1.
Lindquist, Catarina
(författare)
Physiology and Pharmacology of GABAA receptors: The Brakes in the Brain
2005
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
Inhibitory neurotransmission in the brain is mostly mediated by gamma-aminobutyric acid type A (GABAA) receptors. These receptors are involved in both phasic inhibition (point-to-point inhibition, synaptic transmission) and tonic inhibition (diffuse form of inhibition, brain homeostasis). In this thesis the functional and pharmacological properties of GABAA receptors expressed in brain slices or in Sf 9 cells were studied. GABAA receptors expressed extrasynaptically are believed to be involved in tonic inhibition. In hippocampal dentate gyrus granule cells we identified and characterized three types of extrasynaptic receptor types (GABARex) that varied in their affinity for GABA, maximal single-channel conductance and sensitivity to drugs. For the first time we showed how the GABA concentration determines the conductance of GABAA receptors in brain tissue. There is thus a direct link between the extracellular GABA concentration and the level of the tonic inhibition, providing dynamic control. It is only within the last ten years or so that the tonic inhibition was discovered and only recently has it gained widespread interest. One reason is that it has become quite clear that the first site of action and probably often the most important site of action of drugs are the extrasynaptic receptors. We found that a drug now in clinical trials (THIP) at the clinically relevant concentration activates these extrasynaptic receptors. It has been assumed that spontaneous openings of the receptors are only functionally significant in receptor complexes containing the epsilon-subunit or mutations. We show that alpha/beta and alpha/beta/gamma?receptors can open spontaneously and be modified by drugs. The capacity to open spontaneously may be vital for fast responses such as at synapses. This suggests that the functional properties of receptors located at synapses and outside of synapses (extrasynaptic receptors: GABARex) differ. Those at synapses open rapidly (ms) whereas those at extrasynaptic sites open after a delay of ten to hundreds of seconds. This functional difference is very important in terms of brain function as it ensures fast flow of information (synaptic transmission) but in a controlled way that is set by the gain and the time window for synaptic transmission integration via the tonic inhibition. By using the compound SR95531, we constructed a model that accounts for activation and inhibition of both phasic- and tonic-like currents in an expression system. This model can be used to calculate what concentrations of the inhibitor to use to specifically block certain GABARex receptors in brain tissue to study how a particular population of GABARex contributes to the tonic inhibition and how it affects both excitatory and inhibitory synaptic transmission.
2.
3.
Lundälv, Jörgen, 1966
(författare)
Bioterrorism och media
2004
Bok (övrigt vetenskapligt/konstnärligt) abstract
Attacker med biologiska och kemiska preparat är ett nytt hot mot institutioner i världen bl.a massmedia. I USA har ett antal medieföretag attackerats med brev som visat sig innehålla mjältbrand. I Sverige utsätts medier för hot och risker med jämna mellanrum. Denna guide om säkerhet och beredskap ger ny kunskap om vad bioterrorism innebär och vilka hotbilder som finns mot medieföretag i Sverige. Den vänder sig också till informationsstrateger vid myndigheter och företag liksom till hälso- och sjukvårdspersonal med intresse för epidemiologiska frågor. Guiden inleds med företal av Gorm Albrechtsen, f.d. chefredaktör vid Herning Folkeblad i Danmark som utsatts för misstänkta pulverbrev samt av Åke Sellström, avdelningschef vid Totalförsvarets forskningsinstitut (FOI) och expert på biologiska och kemiska vapen.
4.
Ahlin, Gustav, 1977-
(författare)
In vitro and in silico prediction of drug-drug interactions with transport proteins
2009
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
Drug transport across cells and cell membranes in the human body is crucial for the pharmacological effect of drugs. Active transport governed by transport proteins plays an important role in this process. A vast number of transport proteins with a wide tissue distribution have been identified during the last 15 years. Several important examples of their role in drug disposition and drug-drug interactions have been described to date. Investigation of drug-drug interactions at the transport protein level are therefore of increasing interest to the academic, industrial and regulatory research communities. The gene expression of transport proteins involved in drug transport was investigated in the jejunum, liver, kidney and colon to better understand their influence on the ADMET properties of drugs. In addition, the gene and protein expression of transport proteins in cell lines, widely used for predictions of drug transport and metabolism, was examined. The substrate and inhibitor heterogeneity of many transport proteins makes it difficult to foresee whether the transport proteins will cause drug-drug interactions. Therefore, in vitro assays for OCT1 and OATP1B1, among the highest expressed transport proteins in human liver, were developed to allow investigation of the inhibitory patterns of these proteins. These assays were used to investigate two data sets, consisting of 191 and 135 registered drugs and drug-like molecules for the inhibition of OCT1 and OATP1B1, respectively. Numerous new inhibitors of the transport proteins were identified in the data sets and the properties governing inhibition were determined. Further, antidepressant drugs and statins displayed strong inhibition of OCT1 and OATP1B1, respectively. The inhibition data was used to develop predictive in silico models for each of the two transport proteins. The highly polymorphic nature of some transport proteins has been shown to affect drug response and may lead to an increased risk of drug-drug interactions, and therefore, the OCT1 in vitro assay was used to study the effect of common genetic variants of OCT1 on drug inhibition and drug-drug interactions. The results indicated that OCT1 variants with reduced function were more susceptible to inhibition. Further, a drug-drug interaction of potential clinical significance in the genetic OCT1 variant M420del was proposed. In summary, gene expression of transport proteins was investigated in human tissues and cell lines. In vitro assays for two of the highest expressed liver transport proteins were used to identify previously unknown SLC transport protein inhibitors and to develop predictive in silico models, which may detect previously known drug-drug interactions and enable new ones to be identified at the transport protein level. In addition, the effect of genetic variation on inhibition of the OCT1 was investigated.
5.
Alderborn, Göran, et al.
(författare)
Mechanical strength of tablets
2008. - 3
Ingår i: Pharmaceutical Dosage Forms. - New York : Informa Healthcare. - 9780849390166 - 0849390168
Bokkapitel (övrigt vetenskapligt/konstnärligt)
6.
Alenius, Malin, 1974-
(författare)
Treatment Response in Psychotic Patients in a Naturalistic Setting : Classification, Genes, Drugs, Insight and Social Networks
2009
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
Many patients with psychotic symptoms respond poorly to treatment. Various approaches have been made to classify these patients according to treatment response. However, existing classifications have been criticized for various reasons and a new classification system is needed. Further, no satisfactory explanation of the poor treatment response has been apparent. The general aim of this thesis was therefore to develop and validate a new classification method of functional remission in a naturalistic population of patients with psychosis and to utilize this classification to investigate the population from genetic, drug treatment, insight and social network points of view. Data for this cross-sectional study of patients (n=123) attending the Psychosis Outpatient Care clinic in the county of Jönköping, Sweden, were obtained from patient interviews, blood samples and information from patient files. The new classification method CANSEPT, which combines the CAN rating scale (CAN), the UKU side effect rating scale (SE) and the patient’s previous treatment history (PT), showed validity in discriminating the patients and was accepted well by the patients. CANSEPT was used to group the patients in the other studies in this thesis. The results indicated that the gene polymorphism ABCB1 3435T, was related to worse significant social and clinical needs for patients on olanzapine, while the polymorphism DRD2 Taq1 A1 was related to a greater risk of significant side effects; especially if male, or taking strong dopamine D2-receptor antagonistic drugs. Drug treatment factors were also related to treatment response; longer duration of untreated prodromal and early psychosis was seen for patients with current significant social and clinical needs and non-adherence to treatment was associated with worse significant side effects. Worse treatment outcomes also appeared to be associated with smaller social network groups, worse insight into illness, poorer knowledge of warning signs and worse coping strategies. In summary, CANSEPT was shown to be a useful valid, multidimensional tool for classification of treatment response. Gene polymorphisms, duration of untreated illness, non-adherence to treatment, social networks and knowledge should be taken into consideration when investigating inadequate treatment response.
7.
Almäng, Jan, 1976
(författare)
McDowell's Naturalism
2006
Ingår i: Kvantifikator för en Dag. Essays Dedicated to Dag Westerståhl on his Sixtieth Birthday. - 1652-0459. ; , s. 37-52
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt) abstract
This is an essay on McDowell’s naturalism. It is, pace some commentators, argued that McDowell’s naturalism does not end up in any strange metaphysical positions in the philosophy of mind, because second nature non-reductively supervenes on first nature and have causal powers. Pace certain other commentators, it is also argued that McDowell can be read as drawing a clear line between ethical platonism, and his own naturalized platonism, but only at the cost of landing in standard naturalism.
8.
Alsmark, U. Cecilia, et al.
(författare)
Horizontal gene transfer in eukaryotic parasites : a case study of Entamoeba histolytica and Trichomonas vaginalis
2009
Ingår i: Horizontal Gene Transfer. - Totowa, NJ : Humana Press. - 9781603278522 - 9781603278539 ; , s. 489-500
Bokkapitel (övrigt vetenskapligt/konstnärligt) abstract
Over the past few years it has become apparent that horizontal gene transfer (HGT) has played an important role in the evolution of pathogenic prokaryotes. What is less clear is the exact role that HGT has played in shaping the metabolism of eukaryotic organisms. The main problems are the reliable inference of HGT on a genomic scale as well as the functional assignment of genes in these poorly studied organisms. We have screened the completed genomes of the protists Entamoeba histolytica and Trichomonas vaginalis for cases of HGT from prokaryotes. Using a fast primary screen followed by a conservative phylogenetic approach, we found 68 and 153 recent cases of HGT in the respective organisms. The majority of transferred genes that fall into functional categories code for enzymes involved in metabolism. We found a broad range of prokaryotic lineages represented among the donors, but organisms that share similar environmental niches with E. histolytica and T. vaginalis, such as the gut and the vaginal mucosa, dominate.
9.
Annas, Anita
(författare)
Metabolism-dependent activation of food and environmental mutagens in endothelial cells
2000
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
The endothelial cells of blood vessels have been proposed as a target for toxic effects ofxenobiotics in the cardiovascular system. In the present studies, induction of cytochromeP450 1A (CYP1A) enzymes and metabolic activation of food and environmentalmutagens were examined in endothelial cells of rodents, birds, and humans. Theheterocyclic amine 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and thepolycyclic aromatic hydrocarbons 7,12-dimethylbenz[a]anthracene (DMBA) andbenzo[a]pyrene were used as models for food and environmental mutagens.The results showed that Trp-P-1 was activated into tissue-binding metabolites in endothelial cells, preferentially of capillaries and veins, in rodents pretreated with the aryl hydrocarbon (Ah) receptor agonist β-naphthoflavone (BNF), whereas similar activationdid not occur in vehicle-treated animals. Similarly, exposure to BNF increased the tissue-binding of Trp-P-1 and DMBA in cultured human umbilical vein endothelial cells (HUVEC), as compared with vehicle-treated cells. In contrast, exposure to BNF did not increase the binding of the mutagens in human umbilical artery endothelial cells (HUAEC). The formation of reactive metabolites of Trp-P-1 and DMBA correlated with induction of CYP1A1 protein and/or CYP1A-dependent catalytic activities, such as 7-ethoxyresorufin O-deethylase (EROD) and DMBA hydroxylase, in endothelial cells of rodents and cultured HUVEC. Moreover, exposure to BNF increased the activation ofbenzo[a]pyrene into genotoxic metabolites in HUVEC as compared with vehicle-treated cells.In chicken and eider duck embryos, BNF induced EROD and activation of Trp-P-1 to tissue binding metabolites in the endothelial linings, preferentially of capillaries and veins, in heart and chorioallantoic membrane (CAM). In vehicle-treated embryos, these activities were low.Overall, the present studies show that CYP1A-dependent activation of xenobiotics into tissue binding or genotoxic metabolites can be induced in blood vessel endothelia in various species following exposure to Ah receptor agonists. The results also show that there is a differential response to Ah receptor agonists within the vascular tree; CYP1A and enzymatic activities are preferentially induced in endothelial cells of veins and capillaries, and to lesser extent in arteries. The results suggest that certain endothelial cellsmay be targets for CYP1A-dependent activation of xenobiotics in individuals exposed to Ah receptor agonists.
10.
Appukkuttan, Prasad, et al.
(författare)
Microwave-assisted transition-metal-catalyzed synthesis of N-shifted and ring-expanded buflavine analogues
2007
Ingår i: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 13:22, s. 6452-6460
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt) abstract
Two novel and efficient strategies for the synthesis of hitherto unknown N-shifted and ring-expanded buflavine analogues are presented. Construction of the medium-sized ring system of the title molecules, a difficult task due to the high activation energy needed for the ring-closure with the additional rigidity imposed by the biaryl skeleton, was achieved by using Suzuki-Miyaura biaryl coupling and a ring-closing metathesis reaction as the key steps. The combination of a second-generation Grubbs catalyst and microwave irradiation proved to be highly useful in generating the otherwise difficult to obtain medium-sized ring system of the buflavine analogues.
