A series of 3-aminotetralins were synthesized as potential opioid antagonists. Each proposed target compound was based on a 3-(mono- or dialkylamino )-7 -(hydroxy or methoxy)-2, 2-dimethyl-1-tetralone parent structure. Three synthetic schemes were developed utilizing the common intermediate, ethyl3-benzylamino-2, 2-dimethyl-4-(4- methoxyphenyl)butyrate 3. In Scheme I, compound 3 was modified through a series of six steps to obtain 3-(N-methyl-N-cyclopropanecarboxamido )-7 -methoxy-2, 2-dimethyl- 1-hydroxy-1-phenyltetralin (9). To carry out further synthetic steps on the intermediate 9 required the reduction of the amide function, which proved to be problematic in terms of product isolation. Scheme II was a four-step procedure, which utilized the intermediate ethyl 3- amino-2, 2 dimethyl-4-(4-methoxyphenyl)butyrate (4), also utilized in Scheme I. Ester hydrolysis of the amino ester 4 produced the amino acid 12. Internal cyclization of 12 yielded the key intermediate, 3-amino-7 -methoxy-2, 2-dimethyl-1-tetralone (13). TheNalkylation step was carried out on 13 and this yielded the target compounds, 3-[N- ( cyclopropylmethyl)amino ]- and 3-[N, N-( dicyclopropylmethyl)amino ]-7 -methoxy-2, 2- dimethyl-1-tetralone (14, 15). Subsequently, compounds 14 and 15 were 0-demethylated to obtain the respective target compounds, 3-[N-(cyclopropylmethyl)amino]- and 3-[N, N-(dicyclopropylmethyl)amino ]-7-hydroxy-2, 2-dimethyl-1-tetralone (16, 17). Scheme III was an alternate synthetic route to obtain the target compounds 3-[Nmethyl- N-( cyclopropylmethyl)amino ]-2, 2-dimethyl-7-(hydroxy or methoxy)-1-hydroxy- 1-phenyltetralin (10, 11) without the amide reduction step required in Scheme I. The intermediate 3 was N-methylated to form the 3-N-methyl-N-benzylamino ester 18 by the Eschweiler-Clarke procedure. Compound 18 was converted through a series of four steps to obtain 3-[ N-methyl-N-( cyclopropylmethyl)amino ]-7 -methoxy-2, 2-dimethyl-1- tetralone (22), a target compound which was 0-demethylated to obtain compound 23, the 7-0H analog. The mono- and dialkylated 3-aminotetralins were synthesized and confirmed for purity and correct molecular formula by utilizing 1H NMR, 13C NMR, mass spectrometry, and elemental analysis. The target compounds 14, 15, 16, 17,22 and 23 were converted to their salts and are being analyzed for opioid-related activity in receptor binding assays.

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The role of integrins in various aspects of tumor biology including tumor growth, angiogenesis, invasion and metastasis is well established. However, the integrin-specific involvement in these processes in non-small cell lung cancer (NSCLC) cells has not been thoroughly investigated. This study focuses on the role of integrins in cell motility and anoikis in NSCLC with an in vitro model system using the lung adenocarcinoma cell line A549 and its paclitaxel resistant derivative A549-T24. This research includes the following three parts: In order to demonstrate whether stimulation of the signaling mediated through specific integrins can differentially sensitize A549 and T24 cells to anchorage dependent apoptosis (anoikis), flow cytometry was used to detect the percentage of cells in certain apoptotic stages. T24 cells treated with an antibody to αvβ3 integrin showed more early apoptosis than A549 treated with the same anti-integrin antibody. To determine the involvement of integrins in mediating the motility of A549 and T24 cells, μ-slide chemotaxis chambers was used to detect chemotactic responses of migrating cells with or without treatment with anti-αvβ3 integrin. When treated with the antibody, both T24 and A549 cells attach less and move slower compared to untreated cells. In addition, the anti-integrin antibody caused a greater reduction of velocity of cell movement in T24 cells compared with A549 cells. To understand the survival signaling pathway activated by specific integrin extracellular matrix (ECM) interactions, a western blot analysis was performed to demonstrate that the PI3K pathway was involved in integrin-ECM interactions inactivating BAD for cell survival in T24 cells. Overall, specific integrin modulation in T24 cells resistant to paclitaxel may acquire some of their more-aggressive characteristics including rescuing from anoikis and accelerating cell movement.

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Background and objective: An adequate communication of medicine information to the patient along with a correct medication list form the basis for a safe use of medicines. The aim was to study patients’ experiences of the information and communication about newly initiated drug treatment along with if and how the information was given during discharge.  Study design: A qualitative observational and semistructured interview. Observational data were collected using an observational form. Interview data was recorded with tape recorder and transcribed in verbatim in Microsoft Word. Analysis was performed using content analysis.  Setting: The cardiac ward at Länssjukhuset hospital in Kalmar and telephone interviews within one week after discharge. Six patientes were included. Main outcome measures: Primarily patient experiences of the drug information and communication about newly initiated drug treatment and secondarily which kind of information is given to the patient at discharge.  Results: Six patientes were included. Analysis of patient observations and interviews showed a great variation in experiences of the given information about newly introduced drugs. Eight main categories; clear drug information, sufficient drug information, insufficient drug information, positive experience of communication, obstacles for good communication, feeling of participation, barriers for participation and independently searching for information. All patients recieved a printed medication list at discharge but none recieved a written medication report.  Conclusion: Patients describe varying experiences of the drug information at discharge. Patients are prone to seek information about their medication in different sources following discharge. The information provided should be more individualized so that the patient is given the opportunity to feel involved in the drug treatment.

Lenvatinib är en läkemedelssubstans som ingår i läkemedlen Lenvima och Kisplyx. Lenvatinib är ett cytostatikum och tillhör gruppen proteinkinashämmare. Indikationerna som läkemedelssubstansen lenvatinib har är: Differentierad sköldkörtelcancer, hepatocellulär cancer och endometriecancer. Dosering bör övervakas och initieras av sjukvård- och hälsopersonal med erfarenhet av cancerläkemedel. Hypertoni och proteinuri är två av de vanligaste biverkningarna som uppkommer under behandling med lenvatinib. Incidensen för sköldkörtelcancer i Sverige var för 10 år sedan konstant runt 350–400 fall varje år, men under det senaste decenniet har denna siffra ökat och är nu 550–600 fall. Årligen diagnostiseras ungefär 500 fall hepatocellulär cancer. Den vanligaste gynekologiska tumörformen i Sverige är endometriecancer och drabbar framför allt äldre kvinnor.    Syftet med detta examensarbete som är en litteraturstudie, var att undersöka läkemedlet Lenvima samt dess toxicitet och biverkningar. Denna substans har ett flertal indikationer för cancer, men har också en brist då läkemedlet bidrar till biverkningar och toxicitet. I detta arbete användes fem vetenskapliga artiklar vilka valdes med hjälp av databasen PubMed. Sökorden som användes var ”lenvatinib”, ”lenvatinib thyroid cancer”, ”lenvatinib hepatocellular carcinoma”, ”lenvatinib molecular” och ”lenvatinib endometrial cancer”. Alla de vetenskapliga artiklarna som har studerats under detta examensarbete påvisar resultat som bevisar att lenvatinib är en potentiell läkemedelssubstans vid indikationerna differentierad sköldkörtelcancer, hepatocellulär cancer och endometriecancer trots biverkningar och toxicitet. En av studierna påvisar att en lägre startdos bör rekommenderas för att minska toxiciteten. Lenvatinib har påvisats sig ha terapeutiska effekter för olika solida tumörer. Lenvatinib i kombination med pembrolizumab gav resultat i studier som gjorde att läkemedelssubstanserna godkändes för behandling vid avancerat endometriecancer.  Om en tidig identifiering av behandlingsrelaterade biverkningar tillämpas under studier leder det till att dosavbrott samt dosminskning och biverkningar kan minska. Food and Drug Administration godkände lenvatinib som förstahandsbehandling för patienter med icke-operabelt hepatocellulär cancer och lenvatinib i kombination med pembrolizumab är en godkänd indikation för avancerad endometriecancer. I samtliga fall skall behandlingen fortsätta så länge det observeras en klinisk nytta eller tills en oacceptabel toxicitet uppstår. / Lenvatinib is the active medical substance in the pharmaceutical drugs Lenvima and Kisplyx. Lenvatinib is an anti-cancer drug belonging to the protein kinase inhibitor group. Indications for the usage of Lenvatinib include differentiated thyroid cancer, hepatic cell carcinoma, and endometrial cancer. Dosage should be monitored and initiated by health care and health professionals with experience in cancer treatment. Hypertension and proteinuria are the most common adverse events from the treatment with lenvatinib. The goal is that >90% of the patients with thyroid cancer should be treated, investigated, and followed up according to the recommendations of the healthcare program. The incidence of thyroid cancer in Sweden was constant at around 350-400 cases each year ten years ago, but the disease has increased to 550-600 cases/year during the last decade. Each year about 500 patients are diagnosed with hepatic cellular carcinoma. In Sweden, the most common form of gynecological tumor is endometrial cancer, which primarily affects older women.   This literature study aimed to investigate the pharmaceutical drug Lenvima, containing the active drug substance lenvantinib. This substance has several indications for cancer treatment but can also contribute to adverse events and toxicity. In this study, five scientific articles from the database PubMed were selected. The keywords used for the search were “Lenvatinib,” “lenvatinib thyroid cancer,” “lenvatinib hepatocellular carcinoma,” “lenvatinib molecular,” and “lenvatinib endometrial cancer.”  All the scientific articles used for this thesis prove that lenvatinib is a potential substance as cytostatic for several indications, despite adverse effects and toxicity. One of the studies shows that a lower starting dose should be recommended to lower the toxicity. Lenvatinib has been shown to have therapeutic effects on different solid tumors. Lenvatinib, in combination with pembrolizumab, showed results in studies that approved them for treatment for advanced endometrial carcinoma.   If an early identification of treatment-related adverse events is applied during the studies, this leads to an interruption and decreased dosage in time to reduce the serious adverse events. Food and Drug Administration approved Lenvatinib as the firsthand treatment for patients with non-operable hepatocellular carcinoma, and lenvatinib, in combination with pembrolizumab, is an approved indication for advanced endometrial cancer. The treatment should continue as long as there is a clinical benefit or until non-acceptable toxicity occurs.