| 1. |
- Albrechtsen, A., et al.
(författare)
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Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes
- 2013
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 56:2, s. 298-310
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Tidskriftsartikel (refereegranskat)abstract
- Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) > 1% with common metabolic phenotypes. The study comprised three stages. We performed medium-depth (8x) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI > 27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case-control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans. Exome sequencing identified 70,182 polymorphisms with MAF > 1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 x 10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 x 10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 x 10(-10)). We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.
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| 2. |
- Andersen, Mette, et al.
(författare)
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Type 2 diabetes susceptibility gene variants predispose to adult-onset autoimmune diabetes
- 2014
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 57:9, s. 1859-1868
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Latent autoimmune diabetes in adults (LADA) is phenotypically a hybrid of type 1 and type 2 diabetes. Genetically LADA is poorly characterised but does share genetic predisposition with type 1 diabetes. We aimed to improve the genetic characterisation of LADA and hypothesised that type 2 diabetes-associated gene variants also predispose to LADA, and that the associations would be strongest in LADA patients with low levels of GAD autoantibodies (GADA). Methods We assessed 41 type 2 diabetes-associated gene variants in Finnish (phase I) and Swedish (phase II) patients with LADA (n=911) or type 1 diabetes (n=406), all diagnosed after the age of 35 years, as well as in non-diabetic control individuals 40 years or older (n=4,002). Results Variants in the ZMIZ1 (rs12571751, p=4.1 x 10(-5)) and TCF7L2 (rs7903146, p=5.8 x 10(-4)) loci were strongly associated with LADA. Variants in the KCNQ1 (rs2237895, p=0.0012), HHEX (rs1111875, p=0.0024 in Finns) and MTNR1B (rs10830963, p=0.0039) loci showed the strongest association in patients with low GADA, supporting the hypothesis that the disease in these patients is more like type 2 diabetes. In contrast, variants in the KLHDC5 (rs10842994, p=9.5 x 10(-4) in Finns), TP53INP1 (rs896854, p=0.005), CDKAL1 (rs7756992, p=7.0 x 10(-4); rs7754840, p=8.8 x 10(-4)) and PROX1 (rs340874, p=0.003) loci showed the strongest association in patients with high GADA. For type 1 diabetes, a strong association was seen for MTNR1B (rs10830963, p=3.2 x 10(-6)) and HNF1A (rs2650000, p=0.0012). Conclusions/interpretation LADA and adult-onset type 1 diabetes share genetic risk variants with type 2 diabetes, supporting the idea of a hybrid form of diabetes and distinguishing them from patients with classical young-onset type 1 diabetes.
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| 3. |
- Andersson, Maria, et al.
(författare)
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Inhibition of kainic acid binding to glutamate receptors by extracts of Gastrodia
- 1995
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Ingår i: Phytochemistry. - 0031-9422. ; 38:4, s. 835-836
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Tidskriftsartikel (refereegranskat)abstract
- S-(4-hydroxybenzyl)glutathione was isolated as the major principle responsible for the inhibition of the in vitro binding of kainic acid to brain glutamate receptors by water extracts of the plant Gastrodia elata. The affinity (IC50 value) of the compound is slightly lower compared to glutamate and glutathione.
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| 4. |
- Andersson, Maria, et al.
(författare)
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Minor components with smooth muscle relaxing properties from scented myrrh (Commiphora guidotti)
- 1997
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Ingår i: Planta Medica. - : Georg Thieme Verlag KG. - 0032-0943 .- 1439-0221. ; 63:3, s. 251-254
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Tidskriftsartikel (refereegranskat)abstract
- All sesquiterpenes present in a sample of scented myrrh were isolated and characterised. Seven compounds, with cadinane, guaiane, oplopane, and eudesmane skeletons, were obtained, of which two are new and two are reported from a natural source for the first time. The major component, T-cadinol, has previously been shown to possess smooth muscle-relaxing properties, and the major purpose of the investigation was to compare the effects of the minor and more polar sesquiterpenes with that of T-cadinol in the rat aorta. Like T-cadinol, the minor sesquiterpenes are more efficient in reducing K(+)-induced contractions than those induced by the alpha-adrenoceptor agonist phenylephrine, however, they were all less potent than T-cadinol.
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| 5. |
- Berglund, Magnus, et al.
(författare)
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SAR studies of capsazepinoid bronchodilators 3: The thiourea part (coupling region) and the 2-(4-chlorophenyl)ethyl moiety (C-region).
- 2008
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896. ; 16:5, s. 2529-2540
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Tidskriftsartikel (refereegranskat)abstract
- Certain derivatives and analogues of capsazepine are potent in vitro inhibitors of bronchoconstriction in human small airways. During an investigation of the dependency of the potency on the structural features of the capsazepinoids in the thiourea moiety (coupling region) and the 2-(4-chlorophenyl)ethyl moiety (C-region), it was revealed that capsazepinoids with a thiourea or an amide link between the B-ring and the C-region in general have a good bronchorelaxing activity, while urea is a less attractive choice. Further, it was shown that 1,2,3,4-tetrahydroisoquinolines with a 2-(phenyl)ethyl derivative as the C-region are considerably more potent than those with an octyl group, while 2,3,4,5-tetrahydro-1H-2-benzazepines were found to be more insensitive to the nature of the C-region.
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| 6. |
- Berglund, Magnus, et al.
(författare)
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SAR studies of capsazepinoid bronchodilators. Part 2: Chlorination and catechol replacement in the A-ring.
- 2008
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896. ; 16:5, s. 2513-2528
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Tidskriftsartikel (refereegranskat)abstract
- Capsazepine as well as its derivatives and analogues are general inhibitors of constriction of human small airways. From a systematic variation of the capsazepine structure, divided into four regions, SARs were established. This paper concerns the chlorination of the A-ring as well as the replacement of the catechol with bioisosteric groups. It is revealed that chlorination of the A-ring has a profound effect on activity. Moreover, di-chlorination of the 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline structure results in a 10-fold increase in potency compared to capsazepine.
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| 7. |
- Dalence, Maria, et al.
(författare)
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SAR studies of capsazepinoid bronchodilators. Part 1: The importance of the catechol moiety and aspects of the B-ring structure.
- 2008
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896. ; 16:5, s. 2499-2512
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Tidskriftsartikel (refereegranskat)abstract
- Capsazepine as well as its derivatives and analogues are general inhibitors of constriction of human small airways. From a systematic variation of the capsazepine structure, divided into four regions, SARs were established. This part concerns the catechol moiety of the A-ring as well as the 2,3,4,5-tetrahydro-1H-2-azepine moiety (the B-ring) of capsazepine. It is revealed that a conformational constrain (as a fused ring) is important and that compounds with a six-membered B-ring (as a 1,2,3,4-tetrahydroisoquinoline) in general are more potent than the corresponding isoindoline, 2,3,4,5-tetrahydro-1H-2-benzazepine and 2,3,4,5-tetrahydro-1H-3-benzazepine derivatives.
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| 8. |
- Damon, Maria, 1977, et al.
(författare)
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Grandfathering: Environmental Uses and Impacts
- 2019
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Ingår i: Review of Environmental Economics and Policy. - : University of Chicago Press. - 1750-6824 .- 1750-6824 .- 1750-6816. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- “Grandfathering” grants preferential treatment to existing resource users over new entrants based on prior use. Grandfathering is based on the concept of first-in-time or prior appropriation and has been applied to a broad range of environmental and resource issues. We synthesize legal, economic, and political science perspectives and find that grandfathering removes incentives for users to anticipate regulations with proactive abatement. We analyze institutions ranging from long-enduring common-property regimes to climate negotiations to identify how grandfathering can be detrimental to sustainability, but we also show that it can be the only possible mechanism for bringing stakeholders to the table.
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| 9. |
- Damon, Maria, 1977, et al.
(författare)
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Policy Instruments for Sustainable Development at Rio +20
- 2012
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Ingår i: Journal of Environment and Development. - : SAGE Publications. - 1070-4965. ; 21:2, s. 143-151
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Tidskriftsartikel (refereegranskat)abstract
- Twenty years ago, governments gathered for the United Nations Conference on Environment and Development in Rio de Janeiro. The “Rio Declaration” laid out several principles of sustainable development, including the central role of policy instruments. In this article, we take stock of where we stand today in implementing sound and effective environmental policy instruments throughout the world, particularly in developing and transitional economies. We argue that, as our experience with market-based environmental policies has deepened over the past two decades, so has the ability to adapt instruments to complicated and heterogeneous contexts—but we are only just beginning, and the need to be further along is dire. One key factor may be that economists have not yet meaningfully accounted for the importance of political feasibility, which often hinges on risks to competitiveness and employment, or on the distribution of costs rather than on considerations of pure efficiency alone.
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| 10. |
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| 11. |
- Eklund, Annika, 1981-, et al.
(författare)
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The impact of transition programs on well-being, experiences of work environment and turnover intention among early career hospital nurses
- 2024
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Ingår i: Work. - 1051-9815 .- 1875-9270. ; , s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- Abstract: BACKGROUND: Transition programs for newly graduated nurses in hospital settings are reported to provide learning opportunities, strengthening confidence, workplace integration and skills, retention and job satisfaction. Still, our knowledge of long-term effects is scarce and few studies have used control groups. OBJECTIVE: To explore the long-term impact of having attended a transition program on the nurses’ experiences of the first years of practice. More specifically, ideology-infused psychological contract, ethical stress, perceived organizational support, job satisfaction, opportunities for learning, and intention to stay in the nursing profession, were explored as outcome variables. METHODS: A questionnaire survey was carried out among registered nurses from November 2019 to January 2020, with a 54% response rate. The analysis was based on 149 nurses who had attended a transition program, and 72 who had not attended. The nurses had seniority between one and three years. Independent samples t-test were used to investigate differences between the groups. RESULTS: The two groups showed small and non-significant differences in the outcome variables. However, regarding the frequency of ethical value conflicts induced by insufficient resources, as well as experiences of ethical value conflict distress, the group of nurses who had attended a transition program showed statistically significantly higher mean values, although the effect sizes were small. CONCLUSION: Newly graduated nurses need more than transition programs and skills training to progress in their nursing role and develop competence, increase job satisfaction, and reduce stress. Achieving these goals requires a long-term supportive learning environment that is integrated into everyday work.
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| 12. |
- Ferrannini, E., et al.
(författare)
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Mannose is an insulin-regulated metabolite reflecting whole-body insulin sensitivity in man
- 2020
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Ingår i: Metabolism: Clinical and Experimental. - : Elsevier BV. - 0026-0495. ; 102
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Tidskriftsartikel (refereegranskat)abstract
- Mannose is a glucose-associated serum metabolite mainly released by the liver. Recent studies have shown several unexpected pleiotropic effects of mannose including increased regulatory T cells (Tregs), prevention of auto-immune disease and ability to reduce growth of human cancer cells. We have previously shown in large cohorts that elevated serum mannose levels are associated with future development of type 2 diabetes (T2D) and cardiovascular disease. However, potential direct effects of mannose on insulin sensitivity in vivo or in vitro are unknown. We here show that administration of mannose (0.1 g/kg BW twice daily) for one week in man did not elicit negative effects on meal-modified glucose tolerance, markers of inflammation or insulin levels. Tregs number and insulin signaling in human liver cells were unchanged. These data suggest that mannose is a marker, and not a mediator, of insulin resistance. To verify this, we examined serum mannose levels during long-term euglycemic hyperinsulinemic clamps in non-diabetic and T2D individuals. Mannose was reduced by insulin infusion in proportion to whole-body insulin sensitivity. Thus, mannose is a biomarker of insulin resistance which may be useful for the early identification of diabetic individuals with insulin resistance and increased risk of its complications. © 2019 Elsevier Inc.
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| 13. |
- Kadfak, Alin, et al.
(författare)
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Dags att i grunden förändra vår relation till havet
- 2021
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Ingår i: Göteborgs-Posten. - 1103-9345. ; :8 jun 2021
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Tidskriftsartikel (populärvet., debatt m.m.)abstract
- Debatt: Med djup oro ser vi dramatiska förändringar med konsekvenser för både människor och djur. Nu behöver vi alla på ett fundamentalt sätt förändra vårt förhållande till havet. Det skriver 78 forskare, som i dag vill uppmärksamma Världshavsdagen och FN:s årtionde för havsforskning för hållbar utveckling.
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| 14. |
- Karlsson, Anders, et al.
(författare)
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The TRANSFOR success story: International forestry education through exchange
- 2010
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Ingår i: Forestry Chronicle. - : Canadian Institute of Forestry. - 0015-7546 .- 1499-9315. ; 86, s. 57-62
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Tidskriftsartikel (refereegranskat)abstract
- The TRANSFOR (Transatlantic Education for Global Sustainable Forest Sector Development) program has promoted international student and staff exchanges among four Canadian (Alberta, British Columbia, New Brunswick and Toronto) universities and universities in four European countries (Germany [Freiburg], Finland [Joensuu], Sweden [Swedish University of Agricultural Sciences, Umea] and the United Kingdom [Bangor University, Wales]). The program incorporated five components: one or two semester study visits for undergraduate forestry students, working internships, summer field courses, study visits for academic staff, and TRANSFOR project meetings. The summer field courses were a highly innovative part of the program and allowed students to spend three to four weeks learning about forestry activities and challenges on a continent different from that of their home institution. The program fostered internationally focused understanding of forest ecology and management, as well as economic and cultural factors, as will be required to develop effective international standards for sustainable forest management. Most student participants reported that it was a very positive experience and a high point of their education.
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| 15. |
- Lahermo, P, et al.
(författare)
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A quality assessment survey of SNP genotyping laboratories
- 2006
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 27:7, s. 711-714
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- To survey the quality of SNP genotyping, a joint Nordic quality assessment (QA) round was organized between 11 laboratories in the Nordic and Baltic countries. The QA round involved blinded genotyping of 47 DNA samples for 18 or six randomly selected SNPs. The methods used by the participating laboratories included all major platforms for small- to medium-size SNP genotyping. The laboratories used their standard procedures for SNP assay design, genotyping, and quality control. Based on the joint results from all laboratories, a consensus genotype for each DNA sample and SNP was determined by the coordinator of the survey, and the results from each laboratory were compared to this genotype. The overall genotyping accuracy achieved in the survey was excellent. Six laboratories delivered genotype data that were in full agreement with the consensus genotype. The average accuracy per SNP varied from 99.1 to 100% between the laboratories, and it was frequently 100% for the majority of the assays for which SNP genotypes were reported. Lessons from the survey are that special attention should be given to the quality of the DNA samples prior to genotyping, and that a conservative approach for calling the genotypes should be used to achieve a high accuracy.
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| 16. |
- Mahmutovic, Lejla, et al.
(författare)
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Association of IRS1 genetic variants with glucose control and insulin resistance in type 2 diabetic patients from Bosnia and Herzegovina
- 2019
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Ingår i: Drug Metabolism and Personalized Therapy. - : Walter de Gruyter GmbH. - 2363-8907 .- 2363-8915. ; 34:1
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies reported conflicting results regarding association of insulin receptor substrate 1 (IRS1) gene variation with type 2 diabetes (T2D) and insulin resistance (IR) in different ethnic groups. We examined the association of rs7578326, rs2943641, and rs4675095 in the IRS1 gene with T2D and related traits in a population from Bosnia and Herzegovina, which is one of the European countries with the highest T2D prevalence of 12.5%. Our study included 390 T2D patients and 252 control subjects. Biochemical parameters, including fasting glucose (FG), fasting insulin (FI), homeostasis model assessment insulin resistance index (HOMA-IR), and HbA 1c were measured in all participants. Genotyping analysis was performed by Mass Array Sequenom iPlex platform. Our results demonstrated that rs7578326 and rs4675095 variants were associated with increased FG levels. The rs7578326 was also associated with higher FI, HOMA-IR (B = 0.08, 95% CI [0.01, 0.15], p add = 0.025; B = 0.079, 95% CI [0.006, 0.150], p add = 0.033, respectively) in T2D, and with HbA 1c (B = 0.034, 95% CI [0.003, 0.065], p dom = 0.035) in non-drug-treated T2D. In contrast, rs2943641 C allele was associated with lower FG levels in control subjects (B = -0.17, 95% CI [-0.03, -0.002], p add = 0.030) and HbA 1c (B = 0.03, 95% CI [0.002, 0.06], p dom = 0.040) in non-drug-treated T2D. We report the association between common variants in IRS1 gene with insulin resistance, glucose, and HbA 1c levels in Bosnia and Herzegovina's population.
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| 17. |
- Martin, Maria A., et al.
(författare)
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Ten new insights in climate science 2021 : a horizon scan
- 2021
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Ingår i: Global Sustainability. - : Cambridge University Press (CUP). - 2059-4798. ; 4, s. 1-20
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Forskningsöversikt (refereegranskat)abstract
- Non-technical summary: We summarize some of the past year's most important findings within climate change-related research. New research has improved our understanding about the remaining options to achieve the Paris Agreement goals, through overcoming political barriers to carbon pricing, taking into account non-CO2 factors, a well-designed implementation of demand-side and nature-based solutions, resilience building of ecosystems and the recognition that climate change mitigation costs can be justified by benefits to the health of humans and nature alone. We consider new insights about what to expect if we fail to include a new dimension of fire extremes and the prospect of cascading climate tipping elements.Technical summary: A synthesis is made of 10 topics within climate research, where there have been significant advances since January 2020. The insights are based on input from an international open call with broad disciplinary scope. Findings include: (1) the options to still keep global warming below 1.5 °C; (2) the impact of non-CO2 factors in global warming; (3) a new dimension of fire extremes forced by climate change; (4) the increasing pressure on interconnected climate tipping elements; (5) the dimensions of climate justice; (6) political challenges impeding the effectiveness of carbon pricing; (7) demand-side solutions as vehicles of climate mitigation; (8) the potentials and caveats of nature-based solutions; (9) how building resilience of marine ecosystems is possible; and (10) that the costs of climate change mitigation policies can be more than justified by the benefits to the health of humans and nature.Social media summary: How do we limit global warming to 1.5 °C and why is it crucial? See highlights of latest climate science.
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| 18. |
- Nyman, Ulf, et al.
(författare)
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Revised Swedish guidelines on intravenous iodine contrast medium-induced acute kidney injury 2022: A summary
- 2023
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Ingår i: Acta Radiologica. - : SAGE Publications. - 0284-1851 .- 1600-0455. ; 64:5
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Forskningsöversikt (refereegranskat)abstract
- The Swedish Society of Uroradiology has revised their computed tomography (CT) guidelines regarding iodine contrast media-induced acute kidney injury (CI-AKI). They are more cautious compared to the European Society of Urogenital Radiology and the American College of Radiology since the actual risk of CI-AKI remains uncertain in patients with moderate to severe kidney damage due to a lack of prospective controlled studies and mainly based on retrospective propensity score-matched studies with low-grade evidence. Another source of uncertainty is the imprecision of glomerular filtration rate (GFR) estimating equations. However, randomized hydration studies indictae an upper limit risk of CI-AKI of about 5% for outpatients with a GFR in the range of 30-44 or 45-59 mL/min/1.73m(2) combined with multiple risk factors. Apart from GFR limits, the guideline also includes limits for systemic contrast medium exposure expressed in gram-iodine/GFR ratio.
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| 19. |
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| 20. |
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| 21. |
- Rydberg Sterner, Therese, et al.
(författare)
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The Gothenburg H70 Birth cohort study 2014-16: design, methods and study population.
- 2019
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Ingår i: European journal of epidemiology. - : Springer Science and Business Media LLC. - 1573-7284 .- 0393-2990. ; 34:2, s. 191-209
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Tidskriftsartikel (refereegranskat)abstract
- To improve health care for older persons, we need to learn more about ageing, e.g. identify protective factors and early markers for diseases. The Gothenburg H70 Birth Cohort Studies (the H70 studies) are multidisciplinary epidemiological studies examining representative birth cohorts of older populations in Gothenburg, Sweden. So far, six birth cohorts of 70-year-olds have been examined over time, and examinations have been virtually identical between studies. This paper describes the study procedures for the baseline examination of the Birth cohort 1944, conducted in 2014-16. In this study, all men and women born 1944 on specific dates, and registered as residents in Gothenburg, were eligible for participation (n=1839). A total of 1203 (response rate 72.2%; 559 men and 644 women; mean age 70.5years) agreed to participate in the study. The study comprised sampling of blood and cerebrospinal fluid, psychiatric, cognitive, and physical health examinations, examinations of genetics and family history, use of medications, social factors, functional ability and disability, physical fitness and activity, body composition, lung function, audiological and ophthalmological examinations, diet, brain imaging, as well as a close informant interview, and qualitative studies. As in previous examinations, data collection serves as a basis for future longitudinal follow-up examinations. The research gained from the H70 studies has clinical relevance in relation to prevention, early diagnosis, clinical course, experience of illness, understanding pathogenesis and prognosis. Results will increase our understanding of ageing and inform service development, which may lead to enhanced quality of care for older persons.
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| 22. |
- Saxena, Richa, et al.
(författare)
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Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels
- 2007
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 316:5829, s. 1331-1336
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Tidskriftsartikel (refereegranskat)abstract
- New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single-nucleotide polymorphisms (SNPs) in 1464 patients with T2D and 1467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D), we identified and confirmed three loci associated with T2D - in a noncoding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1 - and replicated associations near HHEX and in SLC30A8 found by a recent whole-genome association study. We identified and confirmed association of a SNP in an intron of glucokinase regulatory protein (GCKR) with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases.
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| 23. |
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| 24. |
- Skogvall, Staffan, et al.
(författare)
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Discovery of a potent and long-acting bronchorelaxing capsazepinoid, RESPIR 4-95
- 2008
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Ingår i: Pulmonary Pharmacology & Therapeutics. - : Elsevier BV. - 1522-9629 .- 1094-5539. ; 21:1, s. 125-133
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Current drugs including beta-agonists have limited smooth muscle relaxant effects on human small airways. Yet this is a major site of obstruction in asthma and chronic obstructive pulmonary disease (COPD). OBJECTIVE: This study explores human small airway relaxant effects of RESPIR 4-95, a novel chemical analogue (capsazepinoid) to capsazepine. Capsazepine was recently shown to relax small airways in a way which was independent of its TRPV(1) antagonism and independent of current bronchodilator drug mechanisms. METHOD: In vitro preparations of human small airways, 0.5-1.5mm in diameter and responding with reproducible contractions to leukotriene D(4) (LTD(4)) for 12h, were used. RESULTS: RESPIR 4-95 reversibly prevented LTD(4)-induced contractions as well as relaxed the established tonic contraction by LTD(4). RESPIR 4-95 exhibited marked improvements over the reference capsazepinoid, capsazepine, by being 10 times more potent, exhibiting twice as long duration of action after wash-out (9h), and inhibiting equally well LTD(4)-, histamine-, prostaglandin D(2) (PGD(2))-, and acetylcholine (ACh)-induced contractions. RESPIR 4-95 was distinguished from l-type calcium channel antagonist nifedipine by its greater efficacy and potency and by exhibiting increased relaxant effect by repeated exposures. Furthermore, RESPIR 4-95 was more efficacious and longer acting than the long-acting beta-agonist formoterol. CONCLUSION: Efficacy, potency, duration of action, and inexhaustibility of its relaxation of human small airways make RESPIR 4-95 an interesting lead compound for further developments aiming at drug treatment of small airway obstruction in asthma and COPD. Further work is warranted to unveil the molecular biology behind its relaxant actions.
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| 25. |
- Skogvall, Staffan, et al.
(författare)
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Effects of capsazepine on human small airway responsiveness unravel a novel class of bronchorelaxants.
- 2007
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Ingår i: Pulmonary Pharmacology & Therapeutics. - : Elsevier BV. - 1522-9629 .- 1094-5539. ; 20, s. 273-280
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Tidskriftsartikel (refereegranskat)abstract
- Capsazepine is known as a transient receptor potential channel vanilloid subfamily 1 (TRPV1) antagonist that inhibits bronchoconstriction evoked in animals by TRPV1 agonists. In this study, effects of capsazepine and chemically related analogues, so called capsazepinoids, were examined in vitro on contractile effects in human small airway preparations. Repeated cycles with 1 h of LTD4-free physiological saline solution followed by 30 min exposure to LTD4 (10 nM) demonstrated that the contractile responsiveness of the preparations exhibited little change over time despite repeated challenges (> 12 h). Capsazepine (1-100 mu M) reversibly and concentration-dependently inhibited the contractile response to LTD4 with EC50 similar to 10 mu M and similar to 90% relaxation at 100 mu M. Capsazepine (10 M) was approximately equally effective to attenuate the contractions evoked by several different inflammatory contractile agonists (LTD4, PGD(2), histamine), and it relaxed preparations with established tonic contraction due to LTD4. Higher concentrations of capsazepine were needed to relax ACh-contractions. The effect of capsazepine on LTD4-induced contractions was not significantly reduced by pre-treating the preparations with either of propranotol (10 mu M) + atropine (1 mu M), L-NAME (1 mM), indomethacin (1 mu M), iberiotoxin (0.1 mu M), capsaicin (10 mu M), and nifedipine (10 mu M). Although the mechanism of action of the present capsazepine-induced bronchorelaxation remains unknown it emerged here that they represent a generally effective principle exerting a functional antagonism against contractile mediators but distinct from beta receptor agonists and inhibitors of L-type calcium channels. The inhibitory effect of capsazepine is shared by chemical analogues, but not with other TRPV1 antagonists, suggesting the possibility that capsazepine represents a novel class of bronchorelaxants effective in human small airways. These findings were not predicted by previous observations that have concerned quite limited effects of capsazepine on airway tone in different animal test systems. If potency can be further increased and the results translated to in vivo, compounds representing the capsazepinoid class of bronchorelaxants might become useful in the treatment of patients suffering from asthma and COPD.
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