The Negative Impact of Biological Variation in the Effect and Clearance of Warfarin on Methods for Prediction of Dose Requirements

1986 ◽  
Vol 56 (03) ◽  
pp. 371-375 ◽  
Author(s):  
Peretz Weiss ◽  
Hillel Halkin ◽  
Shlomo Almog
Keyword(s):  
Individual Variation ◽  
Negative Impact ◽  
Warfarin Dose ◽  
Empirical Therapy ◽  
Maintenance Phase ◽  
Individual Variability ◽  
Dose Prediction ◽  
Group I ◽  
Over Time ◽  
Variance Explained

SummaryWithin-individual variation over time in the clearance (Cl) and effect (PT%) of warfarin, was measured in 25 inpatients (group I) studied after standard single or individualized split loading doses and 1-3 times (n = 16) 8-16 weeks later during maintenance. Mean Cl (2.5 α 0.9 ml/min) was similar in both phases but significant changes occurred in 6/16 patients, exceeding those expected from within-individual variation alone (defined by its 95% tolerance limits -24% to +62%). Initial PT% (21 α 5) was unaffected by dosing schedule, total or free plasma warfarin, varying between patients by only 18-24%. Mean initial and maintenance dose-PT% ratios (8.2 mg/d: 21% and 4.1 mg/d: 40%) were similar but significant changes in sensitivity to warfarin occurred in 4/16 patients. In group I and 64 other outpatients on maintenance therapy, between-individual variability was 36-52% for Cl and 49-56% for effect. PT% correlated best (r = 0.56) with free and total plasma warfarin but poorly with dose (r = 0.29), with only 30% of PT% variance explained at best, due to high between patient variability.Warfarin dose prediction whether based on extrapolation from initial effects to the maintenance phase, or on iterative methods not allowing for between- or within-patient variation in warfarin clearance or effect which may occur independently over time, have not improved on empirical therapy. This, due to the elements of biological variability as well as the intricacy of the warfarin - prothrombin complex interaction not captured by any kinetic-dynamic model used for prediction to date.

Inter-individual variation shapes the human microbiome

2019 ◽  
Vol 42 ◽  
Author(s):  
Emily F. Wissel ◽  
Leigh K. Smith
Keyword(s):  
Individual Differences ◽  
Individual Variation ◽  
Human Microbiome ◽  
Individual Variability ◽  
Microbiota Composition ◽  
Target Article ◽  
Microbiome Research

Abstract The target article suggests inter-individual variability is a weakness of microbiota-gut-brain (MGB) research, but we discuss why it is actually a strength. We comment on how accounting for individual differences can help researchers systematically understand the observed variance in microbiota composition, interpret null findings, and potentially improve the efficacy of therapeutic treatments in future clinical microbiome research.

Has Aid Helped in Pakistan?

1997 ◽  
Vol 36 (4II) ◽  
pp. 947-957 ◽  
Author(s):  
Shahrukh Rafi Khan
Keyword(s):  
Economic Growth ◽  
Negative Impact ◽  
Negative Association ◽  
Causal Impact ◽  
The Impact ◽  
Over Time

This paper has a two-fold objective: first, to examine the terms on which Pakistan receives aid and whether its debt situation is sustainable, and second, to examine the impact of aid and debt on economic growth. It is found that there is little encouraging that can be said about how the terms on which Pakistan has received aid over time have changed, and its current debt situation is not sustainable. Also reported is the analysis done elsewhere which shows that aid has a negative (Granger) causal impact on GDP, and aid has a robust negative impact on economic growth after controlling for supplyside shocks. We provide various reasons for this negative association.

Pharmacogenetic algorithm for predicting daily dose of warfarin in Caucasian patients of Czech origin

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Aleš Tomek ◽  
Tereza Růžičková ◽  
Vojtěch Kaplan ◽  
Zuzana Lacinová ◽  
Simona Kumstýřová ◽  
...  
Keyword(s):  
Validation Cohort ◽  
Warfarin Dose ◽  
Therapeutic Index ◽  
Coefficient Of Determination ◽  
Dose Prediction ◽  
Pharmacogenetic Algorithm ◽  
Daily Dose ◽  
Caucasian Patients ◽  
Variant Alleles ◽  
Initiation Of Therapy

Abstract Objectives Warfarin use is limited by a low therapeutic index and significant interindividual variability of the daily dose. The most important factor predicting daily warfarin dose is individual genotype, polymorphisms of genes CYP2C9 (warfarin metabolism) and VKORC1 (sensitivity for warfarin). Algorithms using clinical and genetic variables could predict the daily dose before the initiation of therapy. The aim of this study was to develop and validate an algorithm for the prediction of warfarin daily dose in Czech patients. Methods Detailed clinical data of patients with known and stable warfarin daily dose were collected. All patients were genotyped for polymorphisms in genes CYP2C9 and VKORC1. Results Included patients were divided into derivation (n=175) and validation (n=223) cohorts. The final algorithm includes the following variables: Age, height, weight, treatment with amiodarone and presence of variant alleles of genes CYP2C9 and VKORC1. The adjusted coefficient of determination is 72.4% in the derivation and 62.3% in the validation cohort (p<0.001). Conclusions Our validated algorithm for warfarin daily dose prediction in our Czech cohort had higher precision than other currently published algorithms. Pharmacogenetics of warfarin has the potential in the clinical practice in specialized centers.

scholarly journals Phenotyping of CYP 4501A2 Activity by Total Overnight Salivary Caffeine Assessment (TOSCA) in Patients on Warfarin Treatment: A Cross-Sectional Study

2017 ◽  
Vol 24 (6) ◽  
pp. 928-935 ◽  
Author(s):  
Giovanni Tarantino ◽  
Domenico Capone ◽  
Paola Contaldi ◽  
Adriana Gianno ◽  
Mosca Teresa ◽  
...  
Keyword(s):  
Adverse Events ◽  
Drug Concentration ◽  
Ethical Issues ◽  
Single Point ◽  
Warfarin Dose ◽  
Individual Variability ◽  
Bleeding Complications ◽  
Close Monitoring ◽  
Cross Sectional ◽  
Warfarin Sodium

Warfarin is an oral anticoagulant, commonly used for primary and secondary prevention of venous and arterial thromboembolic events. The drug is characterized by narrow therapeutic index, widespread individual variability in clinical response, and high rates of adverse events, particularly bleeding complications. For these reasons, a close monitoring of the dosage, using the frequent assessment of coagulation status by means of International Normalized Ratio value, is mandatory. Warfarin is metabolized by hepatic cytochrome P-450. High CYP 450 activity may lead to low drug concentration and requires high warfarin doses to reach efficacy; conversely, low CYP 450 activity is responsible for high drug concentration and needs for low doses to avoid potential toxicity risks. The major isoforms of CYP involved in the metabolism of warfarin sodium are CYP1A2 (for the R-warfarin) and CYP2C9 (for the S-warfarin). The probes for testing CYP1A2 are phenacetin and caffeine while for CYP2C9 tolbutamide. Although S-warfarin has major activity, it was decided to exclude its phenotyping for ethical issues, being mandatory to use a drug (tolbutamide). Instead, it was chosen to test the 1A2 isoform, as the activity of the latter isoform could be investigated by using caffeine contained in the caffeinated beverages. Specifically, a single-point concentration of salivary caffeine (total overnight salivary caffeine assessment [TOSCA]) after an overnight period of the caffeinated beverages abstinence was utilized. In the present study, 75 nonsmoker patients regularly receiving warfarin sodium were enrolled. The results have showed a significant association of the warfarin dose with TOSCA values (coefficient = –0.15, standard error = 0.04, 95% confidence interval = –0.24 to –0.06, t = –3.23, P = .002). In conclusion, the phenotyping of CYP1A2 by TOSCA could be useful, if further proven, to help manage patients on warfarin in order to lessen severe adverse events.

Epiphyseal bone-marrow abnormalities and restitution in legg-calvé-perthes disease

1997 ◽  
Vol 38 (5) ◽  
pp. 855-862 ◽  
Author(s):  
P. Hochbergs ◽  
G. Eckervall ◽  
H. Wingstrand ◽  
N. Egund ◽  
K. Jonsson
Keyword(s):  
Bone Marrow ◽  
Mr Imaging ◽  
Perthes Disease ◽  
Mr Images ◽  
Group I ◽  
Radiological Classification ◽  
Signal Changes ◽  
Over Time ◽  
Epiphyseal Bone

Purpose: By means of MR imaging, to determine signal abnormalities in the femoral epiphysis; to determine their location, extent and restitution over time; and to correlate these findings to the Catterall radiological classification. Material and Methods: A total of 247 MR images in 86 patients (101 hips) with Legg-CalvC-Perthes disease were examined. The MR images were taken in the coronal plane, and the images through the center of the femoral head were used for this study. Results: T1-weighted images proved as good as T2-weighted images for the MR evaluation of the extent of the necrosis. In almost every case, the central-cranial part of the epiphysis showed a low initial signal. In Catterall group I, the medial part was never involved. In Catterall III and IV, almost the entire epiphysis showed signal changes. In the period 3–6 years after diagnosis, we still found signal changes in the epiphysis in some hips but there was no correlation with the Catterall classification. After 6 years, the epiphysis showed normal signal intensity in MR imaging. In T1-weighted images, Gd-enhancement occurred in the peripheral regions in the early stages of the disease. The central part of the epiphysis became more enhanced over time and peaked in the period 1–3 years after diagnosis. Conclusion: MR is a valuable modality for monitoring changes in the femoral epiphysis. We propose a new classification of the extent and pattern of epiphyseal bone-marrow abnormalities based on the 4 zones most commonly observed in MR imaging.

scholarly journals Erratum to: Warfarin dose prediction in children using pharmacometric bridging – comparison with published pharmacogenetic dosing algorithms

2013 ◽  
Vol 69 (9) ◽  
pp. 1737-1737
Author(s):  
Anna-Karin Hamberg ◽  
Lena E. Friberg ◽  
Katarina Hanséus ◽  
Britt-Marie Ekman-Joelsson ◽  
Jan Sunnegårdh ◽  
...  
Keyword(s):  
Warfarin Dose ◽  
Dose Prediction

Influence of Tobacco on Physical Fitness Recovery of College Students After Sports

2021 ◽  
Vol 7 (5) ◽  
pp. 3445-3451
Author(s):  
Chen Yake
Keyword(s):  
College Students ◽  
Physical Fitness ◽  
Aerobic Exercise ◽  
Negative Impact ◽  
Control Group ◽  
Exercise Time ◽  
Activity Intensity ◽  
Group I ◽  
The Difference ◽  
Experimental Group

Objectives: In this paper, the effects of tobacco on aerobic exercise ability and physical fitness recovery of college students were studied. Methods: University group sports intervention form: traditional characteristic project (basketball) + Taiji soft ball (R&D intervention project). Exercise time: 3 times/week; Activity duration: 30min; Activity intensity: the heart rate is controlled at 120-140 beats/min. All the college students in the experimental group are students who have never smoked, and the college students in the control group are students who have smoked for more than two years. The other conditions are the same. Results: The exercise time and endurance of experimental groups I and II were significantly lower than those of the control group, and the cardiopulmonary function was significantly lower than that of the control group. The indexes of experimental group II changed significantly compared with experimental group I, and the difference was statistically significant. Conclusion: Cigarette smoke can significantly reduce the aerobic exercise ability and anti fatigue ability. The longer the smoking time, the more serious the adverse effects. Therefore, tobacco smoke and nicotine will damage college students’ aerobic exercise ability and have a negative impact on the recovery of physical fitness after exercise.

scholarly journals The perception of biopsychosocial impacts of COVID-19 during lockdown restrictions over time in the UK – a mixed methods study

2021 ◽  
Vol 4 (Special2) ◽  
pp. 402-414
Author(s):  
Samuel Grimwood ◽  
Kaz Stuart ◽  
Ruth Browning ◽  
Elaine Bidmead ◽  
Thea Winn-Reed
Keyword(s):  
Social Issues ◽  
Negative Impact ◽  
Mixed Methods Study ◽  
Biological Domain ◽  
Data Points ◽  
Integrated Recovery ◽  
Biopsychosocial Health ◽  
The Uk ◽  
The Impact ◽  
Over Time

Background: The COVID-19 pandemic has profoundly impacted the health of individuals physically, mentally, and socially. This study aims to gain a deeper understanding of this impact across the pandemic from a biopsychosocial stance. Methods: A survey created by the research team was employed between November 2020 and February 2021 across social media, relevant organizations, and networks. The survey incorporated 5-time points across the different stages of the pandemic, covering biological, psychological, and social. There were 5 items for each survey (Very Positive affect to Very Negative affect), and analysis was undertaken using SPSS version 16. Descriptive statistics and non-parametric Friedman and Wilcoxon Tests, as well as correlations between the three domains, were implemented. Results: This study included 164 participants (77.0% female and 35.0% male) across 24 out of 38 counties in the UK. The impact of COVID-19 on biological domain was significant across the five data points χ2(4) = 63.99, p < 0.001, psychological χ2(4) = 118.939, p <0.001 and socially χ2(4) = 186.43, p <0.001. Between the 5 data points, 4 out of 5 had a negative impact, however between the first stage of lockdown and the easing of restrictions, findings for biological (Z=-2.35, p <0.05), psychological (Z=-6.61, p < 0.001), and socially (Z = -8.61, p <0.001) were positive. Negative correlations between the three domains across the pandemic are apparent, but in later stages, the biological domain had a positive correlation r = 0.52, p < 0.001. Conclusion: The data shows a negative impact from the self-reported perception of wellbeing from a biopsychosocial stance over time, as well as perceiving the three domains to interact negatively. To address these biopsychosocial issues, the research implies a place-based integrated recovery effort is needed, addressing biological, psychological, and social issues simultaneously. Further research should investigate biopsychosocial health among a more generalizable population.

scholarly journals Human immune system variation during one year

2020 ◽  
Author(s):  
Tadepally Lakshmikanth ◽  
Sayyed Auwn Muhammad ◽  
Axel Olin ◽  
Yang Chen ◽  
Jaromir Mikes ◽  
...  
Keyword(s):  
Immune System ◽  
Individual Variation ◽  
Immune Cell ◽  
Metabolic Health ◽  
Individual Feature ◽  
Human Immune System ◽  
Principal Curve ◽  
Human Immune ◽  
One Year ◽  
Over Time

SUMMARYThe human immune system varies extensively between individuals, but variation within individuals over time has not been well characterized. Systems-level analyses allow for simultaneous quantification of many interacting immune system components, and the inference of global regulatory principles. Here we present a longitudinal, systems-level analysis in 99 healthy adults, 50 to 65 years of age and sampled every 3rd month during one year. We describe the structure of inter-individual variation and characterize extreme phenotypes along a principal curve. From coordinated measurement fluctuations, we infer relationships between 115 immune cell populations and 750 plasma proteins constituting the blood immune system. While most individuals have stable immune systems, the degree of longitudinal variability is an individual feature. The most variable individuals, in the absence of overt infections, exhibited markers of poor metabolic health suggestive of a functional link between metabolic and immunologic homeostatic regulation.HIGHLIGHTSLongitudinal variation in immune cell composition during one yearInter-individual variation can be described along a principal curveImmune cell and protein relationships are inferredVariability over time is an individual feature correlating with markers of poor metabolic health

scholarly journals Individual variation of the masticatory system dominates 3D skull shape in the herbivory-adapted marsupial wombats

2019 ◽  
Author(s):  
Vera Weisbecker ◽  
Thomas Guillerme ◽  
Cruise Speck ◽  
Emma Sherratt ◽  
Hyab Mehari Abraha ◽  
...  
Keyword(s):  
Individual Variation ◽  
Principal Component ◽  
Individual Variability ◽  
Shape Variation ◽  
Mandibular Ramus ◽  
Geometric Morphometric ◽  
Skull Shape ◽  
Marsupial Species ◽  
Masticatory System ◽  
The Individual

AbstractBackgroundWithin-species skull shape variation of marsupial mammals is widely considered low and strongly size-dependent (allometric), possibly due to developmental constraints arising from the altricial birth of marsupials. However, species whose skulls are impacted by strong muscular stresses – particularly those produced through mastication of tough food items – may not display such intrinsic patterns very clearly because of the known plastic response of bone to muscle activity of the individual. In such cases, shape variation should not be dominated by allometry; ordination of shape in a geometric morphometric context through principal component analysis (PCA) should reveal main variation in areas under masticatory stress (incisor region/zygomatic arches/mandibular ramus); but this main variation should emerge from high individual variability and thus have low eigenvalues.ResultsWe assessed the evidence for high individual variation through 3D geometric morphometric shape analysis of crania and mandibles of thre species of grazing-specialized wombats, whose diet of tough grasses puts considerable strain on their masticatory system. As expected, we found little allometry and low Principal Component 1 (PC1) eigenvalues within crania and mandibles of all three species. Also as expected, the main variation was in the muzzle, zygomatic arches, and masticatory muscle attachments of the mandibular ramus. We then implemented a new test to ask if the landmark variation reflected on PC1 was reflected in individuals with opposite PC1 scores and with opposite shapes in Procrustes space. This showed that correspondence between individual and ordinated shape variation was limited, indicating high levels of individual variability in the masticatory apparatus.DiscussionOur results are inconsistent with hypotheses that skull shape variation within marsupial species reflects a constraint pattern. Rather, they support suggestions that individual plasticity can be an important determinant of within-species shape variation in marsupials (and possibly other mammals) with high masticatory stresses, making it difficult to understand the degree to which intrinsic constraint act on shape variation at the within-species level. We conclude that studies that link micro- and macroevolutionary patterns of shape variation might benefit from a focus on species with low-impact mastication, such as carnivorous or frugivorous species.

Sign in / Sign up

Export Citation Format

Share Document