| 1. |
- Itkonen, Matti K., et al.
(author)
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Clopidogrel but Not Prasugrel Significantly Inhibits the CYP2C8-Mediated Metabolism of Montelukast in Humans
- 2018
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In: Clinical Pharmacology and Therapeutics. - : Wiley. - 0009-9236 .- 1532-6535. ; 104:3, s. 495-504
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Journal article (peer-reviewed)abstract
- The oxidation of montelukast is mainly mediated by cytochrome P450 (CYP) 2C8, but other mechanisms may contribute to its disposition. In healthy volunteers, we investigated the effects of two widely used P2Y(12) inhibitors on montelukast pharmacokinetics. Clopidogrel (300mg on day 1 and 75mg on day 2) increased the area under the plasma concentration-time curve (AUC) of montelukast 2.0-fold (90% confidence interval (CI) 1.72-2.28, P < 0.001) and decreased the M6:montelukast AUC(0-7h) ratio to 45% of control (90% CI 40-50%, P < 0.001). Prasugrel (60mg on day 1 and 10mg on day 2) had no clinically meaningful effect on montelukast pharmacokinetics. Our results imply that clopidogrel is at least a moderate inhibitor of CYP2C8, but prasugrel is not a clinically relevant CYP2C8 inhibitor. The different interaction potentials of clopidogrel and prasugrel are important to consider when antiplatelet therapy is planned for patients at risk for polypharmacy with CYP2C8 substrates.
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| 2. |
- Männistö, Ville, et al.
(author)
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Protein Phosphatase 1 Regulatory Subunit 3B Genotype at rs4240624 Has a Major Effect on Gallbladder Bile Composition
- 2021
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In: Hepatology Communications. - : Ovid Technologies (Wolters Kluwer Health). - 2471-254X. ; 5, s. 244-257
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Journal article (peer-reviewed)abstract
- The protein phosphatase 1 regulatory subunit 3B (PPP1R3B) gene is a target of farnesoid X receptor (FXR), which is a major regulator of bile acid metabolism. Both PPP1R3B and FXR have been suggested to take part in glycogen metabolism, which may explain the association of PPP1R3B gene variants with altered hepatic computed tomography attenuation. We analyzed the effect of PPP1R3B rs4240624 variant on bile acid composition in individuals with obesity. The study cohort consisted of 242 individuals from the Kuopio Obesity Surgery Study (73 men, 169 women, age 47.6±9.0years, body mass index 43.2±5.4kg/m2) with PPP1R3B genotype and liver RNA sequencing (RNA-seq) data available. Fasting plasma and gallbladder bile samples were collected from 50 individuals. Bile acids in plasma did not differ based on the PPP1R3B rs4240624 genotype. However, the concentration of total bile acids (109±55 vs. 35±19mM; P=1.0×10−5) and all individual bile acids (also 7α-hydroxy-4-cholesten-3-one [C4]) measured from bile were significantly lower in those with the AG genotype compared to those with the AA genotype. In addition, total cholesterol (P=0.011) and phospholipid (P=0.001) levels were lower in individuals with the AG genotype, but cholesterol saturation index did not differ, indicating that the decrease in cholesterol and phospholipid levels was secondary to the change in bile acids. Liver RNA-seq data demonstrated that expression of PPP1R3B, tankyrase (TNKS), Homo sapiens chromosome 8 clone RP11-10A14.5 (AC022784.1 [LOC157273]), Homo sapiens chromosome 8 clone RP11-375N15.1 (AC021242.1), and Homo sapiens chromosome 8, clone RP11-10A14 (AC022784.6) associated with the PPP1R3B genotype. In addition, genes enriched in transmembrane transport and phospholipid binding pathways were associated with the genotype. Conclusion: The rs4240624 variant in PPP1R3B has a major effect on the composition of gallbladder bile. Other transcripts in the same loci may be important mediators of the variant effect.
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| 3. |
- Nummela, Aleksi, et al.
(author)
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Circulating oxylipin and bile acid profiles of dexmedetomidine, propofol, sevoflurane, and S-ketamine : a randomised controlled trial using tandem mass spectrometry
- 2022
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In: BJA Open. - : Elsevier. - 2772-6096. ; 4
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Journal article (peer-reviewed)abstract
- BackgroundThis exploratory study aimed to investigate whether dexmedetomidine, propofol, sevoflurane, and S-ketamine affect oxylipins and bile acids, which are functionally diverse molecules with possible connections to cellular bioenergetics, immune modulation, and organ protection.MethodsIn this randomised, open-label, controlled, parallel group, Phase IV clinical drug trial, healthy male subjects (n=160) received equipotent doses (EC50 for verbal command) of dexmedetomidine (1.5 ng ml−1; n=40), propofol (1.7 μg ml−1; n=40), sevoflurane (0.9% end-tidal; n=40), S-ketamine (0.75 μg ml−1; n=20), or placebo (n=20). Blood samples for tandem mass spectrometry were obtained at baseline, after study drug administration at 60 and 130 min from baseline; 40 metabolites were analysed.ResultsStatistically significant changes vs placebo were observed in 62.5%, 12.5%, 5.0%, and 2.5% of analytes in dexmedetomidine, propofol, sevoflurane, and S-ketamine groups, respectively. Data are presented as standard deviation score, 95% confidence interval, and P-value. Dexmedetomidine induced wide-ranging decreases in oxylipins and bile acids. Amongst others, 9,10-dihydroxyoctadecenoic acid (DiHOME) –1.19 (–1.6; –0.78), P<0.001 and 12,13-DiHOME –1.22 (–1.66; –0.77), P<0.001 were affected. Propofol elevated 9,10-DiHOME 2.29 (1.62; 2.96), P<0.001 and 12,13-DiHOME 2.13 (1.42; 2.84), P<0.001. Analytes were mostly unaffected by S-ketamine. Sevoflurane decreased tauroursodeoxycholic acid (TUDCA) –2.7 (–3.84; –1.55), P=0.015.ConclusionsDexmedetomidine-induced oxylipin alterations may be connected to pathways associated with organ protection. In contrast to dexmedetomidine, propofol emulsion elevated DiHOMEs, oxylipins associated with acute respiratory distress syndrome, and mitochondrial dysfunction in high concentrations. Further research is needed to establish the behaviour of DIHOMEs during prolonged propofol/dexmedetomidine infusions and to verify the sevoflurane-induced reduction in TUDCA, a suggested neuroprotective agent.Clinical trial registrationNCT02624401.
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| 4. |
- Bjørnland, Kristin, et al.
(author)
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A Nordic multicenter survey of long-term bowel function after transanal endorectal pull-through in 200 patients with rectosigmoid Hirschsprung disease
- 2017
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In: Journal of Pediatric Surgery. - : Elsevier BV. - 1531-5037 .- 0022-3468. ; 52:9, s. 1458-1464
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Transanal endorectal pull-through (ERPT) is the most popular technique to treat Hirschsprung disease (HD). Still, there is limited knowledge on long-term bowel function. This cross-sectional, multicenter study assessed long-term bowel function in a large HD population and examined predictors of poor outcome.METHODS: Patients older than four years or their parents filled out a validated questionnaire on bowel function. Clinical details were recorded retrospectively from medical records.RESULTS: 73/200 (37%) patients reported absolutely no impaired bowel function, meaning no constipation, fecal accidents, stoma, appendicostomy or need for enemas. Seven (4%) had a stoma, and 33 (17%) used antegrade or rectal colonic enemas. Most disarrangements of fecal control and constipation were significantly less common in older age group, but abnormal defecation frequency and social problems remained unchanged. Syndromic patients (n=31) experienced frequent fecal accidents (46%) more often than nonsyndromic (14%, P<0.001). Having a syndrome (adjusted OR 5.6, 95% CI 2.1-15, P=0.001) or a complete transanal ERPT (adjusted OR 2.4, 95% CI 1.1-5.7, P=0.038) was significantly associated with poor outcome defined as having a stoma, an appendicostomy, daily fecal accidents or need of regular rectal wash outs.CONCLUSION: A significant number of HD patients experience bowel problems many years after definite surgery. Fecal control was significantly better in older than younger HD patients, but some continued to have considerable bowel problems also as adults. A total transanal ERPT was associated with poorer outcome. Long-term follow-up of HD patients is warranted. Prognosis Study: Level II.
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| 5. |
- Fanta, Samuel, et al.
(author)
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Pharmacogenetics of cyclosporine in children suggests an age-dependent influence of ABCB1 polymorphisms
- 2008
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In: Pharmacogenetics and genomics. - 1744-6872. ; 18:2, s. 77-90
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To evaluate whether variations in the ABCB1, ABCC2, SLCO1B1, CYP3A4, CYP3A5, or NR1I2 genes are associated with the pharmacokinetics of cyclosporine in pediatric renal transplant candidates, and whether the effects of these variants are related to age. METHODS: A total of 104 pediatric patients (aged 0.36-16.3 years) were genotyped for 17 putatively functionally significant sequence variations in the ABCB1, SLCO1B1, ABCC2, CYP3A4, CYP3A5, and NR1I2 genes. The patients had undergone a pharmacokinetic study with intravenous and oral ciclosporine (INN, cyclosporin) before renal transplantation. RESULTS: In the whole population, the mean+/-SD cyclosporine oral bioavailability was 0.38+/-0.09, volume of distribution was 2.3+/-0.54 l/kg, and systemic clearance normalized by allometric body weight was 0.88+/-0.16 l/h/kg3/4. The prehepatic extraction ratio was 0.51+/-0.13, and the hepatic extraction ratio was 0.24+/-0.04, the former explaining 95% of the variability in oral bioavailability (P<0.0001). In children older than 8 years, the pre-hepatic extraction was 0.64+/-0.09 in those with the ABCB1 c.2677GG genotype, 0.52+/-0.11 in those with the c.2677GT genotype, and 0.41+/-0.03 in those with the c.2677TT genotype (P=0.021, r2=0.334), leading to corresponding differences in oral bioavailability (0.28+/-0.07, 0.36+/-0.07, and 0.44+/-0.04, respectively; P=0.012, r2=0.372). Similar associations were observed with the ABCB1 c.1236C>T variant and the related haplotype c.1199G-c.1236C-c.2677G-c.3435C (P<0.05). The estimated oral dose requirement and clearance of cyclosporine remained largely unexplained by the genetic variations. CONCLUSIONS: Although these data suggest an age-related effect of ABCB1 polymorphism on oral bioavailability, further studies are required on the predictive value of genotyping for individualization of cyclosporine dosing in children.
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| 6. |
- Neuvonen, Aleksi, et al.
(author)
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Smart Retro: Novel Ways to Develop Cities : Baseline Report
- 2014
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Reports (other academic/artistic)abstract
- WHAT WILL your home and neighbourhood look like in twenty years? The radical development in smart solutions, the ageing of building stock, our need to radically cut our greenhouse gas emissions and many other strong drivers are changing the way we live, faster than ever before. That change is particularly significantin areas with older building stock – but it is not deterministic change. This is a baseline report for Smart Retro: a project exploring how we can rein in the strength of emerging trends – like digitalisation and the sharing economy – and use them to steer the development of our cities into a desirable direction.Many smart city projects focus on newly- built areas1. This makes the integration of new smart technologies into “dumb” walls, roads and buildings relatively easy. Unfortunately, the model of building entirely new stock doesn’t solve the challenges and needs of our existing cities: in 30 years, the majority of urban dwellers will most likely still live in neighbourhoods built in the 20th century.The starting point for Smart Retro is therefore existing building stock: smartness must be retrofitted into old buildings and previously constructed areas. The word Retro refers to buildings and areas that are ageing and in need of renovation at an accelerating pace. They require retrofitting with new solutions. These practices are introduced in the Retrofitting Projects section of this report. Smart refers to the inevitable digitalization and the new ways in which we can harness our distributed resources. This development has strong disruptive effects but also opens a plethora of new possibilities.The sustainable city is tomorrow’s necessity: greenhouse gas emissions must be cut by a large margin and resource efficiency needs to be radically improved. Sustainable urban services are an integral part of that advancement – these digital, local services provide new jobs and make our cities more livable. They improve our quality of life. A selection of companies at the frontline of these new service providers are presented in the SmartUps section. Many Nordic areas are dilapidating not only in terms of buildings but also in services and urban activity. That is whyit is important to look at the case studies in the Placemaking section, which demonstrates that the strongest urban vitality often derives from the engagement of locals, good services and suitable infrastructure.THE SMART RETRO PROJECT develops new service concepts with experts and end-users. The most promising services are proofed in real city environments. The project aims to create new services, valuable partnerships, and ultimately, a new model that – in the Nordic context – effectively combines the refurbishment of buildings with service development.This baseline report examines the current state and future prospects of our case areas in Lahti, Stockholm and Oslo, to gain knowledge of emerging practices in the domain of built environment. These examples do not unfortunately reveal how our homes will look in the future. But they do convince us of the radical changes awaiting our urban environment in the coming decades.
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