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  • Berg, Patricia (Helsingin yliopisto, 2014)
    Throughout history, people have moved between places. One approach of studying the relationship between people and the environment they live within is called a phenomenology of landscape. According to this approach, all landscapes are embedded in the social and individual times of memory and there is a right way to move around in the familiar landscape. In this dissertation I present textual references to mobility and travelling in ancient Egyptian non-literary texts from Deir el-Medina. In other words, I examine in what ways the inhabitants of Deir el-Medina wrote about functionally-bound forms of individual movement. The purpose of this study is primarily to examine mobility as expressed in the written media, rather than the practical aspects of travelling. Deir el-Medina is situated on the West Bank of Thebes (modern Luxor). It was built to house the workmen that were employed by the state to build the royal tombs during the New Kingdom (ca. 1550 1069 BCE), and their families and servants. Due to the nature of the work at least some of the villagers were literate. They thus communicated to some extent in writing, and by doing this, produced a vast textual material of which a part has been preserved until today. Of the large number of non-literary texts originating from Deir el-Medina and its surroundings ca. 4,500 non-literary texts have been made available to scholars through publications. Among these, ca 320 texts include references to mobility and travelling and were incorporated in the corpus of this study. This dissertation is the first comprehensive study of mobility among the inhabitants of Deir el-Medina. Within the corpus, references to mobility and travelling are found in a large variety of text types dating from throughout the New Kingdom. A considerable number of various expressions were used when referring to mobility. However, especially in administrative texts, standardized expressions were also used. One might thus argue that the villagers not only moved in the right way within the familiar landscape, but also wrote about moving within their close environment in a standardized manner. Additionally, in administrative texts references to mobility were in general recorded at the beginning of the text. This would indicate that events related to mobility had a high importance ranking in the documentation system of the necropolis administration.
  • Hosia-Randell, Helka (Helsingin yliopisto, 2010)
    Prescribing for older patients is challenging. The prevalence of diseases increases with advancing age and causes extensive drug use. Impairments in cognitive, sensory, social and physical functioning, multimorbidity and comorbidities, as well as age-related changes in pharmacokinetics and pharmacodynamics all add to the complexity of prescribing. This study is a cross-sectional assessment of all long-term residents aged ≥ 65 years in all nursing homes in Helsinki, Finland. The residents’ health status was assessed and data on their demographic factors, health and medications were collected from their medical records in February 2003. This study assesses some essential issues in prescribing for older people: psychotropic drugs (Paper I), laxatives (Paper II), vitamin D and calcium supplements (Paper III), potentially inappropriate drugs for older adults (PIDs) and drug-drug interactions (DDIs)(Paper IV), as well as prescribing in public and private nursing homes. A resident was classified as a medication user if his or her medication record indicated a regular sequence for its dosage. Others were classified as non-users. Mini Nutritional Assessment (MNA) was used to assess residents’ nutritional status, Beers 2003 criteria to assess the use of PIDs, and the Swedish, Finnish, INteraction X-referencing database (SFINX) to evaluate their exposure to DDIs. Of all nursing home residents in Helsinki, 82% (n=1987) participated in studies I, II, and IV and 87% (n=2114) participated in the study III. The residents’ mean age was 84 years, 81% were female, and 70% were diagnosed with dementia. The mean number of drugs was 7.9 per resident; 40% of the residents used ≥ 9 drugs per day, and were thus exposed to polypharmacy. Eighty percent of the residents received psychotropics; 43% received antipsychotics, and 45% used antidepressants. Anxiolytics were prescribed to 26%, and hypnotics to 28% of the residents. Of those residents diagnosed with dementia, 11% received antidementia drugs. Fifty five percent of the residents used laxatives regularly. In multivariate analysis, those factors associated with regular laxative use were advanced age, immobility, poor nutritional status, chewing problems, Parkinson’s disease, and a high number of drugs. Eating snacks between meals was associated with lower risk for laxative use. Of all participants, 33% received vitamin D supplementation, 28% received calcium supplementation, and 20% received both vitamin D and calcium. The dosage of vitamin D was rather low: 21% received vitamin D 400 IU (10 µg) or more, and only 4% received 800 IU (20 µg) or more. In multivariate analysis, residents who received vitamin D supplementation enjoyed better nutritional status, ate snacks between meals, suffered no constipation, and received regular weight monitoring. Those residents receiving PIDs (34% of all residents) more often used psychotropic medication and were more often exposed to polypharmacy than residents receiving no PIDs. Residents receiving PIDs were less often diagnosed with dementia than were residents receiving no PIDs. The three most prevalent PIDs were short-acting benzodiazepine in greater dosages than recommended, hydroxyzine, and nitrofurantoin. These three drugs accounted for nearly 77% of all PID use. Of all residents, less than 5% were susceptible to a clinically significant DDI. The most common DDIs were related to the use of potassium-sparing diuretics, carbamazepine, and codeine. Residents exposed to potential DDIs were younger, had more often suffered a previous stroke, more often used psychotropics, and were more often exposed to PIDs and polypharmacy than were residents not exposed to DDIs. Residents in private nursing homes were less often exposed to polypharmacy than were residents in public nursing homes. Long-term residents in nursing homes in Helsinki use, on average, nearly eight drugs daily. The use of psychotropic drugs in our study was notably more common than in international studies. The prevalence of laxatives equaled other prior international studies. Regardless of the known benefit and recommendation of vitamin D supplementation for elderly residing mostly indoors, the proportion of nursing home residents receiving vitamin D and calcium was surprisingly low. The use of PIDs was common among nursing home residents. PIDs increased the likelihood of DDIs. However, DDIs did not seem a major concern among the nursing home population. Monitoring PIDs and potential drug interactions could improve the quality of prescribing.
  • Rautavirta, Kaija (Helsingin yliopisto, 2010)
    From bark bread to pizza - Food and exceptional circumstances: reactions of Finnish society to crises of food supply This study on the food supply under exceptional circumstances lies within the nutritional, historical and social sciences. The perspective and questions come under nutrition science, but are part of social decision-making. The study focuses on the first and second world wars as well as on contemporary society at the beginning of the 21st century. The main purpose of this study is to explore how Finnish society has responded to crises and what measures it has taken to sustain institutional food services and the food supply of households. The particular study interests include the school catering and food services in hospitals during the world wars. The situation in households is reflected in the counseling work carried out by state-run or civic organisations. Interest also focuses on the action of the scientific community. The decisions made in Finland are projected onto the solutions developed in some other European countries. The study is based primarily on the archive documents and annual reports prepared by food and health care authorities. Major source materials include scientific and professional publications. The evaluation of the situation in contemporary Finnish society is based on corresponding emergency plans and guidelines. The written material is supplemented by discussions with experts. Food rationing during the WWI and WWII differed in extent, details and unity. The food intake of some population groups was occasionally inadequate both in quantity, quality and safety. The counseling of the public focused on promoting self-sufficiency, improving cooking skills and widening food habits. One of the most vulnerable groups in regard to nutrition was long-term patients in institutions. As for future development, the world wars were never-theless important periods for public food services and counseling practices. WWII was also an important period for product development in the food industry. Significant work on food substitutes was carried out by Professor Carl Tigerstedt during WWI. The research of Professors A. I. Virtanen and Paavo Simola during WWII focused on vitamins. Crises threatening societies now differ from those faced a hundred years ago. Finland is bet-ter prepared, but in many ways more vulnerable to and dependent on other actors. Food rationing is a severe means of handling the scarcity of food, which is why contemporary society relies primarily on preparedness planning. Civic organisations played a key role during the world wars, and establishing an emergency food supply remains on their agenda. Although the objective of protecting the population remains the same for nutrition, food production, and food consumption, threat scenarios and the knowledge and skill levels of citizens are constantly changing. Continuous monitoring and evaluation is therefore needed.
  • Udd, Lina (Helsingin yliopisto, 2012)
    The Peutz-Jeghers Syndrome is a rare cancer predisposition condition, caused by mutations inactivating the LKB1 tumor suppressor kinase. This study aimed to further the understanding of this disease, provide potential means of treatment to Peutz-Jeghers patients, and to add to our understanding of cancer formation in general. These aims were pursued through exploring the molecular functions of the LKB1 kinase, studying the tumor formation upon loss of LKB1 function, and through intervening with this tumor formation process. The study was mainly performed in the Lkb1 knockout mouse or derived tissues and cells, but partly also with Peutz-Jeghers patients and patient materials. We found that the LKB1 kinase phosphorylates and thereby activates 13 kinases in the AMP-activated kinase family, any of which could putatively relay the tumor suppressor functions of LKB1. We also found that Cyclooxygenase-2 participates in tumorigenesis in Peutz-Jeghers syndrome by promoting the growth of gastric polyps, and that inhibitor treatment suppresses the polyp formation. We also observed that these Peutz-Jeghers polyps are less differentiated than previously thought, and that signs of poor differentiation can be seen in the gastric epithelium already prior to polyp formation. In addition, we found that the polyp formation process is likely to be enhanced by other genes in addition to LKB1 and Cycloxygenase-2, as alkylating mutagenesis increased polyp formation independently of the activity of the latter. Taken together, these results point to a wide array of molecules and processes interplaying in Peutz-Jeghers tumorigenesis beyond the LKB1 kinase. Both straight molecular targets of LKB1 activity, indirect mediators of LKB1-regulated tumorigenesis, and cooperating processes have been identified. One may expect that these findings will be of use for future studies both characterizing the Peutz-Jeghers syndrome and targeting treatments for this and related tumor diseases.
  • Pasanen, Marja (Helsingfors universitet, 2008)
    Wide interindividual and interethnic variability exists in the plasma concentrations of the cholesterol-lowering drugs HMG-CoA reductase inhibitors (statins) in their efficacy and risk of adverse effects. The risk of muscle toxicity as an adverse effect of statin therapy is known to increase along with elevated plasma statin concentrations. Organic anion-transporting polypeptide 1B1 (OATP1B1) is an uptake transporter located on the basolateral (sinusoidal) membrane of human hepatocytes, encoded by the gene SLCO1B1. OATP1B1 facilitates the hepatic uptake of many endogenous and foreign compounds, such as oestrogen conjugates, bile acids and statins. Taking into consideration the known interindividual and interethnic differences in the disposition of many OATP1B1 substrates, particularly statins, and its functional role in the pharmacokinetics of many drugs, it is important to characterize the diversity of the SLCO1B1 gene in various ethnic groups and to investigate the effects of SLCO1B1 polymorphism on statin disposition and response. The frequencies of SLCO1B1 sequence variations were studied in a population of 468 healthy Finnish volunteers and globally in various ethnic populations. DNA samples from the participants were genotyped for the presence of single nucleotide polymorphisms (SNPs) in SLCO1B1 and the results were analysed using population genetic methods. Secondly, the effects of SLCO1B1 genotypes on the pharmacokinetics and pharmacodynamics of fluvastatin, pravastatin, simvastatin, rosuvastatin and atorvastatin, and on cholesterol homeostasis, were studied in a prospective genotype panel study with 32 healthy volunteers. The subjects ingested a single dose of each investigated statin in five different phases. Blood samples were collected before statin administration and up to 48 hours thereafter to determine the concentrations of plasma statins, statin metabolites, cholesterol and noncholesterol sterols. Functionally significant variants in the SLCO1B1 gene were detected at varying frequencies in different populations. Genetic variation in SLCO1B1 was generally similar to that observed for other autosomal markers, although selective pressure may have acted on SLCO1B1, favouring low-activity variants in the north. The frequency of the low-activity c.521T>C variant allele was 24% (95% CI, 18–32%) in Native American populations, 20% (95% CI, 15–25%) in the Middle East, 18% (95% CI, 14–23%) in Europe, 12% (95% CI, 9.5–15%) in East Asia, 9.4% (95% CI, 6.9–13%) in Central/South Asia and 1.9% (95% CI, 0.7–4.8%) in Sub-Saharan Africa. No carriers of the c.521T>C SNP were found in Oceania. The frequency of the homozygous variant c.521CC genotype was around 2% in Caucasians and around 4% in the Finnish population. The greatest genetic diversity was seen in African populations and SLCO1B1 diversity was generally far greater within than between populations. The SLCO1B1 genotype significantly affected the pharmacokinetics of most of the statins investigated. The mean area under the plasma concentration-time curve (AUC) of simvastatin acid, atorvastatin, pravastatin and rosuvastatin was 3.2-, 2.4-, 1.9- and 1.7-fold, respectively, in subjects with the SLCO1B1 c.521CC variant genotype compared with subjects with the c.521TT control genotype (P < 0.05). The SLCO1B1 genotype had no significant effect on the plasma concentrations of fluvastatin. Despite the considerable effect on the pharmacokinetics of statins, the response to a single dose of any of the statins studied was not affected by the SLCO1B1 genotype. Interestingly, the SLCO1B1 variant genotype was associated with an increased baseline cholesterol synthesis rate, as indicated by a 40% higher desmosterol to cholesterol ratio in subjects with the c.521CC genotype than in those with the c.521TT genotype (P = 0.043). In agreement, there was a tendency toward higher plasma concentrations of absolute desmosterol and lathosterol, as well as lathosterol to cholesterol ratios, and lower plasma concentrations of cholesterol absorption markers in subjects with the variant genotype. In conclusion, the low-activity SLCO1B1 c.521T>C variant occurs at varying frequencies in different ethnic groups and is relatively common in non-African populations. Genetically impaired activity of the hepatic influx transporter OATP1B1, due to the presence of the c.521T>C SNP, leads to elevated plasma concentrations of many but not all statins, thus increasing the risk for muscle toxicity. The SLCO1B1 genotype may partially explain why individual patients respond differently to various statins and may help to identify subjects who are at higher risk of developing statin-induced myopathy.
  • Sistonen, Johanna (Helsingin yliopisto, 2008)
    Pharmacogenetics deals with genetically determined variation in drug response. In this context, three phase I drug-metabolizing enzymes, CYP2D6, CYP2C9, and CYP2C19, have a central role, affecting the metabolism of about 20-30% of clinically used drugs. Since genes coding for these enzymes in human populations exhibit high genetic polymorphism, they are of major pharmacogenetic importance. The aims of this study were to develop new genotyping methods for CYP2D6, CYP2C9, and CYP2C19 that would cover the most important genetic variants altering the enzyme activity, and, for the first time, to describe the distribution of genetic variation at these loci on global and microgeographic scales. In addition, pharmacogenetics was applied to a postmortem forensic setting to elucidate the role of genetic variation in drug intoxications, focusing mainly on cases related to tricyclic antidepressants, which are commonly involved in fatal drug poisonings in Finland. Genetic variability data were obtained by genotyping new population samples by the methods developed based on PCR and multiplex single-nucleotide primer extension reaction, as well as by collecting data from the literature. Data consisted of 138, 129, and 146 population samples for CYP2D6, CYP2C9, and CYP2C19, respectively. In addition, over 200 postmortem forensic cases were examined with respect to drug and metabolite concentrations and genotypic variation at CYP2D6 and CYP2C19. The distribution of genetic variation within and among human populations was analyzed by descriptive statistics and variance analysis and by correlating the genetic and geographic distances using Mantel tests and spatial autocorrelation. The correlation between phenotypic and genotypic variation in drug metabolism observed in postmortem cases was also analyzed statistically. The genotyping methods developed proved to be informative, technically feasible, and cost-effective. Detailed molecular analysis of CYP2D6 genetic variation in a global survey of human populations revealed that the pattern of variation was similar to those of neutral genomic markers. Most of the CYP2D6 diversity was observed within populations, and the spatial pattern of variation was best described as clinal. On the other hand, genetic variants of CYP2D6, CYP2C9, and CYP2C19 associated with altered enzymatic activity could reach extremely high frequencies in certain geographic regions. Pharmacogenetic variation may also be significantly affected by population-specific demographic histories, as seen within the Finnish population. When pharmacogenetics was applied to a postmortem forensic setting, a correlation between amitriptyline metabolic ratios and genetic variation at CYP2D6 and CYP2C19 was observed in the sample material, even in the presence of confounding factors typical for these cases. In addition, a case of doxepin-related fatal poisoning was shown to be associated with a genetic defect at CYP2D6. Each of the genes studied showed a distinct variation pattern in human populations and high frequencies of altered activity variants, which may reflect the neutral evolution and/or selective pressures caused by dietary or environmental exposure. The results are relevant also from the clinical point of view since the genetic variation at CYP2D6, CYP2C9, and CYP2C19 already has a range of clinical applications, e.g. in cancer treatment and oral anticoagulation therapy. This study revealed that pharmacogenetics may also contribute valuable information to the medicolegal investigation of sudden, unexpected deaths.
  • Kajosaari, Lauri (Helsingin yliopisto, 2006)
    Introduction Repaglinide is a short-acting drug, used to reduce postprandial hyperglycaemia in type 2 diabetic patients. Repaglinide is extensively metabolised, and its oral bioavailability is about 60%; its metabolites are mainly excreted into bile. In previous studies, the cytochrome P450 (CYP) 3A4 inhibitors itraconazole and clarithromycin have moderately increased the area under the concentration-time curve (AUC) of repaglinide. Gemfibrozil, a CYP2C8 inhibitor, has greatly increased repaglinide AUC, enhancing and prolonging its blood glucose-lowering effect. Rifampicin has decreased the AUC and effects of repaglinide. Aims The aims of this work were to investigate the contribution of CYP2C8 and CYP3A4 to the metabolism of repaglinide, and to study other potential drug interactions affecting the pharmacokinetics of repaglinide, and the mechanisms of observed interactions. Methods The metabolism of repaglinide was studied in vitro using recombinant human CYP enzymes and pooled human liver microsomes (HLM). The effect of trimethoprim, cyclosporine, bezafibrate, fenofibrate, gemfibrozil, and rifampicin on the metabolism of repaglinide, and the effect of fibrates and rifampicin on the activity of CYP2C8 and CYP3A4 were investigated in vitro. Randomised, placebo-controlled cross-over studies were carried out in healthy human volunteers to investigate the effect of bezafibrate, fenofibrate, trimethoprim, cyclosporine, telithromycin, montelukast and pioglitazone on the pharmacokinetics and pharmacodynamics of repaglinide. Pretreatment with clinically relevant doses of the study drug or placebo was followed by a single dose of repaglinide, after which blood and urine samples were collected to determine pharmacokinetic and pharmacodynamic parameters. Results In vitro, the contribution of CYP2C8 was similar to that of CYP3A4 in the metabolism of repaglinide (< 2 μM). Bezafibrate, fenofibrate, gemfibrozil, and rifampicin moderately inhibited CYP2C8 and repaglinide metabolism, but only rifampicin inhibited CYP3A4 in vitro. Bezafibrate, fenofibrate, montelukast, and pioglitazone had no effect on the pharmacokinetics and pharmacodynamics of repaglinide in vivo. The CYP2C8 inhibitor trimethoprim inhibited repaglinide metabolism by HLM in vitro and increased repaglinide AUC by 61% in vivo (P < .001). The CYP3A4 inhibitor telithromycin increased repaglinide AUC 1.8-fold (P < .001) and enhanced its blood glucose-lowering effect in vivo. Cyclosporine inhibited the CYP3A4-mediated (but not CYP2C8-mediated) metabolism of repaglinide in vitro and increased repaglinide AUC 2.4-fold in vivo (P < .001). The effect of cyclosporine on repaglinide AUC in vivo correlated with the SLCO1B1 (encoding organic anion transporting polypeptide 1, OATP1B1) genotype. Conclusions The relative contributions of CYP2C8 and CYP3A4 to the metabolism of repaglinide are similar in vitro, when therapeutic repaglinide concentrations are used. In vivo, repaglinide AUC was considerably increased by inhibition of both CYP2C8 (by trimethoprim) and CYP3A4 (by telithromycin). Cyclosporine raised repaglinide AUC even higher, probably by inhibiting the CYP3A4-mediated biotransformation and OATP1B1-mediated hepatic uptake of repaglinide. Bezafibrate, fenofibrate, montelukast, and pioglitazone had no effect on the pharmacokinetics of repaglinide, suggesting that they do not significantly inhibit CYP2C8 or CYP3A4 in vivo. Coadministration of drugs that inhibit CYP2C8, CYP3A4 or OATP1B1 may increase the plasma concentrations and blood glucose-lowering effect of repaglinide, requiring closer monitoring of blood glucose concentrations to avoid hypoglycaemia, and adjustment of repaglinide dosage as necessary.
  • Tapaninen, Tuija (Helsingin yliopisto, 2012)
    Aliskiren is an antihypertensive drug approved for clinical use in 2007. It acts by inhibiting renin, the first enzyme in the renin-angiotensin-aldosterone system. Marked interindividual variability exists in the pharmacokinetics of aliskiren. Interestingly, the pharmacokinetic properties of aliskiren suggest an important role for drug transporters in its pharmacokinetics. Aliskiren is poorly absorbed, and therefore, its oral bioavailability is only 2-3%. The elimination of aliskiren occurs mainly as an unchanged drug by biliary and renal excretion, and only a small proportion is metabolized by cytochrome P450 (CYP) 3A4. Organic anion-transporting polypeptide 2B1 (OATP2B1) influx transporter is thought to facilitate the intestinal absorption and hepatic uptake of aliskiren. Based on a more recent finding, OATP1A2 may also contribute to aliskiren absorption. Moreover, aliskiren is a substrate of P-glycoprotein (P-gp) efflux transporter, which can reduce the intestinal absorption of its substrates and enhance their elimination into bile, urine, and intestine. Furthermore, P-gp limits the passage of its substrates across many blood-tissue barriers such as the blood-brain barrier. In previous studies, cyclosporine (an inhibitor of P-gp, OATP2B1, and CYP3A4) as well as ketoconazole and atorvastatin (inhibitors of P-gp and CYP3A4) have raised the area under the plasma aliskiren concentration-time curve (AUC) 5-fold, 1.8-fold, and 1.5-fold, respectively. Considering the interindividual differences in aliskiren pharmacokinetics, information on related pharmacokinetic interactions and genetic variations may improve the safety of aliskiren therapy. This thesis comprises four randomized, placebo-controlled, cross-over pharmacokinetic interaction studies and two prospective genotype panel studies in healthy volunteers to assess the potential pharmacokinetic interactions and genetic variations affecting the pharmacokinetics and pharmacodynamics of aliskiren. The effects of induction and inhibition of P-gp and CYP3A4 were investigated by using rifampicin and itraconazole as a model inducer and inhibitor, respectively. Furthermore, the effects of grapefruit juice, orange juice, and apple juice, all of which have inhibited OATP1A2 and OATP2B1 in vitro, were also examined. Genetic variations of P-gp and OATP2B1 for the pharmacogenetic studies were selected on the basis of previous studies reporting their associations with altered plasma concentrations of the substrates of respective drug transporters, and on the basis of their frequencies in the Finnish population. Therefore, the effects of common haplotypes of the ABCB1 gene encoding P-gp, c.1236C-c.2677G-c.3435C and c.1236T-c.2677T-c.3435T, as well as the effects of c.935G>A single-nucleotide polymorphism (SNP) in the SLCO2B1 gene encoding OATP2B1 were evaluated. In all studies, aliskiren was administered as a single dose. Furthermore, in pharmacokinetic interaction studies, the potentially interacting substances were administered according to relevant dosing schemes. Blood and urine samples were collected for the determination of drug concentrations and plasma renin activity, in addition to which blood pressure was measured. Rifampicin, grapefruit juice, orange juice, and apple juice markedly reduced the plasma concentrations of aliskiren, and the reductions in the AUC values of aliskiren were 56%, 61%, 62%, and 63%, respectively (P < 0.001). In addition, the reduced exposure to aliskiren by rifampicin, orange juice, and apple juice led to the attenuation of the renin-inhibiting effect of aliskiren. During the rifampicin, orange juice, and apple juice phases plasma renin activity 24 hours after aliskiren ingestion was 61% (P = 0.008), 87% (P = 0.037), and 67% (P = 0.036) higher, respectively, than during the placebo or water phases. Itraconazole raised the AUC of aliskiren considerably, 6.5-fold (P < 0.001), and also enhanced the renin-inhibiting effect of aliskiren. Plasma renin activity 24 hours after aliskiren ingestion was 68% lower during the itraconazole phase, than during the placebo phase (P = 0.011). The ABCB1 c.1236C-c.2677G-c.3435C and c.1236T-c.2677T-c.3435T haplotypes and the SLCO2B1 c.935G>A SNP were not significantly associated with the pharmacokinetics or pharmacodynamics of aliskiren. In conclusion, aliskiren was found to be susceptible to transporter-mediated pharmacokinetic interactions of clinical significance. The interactions of rifampicin and itraconazole with aliskiren probably resulted from induction and inhibition of P-gp in the small intestine, respectively, with a minor contribution from a parallel effect on CYP3A4. Grapefruit, orange, and apple juices reduced the absorption of aliskiren from the gastrointestinal tract, possibly by inhibiting intestinal OATP transporters. The genetic variations of P-gp and OATP2B1 examined did not explain the large interindividual differences in aliskiren pharmacokinetics. Clinicians should be aware of the possibility that rifampicin may reduce the antihypertensive efficacy of aliskiren. Itraconazole can markedly raise the plasma concentrations of aliskiren and enhance its renin-inhibiting efficacy, and thus, should not be used with aliskiren. In addition, the inhibition of P-gp by itraconazole may alter the tissue distribution of aliskiren and potentially produce adverse reactions not observed with higher doses of aliskiren alone. Moreover, the concomitant use of aliskiren with grapefruit, orange, or apple juices is best avoided because of the risk of therapeutic failure due to reduced aliskiren exposure.
  • Raaska, Kari (Helsingin yliopisto, 2003)
  • Jaakkola, Tiina (Helsingin yliopisto, 2007)
    Pioglitazone is a thiazolidinedione compound used in the treatment of type 2 diabetes. It has been reported to be metabolised by multiple cytochrome P450 (CYP) enzymes, including CYP2C8, CYP2C9 and CYP3A4 in vitro. The aims of this work were to identify the CYP enzymes mainly responsible for the elimination of pioglitazone in order to evaluate its potential for in vivo drug interactions, and to investigate the effects of CYP2C8- and CYP3A4-inhibiting drugs (gemfibrozil, montelukast, zafirlukast and itraconazole) on the pharmacokinetics of pioglitazone in healthy volunteers. In addition, the effect of induction of CYP enzymes on the pharmacokinetics of pioglitazone in healthy volunteers was investigated, with rifampicin as a model inducer. Finally, the effect of pioglitazone on CYP2C8 and CYP3A enzyme activity was examined in healthy volunteers using repaglinide as a model substrate. Study I was conducted in vitro using pooled human liver microsomes (HLM) and human recombinant CYP isoforms. Studies II to V were randomised, placebo-controlled cross-over studies with 2-4 phases each. A total of 10-12 healthy volunteers participated in each study. Pretreatment with clinically relevant doses with the inhibitor or inducer was followed by a single dose of pioglitazone or repaglinide, whereafter blood and urine samples were collected for the determination of drug concentrations. In vitro, the elimination of pioglitazone (1 µM) by HLM was markedly inhibited, in particular by CYP2C8 inhibitors, but also by CYP3A4 inhibitors. Of the recombinant CYP isoforms, CYP2C8 metabolised pioglitazone markedly, and CYP3A4 also had a significant effect. All of the tested CYP2C8 inhibitors (montelukast, zafirlukast, trimethoprim and gemfibrozil) concentration-dependently inhibited pioglitazone metabolism in HLM. In humans, gemfibrozil raised the area under the plasma concentration-time curve (AUC) of pioglitazone 3.2-fold (P < 0.001) and prolonged its elimination half-life (t½) from 8.3 to 22.7 hours (P < 0.001), but had no significant effect on its peak concentration (Cmax) compared with placebo. Gemfibrozil also increased the excretion of pioglitazone into urine and reduced the ratios of the active metabolites M-IV and M-III to pioglitazone in plasma and urine. Itraconazole had no significant effect on the pharmacokinetics of pioglitazone and did not alter the effect of gemfibrozil on pioglitazone pharmacokinetics. Rifampicin decreased the AUC of pioglitazone by 54% (P < 0.001) and shortened its dominant t½ from 4.9 to 2.3 hours (P < 0.001). No significant effect on Cmax was observed. Rifampicin also decreased the AUC of the metabolites M-IV and M-III, shortened their t½ and increased the ratios of the metabolite to pioglitazone in plasma and urine. Montelukast and zafirlukast did not affect the pharmacokinetics of pioglitazone. The pharmacokinetics of repaglinide remained unaffected by pioglitazone. These studies demonstrate the principal role of CYP2C8 in the metabolism of pioglitazone in humans. Gemfibrozil, an inhibitor of CYP2C8, increases and rifampicin, an inducer of CYP2C8 and other CYP enzymes, decreases the plasma concentrations of pioglitazone, which can necessitate blood glucose monitoring and adjustment of pioglitazone dosage. Montelukast and zafirlukast had no effects on the pharmacokinetics of pioglitazone, indicating that their inhibitory effect on CYP2C8 is negligible in vivo. Pioglitazone did not increase the plasma concentrations of repaglinide, indicating that its inhibitory effect on CYP2C8 and CYP3A4 is very weak in vivo.
  • Koskinen, Mia (Helsingin yliopisto, 2006)
    Background. Hyperlipidemia is a common concern in patients with heterozygous familial hypercholesterolemia (HeFH) and in cardiac transplant recipients. In both groups, an elevated serum LDL cholesterol level accelerates the development of atherosclerotic vascular disease and increases the rates of cardiovascular morbidity and mortality. The purpose of this study is to assess the pharmacokinetics, efficacy, and safety of cholesterol-lowering pravastatin in children with HeFH and in pediatric cardiac transplant recipients receiving immunosuppressive medication. Patients and Methods. The pharmacokinetics of pravastatin was studied in 20 HeFH children and in 19 pediatric cardiac transplant recipients receiving triple immunosuppression. The patients ingested a single 10-mg dose of pravastatin, and plasma pravastatin concentrations were measured up to 10/24 hours. The efficacy and safety of pravastatin (maximum dose 10 to 60 mg/day and 10 mg/day) up to one to two years were studied in 30 patients with HeFH and in 19 cardiac transplant recipients, respectively. In a subgroup of 16 HeFH children, serum non-cholesterol sterol ratios (102 x mmol/mol of cholesterol), surrogate estimates of cholesterol absorption (cholestanol, campesterol, sitosterol), and synthesis (desmosterol and lathosterol) were studied at study baseline (on plant stanol esters) and during combination with pravastatin and plant stanol esters. In the transplant recipients, the lipoprotein levels and their mass compositions were analyzed before and after one year of pravastatin use, and then compared to values measured from 21 healthy pediatric controls. The transplant recipients were grouped into patients with transplant coronary artery disease (TxCAD) and patients without TxCAD, based on annual angiography evaluations before pravastatin. Results. In the cardiac transplant recipients, the mean area under the plasma concentration-time curve of pravastatin [AUC(0-10)], 264.1 * 192.4 ng.h/mL, was nearly ten-fold higher than in the HeFH children (26.6 * 17.0 ng.h/mL). By 2, 4, 6, 12 and 24 months of treatment, the LDL cholesterol levels in the HeFH children had respectively decreased by 25%, 26%, 29%, 33%, and 32%. In the HeFH group, pravastatin treatment increased the markers of cholesterol absorption and decreased those of synthesis. High ratios of cholestanol to cholesterol were associated with the poor cholesterol-lowering efficacy of pravastatin. In cardiac transplant recipients, pravastatin 10 mg/day lowered the LDL cholesterol by approximately 19%. Compared with the patients without TxCAD, patients with TxCAD had significantly lower HDL cholesterol concentrations and higher apoB-100/apoA-I ratios at baseline (1.0 ± 0.3 mmol/L vs. 1.4 ± 0.3 mmol/L, P = 0.031; and 0.7 ± 0.2 vs. 0.5 ± 0.1, P = 0.034) and after one year of pravastatin use (1.0 ± 0.3 mmol/L vs. 1.4 ± 0.3 mmol/L, P = 0.013; and 0.6 ± 0.2 vs. 0.4 ± 0.1, P = 0.005). Compared with healthy controls, the transplant recipients exhibited elevated serum triglycerides at baseline (median 1.3 [range 0.6-3.2] mmol/L vs. 0.7 [0.3-2.4] mmol/L, P=0.0002), which negatively correlated with their HDL cholesterol concentration (r = -0.523, P = 0.022). Recipients also exhibited higher apoB-100/apoA1 ratios (0.6 ± 0.2 vs. 0.4 ± 0.1, P = 0.005). In addition, elevated triglyceride levels were still observed after one year of pravastatin use (1.3 [0.5-3.5] mmol/L vs. 0.7 [0.3-2.4] mmol/L, P = 0.0004). Clinically significant elevations in alanine aminotransferase, creatine kinase, or creatinine ocurred in neither group. Conclusions. Immunosuppressive medication considerably increased the plasma pravastatin concentrations. In both patient groups, pravastatin treatment was moderately effective, safe, and well tolerated. In the HeFH group, high baseline cholesterol absorption seemed to predispose patients to insufficient cholesterol-lowering efficacy of pravastatin. In the cardiac transplant recipients, low HDL cholesterol and a high apoB-100/apoA-I ratio were associated with development of TxCAD. Even though pravastatin in the transplant recipients effectively lowered serum total and LDL cholesterol concentrations, it failed to normalize their elevated triglyceride levels and, in some patients, to prevent the progression of TxCAD.
  • Karonen, Tiina (Helsingin yliopisto, 2012)
    Leukotriene receptor antagonists montelukast and zafirlukast are used for asthma and allergic rhinitis. Their marketing authorisations were granted over 15 years ago, before regulatory guidance for drug interaction studies existed. At that time the knowledge of their metabolic pathways was largely based on in vitro studies, in which the main enzymes catalysing the biotransformation of montelukast and zafirlukast were cytochrome P450 (CYP) 2C9 and CYP3A4. Since then the understanding of the importance of CYP enzymes in drug metabolism has increased markedly and also the role of CYP2C8 has been recognised. Montelukast and zafirlukast are both potent inhibitors of CYP2C8 in vitro, but neither of them has shown inhibitory effect on CYP2C8 in vivo. Montelukast has also been shown to fit well in the active site cavity of CYP2C8 in a crystallography study. These observations led to examine the role of CYP2C8 and CYP3A4 in the metabolism of montelukast in humans, as well as the role of CYP2C8, CYP2C9 and CYP3A4 in the metabolism of zafirlukast in humans. This work was carried out as four randomised, placebo-controlled cross-over drug interaction studies in healthy volunteers. The CYP2C8 inhibitor gemfibrozil resulted in over fourfold increase of the area under the plasma drug concentration-time curve (AUC) of montelukast, almost blocking the formation of its major metabolite M4. The CYP3A4 inhibitor itraconazole had no effect on the total elimination of montelukast, and decreased only the formation of a minor metabolite M5. The pharmacokinetics of zafirlukast was only affected by CYP2C9 inhibition by fluconazole, which resulted in a 1.6-fold increase of the AUC of zafirlukast. Inhibition of CYP2C8 and CYP3A4 had no effect on the pharmacokinetics of zafirlukast. The results of this work elucidated the biotransformation pathways of montelukast and zafirlukast in humans. CYP2C8 accounts for about 80% of the metabolism of montelukast, while CYP3A4 has no significant role in it. The main enzyme in the metabolism of zafirlukast in humans is CYP2C9. Concomitant use of CYP2C8 inhibitors with montelukast, or CYP2C9 inhibitors with zafirlukast may increase the risk of concentration dependent adverse drug reactions. With regard to drug interaction studies, a probe drug should be sensitive and relatively safe: according to the present findings montelukast is a promising candidate for a CYP2C8 probe substrate. These results also highlight the relevance of drug interaction studies and the regulatory guidelines related to them. Especially drugs that have been developed before the existence of these guidelines may be deficiently characterised with regard to their metabolism, leaving the possibility of unrecognized CYP-mediated interactions.
  • Mustonen, Katja (Helsingin yliopisto, 2012)
    Ketoprofen is a non-steroidal anti-inflammatory drug belonging to the 2-arylpropionic acid group. It has been widely used in domestic animals because of its anti-inflammatory, antipyretic and analgesic actions. Ketoprofen is a chiral compound existing in two enantiomeric forms, S (+) and R (-) ketoprofen. Each enantiomer has different pharmacodynamic and pharmacokinetic properties. The commercial products in veterinary medicine are 50:50 racemic mixtures of both enantiomers. Ketoprofen undergoes unidirectional chiral inversion from the R- to the S-enantiomer, the extent of inversion being about 70% in pigs. The aims of this thesis research were to investigate the oral bioavailability, enantiospecific plasma concentrations and efficacy of racemic ketoprofen after oral administration in pigs. Total plasma concentrations of ketoprofen were investigated in a randomized crossover design. Racemic ketoprofen was administered at 3 mg/kg and 6 mg/kg po, and 3 mg/kg im and iv. The bioavailability of oral ketoprofen was almost complete. Bioequivalence could not be detected between oral and intramuscular administration routes. Plasma concentrations of S- and R-ketoprofen after oral (4 mg/kg) and intramuscular (3 mg/kg) routes of administration of racemic ketoprofen in pigs were determined in crossover design. S-ketoprofen was the predominant enantiomer in pig plasma after administration of the racemic mixture via both routes. The maximum plasma concentration of S-ketoprofen was more than twice as high as that of R-ketoprofen, and the terminal half-life was approximately three times greater for S-ketoprofen than R-ketoprofen with both administration routes. The mean (± SD) relative bioavailability (po compared to im) was 83 ± 20% and 63 ± 23% for S-ketoprofen and R-ketoprofen, respectively. Although some differences were detected in the plasma concentrations of ketoprofen enantiomers after different routes of administration, they are probably not relevant in clinical use. Thus, the pharmacological effects of racemic ketoprofen are considered to be comparable after intramuscular and oral routes of administration in growing pigs. The efficacy of orally administered racemic ketoprofen in endotoxemia in pigs was assessed in an E. coli endotoxin challenge trial. The growing pigs were challenged intravenously with E. coli endotoxin and one hour after the challenge were treated with ketoprofen at dose rates of 0.5 mg/kg, 1 mg/kg, 2 mg/kg and 4 mg/kg or with tap water. The body temperature was measured and a total clinical score was calculated after assessing the general behaviour, respiratory rate and locomotion of the pigs. Thromboxane B2 and ketoprofen concentrations were analysed from blood samples. Ketoprofen treatment significantly reduced the rectal temperature and total clinical scores, and lowered the blood thromboxane B2 concentrations when compared to the control group. Ketoprofen plasma concentrations were lower than previously reported in healthy pigs after similar doses. Two mg/kg can be considered a sufficient oral dose of ketoprofen for treating endotoxemia in pigs, as increasing the dose above this did not further increase the effect. Lameness is a common problem among sows and gilts. It often leads to poor animal welfare and economic losses because of unplanned culling. Locomotor disorders cause severe pain, and lame animals need to be treated accordingly. A field trial was conducted to examine the efficacy and compare two doses of oral administration of racemic ketoprofen in the treatment of clinical lameness caused by non-infectious musculoskeletal disorders in sows and gilts. Dose rates of 2 mg/kg and 4 mg/kg of oral ketoprofen were compared to placebo treatment over five consecutive days in a double-blinded study. Lameness was assessed with a five-grade scoring system prior to and on the last day of the treatment. This study demonstrated that oral ketoprofen was efficient in alleviating the signs of non-infectious lameness in sows and gilts. The rate of treatment success was 54.3% for the ketoprofen 4 mg/kg group, 53.2% for the ketoprofen 2 mg/kg group and 20.8% for the pigs in the placebo group. There was no difference in efficacy between the two ketoprofen doses. Oral ketoprofen appeared to be a practical way to alleviate pain and improve the welfare of lame sows. The findings support the use of ketoprofen at a dose rate of 2 mg/kg in treating locomotor disorders in pigs.
  • Webb, Christian (Helsingin yliopisto, 2013)
    The thesis is about random measures whose density with respect to the Lebesgue measure is the exponential of a Gaussian field with a short range logarithmic singularity in its covariance. Such measures are a special case of Gaussian multiplicative chaos. This type of measures arise in a variety of physical and mathematical models. In physics, they arise as the are measure of two-dimensional Liouville quantum gravity and Gibbs measures in certain simple disordered systems. From a mathematical point of view, they are related to extreme value statistics of random variables with logarithmic correlations and are interesting as such from the point of view of random geometry. Questions addressed in the thesis are how to properly define such measures and some geometric properties of these measures. Defining these measures is non-trivial since due to the singularity in the covariance, the field can only be interpreted as a random distribution and not as a random function. It turns out that after a suitable regularization of the field and normalization of the measure, a limiting procedure yields a non-trivial limit object. This normalization is a delicate procedure and at a certain value of the variance of the field, the behavior of this normalization changes drastically - a phase transition occurs. Once the measure is constructed, some simple geometric and probabilistic properties of these measures are considered. Relevant questions are for example: does the measure possess atoms, if not what is its modulus of continuity, what is the probability distribution of the measure of a set.
  • Kalliomäki, Anna (Helsingin yliopisto, 2003)