis. The results introduce stathmin as a possible diagnostic marker for malignant pheochromocytomas, and further evaluations are warranted.

  • 12.
    Burman, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Herrmann, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Tran, Rosetti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Kivelä, Jan-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Lomize, Andrei
    University of Michigan, Little College of Pharmacy.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Cytotoxic potency of small macrocyclic knot proteins: Structure-activity and mechanistic studies of native and chemically modified cyclotides2011In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 9, no 11, p. 4306-4314Article in journal (Refereed)
    Abstract [en]

    The cyclotides are a family of circular and knotted proteins of natural origin with extreme enzymatic and thermal stability and active in a wide range of biological activities make them promising tools for pharmaceutical and crop-protection applications. The cyclotides are divided into two subfamilies depending on the presence (Möbius) or absence (bracelet) of a cis-Pro peptide bond. In the current work we report a series of experiments to give further insight into the structure activity relationship of cyclotides in general, and the differences between subfamilies and the role of their hydrophobic surface in particular. Selective chemical modifications of Glu, Arg, Lys and Trp residues was tested for cytotoxic activity and derivatives in which the Trp residue was modified showed low effect, suggesting the existence of a connection between hydrophobicity and activity. However, over the full set of cyclotides examined, there was no strong correlation between the cytotoxic activity and their hydrophobicity. Instead, it seems more like that the distribution of charged and hydrophobic residues determines the ultimate degree of potency. Furthermore, we found that while the Glu residue is very important in maintaining the activity of the bracelet cyclotide cycloviolacin O2, it is much less important in the Möbius cyclotides. However, despite these differences, a systematic test of mixtures of cyclotides, even from both subfamilies revealed that they act in an additive way.

     

  • 13.
    Byberg, Liisa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Gedeborg, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ahlbom, Anders
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Berglund, Lars G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wolk, Alicja
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Total mortality after changes in leisure time physical activity in 50 year old men: 35 year follow-up of population based cohort (Reprinted from BMJ, vol 338, b688, 2009)2009In: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 43, no 7, p. 482-Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To examine how change in level of physical activity after middle age influences mortality and to compare it with the effect of smoking cessation.

    DESIGN: Population based cohort study with follow-up over 35 years.

    SETTING: Municipality of Uppsala, Sweden.

    PARTICIPANTS: 2205 men aged 50 in 1970-3 who were reexamined at ages 60, 70, 77, and 82 years.

    MAIN OUTCOME MEASURE: Total (all cause) mortality.

    RESULTS: The absolute mortality rate was 27.1, 23.6, and 18.4 per 1000 person years in the groups with low, medium, and high physical activity, respectively. The relative rate reduction attributable to high physical activity was 32% for low and 22% for medium physical activity. Men who increased their physical activity level between the ages of 50 and 60 continued to have a higher mortality rate during the first five years of follow-up (adjusted hazard ratio 2.64, 95% confidence interval 1.32 to 5.27, compared with unchanged high physical activity). After 10 years of follow-up their increased physical activity was associated with reduced mortality to the level of men with unchanged high physical activity (1.10, 0.87 to 1.38). The reduction in mortality associated with increased physical activity (0.51, 0.26 to 0.97, compared with unchanged low physical activity) was similar to that associated with smoking cessation (0.64, 0.53 to 0.78, compared with continued smoking).

    CONCLUSIONS: Increased physical activity in middle age is eventually followed by a reduction in mortality to the same level as seen among men with constantly high physical activity. This reduction is comparable with that associated with smoking cessation

  • 14.
    Cashin, Peter H
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Mahteme, Haile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Graf, Wilhelm
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Karlsson, Henning
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Activity ex vivo of cytotoxic drugs in patient samples of peritoneal carcinomatosis with special focus on colorectal cancer2013In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 13, p. 435-Article in journal (Refereed)
    Abstract [en]

    Background: The optimal choice of cytotoxic drugs for intraperitoneal chemotherapy (IPC) in conjunction with cytoreductive surgery (CRS) for treatment of peritoneal carcinomatosis(PC) is poorly defined. We investigated drug sensitivity ex vivo in patient samples of various PC tumor types and correlated clinical outcome to drug sensitivity within the subset of PC fromcolorectal cancer (CRC). 

    Methods: PC tissue samples (n = 174) from mesothelioma, pseudomyxoma peritonei (PMP), ovarian cancer, CRC or appendix cancer were analyzed ex vivo for sensitivity to oxaliplatin, cisplatin, mitomycin C, melphalan, irinotecan, docetaxel, doxorubicin and 5-FU. Clinicopathological variables and outcome data were collected for the CRC subset. 

    Results: Mesothelioma and ovarian cancer were generally more drug sensitive than CRC, appendix cancer and PMP. Oxaliplatin showed the most favorable ratio between achievable IPC concentration and ex vivo drug sensitivity. Drug sensitivity in CRC varied considerably between individual samples. Ex vivo drug sensitivity did not obviously correlate to time-to-progression (TTP) in individual patients. 

    Conclusions: Drug-sensitivity varies considerably between PC diagnoses and individual patients arguing for individualized therapy in IPC rather than standard diagnosis-specific therapy. However, in the current paradigm of treatment according to diagnosis, oxaliplatin is seemingly the preferred drug for IPC from a drug sensitivity and concentration perspective. Inthe CRC subset, analysis of correlation between ex vivo drug sensitivity and TTP was inconclusive due to the heterogeneous nature of the data.

  • 15. Chen, Leslie Y.
    et al.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Gwilliam, Rhian
    Bentley, David
    Deloukas, Panos
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Gamma-glutamyl carboxylase (GGCX) microsatellite and warfarin dosing2005In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 106, no 10, p. 3673-4Article in journal (Refereed)
  • 16. D'Arcy, Padraig
    et al.
    Brnjic, Slavica
    Olofsson, Maria Hägg
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Lindsten, Kristina
    de Cesare, Michelandrea
    Perego, Paola
    Sadeghi, Behnam
    Hassan, Moustapha
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Linder, Stig
    Inhibition of proteasome deubiquitinating activity as a new cancer therapy2011In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 17, no 12, p. 1636-1640Article in journal (Refereed)
    Abstract [en]

    Ubiquitin-tagged substrates are degraded by the 26S proteasome, which is a multisubunit complex comprising a proteolytic 20S core particle capped by 19S regulatory particles. The approval of bortezomib for the treatment of multiple myeloma validated the 20S core particle as an anticancer drug target. Here we describe the small molecule b-AP15 as a previously unidentified class of proteasome inhibitor that abrogates the deubiquitinating activity of the 19S regulatory particle. b-AP15 inhibited the activity of two 19S regulatory-particle-associated deubiquitinases, ubiquitin C-terminal hydrolase 5 (UCHL5) and ubiquitin-specific peptidase 14 (USP14), resulting in accumulation of polyubiquitin. b-AP15 induced tumor cell apoptosis that was insensitive to TP53 status and overexpression of the apoptosis inhibitor BCL2. We show that treatment with b-AP15 inhibited tumor progression in four different in vivo solid tumor models and inhibited organ infiltration in an acute myeloid leukemia model. Our results show that the deubiquitinating activity of the 19S regulatory particle is a new anticancer drug target.

  • 17. De Fazio, Salvatore
    et al.
    Gallelli, Luca
    De Siena, Antonella
    De Sarro, Giovambattista
    Scordo, Maria Gabriella
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Role of CYP3AS in abnormal clearance of methadone2008In: The Annals of Pharmacotherapy, ISSN 1060-0280, E-ISSN 1542-6270, Vol. 42, no 6, p. 893-897Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To report a case of unusually low concentrations of methadone in a polydrug abuser during maintenance treatment with methadone. CASE SUMMARY: A 25-year-old man (weight 55 kg, height 165 cm) with a 12-year history of polydrug abuse was admitted to an opiates withdrawal methadone program. At the time of our observation, he was using both cannabinoids and heroin; no other medical conditions were discovered. Within the opiates withdrawal methadone program, under medical supervision, the patient started methadone therapy (20 mg/day). Two weeks later, an Abuscreen assay for methadone screening in the urine was negative and, to prevent the development of withdrawal symptoms, the dose of methadone was increased to 60 mg/day. One day later, the patient was asked to collect another urine sample in the presence of a nurse. The Abuscreen for methadone in urine remained negative. Evaluation of urinary samples collected over 24 hours documented low concentrations of methadone and high levels of 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (the primary metabolite of methadone). Evaluation for the presence of the most common polymorphisms in the cytochrome P450 and P-glycoprotein genes showed that the patient was heterozygous for the CYP3A5*1 allele and for 2 single nucleotide polymorphisms in the P-glyooprotein gene (1236C/T and 3435C/T). DISCUSSION: In this patient, poor methadone adherence was ruled out because of the presence of physicians and nurses during both methadone maintenance treatment and Abuscreen screening. Moreover, because the patient reported only heroin and cannabis at the time of evaluation, drug interactions were ruled out as possible causes for the rapid clearance of methadone. CONCLUSIONS: In this case, CYP3A5 polymorphism may have played a role in the rapid methadone metabolism.

  • 18. De Luca, C.
    et al.
    Scordo, Gabriella Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Cesareo, E.
    Raskovic, D.
    Genovesi, G.
    Korkina, L.
    Idiopathic environmental intolerances (IEI): from molecular epidemiology to molecular medicine2010In: Indian Journal of Experimental Biology, ISSN 0019-5189, Vol. 48, no 7, p. 625-635Article, review/survey (Refereed)
    Abstract [en]

    Inherited or acquired impairment of xenobiotics metabolism is a postulated mechanism underlying environment-associated pathologies such as multiple chemical sensitivity, fibromyalgia, chronic fatigue syndrome, dental amalgam disease, and others, also collectively named idiopathic environmental intolerances (IEI). In view of the poor current knowledge of their etiology and pathogenesis, and the absence of recognised genetic and metabolic markers of the diseases. They are often considered "medically unexplained syndromes",. These disabling conditions share the features of polysymptomatic multi-organ syndromes, considered by part of the medical community to be aberrant responses triggered by exposure to low-dose organic and inorganic chemicals and metals, in concentrations far below average reference levels admitted for environmental toxicants. A genetic predisposition to altered biotransformation of environmental chemicals, drugs, and metals, and of endogenous low-molecular weight metabolites, caused by polymorphisms of genes coding for xenobiotic metabolizing enzymes, their receptors and transcription factors appears to be involved in the susceptibility to these environment-associated pathologies, along with epigenetic factors. Free radical/antioxidant homeostasis may also be heavily implicated, indirectly by affecting the regulation of xenobiotic metabolizing enzymes, and directly by causing increased levels of oxidative products, implicated in the chronic damage of cells and tissues, which is in part correlated with clinical symptoms. More systematic studies of molecular epidemiology, toxico- and pharmaco-genomics, elucidating the mechanisms of regulation, expression, induction, and activity of antioxidant/detoxifying enzymes, and the possible role of inflammatory mediators, promise a better understanding of this pathologically increased sensitivity to low-level chemical stimuli, and a solid basis for effective individualized antioxidant- and/or chelator-based treatments.

  • 19. De Luca, Chiara
    et al.
    Scordo, Maria G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Cesareo, Eleonora
    Pastore, Saveria
    Mariani, Serena
    Maiani, Gianluca
    Stancato, Andrea
    Loreti, Beatrice
    Valacchi, Giuseppe
    Lubrano, Carla
    Raskovic, Desanka
    De Padova, Luigia
    Genovesi, Giuseppe
    Korkina, Liudmila G.
    Biological definition of multiple chemical sensitivity from redox state and cytokine profiling and not from polymorphisms of xenobiotic-metabolizing enzymes2010In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 248, no 3, p. 285-292Article in journal (Refereed)
    Abstract [en]

    Background: Multiple chemical sensitivity (MCS) is a poorly clinically and biologically defined environment-associated syndrome. Although dysfunctions of phase I/phase II metabolizing enzymes and redox imbalance have been hypothesized, corresponding genetic and metabolic parameters in MCS have not been systematically examined. Objectives: We sought for genetic, immunological, and metabolic markers in MCS. Methods: We genotyped patients with diagnosis of MCS. suspected MCS and Italian healthy controls for allelic variants of cytochrome P450 isoforms (CYP2C9, CYP2C19, CYP2D6, and CYP3A5), UDP-glucuronosyl transferase (UGT1A1), and glutathione S-transferases (GSTP1. GSTM1, and GSTT1). Erythrocyte membrane fatty acids, antioxidant (catalase, superoxide dismutase (SOD)) and glutathione metabolizing (GST, glutathione peroxidase (Gpx)) enzymes, whole blood chemiluminescence, total antioxidant capacity, levels of nitrites/nitrates, glutathione, HNE-protein adducts, and a wide spectrum of cytokines in the plasma were determined. Results: Allele and genotype frequencies of CYPs, UGT, GSTM, GSTT, and GSTP were similar in the Italian MCS patients and in the control populations. The activities of erythrocyte catalase and GST were lower, whereas Gpx was higher than normal. Both reduced and oxidised glutathione were decreased, whereas nitrites/nitrates were increased in the MCS groups. The MCS fatty acid profile was shifted to saturated compartment and IFNgamma, IL-8, IL-10, MCP-1. PDGFbb, and VEGF were increased. Conclusions: Altered redox and cytokine patterns suggest inhibition of expression/activity of metabolizing and antioxidant enzymes in MCS. Metabolic parameters indicating accelerated lipid oxidation, increased nitric oxide production and glutathione depletion in combination with increased plasma inflammatory cytokines should be considered in biological definition and diagnosis of MCS. (C) 2010 Elsevier Inc. All rights reserved.

  • 20. Dyrager, Christine
    et al.
    Wickström, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Fridén-Saxin, Maria
    Friberg, Annika
    Dahlén, Kristian
    Wallén, Erik A. A.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Grotli, Morten
    Luthman, Kristina
    Inhibitors and promoters of tubulin polymerization: Synthesis and biological evaluation of chalcones and related dienones as potential anticancer agents2011In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 19, no 8, p. 2659-2665Article in journal (Refereed)
    Abstract [en]

    A series of dihalogenated chalcones and structurally related dienones were synthesized and evaluated for their antiproliferative activity in 10 different cancer cell lines and for their effect on microtubule assembly. All compounds showed cytotoxic activity, with IC50 values in the 5-280 mu M range depending on the chalcone structure and the cell line. Five of the compounds were found to be tubulin polymerization inhibitors. In contrast, one of the compounds was found to stabilize tubulin to the same extent as the anticancer drug docetaxel. Molecular modeling suggested that the tubulin inhibitors bind to the colchicine binding site of beta-tubulin while the novel tubulin stabilization agent seems to interact with the paclitaxel binding site.

  • 21. Eriksson, Mathilda
    et al.
    Hassan, Saadia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Linder, Stig
    Karolinska Institutet.
    Ramqvist, Torbjörn
    Lövborg, Henrik
    Vikinge, Trine
    Figgemeier, Egbert
    Müller, Jürgen
    Stetefeld, Jörg
    Dalianis, Tina
    Ozbek, Suat
    Utilization of a right-handed coiled-coil protein from archaebacterium Staphylothermus marinus as a carrier for cisplatin2009In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 29, no 1, p. 11-18Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    The nano-sized right-handed coiled-coil (RHCC) protein, originating from the archaebacterium Staphylothermus marinus, is stable at high salt concentrations, high temperatures, high pressures and extremes of pH. Its crystal structure reveals four hydrophobic cavities which can incorporate heavy metals. Nano-sized compounds have been used to carry cytotoxic drugs to tumours, avoiding delivery to healthy tissue, in part due to enhanced permeability in tumour blood vessels (enhanced permeability and retention effect).

    MATERIALS AND METHODS:

    The ability of RHCC to carry the platinum-containing chemotherapeutic drug cisplatin to cells, while retaining the cytotoxic potential was tested both in vitro and in vivo.

    RESULTS:

    RHCC was able to bind and enter cells in vitro and was not severely toxic or immunogenic in mice. Moreover, RHCC incorporated cisplatin, without inhibiting the cytotoxic potential of the drug against tumour cell lines in vitro or in vivo.

    CONCLUSION:

    RHCC can be used as a carrier of cisplatin without abrogating the effect of the drug.

  • 22.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    On the Prediction of Warfarin Dose2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Warfarin is one of the most widely used anticoagulants in the world. Treatment is complicated by a large inter-individual variation in the dose needed to reach adequate levels of anticoagulation i.e. INR 2.0 – 3.0. The objective of this thesis was to evaluate which factors, mainly genetic but also non-genetic, that affect the response to warfarin in terms of required maintenance dose, efficacy and safety with special focus on warfarin dose prediction.

    Through candidate gene and genome-wide studies, we have shown that the genes CYP2C9 and VKORC1 are the major determinants of warfarin maintenance dose. By combining the SNPs CYP2C9 *2, CYP2C9 *3 and VKORC1 rs9923231 with the clinical factors age, height, weight, ethnicity, amiodarone and use of inducers (carbamazepine, phenytoin or rifampicin) into a prediction model (the IWPC model) we can explain 43 % to 51 % of the variation in warfarin maintenance dose. Patients requiring doses < 29 mg/week and doses ≥ 49 mg/week benefitted the most from pharmacogenetic dosing. Further, we have shown that the difference across ethnicities in percent variance explained by VKORC1 was largely accounted for by the allele frequency of rs9923231. Other novel genes affecting maintenance dose (NEDD4 and DDHD1), as well as the replicated CYP4F2 gene, have small effects on dose predictions and are not likely to be cost-effective, unless inexpensive genotyping is available.

    Three types of prediction models for warfarin dosing exist: maintenance dose models, loading dose models and dose revision models. The combination of these three models is currently being used in the warfarin treatment arm of the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) study. Other clinical trials aiming to prove the clinical validity and utility of pharmacogenetic dosing are also underway.

    The future of pharmacogenetic warfarin dosing relies on results from these ongoing studies, the availability of inexpensive genotyping and the cost-effectiveness of pharmacogenetic driven warfarin dosing compared with new oral anticoagulant drugs.

    List of papers
    1. The largest prospective warfarin-treated cohort supports genetic forecasting
    Open this publication in new window or tab >>The largest prospective warfarin-treated cohort supports genetic forecasting
    Show others...
    2009 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 113, no 4, p. 784-792Article in journal (Refereed) Published
    Abstract [en]

    Genetic variants of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) are known to influence warfarin dose, but the effect of other genes has not been fully elucidated. We genotyped 183 polymorphisms in 29 candidate genes in 1496 Swedish patients starting warfarin treatment, and tested for association with response. CYP2C9*2 and *3 explained 12% (P = 6.63 x 10(-34)) of the variation in warfarin dose, while a single VKORC1 SNP explained 30% (P = 9.82 x 10(-100)). No SNP outside the CYP2C gene cluster and VKORC1 regions was significantly associated with dose after correction for multiple testing. During initiation of therapy, homozygosity for CYP2C9 and VKORC1 variant alleles increased the risk of over-anticoagulation, hazard ratios 21.84 (95% CI 9.46; 50.42) and 4.56 (95% CI 2.85; 7.30), respectively. One of 8 patients with CYP2C9*3/*3 (12.5%) experienced severe bleeding during the first month compared with 0.27% of other patients (P = .066). A multiple regression model using the predictors CYP2C9, VKORC1, age, sex, and druginteractions explained 59% of the variance in warfarin dose, and 53% in an independent sample of 181 Swedish individuals. In conclusion, CYP2C9 and VKORC1 significantly influenced warfarin dose and predicted individuals predisposed to unstable anticoagulation. Our results strongly support that initiation of warfarin guided by pharmacogenetics would improve clinical outcome.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-98487 (URN)10.1182/blood-2008-04-149070 (DOI)000262646200006 ()18574025 (PubMedID)
    Available from: 2009-02-24 Created: 2009-02-24 Last updated: 2017-12-13
    2. Estimation of the warfarin dose with clinical and pharmacogenetic data
    Open this publication in new window or tab >>Estimation of the warfarin dose with clinical and pharmacogenetic data
    Show others...
    2009 (English)In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 360, no 8, p. 753-764Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Genetic variability among patients plays an important role in determining the dose of warfarin that should be used when oral anticoagulation is initiated, but practical methods of using genetic information have not been evaluated in a diverse and large population. We developed and used an algorithm for estimating the appropriate warfarin dose that is based on both clinical and genetic data from a broad population base.

    METHODS: Clinical and genetic data from 4043 patients were used to create a dose algorithm that was based on clinical variables only and an algorithm in which genetic information was added to the clinical variables. In a validation cohort of 1009 subjects, we evaluated the potential clinical value of each algorithm by calculating the percentage of patients whose predicted dose of warfarin was within 20% of the actual stable therapeutic dose; we also evaluated other clinically relevant indicators.

    RESULTS: In the validation cohort, the pharmacogenetic algorithm accurately identified larger proportions of patients who required 21 mg of warfarin or less per week and of those who required 49 mg or more per week to achieve the target international normalized ratio than did the clinical algorithm (49.4% vs. 33.3%, P<0.001, among patients requiring < or = 21 mg per week; and 24.8% vs. 7.2%, P<0.001, among those requiring > or = 49 mg per week).

    CONCLUSIONS: The use of a pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin produces recommendations that are significantly closer to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach. The greatest benefits were observed in the 46.2% of the population that required 21 mg or less of warfarin per week or 49 mg or more per week for therapeutic anticoagulation.

    Keyword
    Pharmacogenetics
    National Category
    Medical and Health Sciences
    Research subject
    Clinical Pharmacology
    Identifiers
    urn:nbn:se:uu:diva-98505 (URN)10.1056/NEJMoa0809329 (DOI)000263411300005 ()19228618 (PubMedID)
    Note

    Co-author: Mia Wadelius, Uppsala universitet, Institutionen för medicinska vetenskaper, forskargrupp Clinical pharmacogenetics and osteoporosis, ingår i the International Warfarin Pharmacogenetics Consortium.

    Available from: 2009-02-24 Created: 2009-02-24 Last updated: 2017-12-13Bibliographically approved
    3. Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across three racial groups
    Open this publication in new window or tab >>Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across three racial groups
    Show others...
    2010 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 115, no 18, p. 3827-3834Article in journal (Refereed) Published
    Abstract [en]

    Warfarin dosing algorithms incorporating CYP2C9 and VKORC1-1639G>A improve dose prediction compared to algorithms based solely on clinical and demographic factors. However these algorithms better capture dose variability among Whites compared to Asians or Blacks. Herein we evaluate whether other VKORC1 polymorphisms and haplotypes explain additional variation in warfarin dose beyond that explained by VKORC1-1639G>A among Asians (n=1103), Blacks (n=670) and Whites (n=3113). Participants were recruited from 11 countries as part of the International Warfarin Pharmacogenetics Consortium effort. Evaluation of the effects of individual VKORC1 SNPs and haplotypes on warfarin dose employed both univariate and multivariable linear regression. VKORC1-1639G>A and 1173C>T individually explained the greatest variance in dose in all three racial groups. Incorporation of additional VKORC1 SNPs or haplotypes did not further improve dose prediction. VKORC1 explained greater variability in dose among Whites as compared to Blacks and Asians. Differences in the percent variance in dose explained by VKORC1 across race was largely accounted for by the frequency of the -1639 A (or 1173 T) allele. Thus, clinicians should recognize that although at a population level, the contribution of VKORC1 towards dose requirements is higher in Whites compared to non-whites; genotype predicts similar dose requirements across racial groups.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-124680 (URN)10.1182/blood-2009-12-255992 (DOI)000277335900027 ()20203262 (PubMedID)
    Available from: 2010-05-05 Created: 2010-05-05 Last updated: 2017-12-12
    4. Genetic determinants of warfarin response, efficacy and safety: a RE-LY genomics substudy
    Open this publication in new window or tab >>Genetic determinants of warfarin response, efficacy and safety: a RE-LY genomics substudy
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Keyword
    Warfarin, GWAS, Prediction
    National Category
    Cardiac and Cardiovascular Systems
    Research subject
    Clinical Pharmacology
    Identifiers
    urn:nbn:se:uu:diva-172004 (URN)
    Available from: 2012-04-16 Created: 2012-03-31 Last updated: 2012-06-08
    5. Prediction of warfarin dose: why, when and how?
    Open this publication in new window or tab >>Prediction of warfarin dose: why, when and how?
    2012 (English)In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 13, no 4, p. 429-440Article, review/survey (Refereed) Published
    Abstract [en]

    Prediction models are the key to individualized drug therapy. Warfarin is a typical example of where pharmacogenetics could help the individual patient by modeling the dose, based on clinical factors and genetic variation in CYP2C9 and VKORC1. Clinical studies aiming to show whether pharmacogenetic warfarin dose predictions are superior to conventional initiation of warfarin are now underway. This review provides a broad view over the field of warfarin pharmacogenetics from basic knowledge about the drug, how it is monitored, factors affecting dose requirement, prediction models in general and different types of prediction models for warfarin dosing.

    Keyword
    dosing algorithm, human CYP2C9 protein, human VKORC1 protein, pharmacogenetics models, statistical regression analysis, warfarin
    National Category
    Medical and Health Sciences
    Research subject
    Clinical Pharmacology
    Identifiers
    urn:nbn:se:uu:diva-170013 (URN)10.2217/pgs.11.184 (DOI)000301098000018 ()22379999 (PubMedID)
    Funder
    Swedish Research Council, K2012-66X-22105-01-3
    Available from: 2012-03-07 Created: 2012-03-07 Last updated: 2017-12-07Bibliographically approved
  • 23.
    Eriksson, Niclas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Prediction of warfarin dose: why, when and how?2012In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 13, no 4, p. 429-440Article, review/survey (Refereed)
    Abstract [en]

    Prediction models are the key to individualized drug therapy. Warfarin is a typical example of where pharmacogenetics could help the individual patient by modeling the dose, based on clinical factors and genetic variation in CYP2C9 and VKORC1. Clinical studies aiming to show whether pharmacogenetic warfarin dose predictions are superior to conventional initiation of warfarin are now underway. This review provides a broad view over the field of warfarin pharmacogenetics from basic knowledge about the drug, how it is monitored, factors affecting dose requirement, prediction models in general and different types of prediction models for warfarin dosing.

  • 24.
    Eriksson, Niclas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wallentin, Lars
    Berglund, Lars
    Axelsson, Tomas
    Connoly, Stuart
    Eikelboom, John
    Ezekowitz, Michael
    Oldgren, Jonas
    Pare, Guillaume
    Reilly, Paul
    Siegbahn, Agneta
    Syvanen, Ann-Christine
    Wadelius, Claes
    Yusuf, Salim
    Wadelius, Mia
    Genetic determinants of warfarin response, efficacy and safety: a RE-LY genomics substudyManuscript (preprint) (Other academic)
  • 25. Fayad, Walid
    et al.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Brnjic, Slavica
    Olofsson, Maria Hägg
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Linder, Stig
    Identification of a novel topoisomerase inhibitor effective in cells overexpressing drug efflux transporters2009In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, no 10, p. e7238-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Natural product structures have high chemical diversity and are attractive as lead structures for discovery of new drugs. One of the disease areas where natural products are most frequently used as therapeutics is oncology.

    METHOD AND FINDINGS:

    A library of natural products (NCI Natural Product set) was screened for compounds that induce apoptosis of HCT116 colon carcinoma cells using an assay that measures an endogenous caspase-cleavage product. One of the apoptosis-inducing compounds identified in the screen was thaspine (taspine), an alkaloid from the South American tree Croton lechleri. The cortex of this tree is used for medicinal purposes by tribes in the Amazonas basin. Thaspine was found to induce conformational activation of the pro-apoptotic proteins Bak and Bax, mitochondrial cytochrome c release and mitochondrial membrane permeabilization in HCT116 cells. Analysis of the gene expression signature of thaspine-treated cells suggested that thaspine is a topoisomerase inhibitor. Inhibition of both topoisomerase I and II was observed using in vitro assays, and thaspine was found to have a reduced cytotoxic effect on a cell line with a mutated topoisomerase II enzyme. Interestingly, in contrast to the topoisomerase II inhibitors doxorubicin, etoposide and mitoxantrone, thaspine was cytotoxic to cell lines overexpressing the PgP or MRP drug efflux transporters. We finally show that thaspine induces wide-spread apoptosis in colon carcinoma multicellular spheroids and that apoptosis is induced in two xenograft mouse models in vivo.

    CONCLUSIONS:

    The alkaloid thaspine from the cortex of Croton lechleri is a dual topoisomerase inhibitor effective in cells overexpressing drug efflux transporters and induces wide-spread apoptosis in multicellular spheroids.

  • 26. Fayad, Walid
    et al.
    Rickardson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Haglund, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Hägg Olofsson, Maria
    D'Arcy, Padraig
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Linder, Stig
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Identification of Agents that Induce Apoptosis of Multicellular Tumour Spheroids: Enrichment for Mitotic Inhibitors with Hydrophobic Properties2011In: Chemical Biology and Drug Design, ISSN 1747-0277, E-ISSN 1747-0285, Vol. 78, no 4, p. 547-557Article in journal (Refereed)
    Abstract [en]

    Cell-based anticancer drug screening generally utilizes rapidly proliferating tumour cells grown as monolayer cultures. Hit compounds from such screens are not necessarily effective on hypoxic and slowly proliferating cells in 3-D tumour tissue. The aim of this study was to examine the potential usefulness of 3-D cultured tumour cells for anticancer drug screening. We used colon carcinoma multicellular spheroids containing hypoxic and quiescent cells in core areas for this purpose. Three libraries (similar to 11 000 compounds) were screened using antiproliferative activity and/or apoptosis as end-points. Screening of monolayer and spheroid cultures was found to identify different sets of hit compounds. Spheroid screening enriched for hydrophobic compounds: median XLogP values of 4.3 and 4.4 were observed for the hits in two independent screening campaigns. Mechanistic analysis revealed that the majority of spheroid screening hits were microtubuli inhibitors. One of these inhibitors was examined in detail and found to be effective against non-dividing cells in the hypoxic centres of spheroids. Spheroid screening represents a conceptually new strategy for anticancer drug discovery. Our findings have implications for drug library design and hit selection in projects aimed to develop drugs for the treatment of solid tumours.

  • 27.
    Felth, Jenny
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Haglund, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Rosén, Josefin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Rickardson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Screening for natural compounds with anticancer activity in colon cancer cells identifies cytotoxic gambogic acid analoguesManuscript (preprint) (Other academic)
  • 28.
    Felth, Jenny
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Rickardson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Rosén, Josefin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Wickström, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Lindskog, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Cytotoxic effects of cardiac glycosides in colon cancer cells, alone and in combination with standard chemotherapeutic drugs2009In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 72, no 11, p. 1969-1974Article in journal (Refereed)
    Abstract [en]

    Cardiac glycosides have been reported to exhibit cytotoxic activity against several different cancer types, but studies against colorectal cancer are lacking. In a screening procedure aimed at identifying natural products with activity against colon cancer, several cardiac glycosides were shown to be of interest, and five of these were further evaluated in different colorectal cancer cell lines and primary cells from patients. Convallatoxin (1), oleandrin (4), and proscillaridin A (5) were identified as the most potent compounds (submicromolar IC50 values), and digitoxin (2) and digoxin (3), which are used in cardiac disease, exhibited somewhat lower activity (IC50 values 0.27−4.1 μM). Selected cardiac glycosides were tested in combination with four clinically relevant cytotoxic drugs (5-fluorouracil, oxaliplatin, cisplatin, irinotecan). The combination of 2 and oxaliplatin exhibited synergism including the otherwise highly drug-resistant HT29 cell line. A ChemGPS-NP application comparing modes of action of anticancer drugs identified cardiac glycosides as a separate cluster. These findings demonstrate that such substances may exhibit significant activity against colorectal cancer cell lines, by mechanisms disparate from currently used anticancer drugs, but at concentrations generally considered not achievable in patient plasma.

  • 29.
    Friberg, Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Hassan, Saadia Bashir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Lindhagen, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Pharmacokinetic-Pharmacodynamic modelling of the schedule-dependent effect of the anti-cancer agent CHS 828 in a rat hollow fibre model2005In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 25, no 1, p. 163-173Article in journal (Refereed)
    Abstract [en]

    N-(6-Chlorophenoxyhexyl)-N'-cyano-N''-4-pyridylguanidine (CHS 828) is a novel anticancer agent that shows schedule-dependent effects in vitro and in vivo, as well as in Phase I clinical trials. A rat hollow fibre model was used to investigate whether this dependency is due to pharmacokinetic and/or pharmacodynamic factors. The effect on two cell lines, MDA-MB-231 (breast cancer) and CCRF-CEM (leukaemia) were studied after CHS 828 was administered orally as a single dose or in a 5-day schedule, at different total dose levels. The 5-day schedules were associated with greater effects on both cell lines compared with single doses. A one-compartment pharmacokinetic model, with a half-life of 2.3h and a consecutive zero- and first-order process to describe dissolution and absorption, fit the concentration data. Pharmacokinetics were dose-dependent, as the fraction absorbed decreased with increasing dose. Clearance increased with accumulative exposure. Twenty hours after administration, concentrations started to increase again, probably due to coprophagy. Pharmacokinetic-pharmacodynamic models characterized the cell growth and cell kill over time and showed that schedule-dependent antitumour effects were present also when the dose-dependent pharmacokinetics were accounted for. The prolonged schedules of CHS 828 were therefore associated with greater antitumour effects than single doses of the same total exposure.

  • 30.
    Frost, Britt-Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Gustafsson, G
    Forestier, E
    Jonsson, O G
    Kanerva, J
    Nygaard, R
    Schmiegelow, K
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Lönnerholm, Gudmar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Increased in vitro cellular drug resistance is related to poor outcome in high-risk childhood acute lymphoblastic leukaemia2003In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 122, no 3, p. 376-385Article in journal (Refereed)
    Abstract [en]

    Summary. We determined the in vitro cellular drug resistance in 370 children with newly diagnosed acute lymphoblastic leukaemia (ALL). The resistance to each of 10 drugs was measured by the fluorometric microculture cytotoxicity assay (FMCA) and was related to clinical outcome. The median follow-up time was 41 months. Risk-group stratified analyses indicated that in vitro resistance to dexamethasone, doxorubicin and amsacrine were each significantly related to the probability of disease-free survival. In the high-risk (HR) group, increased in vitro resistance to dexamethasone (P = 0·014), etoposide (P = 0·025) and doxorubicin (P = 0·05) was associated with a worse clinical outcome. Combining the results for these drugs provided a drug resistance score with an independent prognostic significance superior to that of any other factor studied, with a relative risk of relapse in the most resistant group 9·8 times that in the most sensitive group (P = 0·007). The results in the intermediate-risk (IR) and standard-risk (SR) groups were less clear cut. In conclusion, our data indicate that in vitro testing of cellular drug resistance can be used to predict the clinical outcome in HR ALL, while the final evaluation of the results in IR and SR patients must await longer follow-up.

  • 31.
    Fryknäs, Mårten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Dhar, Sumeer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Öberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rickardson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Rydåker, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Göransson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Gustafsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    STAT1 signaling is associated with acquired crossresistance to doxorubicin and radiation in myeloma cell lines2007In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 120, no 1, p. 189-195Article in journal (Refereed)
    Abstract [en]

    The myeloma cell line RPMI 8226/S and its doxorubicin resistant subline 8226/Dox40 were used as models to explore the potential importance of the STAT1 signaling pathway in drug and radiation resistance. The 40-fold doxorubicin resistant subline 8226/Dox40 was found to be crossresistant to single doses of 4 and 8 Gy of radiation. A genome-wide mRNA expression study comparing the 8226/Dox40 cell line to its parental line was performed to identify the underlying molecular mechanisms. Seventeen of the top 50 overexpressed genes have previously been implicated in the STAT1 signaling pathway. STAT1 was over expressed both at the mRNA and protein level. Moreover, analyses of nuclear extracts showed higher abundance of phosphorylated STAT1 (Tyr 701) in the resistant subline. Preexposure of the crossresistant cells to the STAT1 inhibiting drug fludarabine reduced expression of overexpressed genes and enhanced the effects of both doxorubicin and radiation. These results show that resistance to doxorubicin and radiation is associated with increased STAT1 signaling and can be modulated by fludarabine. The data support further development of therapies combining fludarabine and radiation.

  • 32.
    Fryknäs, Mårten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rickardson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wickström, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Dhar, Sumeer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Lövborg, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Gustafsson, Mats G.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Signal Processing. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Phenotype-based screening of mechanistically annotated compounds in combination with gene expression and pathway analysis identifies candidate drug targets in a human squamous carcinoma cell model2006In: Journal of Biomolecular Screening, ISSN 1087-0571, E-ISSN 1552-454X, Vol. 11, no 5, p. 457-468Article in journal (Refereed)
    Abstract [en]

    The squamous cell carcinoma HeLa cell line and an epithelial cell line hTERT-RPE with a nonmalignant phenotype were interrogated for HeLa cell selectivity in response to 1267 annotated compounds representing 56 pharmacological classes. Selective cytotoxic activity was observed for 14 of these compounds dominated by cyclic adenosine monophosphate (cAMP) selective phosphodiesterase (PDE) inhibitors, which tended to span a representation of the chemical descriptor space of the library. The PDE inhibitors induced delayed cell death with features compatible with classical apoptosis. The PDE inhibitors were largely inactive when tested against a cell line panel consisting of hematological and nonsquamous epithelial phenotypes. In a genome-wide DNA microarray analysis, PDE3A and PDE2A were found to be significantly increased in HeLa cells compared to the other cell lines. The pathway analysis software PathwayAssist was subsequently used to extract a list of proteins and small molecules retrieved from Medline abstracts associated with the hit compounds. The resulting list consisted of major parts of the cAMP-protein kinase A pathway linking to ERK, P38, and AKT. This molecular network may provide a basis for further exploitation of novel candidate targets for the treatment of squamous cell carcinoma.

  • 33.
    Gillespie, Ulrika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Alassaad, Anna
    Hospital Pharmacy, University Hospital of Uppsala, Sweden.
    Henrohn, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Garmo, Hans
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Toss, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Kettis-Lindblad, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Mörlin, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    A comprehensive pharmacist intervention to reduce morbidity in patients 80 years or older: a randomized controlled trial2009In: Archives of Internal Medicine, ISSN 0003-9926, E-ISSN 1538-3679, Vol. 169, no 9, p. 894-900Article in journal (Refereed)
    Abstract [en]

    BACKGROUND

    Patients 80 years or older are underrepresented in scientific studies. The objective of this study was to investigate the effectiveness of interventions performed by ward-based pharmacists in reducing morbidity and use of hospital care among older patients.

    METHODS

    A randomized controlled study of patients 80 years or older was conducted at the University Hospital of Uppsala, Uppsala, Sweden. Four hundred patients were recruited consecutively between October 1, 2005, and June 30, 2006, and were randomized to control (n = 201) and intervention (n = 199) groups. The interventions were performed by ward-based pharmacists. The control group received standard care without direct involvement of pharmacists at the ward level. The primary outcome measure was the frequency of hospital visits (emergency department and readmissions [total and drug-related]) during the 12-month follow-up period.

    RESULTS

    Three hundred sixty-eight patients (182 in the intervention group and 186 in the control group) were analyzed. For the intervention group, there was a 16% reduction in all visits to the hospital (quotient, 1.88 vs 2.24; estimate, 0.84; 95% confidence interval [CI], 0.72-0.99) and a 47% reduction in visits to the emergency department (quotient, 0.35 vs 0.66; estimate, 0.53; 95% CI, 0.37-0.75). Drug-related readmissions were reduced by 80% (quotient, 0.06 vs 0.32; estimate, 0.20; 95% CI, 0.10-0.41). After inclusion of the intervention costs, the total cost per patient in the intervention group was $230 lower than that in the control group.

    CONCLUSION

    If implemented on a population basis, the addition of pharmacists to health care teams would lead to major reductions in morbidity and health care costs.

  • 34. Gleissman, Helena
    et al.
    Segerström, Lova
    Hamberg, Mats
    Ponthan, Frida
    Lindskog, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Johnsen, John Inge
    Kogner, Per
    Omega-3 fatty acid supplementation delays the progression of neuroblastoma in vivo2011In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 128, no 7, p. 1703-1711Article in journal (Refereed)
    Abstract [en]

    Epidemiological and preclinical studies have revealed that omega-3 fatty acids have anticancer properties. We have previously shown that the omega-3 fatty acid docosahexaenoic acid (DHA) induces apoptosis of neuroblastoma cells in vitro by mechanisms involving intracellular peroxidation of DHA by means of 15-lipoxygenase or autoxidation. In our study, the effects of DHA supplementation on neuroblastoma tumor growth in vivo were investigated using two complementary approaches. For the purpose of prevention, DHA as a dietary supplement was fed to athymic rats before the rats were xenografted with human neuroblastoma cells. For therapeutic purposes, athymic rats with established neuroblastoma xenografts were given DHA daily by gavage and tumor growth was monitored. DHA levels in plasma and tumor tissue were analyzed by gas liquid chromatography. DHA delayed neuroblastoma xenograft development and inhibited the growth of established neuroblastoma xenografts in athymic rats. A revised version of the Pediatric Preclinical Testing Program evaluation scheme used as a measurement of treatment response showed that untreated control animals developed progressive disease, whereas treatment with DHA resulted in stable disease or partial response, depending on the DHA concentration. In conclusion, prophylactic treatment with DHA delayed neuroblastoma development, suggesting that DHA could be a potential agent in the treatment of minimal residual disease and should be considered for prevention in selected cases. Treatment results on established aggressive neuroblastoma tumors suggest further studies aiming at a clinical application in children with high-risk neuroblastoma.

  • 35.
    Glimelius, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Garmo, Hans
    Berglund, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Fredriksson, L. A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Kohnke, Hugo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Byström, P.
    Sørbye, H.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Prediction of irinotecan and 5-fluorouracil toxicity and response in patients with advanced colorectal cancer2011In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 11, no 1, p. 61-71Article in journal (Refereed)
    Abstract [en]

    Irinotecan and 5-fluorouracil (5-FU) are used to treat metastatic colorectal cancer. Irinotecan's active metabolite is inactivated by UDP-glucuronosyltransferase 1A1 (UGT1A1), which is deficient in Gilbert's syndrome. Irinotecan and metabolites are transported by P-glycoprotein, encoded by ABCB1. 5-FU targets folate metabolism through inhibition of thymidylate synthase (TYMS). Methylenetetrahydrofolate reductase (MTHFR) generates active folate necessary for haematopoiesis. We retrospectively genotyped 140 Swedish and Norwegian irinotecan and 5-FU-treated colorectal cancer patients from the Nordic VI clinical trial for selected variants of UGT1A1, ABCB1, TYMS and MTHFR. We found an increased risk of clinically relevant early toxicity in patients carrying the ABCB1 3435 T/T genotype, Odds ratio (OR)=3.79 (95% confidence interval (CI)=1.09-13.2), and in patients carrying the UGT1A1(*)28/(*)28 genotype, OR=4.43 (95% CI=1.30-15.2). Patients with UGT1A1(*)28/(*)28 had an especially high risk of neutropenia, OR=6.87 (95% CI=1.70-27.7). Patients who had reacted with toxicity during the first two cycles were in total treated with fewer cycles (P<0.001), and less often responded to treatment (P<0.001). Genetic variation in ABCB1 was associated with both early toxicity and lower response to treatment. Carriers of the ABCB1 1236T-2677T-3435T haplotype responded to treatment less frequently (43 vs 67%, P=0.027), and survived shorter time, OR=1.56 (95% CI=1.01-2.45).

  • 36. Grudén, Sofie
    et al.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Riskfyllt att använda loperamid (Immodium m fl) till barn under tre år2008In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 105, no 51, p. 3750-3750Article in journal (Other academic)
  • 37. Grudén, Sofie
    et al.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Är något SSRI-preparat att föredra vad gäller sexuella biverkningar?2008In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, no 26, p. 1949-1949Article in journal (Other academic)
  • 38.
    Gullbo, Joachim
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Preclinical Development of New Alkylating Oligopeptides for Cancer Therapy2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Oligopeptides can be used to carry cytotoxic agents in cancer chemotherapy, using tumour-associated proteins as the molecular target for selectivity. During the seventies and eighties Peptichemio, a cocktail of six alkylating oligopeptides carrying m-L-sarcolysin, was investigated in a wide variety of human malignancies. Positive clinical results were suggested to result from rapid and effective DNA-crosslinking following uptake in neoplastic cells, but also from antimetabolic properties of the drug. Although m-L-sarcolysin never reached widespread clinical use, the well established para-isomer melphalan still, after nearly fifty years, has a place in cancer chemotherapy.

    The present study was undertaken to synthesise the melphalan containing analogue of the tripeptide P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester, the main contributor to Peptichemio’s activity) and similar compounds, preferably dipeptides. The new compounds compared favourably with melphalan, m-L-sarcolysin and P2, considering their potency in vitro. Structure activity relationship analysis showed that the activity of melphalan dipeptides depended on the amino acid composition, sequence and end group modifications, but only to a minor degree on lipophilicity. Results suggested that the dipeptides, to exert their full cytotoxic activity, had to interact with specific biomolecules such as dipeptide transporters or peptidases. Although no active transport could be demonstrated the influence of peptide hydrolysis was obvious, thereby suggesting a rationale for increased activity as well as potential tumour selectivity in comparison with melphalan.

    Preliminary in vivo studies in mice supported the results, despite equal alkylating capacity the dipeptide J1 (melphalanyl-p-L-fluorophenylalanine ethyl ester) and the tripeptide J3 (L-prolyl-melphalanyl-p-L-fluorophenylalanine ethyl ester) were more active than was melphalan on human tumour cells implanted in test animals although all drugs produced expected side effects, notably leukopenia, of similar magnitude.

    In conclusion, oligopeptide derivatives of melphalan seem to provide improved cytotoxic activity and therapeutic index. Further development of such oligopeptides for clinical use seems worthwhile.

    List of papers
    1. Antitumor activity of the alkylating oligopeptides J1 (L-melphalanyl-p-L-fluorophenylalanine ethyl ester) and P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester): comparison with melphalan
    Open this publication in new window or tab >>Antitumor activity of the alkylating oligopeptides J1 (L-melphalanyl-p-L-fluorophenylalanine ethyl ester) and P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester): comparison with melphalan
    Show others...
    2003 In: Anti-Cancer Drugs, Vol. 14, no 8, p. 617-624Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91097 (URN)
    Available from: 2003-11-19 Created: 2003-11-19Bibliographically approved
    2. Structure activity relationship for alkylating dipeptide nitrogen mustard derivatives
    Open this publication in new window or tab >>Structure activity relationship for alkylating dipeptide nitrogen mustard derivatives
    Show others...
    2003 (English)In: Oncology Research, ISSN 0965-0407, E-ISSN 1555-3906, Vol. 14, no 3, p. 113-132Article in journal (Refereed) Published
    Abstract [en]

    The strategy of using small peptides for effective targeting of tumor cells in chemotherapy has proven beneficial. Recently we showed that J1 (L-melphalanyl-p-L-fluorophenylalanine ethyl ester), an alkylating nitrogen mustard-containing dipeptide, exhibited strong cytotoxic activity in fresh human tumor samples in addition to rapid and pronounced inhibition of macromolecular syntheses and cellular respiration in the human tumor lymphoma cell line U-937 GTB. In this study, an additional series of 17 nitrogen mustard-containing dipeptides has been synthesized and analyzed for cytotoxic activity in a panel of 10 human tumor cell lines. The results were compared to the single amino acid mustard derivative melphalan and its ethyl and isopropyl esters. Also P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester), a tripeptide that previously has shown impressive effects in human tumor cells, was used as reference. The tested compounds displayed various activities in the different cell lines but also showed a high correlation, indicating a similar mechanism of action. Factors like amino acid composition, amino acid sequence, modifications of the C- and N-termini, and to a minor extent the lipophilicity of the dipeptide derivatives appear to influence the in vitro activity. The results indicate that the activity of these compounds not only relies on their chemical reactivity, but also on active biological interactions such as transport across membranes and/or enzymatic liberation of reactive molecular entities.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-91098 (URN)14760861 (PubMedID)
    Available from: 2003-11-19 Created: 2003-11-19 Last updated: 2017-12-14Bibliographically approved
    3. Antitumor activity of the novel melphalan containing tripeptide J3 (L-prolyl-melphalanyl-p-L-fluorophenylalanine ethyl ester): Comparison with its m-L-sarcolysin analogue P2
    Open this publication in new window or tab >>Antitumor activity of the novel melphalan containing tripeptide J3 (L-prolyl-melphalanyl-p-L-fluorophenylalanine ethyl ester): Comparison with its m-L-sarcolysin analogue P2
    Show others...
    2003 (English)In: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 2, no 12, p. 1331-1339Article in journal (Refereed) Published
    Abstract [en]

    Peptichemio (PTC), a mixture of six oligopeptides all containing m-L-sarcolysin, has previously shown impressive results in clinical trials. The tripeptide P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester) has been suggested as the main contributor to PTC activity. In contrast to its analogue melphalan, m-L-sarcolysin never reached clinical use. To allow a direct comparison, the corresponding melphalan containing tripeptide J3 (L-prolyl-L-melphalanyl-p-L-fluorophenylalanine ethyl ester) was synthesized and its activity was compared with that of P2; the activities of melphalan and m-L-sarcolysin were studied in parallel. Cytotoxic activity in human tumor cell lines and some fresh human tumor specimens were analyzed as well as effects on cellular metabolism, macromolecular synthesis, and preliminary evaluation of the cell death characteristics. The results show that melphalan and m-L-sarcolysin display similar activity in these systems and that the tripeptides were more active than their parent monomers. Surprisingly however, the melphalan containing tripeptide J3 demonstrated a significantly more rapid and stronger activity than the m-L-sarcolysin analogue P2. Finally, the in vivo toxicity and activity of melphalan and J3 were investigated in mice bearing human leukemia cells in s.c. fibers. The in vitro results seem translatable into the in vivo situation, demonstrating better antileukemic effect of J3 but similar side effects as melphalan.

    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:uu:diva-91099 (URN)14707274 (PubMedID)
    Available from: 2003-11-19 Created: 2003-11-19 Last updated: 2017-12-14Bibliographically approved
    4. Activity of hydrolytic enzymes in tumour cells is a determinant for anti-tumour efficacy of the melphalan containing prodrug J1
    Open this publication in new window or tab >>Activity of hydrolytic enzymes in tumour cells is a determinant for anti-tumour efficacy of the melphalan containing prodrug J1
    Show others...
    Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-91100 (URN)
    Available from: 2003-11-19 Created: 2003-11-19Bibliographically approved
    5. Antitumor efficacy and acute toxicity of the novel dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) in vivo
    Open this publication in new window or tab >>Antitumor efficacy and acute toxicity of the novel dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) in vivo
    Show others...
    Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-91101 (URN)
    Available from: 2003-11-19 Created: 2003-11-19Bibliographically approved
  • 39.
    Gullbo, Joachim
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Dhar, Sumeer
    Luthman, Kristina
    Ehrsson, Hans
    Lewensohn, Rolf
    Nygren, Peter
    Larsson, Rolf
    Antitumor activity of the alkylating oligopeptides J1 (L-melphalanyl-p-L-fluorophenylalanine ethyl ester) and P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester): comparison with melphalan2003In: Anti-Cancer Drugs, Vol. 14, no 8, p. 617-624Article in journal (Refereed)
  • 40.
    Gullbo, Joachim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Rickardson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Darcy, Padraig
    Hägg, Maria
    Wickström, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Hassan, Sadia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Westman, Gunnar
    Brnjic, Slavica
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Linder, Stig
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Phenotype-based drug screening in primary ovarian carcinoma cultures identifies intracellular iron depletion as a promising strategy for cancer treatment2011In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 82, no 2, p. 139-147Article in journal (Refereed)
    Abstract [en]

    Primary cultures of patient tumor cells (PCPTC) have been used for prediction of diagnosis-specific activity and individual patient response to anticancer drugs, but have not been utilized as a model for identification of novel drugs in high throughput screening. In the present study, ovarian carcinoma cells from three patients were tested in response to a library of 3000 chemically diverse compounds. Eight hits were retrieved after counter screening using normal epithelial cells, and one of the two structurally related hit compounds was selected for further preclinical evaluation. This compound, designated VLX 50, demonstrated a broad spectrum of activity when tested in a panel of PCPTCs representing different forms of leukemia and solid tumors and displayed a high tumor to normal cell activity. VLX 50 induced delayed cell death with some features of classical apoptosis. Significant in vivo activity was confirmed on primary cultures of human ovarian carcinoma cells in mice using the hollow fiber model. Mechanistic exploration was performed using gene expression analysis of drug exposed tumor cells to generate a drug-specific signature. This query signature was analyzed using the Gene Set Enrichment Analysis and the Connectivity Map database. Strong connections to hypoxia inducible factor 1 and iron chelators were retrieved. The mechanistic hypothesis of intracellular iron depletion leading to hypoxia signaling was confirmed by a series of experiments. The results indicate the feasibility of using PCPTC for cancer drug screening and that intracellular iron depletion could be a potentially important strategy for cancer therapy.

  • 41.
    Gullbo, Joachim
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Lindhagen, Elin
    Bashir-Hassan, Saadia
    Tullberg, Marcus
    Ehrsson, Hans
    Lewensohn, Rolf
    Nygren, Peter
    de la Torres, Manuel
    Luthman, Kristina
    Larsson, Rolf
    Antitumor efficacy and acute toxicity of the novel dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) in vivoArticle in journal (Refereed)
  • 42.
    Gullbo, Joachim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Tullberg, Marcus
    Våbeno, Jon
    Ehrsson, Hans
    Lewensohn, Rolf
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Luthman, Kristina
    Structure activity relationship for alkylating dipeptide nitrogen mustard derivatives2003In: Oncology Research, ISSN 0965-0407, E-ISSN 1555-3906, Vol. 14, no 3, p. 113-132Article in journal (Refereed)
    Abstract [en]

    The strategy of using small peptides for effective targeting of tumor cells in chemotherapy has proven beneficial. Recently we showed that J1 (L-melphalanyl-p-L-fluorophenylalanine ethyl ester), an alkylating nitrogen mustard-containing dipeptide, exhibited strong cytotoxic activity in fresh human tumor samples in addition to rapid and pronounced inhibition of macromolecular syntheses and cellular respiration in the human tumor lymphoma cell line U-937 GTB. In this study, an additional series of 17 nitrogen mustard-containing dipeptides has been synthesized and analyzed for cytotoxic activity in a panel of 10 human tumor cell lines. The results were compared to the single amino acid mustard derivative melphalan and its ethyl and isopropyl esters. Also P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester), a tripeptide that previously has shown impressive effects in human tumor cells, was used as reference. The tested compounds displayed various activities in the different cell lines but also showed a high correlation, indicating a similar mechanism of action. Factors like amino acid composition, amino acid sequence, modifications of the C- and N-termini, and to a minor extent the lipophilicity of the dipeptide derivatives appear to influence the in vitro activity. The results indicate that the activity of these compounds not only relies on their chemical reactivity, but also on active biological interactions such as transport across membranes and/or enzymatic liberation of reactive molecular entities.

  • 43.
    Gullbo, Joachim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wallinder, Charlotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Tullberg, Marcus
    Lövborg, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Ehrsson, Hans
    Lewensohn, Rolf
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Luthman, Kristina
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Antitumor activity of the novel melphalan containing tripeptide J3 (L-prolyl-melphalanyl-p-L-fluorophenylalanine ethyl ester): Comparison with its m-L-sarcolysin analogue P22003In: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 2, no 12, p. 1331-1339Article in journal (Refereed)
    Abstract [en]

    Peptichemio (PTC), a mixture of six oligopeptides all containing m-L-sarcolysin, has previously shown impressive results in clinical trials. The tripeptide P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester) has been suggested as the main contributor to PTC activity. In contrast to its analogue melphalan, m-L-sarcolysin never reached clinical use. To allow a direct comparison, the corresponding melphalan containing tripeptide J3 (L-prolyl-L-melphalanyl-p-L-fluorophenylalanine ethyl ester) was synthesized and its activity was compared with that of P2; the activities of melphalan and m-L-sarcolysin were studied in parallel. Cytotoxic activity in human tumor cell lines and some fresh human tumor specimens were analyzed as well as effects on cellular metabolism, macromolecular synthesis, and preliminary evaluation of the cell death characteristics. The results show that melphalan and m-L-sarcolysin display similar activity in these systems and that the tripeptides were more active than their parent monomers. Surprisingly however, the melphalan containing tripeptide J3 demonstrated a significantly more rapid and stronger activity than the m-L-sarcolysin analogue P2. Finally, the in vivo toxicity and activity of melphalan and J3 were investigated in mice bearing human leukemia cells in s.c. fibers. The in vitro results seem translatable into the in vivo situation, demonstrating better antileukemic effect of J3 but similar side effects as melphalan.

  • 44.
    Gullbo, Joachim
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wickström, Malin
    Tullberg, Marcus
    Ehrsson, Hans
    Lewensohn, Rolf
    Nygren, Peter
    Luthman, Kristina
    Larsson, Rolf
    Activity of hydrolytic enzymes in tumour cells is a determinant for anti-tumour efficacy of the melphalan containing prodrug J1Article in journal (Refereed)
  • 45.
    Gunes, Arzu
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Pharmacogenetics and Antipsychotic Treatment in Schizophrenia with Special Focus on Adverse Drug Reactions2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Genetically determined differences in drug metabolism and disposition and drug targets play a pivotal role in the interindividual variability in the clinical outcome of antipsychotic treatment. The aim of this thesis was to study the impact of polymorphisms in genes involved in the pharmacokinetics and pharmacodynamics of antipsychotics, with special focus on their extrapyramidal and metabolic adverse effects.

    Polymorphisms in serotonin 2A and 2C receptor coding genes (HTR2A and HTR2C) were found to be associated with the risk to develop extrapyramidal side effects (EPS) in patients on short term perphenazine treatment. A further study in a larger group of patients on long term treatment with various classical antipsychotics confirmed the association between occurrence of EPS and HTR2C polymorphisms. In another study, dose corrected steady state serum clozapine and N-desmethylclozapine concentrations (C/D) and insulin elevation during clozapine therapy were found to correlate with CYP1A2 but not with CYP2D6 polymorphisms. Furthermore, HTR2C and HTR2A polymorphisms were found to have significant influences on BMI and C-peptide levels in patients treated with olanzapine and clozapine. Evaluation of the impact of polymorphisms in genes encoding CYP3A4, CYP3A5 and P-glycoprotein (ABCB1) in addition to CYP2D6 on the steady state plasma levels of risperidone, 9-hydroxyrisperidone and their active moiety revealed a significant influence of ABCB1 genotype on 9-hydroxyrisperidone and active moiety C/Ds, while CYP2D6 genotype associated with risperidone C/Ds but not with 9-hydroxyrisperidone or active moiety C/D.

    We have shown that polymorphisms in genes involved in the pharmacokinetics and the pharmacodynamics of antipsychotic drugs play a role in the occurrence of adverse effects, both EPS and metabolic disturbances, induced by antipsychotic treatment. Genotyping for HTR2A, HTR2C, CYP1A2, CYP2D6 and ABCB1 polymorphisms may therefore potentially provide useful information to identify patients at higher risk to develop EPS or metabolic adverse during schizophrenia treatment with antipsychotic drugs.

    List of papers
    1. Serotonin and dopamine receptor gene polymorphisms and the risk of extrapyramidal side effects in perphenazine-treated schizophrenic patients
    Open this publication in new window or tab >>Serotonin and dopamine receptor gene polymorphisms and the risk of extrapyramidal side effects in perphenazine-treated schizophrenic patients
    2007 (English)In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 190, no 4, p. 479-484Article in journal (Refereed) Published
    Abstract [en]

    Rationale: Perphenazine, a classical antipsychotic drug, has the potential to induce extrapyramidal side effects (EPS). Dopaminergic and serotonergic pathways are involved in the therapeutic and adverse effects of the drug. Objectives: To evaluate the impact of polymorphisms in the dopamine D 2 and D3 and serotonin 2A and 2C receptor genes (DRD2, DRD3, HTR2A, and HTR2C) on short-term effects of perphenazine monotherapy in schizophrenic patients. Materials and methods: Forty-seven Estonian inpatients were evaluated before and after 4-6 weeks of treatment by Simpson-Angus rating scale, Barnes scale, and Positive and Negative Symptom Scale. Genotyping was performed for common DRD2, DRD3, HTR2A, and HTR2C gene polymorphisms, previously reported to influence receptor expression and/or function. Results: Most of the patients (n = 37) responded to the treatment and no significant association was observed between the polymorphisms and antipsychotic response. The 102C allele of HTR2A and the -697C and 23Ser alleles of HTR2C were more frequent among patients with EPS (n = 25) compared to patients without EPS (n = 22) (p = 0.02, 0.01, and 0.02, respectively). The difference between patients with and without EPS in variant allele frequencies remained significant after multiple model analyses including age, gender, and duration of antipsychotic treatment as covariants. There was no significant association between EPS occurrence and polymorphisms in the DRD2 and DRD3 genes. Conclusions: An association was observed between polymorphisms in HTR2A and HTR2C genes and occurrence of acute EPS in schizophrenic patients treated with perphenazine monotherapy. Larger study populations are needed to confirm our findings.

    Keyword
    Perphenazine, Receptor gene polymorphisms, Extrapyramidal side effects, Schizophrenia
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97080 (URN)10.1007/s00213-006-0622-x (DOI)000243926900008 ()17102980 (PubMedID)
    Available from: 2008-04-17 Created: 2008-04-17 Last updated: 2017-12-14Bibliographically approved
    2. Further evidence for association between 5-HT2C receptor gene polymorphisms and extrapyramidal side effects in male schizophrenic patients
    Open this publication in new window or tab >>Further evidence for association between 5-HT2C receptor gene polymorphisms and extrapyramidal side effects in male schizophrenic patients
    2008 (English)In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 64, no 5, p. 477-482Article in journal (Refereed) Published
    Abstract [en]

     

    RATIONALE: Antipsychotic-induced extrapyramidal side effects (EPS) are still a major problem in the treatment of schizophrenia. Serotonin 2C receptors (5-HT(2C)) have regulatory effects on dopaminergic pathways in brain regions involved with EPS. Polymorphisms in the 5-HT(2C) gene (HTR2C) have been suggested to be associated with the risk of developing EPS. OBJECTIVE: Our purpose was to evaluate the impact of polymorphisms in the HTR2C gene on the occurrence of EPS in male schizophrenic patients. METHODS: Ninety-nine male Caucasian chronic schizophrenic patients on long-term treatment with classical antipsychotics were genotyped for the -997 G/A, -759 C/T, -697 G/C and Cys23Ser polymorphisms of HTR2C. EPS (dystonia, parkinsonism, tardive dyskinesia) were assessed by the Simpson-Angus Scale and the Abnormal Involuntary Movement Scale. Fifty-one patients had current or previous history of EPS, whereas 48 patients had no symptoms or history of EPS. To rule out a possible association between HTR2C polymorphisms and schizophrenia, 112 healthy male volunteers were also genotyped. RESULTS: Allele frequencies of -997A, -759T and -697C did not differ between the groups, whereas patients with EPS had a significantly (p = 0.025) higher frequency of the 23Ser allele (0.29) than did patients without EPS (0.15) or healthy volunteers (0.13). A similar trend was observed for a haplotype including the -997G, -759C, -697C and 23Ser alleles (p = 0.04). CONCLUSIONS: Results confirm previously reported associations between the HTR2C 23Ser allele and EPS occurrence and suggest the novel finding of an HTR2C haplotype association with EPS in male chronic schizophrenic patients.

    Keyword
    Extrapyramidal side effects, 5-HT2C, Serotonin, Polymorphism, Antipsychotics
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97081 (URN)10.1007/s00228-007-0450-x (DOI)000254183200005 ()18205001 (PubMedID)
    Available from: 2008-04-17 Created: 2008-04-17 Last updated: 2017-12-14Bibliographically approved
    3. Impact of CYP1A2 and CYP2D6 polymorphisms on drug metabolism and on insulin and lipid elevations and insulin resistance in clozapine-treated patients
    Open this publication in new window or tab >>Impact of CYP1A2 and CYP2D6 polymorphisms on drug metabolism and on insulin and lipid elevations and insulin resistance in clozapine-treated patients
    2007 (English)In: Journal of Clinical Psychiatry, ISSN 0160-6689, E-ISSN 1555-2101, Vol. 68, no 5, p. 697-704Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVE: Adverse metabolic effects of atypical antipsychotics have increasingly been recognized. Recently, we found that levels of insulin and triglycerides increased by increasing serum clozapine concentration in clozapine-treated patients. As these insulin and triglyceride elevations probably are drug concentration-dependent, they also would be expected to be drug metabolism-related. The genetically polymorphic cytochromes P450 CYP1A2 and CYP2D6 catalyze the metabolism of clozapine. The aim of this study was to evaluate the impact of CYP1A2 and CYP2D6 polymorphisms on serum drug and metabolite levels and on insulin and triglyceride elevations and insulin resistance in patients receiving clozapine. METHOD: Seventeen clozapine-treated patients were genotyped for CYP1A2 and CYP2D6 by polymerase chain reaction-based methods. Serum concentrations of clozapine and its N-desmethylmetabolite, blood glucose, and serum levels of insulin, C-peptide, triglycerides, and cholesterol were analyzed, and homeostasis model assessment index for insulin resistance (HOMA-IR) was determined. RESULTS: Clozapine and N-desmethylclozapine concentration-to-dose (C/D) ratios were significantly higher in patients carrying 2 CYP1A2 single nucleotide polymorphisms (SNPs), previously suggested to cause low enzyme activity, compared to those with no such SNPs (p < .05). In contrast, clozapine and N-desmethylclozapine C/D ratios were not related to the CYP2D6 genotype. Furthermore, patients with elevated insulin levels more frequently carried CYP1A2*1C and/or *1D alleles, had higher clozapine and N-desmethylclozapine C/D ratios, and had higher lipid levels and HOMA-IR, compared to patients with normal insulin levels (p < .05). CONCLUSION: CYP1A2 variants *1C and *1D seem to be associated with higher serum clozapine concentrations and an increased risk of developing insulin and lipid elevations and insulin resistance on a given dose of clozapine.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97082 (URN)000246740300025 ()17503978 (PubMedID)
    Available from: 2008-04-17 Created: 2008-04-17 Last updated: 2017-12-14Bibliographically approved
    4. Association between HTR2C and HTR2A polymorphisms and metabolic abnormalities in patients treated with olanzapine and clozapine
    Open this publication in new window or tab >>Association between HTR2C and HTR2A polymorphisms and metabolic abnormalities in patients treated with olanzapine and clozapine
    2009 (English)In: Journal of Clinical Psychopharmacology, ISSN 0271-0749, E-ISSN 1533-712X, Vol. 29, no 1, p. 65-68Article in journal (Refereed) Published
    Abstract [en]

    Serotonin 2C and 2A receptor (5-HT2C and 5-HT2A) antagonisms are hypothesized to play a role in the metabolic adverse effects induced by olanzapine and clozapine. Associations between polymorphisms in 5-HT2C and 5-HT2A receptor coding genes, HTR2C and HTR2A, with antipsychotic-induced weight gain have been reported. The impact of HTR2C and HTR2A polymorphisms on body mass index (BMI), glucose-insulin homeostasis, and blood lipid levels was evaluated in 46 patients with schizophrenia or schizoaffective disorder and treated with olanzapine (n = 28) or clozapine (n = 18) for at least 6 months. Olanzapine-treated patients with HTR2C haplotype C (-759C, -697C, and 23Ser) had higher BMI (P = 0.029) and C peptide levels (P = 0.029) compared with patients with haplotype B (-759T, -697C, and 23Cys). The frequency of patients homozygous for the HTR2C haplotype A (-759C, -697G, and 23Cys) was significantly higher among clozapine-treated patients with obesity (BMI >/= 30 kg/m) compared with nonobese patients (P = 0.015; odds ratio, 28; 95% confidence interval, 2-380). Patients carrying the HTR2A haplotype 2 (-1438A, 102T, and 452His) had significantly higher C peptide levels compared with haplotype 3 (-1438A, 102T, and 452Tyr) carriers in the olanzapine group (P = 0.034) and in the overall study population (P = 0.019). None of the haplotypes were associated with serum levels of insulin, triglycerides, and cholesterol or with homeostasis model assessment index for insulin resistance. In conclusion, both HTR2C and HTR2A gene polymorphisms seem to be associated with the occurrence of metabolic abnormalities in patients treated with olanzapine or clozapine.

    Keyword
    olanzapine, clozapine, weight gain, serotonin, receptor, polymorphism
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97083 (URN)10.1097/JCP.0b013e31819302c3 (DOI)000262558200014 ()19142110 (PubMedID)
    Available from: 2008-04-17 Created: 2008-04-17 Last updated: 2017-12-14Bibliographically approved
    5. ABCB1 polymorphisms influence steady-state plasma levels of 9-hydroxyrisperidone and risperidone active moiety
    Open this publication in new window or tab >>ABCB1 polymorphisms influence steady-state plasma levels of 9-hydroxyrisperidone and risperidone active moiety
    2008 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 30, no 5, p. 628-633Article in journal (Refereed) Published
    Abstract [en]

    Risperidone is metabolized to its active metabolite, 9-hydroxy risperidone, mainly by the cytochrome P450 enzymes CYP2D6 and 3A4. Its antipsychotic effect is assumed to be related to the active moiety, that is, the sum of risperidone and 9-hydroxyrisperidone. Both risperidone and 9-hydroxyrisperidone are substrates of P-glycoprotein (P-gp), a transport protein involved in drug absorption, distribution, and elimination. The aim of the present study was to evaluate the influence of polymorphisrns in genes encoding CYP3A5 and P-gp (ABCB1) on the steady-state plasma levels of risperidone, 9-hydroxyrisperidone, and the active moiety, taking CYP2D6 genotype status into account. Forty-six white patients with schizophrenia treated with risperidone (1-10 mg/d) in monotherapy for 4-6 weeks were genotyped, and their plasma concentrations of risperidone and 9-hydroxyrisperidone were measured. Dose-corrected plasma concentrations (C/D) of risperidone, 9-hydroxyrisperidone, and active moiety showed up to 68-, 9-, and 10-fold interindividual variation, respectively. Six patients carried 1 CYP3A5*1 allele and therefore were likely to express the CYP3A5 enzyme. The CYP3A5 genotype did not influence risperidone, 9-hydroxyrisperidone, or active moiety C/Ds. The CYP2D6 genotype in these 46 patients was again associated with risperidone C/D (P = 0.001) but not with 9-hydroxyrisperidone C/D or active moiety C/D, as previously shown by our group in 37 of these patients. Patients homozygous for the ABCB1 3435T/2677T/1236T haplotype had significantly lower C/Ds of 9-hydroxyrisperidone (P = 0.026) and active moiety (P = 0.028) than patients carrying other ABCB1 genotypes. In conclusion, our results confirmed the significant effect of CYP2D6 genotype oil the steady-state plasma levels of risperidone and showed that ABCB1 polymorphisins have a moderate effect oil those of 9-hydroxyrisperidone and the active moiety.

    Keyword
    risperidone, 9-hydroxyrisperidone, ABCB1, CYP3A4, CYP3A5
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97084 (URN)10.1097/FTD.0b013e3181858ca9 (DOI)000259730700012 ()
    Available from: 2008-04-17 Created: 2008-04-17 Last updated: 2017-12-14Bibliographically approved
  • 46.
    Gunes, Arzu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Dahl, Maija-Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Variation in CYP1A2 activity and its clinical implications: influence of environmental factors and genetic polymorphisms2008In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 9, no 5, p. 625-637Article, review/survey (Refereed)
    Abstract [en]

    CYP1A2 is involved in the metabolism of several widely used drugs and endogenous compounds, and in the activation of procarcinogens. Both genetic and environmental factors influence the activity of this enzyme. The current knowledge regarding factors influencing the activity of CYP1A2 is summarized in this review. Substrates, inhibitors and inducers of CYP1A2 activity, as well as phenotyping probes, are discussed. The functional significance and clinical importance of CYP1A2 gene polymorphisms are reviewed and interethnic differences in the distribution of CYP1A2 variant alleles and haplotypes are summarized. Finally, future perspectives for the possible clinical applications of CYP1A2 genotyping are discussed.

  • 47.
    Gunes, Arzu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Dahl, Marja-Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Spina, Edoardo
    Scordo, Maria Gabriella
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Further evidence for association between 5-HT2C receptor gene polymorphisms and extrapyramidal side effects in male schizophrenic patients2008In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 64, no 5, p. 477-482Article in journal (Refereed)
    Abstract [en]

     

    RATIONALE: Antipsychotic-induced extrapyramidal side effects (EPS) are still a major problem in the treatment of schizophrenia. Serotonin 2C receptors (5-HT(2C)) have regulatory effects on dopaminergic pathways in brain regions involved with EPS. Polymorphisms in the 5-HT(2C) gene (HTR2C) have been suggested to be associated with the risk of developing EPS. OBJECTIVE: Our purpose was to evaluate the impact of polymorphisms in the HTR2C gene on the occurrence of EPS in male schizophrenic patients. METHODS: Ninety-nine male Caucasian chronic schizophrenic patients on long-term treatment with classical antipsychotics were genotyped for the -997 G/A, -759 C/T, -697 G/C and Cys23Ser polymorphisms of HTR2C. EPS (dystonia, parkinsonism, tardive dyskinesia) were assessed by the Simpson-Angus Scale and the Abnormal Involuntary Movement Scale. Fifty-one patients had current or previous history of EPS, whereas 48 patients had no symptoms or history of EPS. To rule out a possible association between HTR2C polymorphisms and schizophrenia, 112 healthy male volunteers were also genotyped. RESULTS: Allele frequencies of -997A, -759T and -697C did not differ between the groups, whereas patients with EPS had a significantly (p = 0.025) higher frequency of the 23Ser allele (0.29) than did patients without EPS (0.15) or healthy volunteers (0.13). A similar trend was observed for a haplotype including the -997G, -759C, -697C and 23Ser alleles (p = 0.04). CONCLUSIONS: Results confirm previously reported associations between the HTR2C 23Ser allele and EPS occurrence and suggest the novel finding of an HTR2C haplotype association with EPS in male chronic schizophrenic patients.

  • 48.
    Gunes, Arzu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Scordo, Maria Gabriella
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Jaanson, Peeter
    Dahl, Marja-Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Serotonin and dopamine receptor gene polymorphisms and the risk of extrapyramidal side effects in perphenazine-treated schizophrenic patients2007In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 190, no 4, p. 479-484Article in journal (Refereed)
    Abstract [en]

    Rationale: Perphenazine, a classical antipsychotic drug, has the potential to induce extrapyramidal side effects (EPS). Dopaminergic and serotonergic pathways are involved in the therapeutic and adverse effects of the drug. Objectives: To evaluate the impact of polymorphisms in the dopamine D 2 and D3 and serotonin 2A and 2C receptor genes (DRD2, DRD3, HTR2A, and HTR2C) on short-term effects of perphenazine monotherapy in schizophrenic patients. Materials and methods: Forty-seven Estonian inpatients were evaluated before and after 4-6 weeks of treatment by Simpson-Angus rating scale, Barnes scale, and Positive and Negative Symptom Scale. Genotyping was performed for common DRD2, DRD3, HTR2A, and HTR2C gene polymorphisms, previously reported to influence receptor expression and/or function. Results: Most of the patients (n = 37) responded to the treatment and no significant association was observed between the polymorphisms and antipsychotic response. The 102C allele of HTR2A and the -697C and 23Ser alleles of HTR2C were more frequent among patients with EPS (n = 25) compared to patients without EPS (n = 22) (p = 0.02, 0.01, and 0.02, respectively). The difference between patients with and without EPS in variant allele frequencies remained significant after multiple model analyses including age, gender, and duration of antipsychotic treatment as covariants. There was no significant association between EPS occurrence and polymorphisms in the DRD2 and DRD3 genes. Conclusions: An association was observed between polymorphisms in HTR2A and HTR2C genes and occurrence of acute EPS in schizophrenic patients treated with perphenazine monotherapy. Larger study populations are needed to confirm our findings.

  • 49.
    Gustafsson, Mats G.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wallman, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wickenberg-Bolin, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Göransson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Andersson, Claes R.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Improving Bayesian credibility intervals for classifier error rates using maximum entropy empirical priors2010In: Artificial Intelligence in Medicine, ISSN 0933-3657, E-ISSN 1873-2860, Vol. 49, no 2, p. 93-104Article in journal (Refereed)
    Abstract [en]

    Objective:

    Successful use of classifiers that learn to make decisions from a set of patient examples require robust methods for performance estimation. Recently many promising approaches for determination of an upper bound for the error rate of a single classifier have been reported but the Bayesian credibility interval (Cl) obtained from a conventional holdout test still delivers one of the tightest bounds. The conventional Bayesian CI becomes unacceptably large in real world applications where the test set sizes are less than a few hundred. The source of this problem is that fact that the Cl is determined exclusively by the result on the test examples. In other words, there is no information at all provided by the uniform prior density distribution employed which reflects complete lack of prior knowledge about the unknown error rate. Therefore, the aim of the study reported here was to study a maximum entropy (ME) based approach to improved prior knowledge and Bayesian CIs, demonstrating its relevance for biomedical research and clinical practice.

    Method and material:

    It is demonstrated how a refined non-uniform prior density distribution can be obtained by means of the ME principle using empirical results from a few designs and tests using non-overlapping sets of examples.

    Results:

    Experimental results show that ME based priors improve the CIs when employed to four quite different simulated and two real world data sets.

    Conclusions:

    An empirically derived ME prior seems promising for improving the Bayesian Cl for the unknown error rate of a designed classifier.

  • 50. Güzey, C.
    et al.
    Scordo, Maria Gabriella
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Spina, E.
    Landsem, Veslemøy Malm
    Spigset, O.
    Antipsychotic-induced extrapyramidal symptoms in patients with schizophrenia: associations with dopamine and serotonin receptor and transporter polymorphisms2007In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 63, no 3, p. 233-241Article in journal (Refereed)
    Abstract [en]

    Background: Little is known about the influence of polymorphisms of the dopamine and serotonin system on the risk for extrapyramidal symptoms (EPS) during treatment with antipsychotic drugs. Methods: Of 119 subjects with schizophrenia treated with antipsychotics, 63 had current or previous EPS (acute dystonia, parkinsonism, tardive dyskinesia), and 56 had no such symptoms. All subjects were genotyped for a total of eight dopamine and serotonin receptor and transporter polymorphisms: the Taq1A polymorphism of the dopamine D2 receptor (DRD2) gene, the Msc1 polymorphism of the dopamine D3 receptor (DRD3) gene, the variable number of tandem repeat (VNTR) polymorphism of the dopamine transporter (DAT1) gene, four polymorphisms (102T/C, His452Tyr, 516 C/T, and Thr25Asn) of the serotonin 5-HT2A receptor (5HTR2A) gene, and the 5HTTLPR polymorphism of the serotonin transporter (5HTT) gene. Results: The frequency of the A1 allele of the DRD2 Taq1A polymorphism was significantly higher in the EPS group than in the control group [16% vs. 7%, P=0.040; odds ratio (OR) 2.4; 95% confidence interval (CI) 1.1-5.7]. Also, the 9 repeat allele of the DAT1 VNTR polymorphism was significantly more common in the EPS group (42% vs. 28%, P=0.030; OR 1.9; 95% CI 1.1-3.3). Being a carrier of both DRD2 Taq1A A1 and DAT1 VNTR 9 repeat alleles was also significantly associated with the occurrence of EPS (19% vs. 6%, P=0.040; OR 4.0; 95% CI 1.05-15.2) No significant differences in allele frequencies were found for the other polymorphisms. Conclusion: Presence of the Taq1A A1 allele of the DRD2 and the 9 repeat allele of the DAT1 VNTR polymorphisms might be risk factors for EPS caused by antipsychotic drugs.

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