1.
Tour, Jeanette, et al.
(författare)
Gene-to-gene interactions regulate endogenous pain modulation in fibromyalgia patients and healthy controls-antagonistic effects between opioid and serotonin-related genes.
2017
Ingår i: Pain. - : Ovid Technologies (Wolters Kluwer Health). - 0304-3959 .- 1872-6623. ; 158:7, s. 1194-1203
Tidskriftsartikel (refereegranskat) abstract
Chronic pain is associated with dysfunctional endogenous pain modulation, involving both central opioid and serotonergic (5-HT) signaling. Fibromyalgia (FM) is a chronic pain syndrome, characterized by widespread musculoskeletal pain and reduced exercise-induced hypoalgesia (EIH). In this study, we assessed the effects of 3 functional genetic polymorphisms on EIH in 130 patients with FM and 132 healthy controls. Subjects were genotyped regarding the mu-opioid receptor (OPRM1) gene (rs1799971), the serotonin transporter (5-HTT) gene (5-HTTLPR/rs25531), and the serotonin-1a receptor (5-HT1a) gene (rs6296). The patients with FM had increased pain sensitivity and reduced EIH compared with healthy controls. None of the polymorphisms had an effect on EIH on their own. We found significant gene-to-gene interactions between OPRM1 x 5-HTT and OPRM1 x 5-HT1a regarding activation of EIH, with no statistically significant difference between groups. Better EIH was found in individuals with genetically inferred strong endogenous opioid signaling (OPRM1 G) in combination with weak 5-HT tone (5-HTT low/5-HT1a G), compared with strong 5-HT tone (5-HTT high/5-HT1a CC). Based on the proposed mechanisms of these genetic variants, the findings indicate antagonistic interactions between opioid and serotonergic mechanisms during EIH. Moreover, despite different baseline pain level, similar results were detected in FM and controls, not supporting an altered interaction between opioid and 5-HT mechanisms as the basis for dysfunction of EIH in patients with FM. In summary, our results suggest that, by genetic association, the mu-opioid receptor interacts with 2 major serotonergic structures involved in 5-HT reuptake and release, to modulate EIH.
2.
Webb, Dominic-Luc, et al.
(författare)
The type 2 CCK/gastrin receptor antagonist YF476 acutely prevents NSAID-induced gastric ulceration while increasing iNOS expression
2013
Ingår i: Naunyn-Schmiedeberg's Archives of Pharmacology. - : Springer Verlag (Germany). - 0028-1298 .- 1432-1912. ; 386:1, s. 41-49
Tidskriftsartikel (refereegranskat) abstract
YF476 differs from the proton pump inhibitor (PPI) esomeprazole in mode of action by antagonizing the type 2 receptor of cholecystokinin/gastrin (CCK-2R). YF476 protection against diclofenac-induced gastric ulcers was compared to esomeprazole and correlated with plasma levels of hormones related to gastric pH (gastrin, ghrelin, and somatostatin), gastric gene expression of these hormones, their receptors, and inducible nitric oxide synthase (iNOS). YF476 or esomeprazole pretreatments were followed by diclofenac. Four hours later, gastric tissue was excised and analyzed for ulcer index. An intragastrically implanted Bravo capsule measured pH for 5 days during YF476 plus pentagastrin treatment. Changes in gene expression were assayed for gastrin, ghrelin, and somatostatin; their receptors; and iNOS. YF476 acutely (within 4 h) protected against diclofenac-induced gastric ulcers equivalent to esomeprazole. Gastric pH recorded during 5 days in the presence of pentagastrin was 1.83 (+/- 0.06). YF476 raised pH to 3.67 (+/- 0.09) and plasma ghrelin, gastrin, and somatostatin increased. YF476 increased gene expression of somatostatin receptor and gastrin, while ghrelin receptor decreased; transcripts coding ghrelin, somatostatin, and CCK-2R remained unchanged. In the presence of diclofenac, esomeprazole increased expression of all these transcripts and that of iNOS, while YF476 yielded only decreased CCK-2R and increased iNOS transcripts. YF476 is a potential new preventative treatment for patients at risk of nonsteroidal antiinflammatory drug (NSAID)-induced ulceration. Gastric gene expressions of ghrelin, gastrin, and somatostatin and their receptors differ between esomeprazole and YF476. Despite these differences and different modes of action to raise gastric pH, both drugs acutely increase iNOS, suggesting iNOS expression parallels pH.
3.
Senek, Marina, et al.
(författare)
Levodopa/carbidopa microtablets in Parkinson's disease : a study of pharmacokinetics and blinded motor assessment
2017
Ingår i: European Journal of Clinical Pharmacology. - Heidelberg, Germany : Springer. - 0031-6970 .- 1432-1041 .- 0014-2999. ; 73:5, s. 563-571
Tidskriftsartikel (refereegranskat) abstract
Background: Motor function assessments with rating scales in relation to the pharmacokinetics of levodopa may increase the understanding of how to individualize and fine-tune treatments.Objectives: This study aimed to investigate the pharmacokinetic profiles of levodopa-carbidopa and the motor function following a single-dose microtablet administration in Parkinson’s disease.Methods: This was a single-center, open-label, single-dose study in 19 patients experiencing motor fluctuations. Patients received 150% of their individual levodopa equivalent morning dose in levodopa-carbidopa microtablets. Blood samples were collected at pre-specified time points. Patients were video recorded and motor function was assessed with six UPDRS part III motor items, dyskinesia score, and the treatment response scale (TRS), rated by three blinded movement disorder specialists.Results: AUC0–4/dose and Cmax/dose for levodopa was found to be higher in Parkinson’s disease patients compared with healthy subjects from a previous study, (p = 0.0008 and p = 0.026, respectively). The mean time to maximum improvement in sum of six UPDRS items score was 78 min (±59) (n = 16), and the mean time to TRS score maximum effect was 54 min (±51) (n = 15). Mean time to onset of dyskinesia was 41 min (±38) (n = 13).Conclusions: In the PD population, following levodopa/carbidopa microtablet administration in fasting state, the Cmax and AUC0–4/dose were found to be higher compared with results from a previous study in young, healthy subjects. A large between subject variability in response and duration of effect was observed, highlighting the importance of a continuous and individual assessment of motor function in order to optimize treatment effect.
4.
Thomas, Ilias, et al.
(författare)
Sensor-based algorithmic dosing suggestions for oral administration of levodopa/carbidopa microtablets for Parkinson's disease : a first experience
2019
Ingår i: Journal of Neurology. - : Springer Science and Business Media LLC. - 0340-5354 .- 1432-1459. ; 266:3, s. 651-658
Tidskriftsartikel (refereegranskat) abstract
OBJECTIVE: Dosing schedules for oral levodopa in advanced stages of Parkinson's disease (PD) require careful tailoring to fit the needs of each patient. This study proposes a dosing algorithm for oral administration of levodopa and evaluates its integration into a sensor-based dosing system (SBDS).MATERIALS AND METHODS: In collaboration with two movement disorder experts a knowledge-driven, simulation based algorithm was designed and integrated into a SBDS. The SBDS uses data from wearable sensors to fit individual patient models, which are then used as input to the dosing algorithm. To access the feasibility of using the SBDS in clinical practice its performance was evaluated during a clinical experiment where dosing optimization of oral levodopa was explored. The supervising neurologist made dosing adjustments based on data from the Parkinson's KinetiGraph™ (PKG) that the patients wore for a week in a free living setting. The dosing suggestions of the SBDS were compared with the PKG-guided adjustments.RESULTS: The SBDS maintenance and morning dosing suggestions had a Pearson's correlation of 0.80 and 0.95 (with mean relative errors of 21% and 12.5%), to the PKG-guided dosing adjustments. Paired t test indicated no statistical differences between the algorithmic suggestions and the clinician's adjustments.CONCLUSION: This study shows that it is possible to use algorithmic sensor-based dosing adjustments to optimize treatment with oral medication for PD patients.
5.
Walladbegi, Java, et al.
(författare)
Innovative intraoral cooling device better tolerated and equally effective as ice cooling.
2017
Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 80:5, s. 965-972
Tidskriftsartikel (refereegranskat) abstract
PURPOSE: Most of the patients who receive myeloablative therapy prior to stem cell transplantation develop oral mucositis (OM). This adverse reaction manifests as oral mucosal erythema and ulcerations and may require high doses of morphine for pain alleviation. OM may also interfere with food intake and result in weight loss, a need for parenteral nutrition, and impaired quality of life. To date, there have been very few studies of evidence-based interventions for the prevention of OM. Cryotherapy, using ice chips, has been shown to reduce in an efficient manner the severity and extent of OM, although clinical applications are still limited due to several shortcomings, such as adverse tooth sensations, problems with infectious organisms in the water, nausea, and uneven cooling of the oral mucosa. The present proof-of-concept study was conducted to compare the tolerability, temperature reduction, and cooling distribution profiles of an intra-oral cooling device and ice chips in healthy volunteers who did not receive myeloablative treatment, and therefore, did not experience the symptoms of OM.METHODS: Twenty healthy volunteers used the cooling device and ice chips for a maximum of 60 min each, using a cross-over design. The baseline and final temperatures were measured at eight intra-oral locations using an infra-red thermographic camera. The thermographic images were analysed using two digital software packages. A questionnaire was used to assess the tolerability levels of the two interventions.RESULTS: The intra-oral cooling device was significantly better tolerated than the ice-chips (p = 0.0118). The two interventions were equally effective regarding temperature reduction and cooling distribution.CONCLUSIONS: The intra-oral cooling device shows superior tolerability in healthy volunteers. Furthermore, this study shows that temperature reduction and cooling distribution are achieved equally well using either method.
6.
Andersson, Åsa C., et al.
(författare)
Manipulated Oral and Rectal Drugs in a Paediatric Swedish University Hospital, a Registry-Based Study Comparing Two Study-Years, Ten Years Apart
2023
Ingår i: Pharmaceuticals. - : MDPI. - 1424-8247. ; 16:1
Tidskriftsartikel (refereegranskat) abstract
This is a registry-based study with the aim of describing and comparing the frequency of manipulations of solid oral and rectal medicines in 2009 and 2019 at inpatient units and an emergency department in a paediatric hospital within a Swedish university hospital. All patients aged 1 month-18 years with oral or rectal administrations were included. In total, 140,791 oral and rectal administrations were included in 2009, and 167,945 oral and rectal administrations were included in 2019. The frequency of patients receiving at least one manipulated oral medicine decreased between the study years, both in inpatient units and in the emergency department (from 19% to 17%, p = 0.0029 and from 11% to 5%, p < 0.0001, respectively). The frequency of patients receiving a manipulated rectal medicine also decreased between the study years, both in inpatient units and in the emergency department (from 22% to 10%, p < 0.0001 and from 35% to 7% 2019, p < 0.0001, respectively). The results show a decrease in the manipulation of both oral and rectal medicines to paediatric patients in 2019 compared to 2009. Even though this implies a safer practice, there is still a pronounced lack of child-friendly dosage forms and suitable strengths enabling the safe administration of medicines to sick children.
7.
Ohlsson, Anna B., et al.
(författare)
UV-B Exposure of Indoor-Grown Picea abies Seedlings Causes an Epigenetic Effect and Selective Emission of Terpenes
2013
Ingår i: Zeitschrift für Naturforschung C - A Journal of Biosciences. - Tübingen : Verlag der Zeitschrift für Naturforschung. - 0939-5075 .- 1865-7125. ; 68:3-4, s. 139-147
Tidskriftsartikel (refereegranskat) abstract
Terpenoids are involved in various defensive functions in plants, especially conifers. Epigenetic mechanisms, for example DNA methylation, can influence plant defence systems. The purpose of the present study was to investigate the influence of UV-B exposure on the release of terpenoids from spruce seedlings and on needle DNA methylation. Ten-week-old seedlings grown indoors were exposed to UV-B radiation during 4 h, and the volatile compounds emitted from the seedlings were analysed. Analysis of the volatiles 1, 3, and 22 d after this UV-B exposure showed that bornyl acetate, borneol, myrcene, and limonene contents increased during the first 3 days, while at day 22 the level of emission had returned to the control level. UV-B exposure decreased the level of DNA methylation in needles of young seedlings, reflected in methylation changes in CCGG sequences. Exposure of young seedlings to UV-B radiation might be a way to potentiate the general defensive capacity, improving their ability to survive in outdoor conditions. UV-B-induced defence is discussed in the light of epigenetic mechanisms.
8.
Wändell, Per, et al.
(författare)
Association between antithrombotic treatment and hemorrhagic stroke in patients with atrial fibrillation—a cohort study in primary care
2017
Ingår i: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 73:2, s. 215-221
Tidskriftsartikel (refereegranskat) abstract
Objective: The objective of this study was to study the association between antithrombotic treatment and risk of hemorrhagic stroke (HS) in patients with atrial fibrillation (AF) treated in primary health care. Methods: Study population included all adults (n = 12,215) 45 years and older diagnosed with AF at 75 primary care centers in Sweden 2001–2007. Outcome was defined as a first hospital episode with a discharge episode of HS after the AF diagnosis. Association between HS and persistent treatment with antithrombotic agents (warfarin, acetylsalicylic acid (ASA), clopidogrel) was explored using Cox regression analysis, with hazard ratios (HRs) and 95 % CIs. Adjustment was made for age, socioeconomic status, and co-morbid cardiovascular conditions. Results: During a mean of 5.8 years (SD 2.4) of follow-up, 162 patients (1.3 %; 67 women and 95 men) with HS were recorded. The adjusted risk associated with persistent warfarin treatment compared to no antithrombotic treatment consistently showed no increased HS risk, HR for women 0.53 (95 % CI 0.23–1.27) and for men 0.55 (95 % CI 0.29–1.04); corresponding HRs for ASA were, for women, 0.45 (95 % CI 0.14–1.44) and, for men, 0.56 (95 % CI 0.24–1.29). Conclusions: In this clinical setting, we found no evidence pointing to an increased risk of HS with antithrombotic treatment.
