| 1. |
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| 2. |
- Birnir, Bryndis, et al.
(författare)
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The impact of sub-cellular location and intracellular neuronal proteins on properties of GABA(A) receptors
- 2007
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Ingår i: Current Pharmaceutical Design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 13:31, s. 3169-3177
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Tidskriftsartikel (refereegranskat)abstract
- Most studies of GABA(A) receptor accessory proteins have focused on trafficking, clustering and phosphorylation state of the channel-forming subunits and as a result a number of proteins and mechanisms have been identified that can influence the GABA(A) channel expression and function in the cell plasma membrane. In the light of a growing list of intracellular and transmembrane neuronal proteins shown to affect the fate, function and pharmacology of the GABA(A) receptors in neurons, the concept of what constitutes the native GABA(A) receptor complex may need to be re-examined. It is perhaps more appropriate to consider the associated proteins or some of them to be parts of the receptor channel complex in the capacity of ancillary proteins. Here we highlight some of the effects the intracellular environment has on the GABA-activated channel function and pharmacology. The studies demonstrate the need for co-expression of accessory proteins with the GABA(A) channel-forming subunits in heterologous expression systems in order to obtain the full repertoire of GABA(A) receptors characteristics recorded in the native neuronal environment. Further studies e.g. on gene-modified animal models are needed for most of the accessory proteins to establish their significance in normal physiology and in pathophysiology of neurological and psychiatric diseases. The challenge remains to elucidate the effects that the accessory proteins and processes (e.g. phosphorylation) plus the sub-cellular location have on the "fine-tuning" of the functional and pharmacological properties of the GABA(A) receptor channels.
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| 3. |
- El-Salhy, Magdy, 1951-
(författare)
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Triple treatment with octreotide, galanin and serotonin is a promising therapy for colorectal cancer
- 2005
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 11:16, s. 2107-2117
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Tidskriftsartikel (refereegranskat)abstract
- In patients with colorectal cancer, low levels of colonic somatostatin, galanin and serotonin have been found. Based on these findings, the effects of triple treatment with octreotide (a somatostatin analogue), galanin and serotonin on colorectal cancer has been studied. Triple therapy was found to reduce the volume and weight of both rat and human colon carcinoma in xenografts, apparently by necrosis, but also by reducing proliferation and expression of epidermal growth factor of cancer cells, and also by inducing apoptosis. It has been suggested that tumour necrosis results from ischemia in the tumour caused by a reduction in the tumour blood flow, a consequence of reduced number of tumour-feeding blood vessels and by constricting of tumour feeding arterioles. The effects of treating rat colorectal cancer using single, double and triple therapy with octreotide, galanin and serotonin were studied. Of these substances, galanin alone achieved a significant reduction in tumour-feeding blood vessels. Single and double regimes had some effect, but were not nearly so successful as triple treatment. The optimum treatment dose of triple therapy lies between 40 and 80 μg/kg/day, smaller doses had no effect on the tumours at all, while larger doses had no additional effect. The optimal administration route is continuous i.p. infusion, for 14 days. Triple therapy gave no obvious side effects, and had equivalent anti-tumour and therapeutic efficacy as standard treatment with 5-fluorouracil/leucovorin. Although this treatment appears to be a promising option, clinical trials need be conducted to establish whether it can be beneficial in clinical use. © 2005 Bentham Science Publishers Ltd.
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| 4. |
- Karlsson, Miriam, et al.
(författare)
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New proposals for testing drugs with IKr-blocking activity to determine their teratogenic potential
- 2007
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 13:29, s. 2979-2988
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Forskningsöversikt (refereegranskat)abstract
- Drugs blocking the potassium current IKr, either as an intended pharmacologic effect (eg antiarrhythmics dofetilide and almokalant) or as an unwanted side-effect (eg antihistamine astemizole, propulsive drug cisapride, antidepressive drugs and macrolide antibiotics) are potential human teratogens. It is the contention of this paper that the existing repeat dose regimen used in teratology studies to fulfil regulatory requirements, does not properly identify the teratogenic risk of these drugs. Results from conventional studies for dofetilide and almokalant showed high rates of postimplantation embryonic death with few malformed fetuses. For astemizole and cisapride only embryonic death was seen. These latter results were not considered important because they occurred either in the presence of maternal toxicity and/or at high doses. Subsequent studies have shown that IKr-blockers are highly teratogenic when administered on single gestational days (GD) during a sensitive period of rat pregnancy (GD 10-14) when they induce a high incidence of stage-specific malformations. This teratogenic activity of astemizole and cisapride was missed in the original teratology studies. Mechanistically IKr-blockers cause bradycardia and arrhythmia of the embryonic heart and while an embryo may be able to survive a single day exposure to a teratogenic dose, repeat dosing often leads to death of the embryo. With this review we suggest that new drugs identified at the preclinical stage of development as having IKr-blocking properties, should undergo more comprehensive teratology testing including single GD dosing and studies using embryo culture. This would further help identify and characterise their teratogenic potential.
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| 5. |
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| 6. |
- Sharma, Hari Shanker, et al.
(författare)
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Drugs of abuse-induced hyperthermia, blood-brain barrier dysfunction and neurotoxicity : neuroprotective effects of a new antioxidant compound H-290/51
- 2007
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 13:18, s. 1903-1923
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Forskningsöversikt (refereegranskat)abstract
- The psychostimulants, morphine and methamphetamine are well known drugs of abuse that induce brain pathology and/or neurodegeneration resulting in a huge burden on our society. The possible mechanisms of psychostimulants induced neuropathology and neurodegeneration are still not well known. The drugs of abuse results in profound hyperthermia and widespread alterations in neurochemical metabolism in the central nervous system (CNS). It appears that psychostimulants induced hyperthermia and/or release of neurochemicals influence the blood-brain barrier (BBB) dysfunction leading to brain pathology. The drugs of abuse also induce oxidative stress resulting in generation of free radicals and lipid peroxidation. Thus, further research is needed to understand the basic function of BBB disruption and temperature regulation by psychostimulants and to modify them pharmacologically to attenuate brain dysfunction and neuropathology. This review is focused on the problems of morphine and methamphetamine induced hyperthermia and their effects on breakdown of the BBB function leading to brain damage. Works done in our laboratory suggest that hyperthermia caused by these drugs is responsible for BBB disruption and neurodegeneration. This hypothesis is further supported by our observation that pretreatment with a portent antioxidant compound H-290/51 attenuates the BBB disruption and induces marked neuroprotection following morphine induced withdrawal and methamphetamine induced neurotoxicity. The possible mechanisms and functional significance of these findings are discussed.
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| 7. |
- Sharma, Hari Shanker
(författare)
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Neurodegeneration and neuroregeneration : recent advancements and future perspectives.
- 2007
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 13:18, s. 1825-1827
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Tidskriftsartikel (refereegranskat)abstract
- Neuroprotection: Non-Neural Cells Regulate Neuronal Functions The term “Neuroprotection” normally denotes rescue of nerve cells. However, the non-neural cells, i.e., glial cells and endothelial cells are equally important for brain function in normal and in pathological conditions [1,2]. The number of glial cells and endothelial cells far exceeds the number of neural cells in the CNS [2,3]. In spite of this fact, most attention is still focused to rescue nerve cells following CNS injuries and the role of non-neural cells in neurodegeneration or neuroprotection is largely ignored. Thus, the term “neuroprotection” is normally misleading as neurons are in the minority in the CNS and their function depends on the survival of non-neural cells and vice versa. To restore the normal function of the CNS by pharmacological manipulation, revival of glial cells and endothelial cell functions are equally important [4-6]. The nerve cell function is largely dependent on the normal endothelial cell and glial function. Thus, it is imperative that in pathological conditions, reducing damage to endothelial cells and/or glial cells by pharmacological agents will improve nerve cell function. Alternatively, glial cells, endothelial cells are all working to maintain and regulate neuronal function in health and disease [7,8]. Taken together, it appears that both the neural and non-neural components of the CNS are working in synergy for maintaining normal brain function and alterations in any neural or non-neural component will have severe impact on CNS structure and function. Blood-Brain vs. Brain Blood Barriers Our CNS is well equipped with the blood-brain barrier that is anatomically located within the endothelial cells of the brain microvasculature [1]. It is assumed that both the luminal and the abluminal cell membranes of the endothelium are equally “tight” to maintain an effective barrier between blood to brain and brain to blood [1,2]. Interestingly, the endothelial cell function and membrane transport from brain to blood (brain-blood barrier) in relation to neurodegeneration and neurorepair mechanisms are still largely ignored [see7,8]. Thus, it is still unclear whether luminal barrier disruption always accompanied with identical damage to the abluminal barrier function. However, there are reasons to believe that when luminal membrane is permeable, the abluminal side is also showing some alteration in the membrane function. A direct evidence to support or reject this hypothesis is still lacking. Studies carried out in our laboratory suggest that hyperthermia induced breakdown of the blood-brain barrier is also associated with a leaky brain blood-barrier [5,9]. Thus, serotonin transport occurs from brain to the blood causing a massive accumulation of the amine in the circulation leading to a generalized and widespread disruption of the blood-brain barrier [9]. This large increase in plasma serotonin is largely prevented by destruction of the serotoninergic neurons into the brain [see 5,9]. This treatment did not allow brain serotonin to increase and thus, the plasma serotonin concentration is much lower resulting in a minor breakdown of the blood-brain barrier in hyperthermia [5]. This suggests that various endogenous substances, e.g., cytokines, growth factors, growth hormone etc. are released from brain in extra quantity following injury that could be transported into the blood stream to have a generalized effect on the cerebral circulation and/or brain function. However, this is entirely a new subject and requires additional investigation in details to achieve better neuroprotection in future. In this volume, the term “Neuroprotection” is employed in its widest sense to include protection of all the “neural” and “nonneural” components of the CNS. This issue highlights the role of non-neural cells; especially the function of endothelial cells and its surrounding glial cells in neurodegeneration and repair process.......
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| 8. |
- Sharma, Hari Shanker, et al.
(författare)
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Neuroprotective effects of melanocortins in CNS injury
- 2007
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 13:19, s. 1929-1941
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Forskningsöversikt (refereegranskat)abstract
- New compounds having affinity to various melanocortin receptors have recently been identified as possible neuroprotective agents. This review is focused on the role of neuroprotective effects of melanocortins in CNS injury and repair mechanisms. Using selective non-peptidic compounds with varying affinity to melanocortin receptors, our laboratory has shown their anti-edematous effects in the spinal cord injury. This effect of the compounds is related with their ability to attenuate blood-spinal cord barrier permeability. The functional significance and possible therapeutic strategies of these compounds in CNS injury are discussed.
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| 9. |
- Sharma, Hari Shanker
(författare)
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Neurotrophic factors in combination : a possible new therapeutic strategy to influence pathophysiology of spinal cord injury and repair mechanisms
- 2007
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 13:18, s. 1841-1874
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Tidskriftsartikel (refereegranskat)abstract
- Several neurotrophic factors are known to induce neuroprotection in traumatic injuries to the central nervous system (CNS). However, many neurotrophins are unable to attenuate cell death following CNS injuries. New data generated in our laboratory show that a suitable combination of neurotrophic factors may enhance the neuroprotective efficacy of neurotrophins on cell and tissue injury and improve sensory motor functions. This novel aspect of neurotrophins treatment in combination in spinal cord injury (SCI) induced behavioral dysfunctions and spinal cord pathology is examined in a rat model. Our investigations suggest that a suitable combination of neurotrophins will attenuate both neural and non-neural (glial cells and endothelial cells) damage in SCI leading to enhanced neuroprotection. The possible cellular and molecular mechanisms of synergistic effects of some neurotrophins in combination are still speculative and require further investigation.
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| 10. |
- Tolmachev, Vladimir
(författare)
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Imaging of HER-2 overexpression in tumors for guiding therapy
- 2008
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Ingår i: Current pharmaceutical design. - 1381-6128 .- 1873-4286. ; 14:28, s. 2999-3019
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Forskningsöversikt (refereegranskat)abstract
- Human epidermal growth factor receptor type 2 (HER2) is a transmembrane tyrosine kinase receptor, which is overexpressed in a large fraction of breast, ovarian, urinary bladder and a number of other carcinomas. Overexpression of HER2 is associated with poor prognosis. Treatment of patients with HER2-expressing breast cancer with a humanized anti-HER2 monoclonal antibody trastuzumab has resulted in improved survival. Several kinds of other anti-HER2 therapies are under development. Radionuclide molecular imaging of HER2 expression may influence patient management by selecting patients, who would benefit form anti-HER2 therapy. Other applications, such as therapy response monitoring and follow-up are also possible. In this case, the use of radionuclide imaging may overcome problems associated with biopsies, including sampling errors and discordance of expression between primary tumors and metastases. Important preconditions for development of a successful tracer for radionuclide imaging are high affinity of a targeting agent and suitable chemistry of labeling. The paper reviews information concerning major classes of HER2-targeting agents, including full-length monoclonal antibodies, their enzymatically produced fragments, engineered immunoglobulin based tracers, and alternative high affinity binders. Available information suggests that Affibody molecules or other small non-immunoglobulin based tracers have the best potential for development of high-contrast imaging agents for visualization of HER2 in vivo.
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| 11. |
- Fowler, Christopher J
(författare)
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"The tools of the trade"--an overview of the pharmacology of the endocannabinoid system.
- 2008
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Ingår i: Current pharmaceutical design. - 1873-4286. ; 14:23, s. 2254-65
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Tidskriftsartikel (refereegranskat)abstract
- The endocannabinoid system can be manipulated pharmacologically in a variety of ways, including directly acting agonists and inverse agonists, and indirectly acting compounds which affect the synthesis, cellular accumulation and metabolism of the two main endocannabinoids, anandamide and 2-arachidonoylglycerol. In this overview, the most commonly used compounds are discussed, primarily with respect to their targets of action and to their selectivities vis a vis "off targets". For direct acting compounds such as cannabinoid receptor agonists, it is suggested that the use of several compounds with different chemical structures at relevant doses or concentrations is likely to minimise the risk of misinterpreting an "off target" effect as being an action mediated by cannabinoid receptors. For indirectly acting compounds, the same reasoning applies, and in the case of compounds affecting the accumulation of anandamide, it is important to recognize that the molecular target of these compounds is far from clear. Nonetheless, judicious use of the array of pharmacological tools currently available, and combination of these tools with RNA interference techniques and the use of genetically modified animals, provides a powerful approach with which to characterize the endocannabinoid system in the body.
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| 12. |
- Nilsson, Jan, et al.
(författare)
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Oxidized LDL antibodies in treatment and risk assessment of atherosclerosis and associated cardiovascular disease.
- 2007
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Ingår i: Current Pharmaceutical Design. - : Bentham Science Publishers Ltd.. - 1381-6128. ; 13:10, s. 1021-1030
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Forskningsöversikt (refereegranskat)abstract
- Immune responses against oxidized forms of LDL play a critical role in activation and regulation of the inflammatory process that characterizes all stages of atherosclerosis. In humans oxidized LDL is targeted by both IgM and IgG autoantibodies. Immunization of hypercholesterolemic animals with oxidized LDL has been shown to inhibit atherosclerosis demonstrating that at least some of these immune responses have a protective effect. The identification of the structures in oxidized LDL that are responsible for activation of immunity has made it possible to develop novel therapeutic approaches for treatment of atherosclerosis based on active (vaccines) and passive (antibodies) immunization. Studies performed in atherosclerosis-prone mice demonstrate that both peptide-based vaccines and recombinant IgG targeting epitopes in oxidized LDL significantly reduce atherosclerosis. There is also evidence antibodies against oxidized LDL could also be used for imaging atherosclerosis.
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| 13. |
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| 14. |
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