Suodatusta, sekreetiota ja takaisinimeytymistä

Joka neljäs lääkeaine poistuu elimistöstä pääasiassa virtsan mukana. Munuaisten vajaatoiminnassa lääkkeitä suodattuu tavanomaista vähemmän alkuvirtsaan, jolloin lääkkeiden puhdistuma pienenee ja altistus kasvaa. Muutokset voivat vaarantaa turvallisen lääkehoidon toteutuksen.</p

Lihavuusleikkauksen vaikutukset lääkkeiden farmakokinetiikkaan

Lihavuusleikkaus muuttaa ruoansulatuselimistön anatomiaa ja potilaan kehon koostumusta, mikä vaikuttaa lääkkeiden farmakokinetiikkaan. Leikkauksen välittömiä seurauksia ovat lääkkeiden imeytymisen ja ensikierron aineenvaihdunnan muutokset. Lääkkeen jakautumistilavuus, aineenvaihdunta ja eliminaatio saattavat muuttua rasvakudoksen ja maksan rasvoittumisen vähenemisen sekä munuaistoiminnan parantumisen myötä. Lääkepitoisuuksien suurentuminen tai pienentyminen voivat vaikuttaa lääkehoidon tehoon ja haittavaikutusriskiin. Yksittäisten lääkkeiden osalta näyttö on puutteellista, eikä selkeitä yleissuosituksia lääkkeiden lihavuusleikkauksen jälkeisistä annoksista ole saatavilla. Leikkaustekniikka ja yksilölliset potilaskohtaiset tekijät vaikuttavat farmakokinetiikan muutoksiin. Muutosten vaikean ennakoitavuuden takia on tärkeää seurata lääkehoidon kliinistä vastetta, haittavaikutuksia ja tarvittaessa lääkepitoisuuksia 1-2 vuoden ajan leikkauksesta, jolloin paino vähenee eniten

Hydroxychloroquine in the treatment of adult patients with Covid-19 infection in a primary care setting (LIBERTY): A structured summary of a study protocol for a randomised controlled trial

Objectives: The primary objective of this study is to evaluate the therapeutic potential of hydroxychloroquine (HCQ) in the treatment of adult patients with PCR-confirmed Covid-19 infection in a primary open-care setting, as compared to placebo. The study hypothesis is that treatment with HCQ will reduce the risk of hospitalization because of Covid-19 infection, and the sample size estimate of the study is based on the need to test this hypothesis.The secondary objectives of the study are:to evaluate the safety and tolerability of HCQ in the treatment of adult patients with PCR-confirmed Covid-19 infection in a primary open-care setting, as compared to placebo;to collect experience of the use of HCQ in the treatment of Covid-19 infection in outpatients, in order to be able to identify patient characteristics that predict specific treatment responses (favourable or unfavourable); this objective will also be addressed by post-hoc subgroup analysis of the study results and by meta-analysis of pooled patient data from other clinical trials of HCQ in outpatients; andto evaluate the impact of Covid-19 infection and its treatment on the mental health and well-being of the study participants.In addition, if the data allow, the study has the following exploratory objectives:to evaluate the extent and duration of SARS-CoV-2 viral shedding by PCR testing of nasopharyngeal swab samples in study subjects treated with HCQ, as compared to placebo;to evaluate the extent and time course of SARS-CoV-2 virus-specific antibody responses in serum of study subjects treated with HCQ, as compared to placebo;to evaluate other possible biomarker changes in blood in study subjects treated with HCQ, as compared to placebo;to explore the possible effects of genetic variation in drug metabolizing enzymes on HCQ-related outcomes in the study population;to explore the associations of HCQ-related outcome variables with other patient characteristics, e.g. HLA haplotypes, HCQ concentrations, demographic variables, disease history and concomitant medications.Trial design: This is a phase 2, placebo-controlled, double-blind, randomized, parallel-group treatment trial comparing HCQ with placebo in outpatients with Covid-19 infection. Participants will be randomized in a 1:1 ratio to the two treatment arms.Participants:Main inclusion criteria: 1. Males and females >40 years of age, or 18-40 years of age with one or both of the following: i. diabetes mellitus (type 1 or type 2); ii. BMI > 35 kg/m(2);2. Valid independent informed consent obtained;3. Symptoms typical of Covid-19 infection, according to criteria specified in the study protocol. The onset of symptoms must be within 5 days of enrolment;4. Positive SARS-CoV-2 PCR test result of a nasopharyngeal swab sample.Main exclusion criteria:1. Suspected severe or moderately severe pneumonia, presenting with any of the following: respiratory rate > 26 breaths/min; significant respiratory distress; or SpO(2) <= 94% on room air;2. Requiring treatment in the hospital, according to the treating physician's judgement;3. Any contraindication to treatment with HCQ;4. Pregnancy or lactation.The trial will be conducted at seven study sites in a primary public health care setting in the region of Satakunta, Finland.Intervention and comparator: Participants will be randomized to receive either HCQ capsules at 300 mg twice a day for one day and then 200 mg twice a day for 6 days, or placebo capsules for 7 days.Main outcomes: The primary endpoint of the study is the number of hospitalizations due to Covid-19 infection within four weeks of entry into the study.The secondary endpoints of the study include the following:duration and severity of Covid-19-related symptoms, as reported by daily self-assessments;number of Intensive Care Unit treatment episodes due to Covid-19 infection within four weeks of entry into the study;number of deaths due to Covid-19 infection within four weeks of entry into the study;number of treatment-related adverse events (AEs) and serious AEs (SAEs);all-cause hospitalizations and mortality within six months of entry into the study; andself-assessed symptoms of anxiety, as assessed with repeated administration of the Generalized Anxiety Disorder 7-item scale (GAD-7).The exploratory endpoints of the study include the following:extent and duration of SARS-CoV-2 viral shedding and virus-specific antibody responses in serum; andpossible other blood biomarker changes.Randomisation: Eligible study participants are randomly allocated into two treatment arms (1:1 ratio). The randomization list has been generated using Viedoc (TM) (Viedoc Technologies AB, Uppsala, Sweden) that is used as an electronic data capture system for this study.Blinding (masking): The participants and all study personnel remain blinded to the treatment allocation by having both IMPs packed in identical containers. Masking of the treatments was performed by re-formulation of the IMPs so that the HCQ capsules and the placebo capsules have identical appearance.Numbers to be randomised (sample size): 600 participants are to be randomised with 300 in each arm.Trial Status: Protocol version 2, dated 14 July 2020; recruitment is expected to start in December, 2020, and to be completed in June, 2021.Trial registration: EudraCT 2020-002038-33, registered 26 June 2020Full protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). The protocol has been redacted to conform with privacy regulations by deleting the names and contact information of individuals mentioned in the protocol but not listed as authors in this communication. In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol

Quantification of porcine myocardial perfusion with modified dual bolus MRI : a prospective study with a PET reference

Abstract Background The reliable quantification of myocardial blood flow (MBF) with MRI, necessitates the correction of errors in arterial input function (AIF) caused by the T1 saturation effect. The aim of this study was to compare MBF determined by a traditional dual bolus method against a modified dual bolus approach and to evaluate both methods against PET in a porcine model of myocardial ischemia. Methods Local myocardial ischemia was induced in five pigs, which were subsequently examined with contrast enhanced MRI (gadoteric acid) and PET (O-15 water). In the determination of MBF, the initial high concentration AIF was corrected using the ratio of low and high contrast AIF areas, normalized according to the corresponding heart rates. MBF was determined from the MRI, during stress and at rest, using the dual bolus and the modified dual bolus methods in 24 segments of the myocardium (total of 240 segments, five pigs in stress and rest). Due to image artifacts and technical problems 53% of the segments had to be rejected from further analyses. These two estimates were later compared against respective rest and stress PET-based MBF measurements. Results Values of MBF were determined for 112/240 regions. Correlations for MBF between the modified dual bolus method and PET was rs = 0.84, and between the traditional dual bolus method and PET rs = 0.79. The intraclass correlation was very good (ICC = 0.85) between the modified dual bolus method and PET, but poor between the traditional dual bolus method and PET (ICC = 0.07). Conclusions The modified dual bolus method showed a better agreement with PET than the traditional dual bolus method. The modified dual bolus method was found to be more reliable than the traditional dual bolus method, especially when there was variation in the heart rate. However, the difference between the MBF values estimated with either of the two MRI-based dual-bolus methods and those estimated with the gold-standard PET method were statistically significant

Quantification of porcine myocardial perfusion with modified dual bolus MRI-A prospective study with a PET reference

BackgroundThe reliable quantification of myocardial blood flow (MBF) with MRI, necessitates the correction of errors in arterial input function (AIF) caused by the T1 saturation effect. The aim of this study was to compare MBF determined by a traditional dual bolus method against a modified dual bolus approach and to evaluate both methods against PET in a porcine model of myocardial ischemia.MethodsLocal myocardial ischemia was induced in five pigs, which were subsequently examined with contrast enhanced MRI (gadoteric acid) and PET (O-15 water). In the determination of MBF, the initial high concentration AIF was corrected using the ratio of low and high contrast AIF areas, normalized according to the corresponding heart rates. MBF was determined from the MRI, during stress and at rest, using the dual bolus and the modified dual bolus methods in 24 segments of the myocardium (total of 240 segments, five pigs in stress and rest). Due to image artifacts and technical problems 53% of the segments had to be rejected from further analyses. These two estimates were later compared against respective rest and stress PET-based MBF measurements.ResultsValues of MBF were determined for 112/240 regions. Correlations for MBF between the modified dual bolus method and PET was rs = 0.84, and between the traditional dual bolus method and PET rs = 0.79. The intraclass correlation was very good (ICC = 0.85) between the modified dual bolus method and PET, but poor between the traditional dual bolus method and PET (ICC = 0.07).ConclusionsThe modified dual bolus method showed a better agreement with PET than the traditional dual bolus method. The modified dual bolus method was found to be more reliable than the traditional dual bolus method, especially when there was variation in the heart rate. However, the difference between the MBF values estimated with either of the two MRI-based dual-bolus methods and those estimated with the gold-standard PET method were statistically significant.</div

Quantification of Myocardial Blood Flow by Machine Learning Analysis of Modified Dual Bolus MRI Examination

Contrast-enhanced magnetic resonance imaging (MRI) is a promising method for estimating myocardial blood flow (MBF). However, it is often affected by noise from imaging artefacts, such as dark rim artefact obscuring relevant features. Machine learning enables extracting important features from such noisy data and is increasingly applied in areas where traditional approaches are limited. In this study, we investigate the capacity of machine learning, particularly support vector machines (SVM) and random forests (RF), for estimating MBF from tissue impulse response signal in an animal model. Domestic pigs (n = 5) were subjected to contrast enhanced first pass MRI (MRI-FP) and the impulse response at different regions of the myocardium (n = 24/pig) were evaluated at rest (n = 120) and stress (n = 96). Reference MBF was then measured using positron emission tomography (PET). Since the impulse response may include artefacts, classification models based on SVM and RF were developed to discriminate noisy signal. In addition, regression models based on SVM, RF and linear regression (for comparison) were developed for estimating MBF from the impulse response at rest and stress. The classification and regression models were trained on data from 4 pigs (n = 168) and tested on 1 pig (n = 48). Models based on SVM and RF outperformed linear regression, with higher correlation (R2SVM  = 0.81, R2RF  = 0.74, R2linear_regression  = 0.60; ρSVM = 0.76, ρRF = 0.76, ρlinear_regression = 0.71) and lower error (RMSESVM = 0.67 mL/g/min, RMSERF = 0.77 mL/g/min, RMSElinear_regression = 0.96 mL/g/min) for predicting MBF from MRI impulse response signal. Classifier based on SVM was optimal for detecting impulse response signals with artefacts (accuracy = 92%). Modified dual bolus MRI signal, combined with machine learning, has potential for accurately estimating MBF at rest and stress states, even from signals with dark rim artefacts. This could provide a protocol for reliable and easy estimation of MBF, although further research is needed to clinically validate the approach.</p

Value of 3T diffusion weighted MRI in comparison with CECT in detection of ovarian cancer and ovarian cancer recurrence

Purpose: To investigate the value of 3T diffusion weighted magnetic resonance imaging (DW-MRI) compared to contrast enhanced computed tomography (CECT), in the preoperative staging of patients with suspected ovarian cancer (OC) or with suspected recurrence of ovarian cancer (ROC).Materials and methods: Thirty-two women (mean age 65 ± 14) with suspected (n = 23) or recurrent (n = 9) ovarian cancer were included prospectively in a single center study. CECT and abdominal 3T DW-MRI were performed. Both methods were used to independently score the presence of 1) ovarian tumor, 2) peritoneal or omental carcinomatosis, 3) pathological lymph nodes (LN), along with 4) liver parenchymal, 5) liver capsular, 6) diaphragmatic, and 7) extra-abdominal metastases. Findings were scored as: 0=benign, 1=suspicious for malignancy, or 2=definitely malignant. In addition, the lowest ADC values were measured in existing primary tumors. The extent of disease burden and correlation to histopathological findings were analyzed.Results: The mean disease score was higher in DW-MRI than in CT (4.9 ± 2.6 vs. 3.5 ± 2.2, P < 0.001). Compared to CT, DW-MRI depicted more LN (P = 0.001) and diaphragmatic (P = 0.024) lesions. The lowest ADC values were significantly lower in malignant tumors (n = 18) than in benign tumors (n = 5) (0.640 x10-3mm2/s ± 159 vs. 0.992 x10-3mm2/s ± 218, P = 0.002).Conclusion: The results of our prospective single center study show incremental value of abdominal 3T DW-MRI in comparison with CECT, especially in detecting diaphragmatic and peritoneal ovarian cancer metastases, excluding lymph nodal metastases and in differentiating malignant adnexal tumors from benign