Sammanfattning Bakgrund Insjuknande i hjärtinfarkt har minskat kraftigt i Sverige de senaste åren men drabbar fortfarande många. Ateroskleros i hjärtats kranskärl är den viktigaste bakomliggande orsaken. Utvecklingen av ateroskleros sker under lång tid och processen är komplex men kan kopplas till inflammatoriska processer, apoB-innehållande lipoprotein och endoteldysfunktion. LDL bedöms av många forskare vara en kausal faktor vid aterosklersutvecklingen. Denna bedömning grundar sig på djurförsök, observationsstudier, resultat från kliniska prövningar med LDL-sänkande läkemedel samt mendelska randomiseringsstudier. Behandlingsrekommendationerna vid sekundärprevention av hjärtinfarktpatienter innefattar behandling med hög dos statin där vissa av rekommendationerna sätter upp ett mål på en LDL-sänking till nivåer under 1.8 mmol/l. Syfte Syftet med detta arbete var att undersöka vilka behandlingseffekter som finns vid läkemedelsbehandling som sänker LDL till låga nivåer vid sekundärprevention för hjärtinfarktpatienter och om de nuvarande behandlingsriktlinjerna på nivåer under 1.8 mmol/l kan anses rimliga. Vidare gjordes en ansats för att belysa frågan om huruvida LDL-sänkning eller pleiotropa effekter kan förklara effekten vid statinbehandling. Resultat Behandling med hög dos statin som sänker LDL till låga nivåer minskar risken för större kardiovaskulära/koronara händelser. Effekten beror främst på minskat antal hjärtinfarkter och revaskulariseringsprocedurer. Effekten på koronar/kardiovaskulär mortalitet förefaller emellertid vara i bästa fall liten. Samma mönster sågs i studier av PCSK9-hämmaren evolocumab och NPC1L1-hämmaren ezetimib. Då dessa läkemedel sänker LDL genom andra mekanismer än statiner indikerar detta att LDL-sänkning i sig har en effekt men pleiotropa effekter kan inte uteslutas. Slutsats Läkemedelsbehandling som sänker LDL till nivåer under 1.8 mmol/l förefaller ha effekt och därmed är det inte orimligt att ha ett sådant behandlingsmål. Det går emellertid inte att finna en optimal nivå för LDL-koncentrationen i plasma baserat på de studier som gjorts. NNT-talen blir relativt höga och en betydande residualrisk kvarstår även vid sänkning till låga LDL-nivåer vilket indikerar potentiell vikt av tidigare insatt LDL-sänkande behandling men även ett behov av nya behandlingsformer / Summary Background Despite substantial reductions in the incidence of myocardial infarction, the incidence remains high. Rupture of an atherosclerotic plaque within the coronary arteries is the most important direct causal factor. Atherosclerosis typically develops slowly and silently and can be described as a build-up of cholesterol-containing plaques within the artery wall. Theories of the causal mechanisms behind atherosclerosis point to a high degree of complexity. Most theories focus on an interaction between inflammatory processes, cholesterol-containing lipoproteins and dysfunction of the endothelial cells within the artery wall. Much focus has been put on the role of cholesterol-containing low-density lipoprotein (LDL). This lipoprotein seems to have a direct causal role in the process. Such a standpoint is based on animal experiments, observational studies, randomized clinical trials with LDL-lowering drugs and Mendelian randomization studies. Treatment guidelines for patients with myocardial infarction therefore recommend LDL-lowering therapy. These guidelines recommend treatment with a high dose statin and some include recommendations to lower LDL to levels below 1.8 mmol/l (69 mg/dl). Objective The aim of this thesis was to look at the treatment effects of lowering LDL to low levels for secondary prevention of myocardial infarction and whether the current recommendations of 1.8 mmol/l or less are reasonable. A second objective was to elucidate the question of whether statins have other, pleiotropic effects beside their LDL-lowering capacity. Searches were conducted in pubmed for randomized clinical statin-trials where low average LDL-levels were obtained. Further, a trial with PCSK9-inhibitor evolocumab and a trial with NPC1L1-inhibitor ezetimibe were included in order that the effects of these drugs could be compared with the effects of statins. Thereby, the question of statin-pleiotropy could be analyzed. Results Treating patients with a high dose statin to obtain lower levels of LDL reduced the risk of major coronary/cardiovascular events when compared with a low dose statin. The absolute risk reduction was however low. The effect was driven mainly by a reduction in the number of myocardial infarctions and coronary revascularization procedures whereas the effects on mortality seem absent or at best rather modest. The same pattern was seen in the FOURIER-trial where PSCK9-inhibitor evolocumab was compared with standard statin treatment. The active treatment group obtained an average LDL-level of 0.78 mmol/l (30 mg/dl). This pattern was also seen in the IMPROVE-IT-trial, where NPC1L1-inhibitor ezetimibe was compared with standard statin treatment. Conclusion Treatment to obtain low levels of LDL have an effect - even at levels below 1.8 mmol/l. LDL-lowering in and of itself seems to have an effect given the results from studies where patients were treated with evolocumab and ezetimibe. The number of patients that need to be treated to prevent one event is however high and a substantial number of patients remain at risk even at very low levels of LDL. This implies the need for other forms of therapy or initiation of LDL-lowering therapies at earlier stages for selected groups of patients before they experience a myocardial infarction

Different catalytic approaches have been applied to new -lactams preparations. olefin metathesis has been successfully performed with 3--methylidene--lactams. It was verified that 3--methylidene--lactams olefin metathesis is applicable to preparation of biologically active -lactam of Ezetimibe-type.

Background: Familial hypercholesterolemia (FH) is a genetic disorder estimated to affect 0,4 % of the world's population (1 in 250). Patients with FH have abnormally high LDL-cholesterol.  Aim: The aim of this study was to estimate the prevalence of FH in Stockholm County and to evaluate the health economic impact of diagnosing people with FH early in life. Methods: Two algorithms were used to estimate the number of people with high LDLcholesterol. The first method applied data on cholesterol measurements from patients in Stockholm County between 2006-2008 and a modified version of Dutch Lipid Clinic Network. The second method was based on dispensed prescriptions of ezetimibe, lomitapide, evolucumab and alirocumab during 2019. A health economic model was created to estimate the economical outcome of diagnosing and treating patients early before undergoing a cardiovascular event. Results: The prevalence of FH in Stockholm County was estimated to 0.63 %, corresponding to a total of 12 000 individuals. The accumulated costs over 20 years for FH is estimated to be more than 1,1 billion SEK for diagnosed and treated patients, and 1,7 billion SEK for undiagnosed and untreated patients. Conclusions: The prevalence of FH in Stockholm County is probably higher than previously suggested. Early diagnosis and treatment is an investment for society and necessary for the patients to prevent cardiovascular events and improve quality of life.

This diploma thesis deals with the use of organocatalysis in an asymmetric allylic substitution reaction of Morita-Baylis-Hillman carbonates by aniline derivatives leading to enantiomerically enriched allylic amines. The first part of the thesis is focused on optimizing the reaction conditions in the organocatalytic reaction with respect to the yields and enantiomeric excesses of the products. In the second part of the thesis prepared enantiomerically enriched allylic amines are used in the cyclization step to give β-lactame cycles that serve as the key intermediates in the total synthesis of Ezetimib as is demonstrated in the final part of the diploma thesis.