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- Ekegren, Jenny, 1976-
(författare)
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Design and Synthesis of Novel HIV-1 Protease Inhibitors Comprising a Tertiary Alcohol in the Transition-State Mimic
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- HIV-1 protease inhibitors are important in the most frequently used regimen for the treatment of HIV/AIDS, the highly active antiretroviral therapy (HAART). For patients with access to this treatment, an HIV infection is no longer lethal, but rather a manageable, chronic infection. However, the HIV-1 protease inhibitors are generally associated with serious shortcomings such as adverse events, development of drug resistance and poor pharmacokinetic properties. Most of the approved inhibitors suffer from high protein binding, rapid metabolism and/or low membrane permeability. In this project, novel HIV-1 protease inhibitors comprising a rarely used tertiary alcohol in the transition-state mimic were designed, synthesized and evaluated. The rationale behind the design was to achieve ‘masking’ of the tertiary alcohol by for example, intramolecular hydrogen bonding, which was believed could enhance transcellular transport. A reliable synthetic protocol was developed and a series of highly potent inhibitors was obtained exhibiting excellent membrane permeation properties in a Caco-2 cell assay. However, the cellular antiviral potencies of these compounds were low. In an attempt to improve the anti-HIV activity, microwave-accelerated, palladium-catalyzed cross-coupling reactions and aminocarbonylation of aryl bromide precursors were employed to produce P1'-extended test compounds. Inhibitors demonstrating up to six times higher antiviral effect were obtained, the best derivatives having para 3- or 4-pyridyl elongations in P1'.Fast metabolic degradation was observed in liver microsome homogenate, which is believed, at least partly, to be attributable to benzylic oxidation of the indanol P2 group of the inhibitors. To enable facile variation of the P2 side chain a new synthetic route was developed using an enantiomerically pure, benzyl-substituted epoxy carboxylic acid as the key intermediate. Cyclic and amino-acid-residue-derived P2 groups were evaluated, and inhibitors equipotent to the series containing an indanol moiety were produced.
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| 2. |
- Hallberg, Jenny
(författare)
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Factors associated with lung function impairment in children and adults with obstructive lung disease
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Obstructive lung diseases are a group of diseases in which there is a limitation in the flow of air into or out of the lungs. Two common such diseases are asthma, which is found in both children and adults, and chronic obstructive pulmonary disease (COPD), mainly found in the population over 50 years of age. Both asthma and COPD seem to have with several different subgroups, or phenotypes, which may be associated with different long term consequences in regard to morbidity and in some cases also mortality. To be able to prevent and treat these diseases in the best possible way, we need to learn more about the different phenotypes and the mechanisms behind them. The aim of this thesis was to study factors that are associated with lung function impairment in children and adults with obstructive lung diseases. The factors that are in focus are age of onset, duration of symptoms, sex, allergy, smoking and the contribution of genes and environment. We have, in the two first papers, measured lung function at age 4 and 8 years in a birth cohort of 4,000 children and found that asthma symptom onset in the first 4 years of life was, on a group level, associated with impaired exhaled flows. This was found irrespective of the persistence of symptoms between the age of 4 and 8. We could also show tracking of impaired flows between the age of 4 and 8. Sensitization to airway allergens was associated with lung function impairment only in children with symptom onset after the age of 4. While male sex was a risk factor for asthma symptoms, girls with asthma symptoms showed a larger negative effect on exhaled flows, at least in the four first years. In paper 3 and 4, we studied symptom data from 45,000 twins from the Swedish Twin Registry to quantify heritability for chronic bronchitis and emphysema, two of the main components seen in COPD. As smoking behaviour has genetic influences, it was necessary to study how heritability for disease was associated with heritability for smoking. The results showed that ~40% of the individuals liability to developing chronic bronchitis/emphysema can be attributed to genetic factors, and that only a small part of these factors were found to be in common with those influencing smoking habits. Women more often reported chronic bronchitis/emphysema, compared to men, and this could not be explained by different smoking habits or different genes. Two hundred of the twins took part in a clinical testing of different lung function measures. The results from this study showed that all lung function measures that were studied had a heritable component, and that it was larger for women than for men. In conclusion, we have studied how several different factors are associated with lung function impairment in children and adults with obstructive lung disease. In summary, the first years of life are of importance for future lung function. Children that outgrow their asthma seem, on a group level, to loose their symptoms rather their lung function impairment, which might be present through life. We have furthermore shown that genes are important for the individuals liability to disease in adult life. Sex differences exist both in children and adult disease, and there are indications of a less favourable outcome for girls/women. More work is now needed to find the individuals that belong to these susceptible groups, and to develop and apply methods to prevent and treat impaired lung function and disease.
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| 3. |
- Johansson, Jenny, 1980-
(författare)
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The Impact of Growth Hormone and Gamma-Hydroxybutyrate (GHB) on Systems Related to Cognition
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Drug dependence is a serious and increasing problem in our society, especially among adolescents. The use of the large variety of substances available can result in a range of physiological and psychological adverse effects on individuals and negative consequences on the society overall. Several different types of drugs induce neurotoxicological damages, which in turn can generate impairment in for example the reward system and affect cognitive parameters. The drug gamma-hydroxybutyrate (GHB) is usually considered a harmless compound among abusers, but has now shown to be highly addictive. Furthermore, GHB can cause memory impairments in both humans and animals. On the contrary, growth hormone (GH) and its main mediator insulin-like growth factor 1 (IGF-1) have recently been suggested to improve memory and learning in several studies. The hormones exhibit certain neuroprotective capabilities and have also previously been demonstrated to reverse opioid induced apoptosis in hippocampal cells. These effects and the fact that GHB is shown to increase GH secretion, which attracted considerable attention among body builders, led us to initiate studies on GHB and its impact on relevant systems in the central nervous system (CNS). Thus, the main purpose of the present investigation was to elucidate some of the underlying mechanisms that could account for the effects exerted by GH and GHB in the CNS.We found that a) GH affects the density and functionality of GABAB-receptors and opioid receptors in the male rat brain, b) GHB induces cognitive deficits and down-regulates GABAB-receptors, c) GHB treatment creates an imbalance between the endogenous opioids Met-enkaphalin-Arg6Phe7 (MEAP) and dynorphin B and increases the levels of MEAP in regions of the brain that are associated with drug dependence, and d) GHB affects the expression of IGF-1 receptors but not the plasma levels of IGF-1. In conclusion, the present work demonstrates that GH interacts with both opioid and GABAB-receptors in the male rat CNS and that GHB has an impact on brain regions associated with cognition and the development of dependence. These observations may be of relevance in many aspects related to addiction and might be translated into humans.
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