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| 2. |
- Svensson, Elin, 1985-, et al.
(författare)
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Evidence-Based Design of Fixed-Dose Combinations : Principles and Application to Pediatric Anti-Tuberculosis Therapy
- 2018
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Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 57:5, s. 591-599
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVES: Fixed-dose combination formulations where several drugs are included in one tablet are important for the implementation of many long-term multidrug therapies. The selection of optimal dose ratios and tablet content of a fixed-dose combination and the design of individualized dosing regimens is a complex task, requiring multiple simultaneous considerations.METHODS: In this work, a methodology for the rational design of a fixed-dose combination was developed and applied to the case of a three-drug pediatric anti-tuberculosis formulation individualized on body weight. The optimization methodology synthesizes information about the intended use population, the pharmacokinetic properties of the drugs, therapeutic targets, and practical constraints. A utility function is included to penalize deviations from the targets; a sequential estimation procedure was developed for stable estimation of break-points for individualized dosing. The suggested optimized pediatric anti-tuberculosis fixed-dose combination was compared with the recently launched World Health Organization-endorsed formulation.RESULTS: The optimized fixed-dose combination included 15, 36, and 16% higher amounts of rifampicin, isoniazid, and pyrazinamide, respectively. The optimized fixed-dose combination is expected to result in overall less deviation from the therapeutic targets based on adult exposure and substantially fewer children with underexposure (below half the target).CONCLUSION: The development of this design tool can aid the implementation of evidence-based formulations, integrating available knowledge and practical considerations, to optimize drug exposures and thereby treatment outcomes.
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| 3. |
- Hebert-Losier, Kim, 1985-, et al.
(författare)
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Factors that Influence the Performance of Elite Sprint Cross-Country Skiers
- 2017
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Ingår i: Sports Medicine. - : Springer Science and Business Media LLC. - 0112-1642 .- 1179-2035. ; 47:2, s. 319-342
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sprint events in cross-country skiing are unique not only with respect to their length (0.8–1.8 km), but also in involving four high-intensity heats of ~3 min in duration, separated by a relatively short recovery period (15–60 min). Objective: Our aim was to systematically review the scientific literature to identify factors related to the performance of elite sprint cross-country skiers. Methods: Four electronic databases were searched using relevant medical subject headings and keywords, as were reference lists, relevant journals, and key authors in the field. Only original research articles addressing physiology, biomechanics, anthropometry, or neuromuscular characteristics and elite sprint cross-country skiers and performance outcomes were included. All articles meeting inclusion criteria were quality assessed. Data were extracted from each article using a standardized form and subsequently summarized. Results: Thirty-one articles met the criteria for inclusion, were reviewed, and scored an average of 66 ± 7 % (range 56–78 %) upon quality assessment. All articles except for two were quasi-experimental, and only one had a fully-experimental research design. In total, articles comprised 567 subjects (74 % male), with only nine articles explicitly reporting their skiers’ sprint International Skiing Federation points (weighted mean 116 ± 78). A similar number of articles addressed skating and classical techniques, with more than half of the investigations involving roller-skiing assessments under laboratory conditions. A range of physiological, biomechanical, anthropometric, and neuromuscular characteristics was reported to relate to sprint skiing performance. Both aerobic and anaerobic capacities are important qualities, with the anaerobic system suggested to contribute more to the performance during the first of repeated heats; and the aerobic system during subsequent heats. A capacity for high speed in all the following instances is important for the performance of sprint cross-country skiers: at the start of the race, at any given point when required (e.g., when being challenged by a competitor), and in the final section of each heat. Although high skiing speed is suggested to rely primarily on high cycle rates, longer cycle lengths are commonly observed in faster skiers. In addition, faster skiers rely on different technical strategies when approaching peak speeds, employ more effective techniques, and use better coordinated movements to optimize generation of propulsive force from the resultant ski and pole forces. Strong uphill technique is critical to race performance since uphill segments are the most influential on race outcomes. A certain strength level is required, although more does not necessarily translate to superior sprint skiing performance, and sufficient strength-endurance capacities are also of importance to minimize the impact and accumulation of fatigue during repeated heats. Lastly, higher lean mass does appear to benefit sprint skiers’ performance, with no clear advantage conferred via body height and mass. Limitations: Generalization of findings from one study to the next is challenging considering the array of experimental tasks, variables defining performance, fundamental differences between skiing techniques, and evolution of sprint skiing competitions. Although laboratory-based measures can effectively assess on-snow skiing performance, conclusions drawn from roller-skiing investigations might not fully apply to on-snow skiing performance. A low number of subjects were females (only 17 %), warranting further studies to better understand this population. Lastly, more training studies involving high-level elite sprint skiers and investigations pertaining to the ability of skiers to maintain high-sprint speeds at the end of races are recommended to assist in understanding and improving high-level sprint skiing performance, and resilience to fatigue. Conclusions: Successful sprint cross-country skiing involves well-developed aerobic and anaerobic capacities, high speed abilities, effective biomechanical techniques, and the ability to develop high forces rapidly. A certain level of strength is required, particularly ski-specific strength, as well as the ability to withstand fatigue across the repeated heats of sprint races. Cross-country sprint skiing is demonstrably a demanding and complex sport, where high-performance skiers need to simultaneously address physiological, biomechanical, anthropometric, and neuromuscular aspects to ensure success.
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| 4. |
- Abulfathi, Ahmed Aliyu, et al.
(författare)
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Clinical Pharmacokinetics and Pharmacodynamics of Rifampicin in Human Tuberculosis
- 2019
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Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 58:9, s. 1103-1129
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Forskningsöversikt (refereegranskat)abstract
- The introduction of rifampicin (rifampin) into tuberculosis (TB) treatment five decades ago was critical for shortening the treatment duration for patients with pulmonary TB to 6months when combined with pyrazinamide in the first 2months. Resistance or hypersensitivity to rifampicin effectively condemns a patient to prolonged, less effective, more toxic, and expensive regimens. Because of cost and fears of toxicity, rifampicin was introduced at an oral daily dose of 600mg (8-12mg/kg body weight). At this dose, clinical trials in 1970s found cure rates of >= 95% and relapse rates of < 5%. However, recent papers report lower cure rates that might be the consequence of increased emergence of resistance. Several lines of evidence suggest that higher rifampicin doses, if tolerated and safe, could shorten treatment duration even further. We conducted a narrative review of rifampicin pharmacokinetics and pharmacodynamics in adults across a range of doses and highlight variables that influence its pharmacokinetics/pharmacodynamics. Rifampicin exposure has considerable inter- and intra-individual variability that could be reduced by administration during fasting. Several factors including malnutrition, HIV infection, diabetes mellitus, dose size, pharmacogenetic polymorphisms, hepatic cirrhosis, and substandard medicinal products alter rifampicin exposure and/or efficacy. Renal impairment has no influence on rifampicin pharmacokinetics when dosed at 600mg. Rifampicin maximum (peak) concentration (C-max) > 8.2 mu g/mL is an independent predictor of sterilizing activity and therapeutic drug monitoring at 2, 4, and 6h post-dose may aid in optimizing dosing to achieve the recommended rifampicin concentration of >= 8 mu g/mL. A higher rifampicin C-max is required for severe forms TB such as TB meningitis, with C-max >= 22 mu g/mL and area under the concentration-time curve (AUC) from time zero to 6h (AUC(6)) >= 70 mu g.h/mL associated with reduced mortality. More studies are needed to confirm whether doses achieving exposures higher than the current standard dosage could translate into faster sputum conversion, higher cure rates, lower relapse rates, and less mortality. It is encouraging that daily rifampicin doses up to 35mg/kg were found to be safe and well-tolerated over a period of 12weeks. High-dose rifampicin should thus be considered in future studies when constructing potentially shorter regimens. The studies should be adequately powered to determine treatment outcomes and should include surrogate markers of efficacy such as C-max/MIC (minimum inhibitory concentration) and AUC/MIC.
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| 5. |
- Bukkems, V. E., et al.
(författare)
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Prediction of Maternal and Fetal Doravirine Exposure by Integrating Physiologically Based Pharmacokinetic Modeling and Human Placenta Perfusion Experiments
- 2022
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Ingår i: Clinical Pharmacokinetics. - : Springer Nature. - 0312-5963 .- 1179-1926. ; 61:8, s. 1129-1141
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objective Doravirine is currently not recommended for pregnant women living with human immunodeficiency virus because efficacy and safety data are lacking. This study aimed to predict maternal and fetal doravirine exposure by integrating human placenta perfusion experiments with pregnancy physiologically based pharmacokinetic (PBPK) modeling.Methods Ex vivo placenta perfusions were performed in a closed-closed configuration, in both maternal-to-fetal and fetal-to-maternal directions (n = 8). To derive intrinsic placental transfer parameters from perfusion data, we developed a mechanistic placenta model. Next, we developed a maternal and fetal full-body pregnancy PBPK model for doravirine in Simcyp, which was parameterized with the derived intrinsic placental transfer parameters to predict in vivo maternal and fetal doravirine exposure at 26, 32, and 40 weeks of pregnancy. The predicted total geometric mean (GM) trough plasma concentration (C-trough) values were compared with the target (0.23 mg/L) derived from in vivo exposure-response analysis.Results A decrease of 55% in maternal doravirine area under the plasma concentration-time curve (AUC)(0-24h) was predicted in pregnant women at 40 weeks of pregnancy compared with nonpregnant women. At 26, 32, and 40 weeks of pregnancy, predicted maternal total doravirine GM C-trough values were below the predefined efficacy target of 0.23 mg/L. Perfusion experiments showed that doravirine extensively crossed the placenta, and PBPK modeling predicted considerable fetal doravirine exposure.Conclusion Substantially reduced maternal doravirine exposure was predicted during pregnancy, possibly resulting in impaired efficacy. Therapeutic drug and viral load monitoring are advised for pregnant women treated with doravirine. Considerable fetal doravirine exposure was predicted, highlighting the need for clinical fetal safety data.
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| 6. |
- de Rouw, Nikki, et al.
(författare)
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Rethinking the Application of Pemetrexed for Patients with Renal Impairment : A Pharmacokinetic Analysis
- 2021
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Ingår i: Clinical Pharmacokinetics. - : ADIS INT LTD. - 0312-5963 .- 1179-1926. ; 60:5, s. 649-654
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Tidskriftsartikel (refereegranskat)abstract
- Background Pemetrexed is used for the treatment for non-small cell lung cancer and mesothelioma. Patients with renal impairment are withheld treatment with this drug as it is unknown what dose is well tolerated in this population. Objective The purpose of our study was to investigate the pharmacokinetics (PK) of pemetrexed in patients with renal impairment. Methods A population PK analysis of pemetrexed was performed using non-linear mixed-effects modelling with phase I data obtained from the manufacturer. Additionally, the impact of renal function on pemetrexed PK was assessed with a simulation study using the developed PK model and a previously developed PK model lacking the phase I data. Results The dataset included 548 paired observations of 47 patients, with a wide range of estimated glomerular filtration rates (eGFR; 14.4-145.6 mL/min). Pemetrexed PK were best described by a three-compartment model with eGFR (calculated using the Chronic Kidney Disease-Epidemiology Collaboration [CKD-EPI] formula) as a linear covariate on renal pemetrexed clearance. Using the developed model, we found that renal clearance accounts for up to 84% (95% confidence interval 69-98%) of total pemetrexed clearance, whereas the manufacturer previously reported a 50% contribution of renal clearance. Conclusion Renal function is more important for the clearance of pemetrexed than previously thought and this should be taken into account in patients with renal impairment. Furthermore, a third compartment may contribute to prolonged exposure to pemetrexed during drug washout.
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| 7. |
- Moafi, Roya, et al.
(författare)
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Haptic-Assisted Surgical Planning (HASP) in a Case of Bilateral Mandible Fracture
- 2022
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Ingår i: International Medical Case Reports Journal. - : Dove Medical Press Limited. - 1179-142X. ; 15, s. 707-712
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Tidskriftsartikel (refereegranskat)abstract
- Restoring normal skeletal anatomy in patients with complex trauma to the mandible can be difficult, the difficulty often increasing with an edentulous mandible. This study describes a case of a displaced edentulous bilateral mandibular fracture, which was preoperatively planned with the in-house haptic-assisted surgery planning system (HASP). A model of the virtually restored mandible was 3D-printed at the hospital and a reconstruction plate was outlined beforehand with the printed mandible as a template and served as a guide during surgery. This case suggests HASP as a valuable preoperative tool in the planning phase when dealing with maxillofacial trauma cases. With the application of virtual planning, the authors could analyze the desired outcome and were further supported in surgery by the guidance of the reconstruction plate outlined on the restored model of the mandible.
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| 8. |
- Mouratidou, N., et al.
(författare)
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Identification of Childhood-Onset Inflammatory Bowel Disease in Swedish Healthcare Registers: A Validation Study
- 2022
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Ingår i: CLINICAL EPIDEMIOLOGY. - 1179-1349. ; 14, s. 591-600
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The Swedish National Patient Register (NPR) is often used in observational studies of childhood-onset inflammatory bowel disease (IBD) (<18 years of age) and its subtypes, but the validity of previously used register-based algorithms for capturing childhood-onset IBD has never been examined. Methods: We identified a random sample of 233 individuals with at least two first ever diagnostic listings of IBD in the NPR between 2002 and 2014. We calculated the test characteristics for different register-based definitions of IBD and its subtypes using the Copenhagen criteria and the revised Porto criteria as gold standard, both based on medical chart review. We made assumptions of the occurrence of undiagnosed IBD in the general child population based on available literature. Results: Out of 233 individuals with at least two diagnostic listings of IBD, 216 had true IBD, resulting in a positive predictive value (PPV) = 93% (95% confidence interval (CI) 89-96), sensitivity = 88% (95% CI 83-92), specificity = 100% (95% CI 100-100), and negative predictive value (NPV) = 100% (95% CI 100-100). The PPV for the NPR-based definitions of IBD subtypes at time of first IBD diagnosis and at end of follow-up were 78% (95% CI 69-86) and 88% (95% CI 80-94), respectively, for Crohn's disease and 74% (95% CI 63-83) and 71% (95% CI 60-80), respectively, for ulcerative colitis. Conclusion: The validity of register-based definitions of childhood-onset IBD in the Swedish NPR is high and can be used to identify patients in observational research.
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| 9. |
- Reinebo, Gustaf, et al.
(författare)
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Effects of Psychological Interventions to Enhance Athletic Performance : A Systematic Review and Meta-Analysis
- 2024
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Ingår i: Sports Medicine. - : Springer. - 0112-1642 .- 1179-2035. ; 54:2, s. 347-373
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Forskningsöversikt (refereegranskat)abstract
- BackgroundPsychological interventions are commonly applied in sports to help athletes enhance their performance, but the effect psychological interventions have on actual performance is unclear despite decades of research.ObjectiveWe conducted a systematic review with meta-analyses to investigate the effects of a wide range of psychological interventions on performance in competitive athletes.MethodsA study protocol was preregistered in PROSPERO, and a literary search was performed in the MEDLINE, PsycINFO, Web of Science, and SPORTDiscus databases. Psychological intervention studies were eligible by using a group design and a quantitative performance outcome with athletes competing at a regional or university level or higher. Included studies were assessed regarding intervention characteristics, research methodology, and risk of bias. A multi-level meta-analysis framework with cluster robust variance estimation was used to quantitatively synthesize the results.ResultsA total of 111 studies met the inclusion criteria, and 25 of these studies (37 effects) could be synthesized into five meta-analyses in which there were similarities in the type of psychological intervention, comparator, and experimental design. Meta-analyses I (multimodal psychological skills training vs control), II (mindfulness- and acceptance-based approaches vs control), and III (imagery vs control) consisted of parallel-group studies, and random-effects models were used to calculate the standardized mean difference. Meta-analyses IV (attentional focus strategies, external vs internal) and V (regulatory focus performance instructions, prevention vs promotion) consisted of counterbalanced crossover design studies, and random-effects models were used to calculate the standardized mean change using change score standardization. Significant results were found in three of the meta-analyses (I, II, and III). Psychological skills training (g = 0.83, 95% confidence interval 0.21–1.45), mindfulness- and acceptance-based approaches (g = 0.67, 95% confidence interval 0.01–1.32), and imagery (g = 0.75, 95% confidence interval 0.14–1.36) outperformed controls with moderate effects. However, when non-randomized trials and subjective performance outcomes were removed in sensitivity analyses, the overall estimates of the effect size were no longer significant in any of the syntheses.ConclusionsThe significant moderate effects for psychological skills training, mindfulness- and acceptance-based approaches, and imagery are not stable, and further trials with robust research methodology, such as randomized controlled trials, are requested for all types of psychological interventions aiming to enhance performance in athletes. Moreover, improved reporting standards and the provision of datasets in open science repositories are important to consider in future trials in sport psychology.
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| 10. |
- Savic, Radojka M., et al.
(författare)
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Population pharmacokinetics of cladribine in patients with multiple sclerosis
- 2017
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Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 56:10, s. 1245-1253
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Tidskriftsartikel (refereegranskat)abstract
- The aims of this study were to characterize the concentration-time course of cladribine (CdA) and its main metabolite 2-chloroadenine (CAde), estimate interindividual variability in pharmacokinetics (PK), and identify covariates explaining variability in the PK of CdA. This population PK analysis was based on the combined dataset from four clinical studies in patients with multiple sclerosis (MS): three phase I studies, including one food and one drug-drug interaction study, and one phase III clinical study. Plasma and urine concentration data of CdA and CAde were modeled simultaneously. The analysis comprised a total of 2619 CdA and CAde plasma and urine concentration observations from 173 patients with MS who received an intravenous infusion or oral tablet doses of CdA as a single agent or in combination with interferon (IFN) beta-1a. CdA PK data were best described by a three-compartment model, while a one-compartment model best described the PK of CAde. CdA renal clearance (CLR) was correlated with creatinine clearance (CLCR), predicting a decrease in the total clearance of 19%, 30% and 40% for patients with mild (CLCR = 65 ml/min), moderate (CLCR = 40 ml/min) and severe (CLCR = 20 ml/min) renal impairment, respectively. Food decreased the extent of CdA absorption by 11.2% and caused an absorption delay. Coadministration with IFN beta-1a was found to increase non-CLR (CLNR) by 21%, resulting in an increase of 11% in total clearance. Both CdA and CAde displayed linear PK after intravenous and oral administration of CdA, with CdA renal function depending on CLCR.
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