Akut hjärtsvikt definieras som en debut eller försämring av hjärtsvikt. Hjärtsvikt är ett allvarligt tillstånd där hjärtat inte upprätthåller adekvat hjärtminutvolym för att möta kroppens metaboliska behov vilket leder till trötthet och försämrad livskvalitet. Symtom som relaterar till systemisk vätskeansamling är vanliga vid akut hjärtsvikt. Vätskeansamling och hypoperfusion ökar morbiditet och mortalitet. Patienter med akut hjärtsvikt behöver således snabba och effektiva behandlingar, men också långtidsbehandling efter utskrivning. Avsvällande/vattendrivande behandling är hörnstenen i den terapeutiska behandlingen och loopdiuretika anses som det mest effektiva och snabbverkande läkemedlet. I dagsläget är empagliflozin ett rekommenderat läkemedel för behandling av kronisk hjärtsvikt med nedsatt ejektionsfraktion, då empagliflozins diuretiska egenskap kan stärka effekten av loopdiuretika.   Syftet med detta examensarbete var att beskriva effekter hos empagliflozin vid behandling av akut hjärtsvikt som en litteraturstudie. En sökning av randomiserade kliniska prövningar gjordes i PubMed där nio artiklar valdes ut för att ingå i detta examenarbete. Resultatet av de granskade artiklarna visade att empagliflozin som tilläggsbehandling till loopdiuretika ökade urinutsöndring hos patienterna. Resultatet visade också en statistiskt signifikant minskning av NT-proBNP i studierna vars behandlingstid var 5, 7, 15 och 30 dagar jämfört med placebo. Vidare minskade empagliflozin också plasmavolymen och mängden urinsyran i plasman. Två av studierna rapporterade en statistiskt signifikant ökning i andel röda blodkroppar i behandlingsgruppen. Insättning av empagliflozin, hos kliniskt stabila sjukhusvårdade patienterna i studien EMPULSE, gav en statistiskt signifikant klinisk nytta definierat som ett hierarkiskt kompositmått av död oavsett orsak, antal hjärtsviktsepisoder, tid till första hjärtsviktsepisod och klinisk meningsfull förbättring i KCCQ-TSS med vinstratio 1,36. Vidare gav empagliflozin en positiv effekt på viktminskning, ökad diuretisk respons, ödemlindring och ökad livskvalitet under 90 dagars behandling. Hos patienter som fick empagliflozin sänktes eGFR något till en början men återställdes senare. Det fanns dock inte någon statistiskt signifikant skillnad i eGFR mellan grupperna. En av studierna visade på en signifikant minskning av biomarkörer hos patienter som fick empagliflozin vilket gav en njurfunktionsskyddande effekt mot akut njurskada.  Slutsatsen var att empagliflozin gav gynnsamma effekter såsom till exempel avsvällande/vätskedrivande effekt och klinisk fördel hos patienter med såväl akut de novo som med dekompenserad kronisk hjärtsvikt vilket betydde att läkemedlet var både säkert och effektivt. I framtiden behöver effekterna dock styrkas genom ytterligare studier med större antal deltagare och under längre behandlingstid efter sjukhusutskrivning.

<p>Aqueous solubility is a key parameter influencing the bioavailability of drugs and drug candidates. In this thesis computational models for the prediction of aqueous drug solubility were explored. High quality experimental solubility data for drugs were generated using a standardised protocol and models were developed using multivariate data analysis tools and calculated molecular descriptors. In addition, structural features associated with either solid-state limited or solvation limited solubility of drugs were identified.</p><p>Solvation, as represented by the octanol-water partition coefficient (log<i>P</i>), was found to be the dominant factor limiting the solubility of drugs, with solid-state properties being the second most important limiting factor.</p><p>The relationship between the chemical structure of drugs and the strength of their crystal lattice was studied for a dataset displaying log<i>P</i>-independent solubility. Large, rigid and flat molecules with an extended ring-structure and a large number of conjugated π-bonds were found to be more likely to have their solubility limited by a strong crystal lattice than were small, spherically shaped molecules with flexible side-chains.</p><p>Finally, the relationship between chemical structure and drug solvation was studied using computer simulated values of the free energy of hydration. Drugs exhibiting poor hydration were found to be large and flexible, to have low polarisability and few hydrogen bond acceptors and donors.</p><p>The relationship between the structural features of drugs and their aqueous solubility discussed in this thesis provide new rules-of-thumb that could guide decision-making in early drug discovery.</p>

<p>The aim of this thesis was to identify some functionality related characteristics of pharmaceutically relevant solid materials and to study the effect of their variation on processing behaviour and product performance. For this purpose, particles with different characteristics were prepared under a variety of conditions by crystal agglomeration, wet granulation and spray drying. The effect of particle size distribution on the evolution of the tablet microstructure during and after compression was investigated. The compression behaviour of particles with different nominal strength and degrees of agglomeration was studied and the influence of the surfactant concentration of amorphous particles on the compression behaviour was examined. The response of the powders to compression was described with the help of various techniques characterising the microstructure and tensile strength of the tablets produced. </p><p>Furthermore, a method suitable for observing drug release from single matrix granules was developed and used to study the effect of granule porosity and compaction pressure on the drug release process. </p><p>The particle size distribution did not influence the evolution of the tablet porosity or the tensile strength during compression, but it could have an effect on the evolution of the tablet microstructure during short-term storage, depending on the instability mechanism. The compression behaviour of particles prepared by crystal agglomeration and wet granulation was dependent on their degree of agglomeration and their failure strength. For particles with similar solid state properties and compression behaviour, the surface energy appears to have an effect on the bonding strength of adsorption bonds acting at interparticulate junctions. Using the method developed to observe the drug release from single matrix granules, reproducible data was obtained enabling the drug release process to be characterised. Depending on the type of matrix and the compaction pressure, the drug release rate could be enhanced or retarded. </p>

Aqueous solubility is a key parameter influencing the bioavailability of drugs and drug candidates. In this thesis computational models for the prediction of aqueous drug solubility were explored. High quality experimental solubility data for drugs were generated using a standardised protocol and models were developed using multivariate data analysis tools and calculated molecular descriptors. In addition, structural features associated with either solid-state limited or solvation limited solubility of drugs were identified. Solvation, as represented by the octanol-water partition coefficient (logP), was found to be the dominant factor limiting the solubility of drugs, with solid-state properties being the second most important limiting factor. The relationship between the chemical structure of drugs and the strength of their crystal lattice was studied for a dataset displaying logP-independent solubility. Large, rigid and flat molecules with an extended ring-structure and a large number of conjugated π-bonds were found to be more likely to have their solubility limited by a strong crystal lattice than were small, spherically shaped molecules with flexible side-chains. Finally, the relationship between chemical structure and drug solvation was studied using computer simulated values of the free energy of hydration. Drugs exhibiting poor hydration were found to be large and flexible, to have low polarisability and few hydrogen bond acceptors and donors. The relationship between the structural features of drugs and their aqueous solubility discussed in this thesis provide new rules-of-thumb that could guide decision-making in early drug discovery.

The aim of this thesis was to identify some functionality related characteristics of pharmaceutically relevant solid materials and to study the effect of their variation on processing behaviour and product performance. For this purpose, particles with different characteristics were prepared under a variety of conditions by crystal agglomeration, wet granulation and spray drying. The effect of particle size distribution on the evolution of the tablet microstructure during and after compression was investigated. The compression behaviour of particles with different nominal strength and degrees of agglomeration was studied and the influence of the surfactant concentration of amorphous particles on the compression behaviour was examined. The response of the powders to compression was described with the help of various techniques characterising the microstructure and tensile strength of the tablets produced. Furthermore, a method suitable for observing drug release from single matrix granules was developed and used to study the effect of granule porosity and compaction pressure on the drug release process. The particle size distribution did not influence the evolution of the tablet porosity or the tensile strength during compression, but it could have an effect on the evolution of the tablet microstructure during short-term storage, depending on the instability mechanism. The compression behaviour of particles prepared by crystal agglomeration and wet granulation was dependent on their degree of agglomeration and their failure strength. For particles with similar solid state properties and compression behaviour, the surface energy appears to have an effect on the bonding strength of adsorption bonds acting at interparticulate junctions. Using the method developed to observe the drug release from single matrix granules, reproducible data was obtained enabling the drug release process to be characterised. Depending on the type of matrix and the compaction pressure, the drug release rate could be enhanced or retarded.

The general aim of this thesis was to improve the understanding of the in vivo pharmacokinetics and, in particular, the metabolism of finasteride, a 5α-reductase inhibitor used in the treatment of enlarged prostate glands and male pattern baldness. CYP3A4 has been identified as the major enzyme involved in the sequential metabolism of finasteride to ω-OH finasteride (M1) and ω-COOH finasteride (M3). The consequences of induced and inhibited metabolism on the pharmacokinetics of finasteride and its metabolites were investigated in humans and pigs. Both studies included bile collection. The collected human and pig samples were used for the metabolite identification. As expected, induced metabolism led to reduced plasma exposure of finasteride and inhibited metabolism had the opposite effect. The interactions were investigated in detail and included examination of the biliary pharmacokinetics of finasteride and its metabolites. In pigs, the study included monitoring of the hepatic extraction over time, deconvolution and the development of a semi-physiological model for comparison of the effects on the gut wall and liver metabolism. For M3, the concentration ratios of bile to plasma and the renal clearance indicated that carrier-mediated processes are involved in the biliary and urinary excretion. This was not, however, the case for finasteride. The metabolite, M1, could not be quantified either in humans or pigs. Instead, two other OH metabolites, M1 isomers, were identified in humans. These metabolites were found to undergo glucuronide conjugation. In humans, one glucuronide was identified intact and in pigs, both glucuronides were identified intact in bile and in urine. In addition, a glucuronide of M3 was identified in human bile. In conclusion, advances have been made in the understanding of the pharmacokinetics of finasteride, in particular in relation to the metabolism. Hopefully, the findings of this comprehensive investigation can be applied to other drugs and novel chemical entities.

Several sophisticated techniques to study in vivo GI transit and regional absorption of pharmaceuticals are available and increasingly used. Examples of such methods are Magnetic Marker Monitoring (MMM) and local drug administration with remotely operated capsules. Another approach is the paracetamol and sulfapyridine double marker method which utilizes observed plasma concentrations of the two substances as markers for GI transit. Common for all of these methods is that they generate multiple types of observations e.g. tablet GI position, drug release and plasma concentrations of one or more substances. This thesis is based on the hypothesis that application of mechanistic nonlinear mixed-effect models could facilitate a better understanding of the interrelationship between such variables and result improved predictions of the processes involved in oral absorption. Mechanistic modeling approaches have been developed for application to data from MMM studies, paracetamol and sulfapyridine double marker studies and for linking in vitro and in vivo drug release. Models for integrating information about tablet GI transit, in vivo drug release and drug plasma concentrations measured in MMM studies was outlined and utilized to describe drug release and absorption properties along the GI tract for felodipine and the investigational drug AZD0837. A mechanistic link between in vitro and in vivo drug release was established by estimation of the mechanical stress in different regions of the GI tract in a unit equivalent to rotation speed in the in vitro experimental setup. The effect of atropine and erythromycin on gastric emptying and small intestinal transit was characterized with a semi-mechanistic model applied to double marker studies in fed and fasting dogs. The work with modeling of in vivo drug absorption has highlighted the need for, and led to, further development of mixed-effect modeling methodology with respect to model diagnostics and the handling of censored observations.

Background: Medications are used to treat, cure, or relieve symptoms of diseases, but there is a risk with the use of medications. Drug-related-problems are known to increase morbidity and mortality. Incorrect medical list and discrepancies in these lists can lead to drug-related problems as side effects, hospitalization, non-compliance, drug interactions and overtreated or undertreated patients. Discrepancies can be for example: more prescriptions than necessary, outdated prescriptions, i.e., medicines that will not be used, prescriptions with incorrect dosing and missing prescriptions i.e., medicines used by patients that cannot be seen in the medication list. Purpose:  The aim of this study was to investigate discrepancies in the Swedish prescription list "My saved prescriptions at the pharmacy". The secondary aim was to investigate how common it is to use this prescription list or the dosage label on the medicine packaging to know which medicines to use and which dosage. Methods: The data collection was performed by four pharmacy students at seven pharmacies in Sweden over a period of three weeks during Jan-Feb. 2021 where the prescription list was investigated together with patients to identify any discrepancies. The study included patients who was over 18 years old, spoke Swedish, had three or more prescribed drugs, and agreed to participate.  Results A total of 215 patients were interviewed, where 61% had one or more discrepancies in their medication list. A total of 1717 prescriptions were analyzed, of which 10% were double prescriptions (n = 167), 8% outdated prescriptions (n = 141) and 3% prescriptions with the wrong dosage (n = 42). When analyzing the primary sources of information used by patients to know which medicine to use, the printout of the list "my saved prescriptions at the pharmacy” dominated (n = 72).  Most used information source to know drug dosage was the dosage label on the medicine packaging (n = 112). Conclusions: It is important to have an updated and correct information in the medication list, to prevent drug-related-problems caused by discrepancies. It becomes even more important when we see that the medication list "My saved prescriptions at the pharmacy" and dosage label (containing the same information in the medication list), are the most used primary sources by patients to know which drug to use and in what dosage. Finally, results show a relationship between the number of prescribed drugs and the number of discrepancies that occur, and therefore we see more discrepancies in elderly patients who are usually ill and are being treated for several diseases.  There are opportunities for further research to study e.g., which drug-related-problems are caused by discrepancies in the medication list as well as the degree of danger in these problems. / Användning av läkemedel som avses behandla, lindra eller bota sjukdomar kan i vissa fall utgöra en risk för patientens hälsa. Läkemedelsrelaterade problem p.g.a. felmedicinering står för en stor andel av morbiditeten och mortaliteten bland patienter. En bidragande orsak är ofullständig information i patientens läkemedelslista.   Syftet med studien var att undersöka antalet avvikelser som förekommer i receptlistan ”Mina sparade recept på apoteket”. Studiens sekundära syfte var att undersöka vilka informationskällor som användes av patienter för att veta vilka läkemedel som ska adminstreras och i vilken dos dosering.  Studiens metod var att intervjua patienter som kom till apoteket för att hämta ut läkemedel till sig själva och uppfyllde inklusionskriterierna för att delta i studien. Studien utfördes av fyra farmaceutstudenter på sju olika apotek i fyra olika städer i Sverige som tillsammans med patienter gick igenom receptlistan för att identifiera avvikelser.  Resultatet blev totalt 1717 recept som studerades varav 21% hade avvikelser. Av recepten var 10% dubbla recept (n = 167), 8% inaktuella recept (n = 141) och 3% recept med fel dosering (n = 42). Vid analys av primära informationskällor som används dominerade utskrift av listan ”Mina sparade recept på apoteket” (n = 72) resp. doseringsetiketten på läkemedelsförpackningen (n = 112).  Resultaten visade även ett samband mellan ökade antal läkemedel och antalet avvikelser.  Avvikelser i läkemedelslistan Mina sparade recept är vanligt förekommande därmed är listan inte alltid aktuell. Det är vanligt att denna lista och doseringsetikett på läkemedels-förpackningar används som primära källor av patienter under deras behandlingstid vilket kan innebära en risk för läkemedelsrelaterade problem. En gemensam nationell läkemedelslista är en möjlig lösning till att förebygga läkemedelsrelaterade problem orskade av infromationsbrist i läkemedelslistor. Det är dock nödvändigt med läkemedelsgenomgångar för att bibehålla uppdateringen av listan.

Background and Objective: Comorbidity and especially cardiovascular diseases are common among patients with chronic obstructive pulmonary disease (COPD). The primary purpose of this study was to identify drugs for the treatment of cardiovascular diseases in COPD patients. The secondary purpose was to analyze whether the use of cardiovascular drugs differs between patients with mild and severe COPD symptoms.     Method: The study was a retrospective cross-sectional study of 421 COPD patients whose drug lists were analyzed and cardiovascular drugs were identified. These drugs were then divided into eight drug groups, based on the drug's ATC (Anatomic Therapeutic Chemical classification system) codes. Only patients with reported cardiovascular diseases were included in the analysis. Patients with mild and severe COPD symptoms were identified. Thereafter, the patients were divided into two groups based on the COPD symptoms. Chi-squared test was performed to see if the use of cardiovascular drugs differs between patients with mild and severe COPD symptoms.  Setting: Primary and secondary care patients with COPD in Gävle and Dalarna.  Main outcome measures: Identify and analyze the use of cardiovascular drugs in COPD patients with mild and severe symptoms.  Results: The results of the survey showed that cardiovascular drugs were used by 274 (65%) of the COPD patients. Among them, 66 % with severe COPD symptoms and 34 % with mild symptoms. The use of the eight cardiovascular drug groups were similar between patients with mild and severe COPD symptoms. There wasn’t any statistically significant difference in the use of cardiovascular drugs between patients with mild and severe COPD symptoms (p= 0,893).   Conclusions: There wasn’t any difference in the use of cardiovascular drugs among patients with mild and severe COPD symptoms. However, this result needs to be substantiated with a follow-up study with a larger study population and longer study time to be generalizable.

Background: Pressurized metered dose inhalers (pMDI) use propellants for pulmonary drug delivery. The propellants used in pMDI:s are strong greenhouse gases. The Powder dose inhaler (PDI) doesn’t use any propellants and contributes less to the carbon footprint. Aim: The purpose of this project is to present data on inhaler use in the Uppsala County Council in Sweden. This project aims to answer questions regarding pressurized metered dose inhalers (pMDI) carbon footprint, how prescriptions of inhaler types with lower carbon footprint compare with pMDI and how the Uppsala County Council compares with other county councils in Sweden. Methods: This cross-sectional study uses prescription data for collected inhalers in Uppsala County Council and similar county councils in Sweden. Calculations of carbon footprint of the propellants in pMDI:s and for the lifecycle of pMDI and PDI. Results: The study showed that the climate load from the greenhouse gases norflurane and apaflurane in pMDIs are 981 477kg CO2e in Uppsala County Council year 2020. Of all the county councils studied, the county council with the highest percentage of pMDIs use was Stockholm County Council, the Uppsala County Council was close second.  Conclusion: Uppsala County Council might need to review if there is a way to lower the amount of pMDI prescriptions to reduce its carbon footprint deviating from the rest of County Councils in Sweden. This project ties into Uppsala County Council goal of reducing the climate impact of medical anesthesia greenhouse gases with 10% by 2022 from 2018.