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- Andreasen, Niels, et al.
(author)
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Amyloid-related biomarkers for Alzheimer's disease.
- 2008
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In: Current medicinal chemistry. - : Bentham Science Publishers Ltd.. - 0929-8673. ; 15:8, s. 766-71
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Research review (peer-reviewed)abstract
- Alzheimer's disease (AD) is an age-related disorder that causes brain damage resulting in progressive cognitive impairment and death. Three decades of progress have given us a detailed understanding of the underlying molecular mechanisms. Over the past 10 years, this knowledge has translated into a range of targets for therapy, the most promising of which is amyloid beta (Abeta). An imbalance between the production and clearance of Abeta is thought by many to represent the earliest event in the pathogenesis of AD. Abeta is known to be subject to oligomerisation, a process that increases its synaptotoxicity. The oligomers may aggregate further to proto-fibrils and fibrils, eventually forming senile plaques, the neuropathological hallmark of AD. In this article we review the key aspects of Abeta as a biomarker for AD, including its pathogenicity, the diagnostic performance of different Abeta assays in different settings, and the potential usefulness of Abeta as a surrogate marker for treatment efficacy in clinical trials of novel Abeta-targeting drugs.
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- El-Seedi, Hesham R., et al.
(author)
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Naturally occurring xanthones; latest investigations : isolation, structure elucidation and chemosystematic significance
- 2009
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In: Current Medicinal Chemistry. - : Bentham Science Publishers Ltd.. - 0929-8673 .- 1875-533X. ; 16:20, s. 2581-2626
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Research review (peer-reviewed)abstract
- In this review, an updated literature survey covering the reports of naturally occurring xanthones in the period of 2005-2008 is presented. In some 143 studies, the isolation of 264 different xanthones from 36 plant species (representing 15 genera in 6 families of higher plants), 7 species of fungi, and 1 lichen species were reported. Of these, 122 compounds were isolated for the first time from nature. We discuss plant origin, the way of separation, and spectral analysis done for structure elucidation, along with a brief discussion of the chemosystematic significance.
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- Gurevich-Panigrahi, Tatiana, et al.
(author)
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Obesity : Pathophysiology and Clinical
- 2009
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In: Current Medicinal Chemistry. - : Bentham Science. - 0929-8673 .- 1875-533X. ; 16:4, s. 506-521
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Journal article (peer-reviewed)abstract
- Obesity is an increasingly serious socioeconomic and clinical problem. Between 1/4 - 1/3 of population in the developed countries can be classified as obese. Four major etiological factors for development of obesity are genetic determinants, environmental factors, food intake and exercise. Obesity increases the risk of the development of various pathologic conditions including: insulin-resistant diabetes mellitus, cardiovascular disease, non-alcoholic fatty liver disease, endocrine problems, and certain forms of cancer. Thus, obesity is a negative determinant for longevity. In this review we provide broad overview of pathophysiology of obesity. We also discuss various available, and experimental therapeutic methods. We highlight functions of adipocytes including fat storing capacity and secretory activity resulting in numerous endocrine effects like leptin, IL-6, adiponectin, and resistin. The anti-obesity drugs are classified according to their primary action on energy balance. Major classes of these drugs are: appetite suppressants, inhibitors of fat absorption (i.e. orlistat), stimulators of thermogenesis and stimulators of fat mobilization. The appetite suppressants are further divided into noradrenergic agents, (i.e. phentermine, phendimetrazine, benzphetamine, diethylpropion), serotoninergic agents (i.e. dexfenfluramine), and mixed noradrenergic-serotoninergic agents (i.e. sibutramine). Thus, we highlight recent advances in the understanding of the central neural control of energy balance, current treatment strategies for obesity and the most promising targets for the development of novel anti-obesity drugs.
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- Johnston, James B., et al.
(author)
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Targeting the EGFR pathway for cancer therapy
- 2006
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In: Current Medicinal Chemistry. - : Bentham Science Publishers Ltd.. - 0929-8673 .- 1875-533X. ; 13:29, s. 3483-3492
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Journal article (peer-reviewed)abstract
- Clinical studies have shown that HER-2/Neu is over-expressed in up to one-third of patients with a variety of cancers, including B-cell acute lymphoblastic leukemia (B-ALL), breast cancer and lung cancer, and that these patients are frequently resistant to conventional chemo-therapies. Additionally, in most patients with multiple myeloma, the malignant cells over-express a number of epidermal growth factor receptors (EGFR)s and their ligands, HB-EGF and amphiregulin, thus this growth-factor family may be an important aspect in the patho-biology of this disease. These and other, related findings have provided the rationale for the targeting of the components of the EGFR signaling pathways for cancer therapy. Below we discuss various aspects of EGFR-targeted therapies mainly in hematologic malignancies, lung cancer and breast cancer. Beside novel therapeutic approaches, we also discuss specific side effects associated with the therapeutic inhibition of components of the EGFR-pathways. Alongside small inhibitors, such as Lapatinib (Tykerb, GW572016), Gefitinib (Iressa, Z131839), and Erlotinib (Tarceva, OSI-774), a significant part of the review is also dedicated to therapeutic antibodies (e.g.: Trastuzumab / Herceptin, Pertuzumab / Omnitarg / rhuMab-2C4, Cetuximab / Erbitux / IMC-C225, Panitumumab / Abenix / ABX-EGF, and also ZD6474). In addition, we summarize, both current therapy development driven by antibody-based targeting of the EGFR-dependent signaling pathways, and furthermore, we provide a background on the history and the development of therapeutic antibodies.
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- Lendvai, Gabor, et al.
(author)
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Radiolabelled Oligonucleotides for Imaging of Gene Expression with PET
- 2009
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In: Current Medicinal Chemistry. - : Bentham Science Publishers Ltd.. - 0929-8673 .- 1875-533X. ; 16:33, s. 4445-4461
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Research review (peer-reviewed)abstract
- Our understanding of altered patterns of gene expression being responsible for many diseases has been growing thanks to modern molecular biological methods. Today, these changes can only be identified when tissue samples are available. Therefore, a noninvasive method allowing us to monitor gene expression in vivo would be valuable, not only as a research tool, but also for patient stratification before treatment and for treatment follow-up. Antisense oligonucleotides (ODN) have been considered to be suitable molecules to trace active genes in vivo, as well as to treat diseases by hybridising to its complementary messenger RNA (mRNA) sequence in the cells thereby preventing the synthesis of the peptide. However, the use of ODNs in the organisms are endangered by many hurdles such as physical barriers to pass and enzyme attack to be avoided. Positron emission tomography (PET) provides a most advanced in vivo imaging technology that allows the exploration of the fate of radionuclide-labelled antisense ODNs in the body; thereby providing information about biodistribution and quantitative accumulation in tissues to assess pharmacokinetic properties of ODNs. This kind of evaluation is important as part of the characterisation of antisense therapeutics but also as part of the development of antisense imaging agents. This review provides a general summary about the antisense concept and displays the present status of the antisense imaging field with the major achievements and remaining challenges on the long journey towards accomplishing in vivo monitoring of gene expression using PET.
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- Lindqvist, Pelle, et al.
(author)
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Carriership of factor v leiden and evolutionary selection advantage.
- 2008
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In: Current Medicinal Chemistry. - 0929-8673. ; 15:15, s. 1541-1544
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Journal article (peer-reviewed)abstract
- Historically, lethal exsanguinations and severe infections have been two major causes of maternal death. Gene mutations that lower the risk of profuse hemorrhage or severe infections would give a survival advantage. A single mutation of coagulation factor V, known as FV Leiden (FVL), can be such a beneficial mutation. FVL is common among Caucasians and today confers an increased risk of thromboembolism. However, the high prevalence of FVL (up to 15%) in the general population suggests that it has given an evolutionary advantage. In this review, we discuss possible mechanisms of the evolutionary survival advantage associated with FVL. In women, FVL confers lower risk of blood loss and profuse hemorrhage in association with delivery and improves the hemoglobin status. In addition, FVL carriers possibly have a survival advantage during sepsis. In conclusion, the high prevalence of FVL may be the result of one or more evolutionary selection advantages.
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- Malm, Johan, et al.
(author)
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Thyroid Hormone Antagonists : Potential Medical Applications and Structure Activity Relationships
- 2009
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In: Current Medicinal Chemistry. - : Bentham Science Publishers Ltd.. - 0929-8673 .- 1875-533X. ; 16:25, s. 3258-3266
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Research review (peer-reviewed)abstract
- Thyroid hormone receptors (TRs) exert profound effects on development, metabolism, and multiple specific organ functions. Principally by regulating crucial genes in a variety of tissues, the thyroid hormones, 3,5,3'-triiodo-L-thyronine (L-T-3, 1) and 3,5,3',5'-tetraiodo-L-thyronine (L-T-4, 2), influence basal calorigenesis and oxygen consumption, cardiac rate and contractility, lipid metabolism, bone structure and strength, and central nervous system functions critical for normal mentation and mood. Elevated levels of circulating and tissue 1 and/or 2 result in the thyrotoxic clinical state, manifested by weight loss despite increased caloric intake; heat intolerance due to increased calorigenesis; cardiac tachyarrhythmias, systolic hypertension, and heart failure; skeletal muscle weakness; and a spectrum of neuropsychiatric symptoms ranging from anxiety to delirium and psychosis. The current standard treatments of endogenous hyperthyroidism causing thyrotoxicosis reduce the overproduction of thyroid hormones by pharmacologically inhibiting their synthesis or release (e.g., with thionamides or lithium, respectively), or by ablating thyroid tissue surgically or with radioiodine. TR-antagonists could hypothetically have significant clinical use in treating thyrotoxic states if they were capable of promptly and completely restoring euthyroid levels of thyroid-specific gene activity. No TR alpha-selective ligands have been prepared up to this date, ligands that potentially would further ameliorate the problem with cardiac disease connected with hyperthyroidism and maybe cardiac arrhythmia. Despite its significant potential use, no TR-antagonist has reached clinical application. Design of TR-antagonists ligands has been based on the attachment of a large extension group at the 5-prime position of 1 or other structurally related analogues. This extension is believed to distort folding of the C-terminal helix ( helix 12) to the body of the ligand binding domain (LBD), which normally forms a coactivator site. Examples of synthetic TR antagonists based on this extension strategy are reviewed, as well as other strategies to achieve functional TR-antagonism.
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