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Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 114
Author(s):  
Justine Heitzmann ◽  
Yann Thoma ◽  
Romain Bricca ◽  
Marie-Claude Gagnieu ◽  
Vincent Leclerc ◽  
...  

Daptomycin is a candidate for therapeutic drug monitoring (TDM). The objectives of this work were to implement and compare two pharmacometric tools for daptomycin TDM and precision dosing. A nonparametric population PK model developed from patients with bone and joint infection was implemented into the BestDose software. A published parametric model was imported into Tucuxi. We compared the performance of the two models in a validation dataset based on mean error (ME) and mean absolute percent error (MAPE) of individual predictions, estimated exposure and predicted doses necessary to achieve daptomycin efficacy and safety PK/PD targets. The BestDose model described the data very well in the learning dataset. In the validation dataset (94 patients, 264 concentrations), 21.3% of patients were underexposed (AUC24h < 666 mg.h/L) and 31.9% of patients were overexposed (Cmin > 24.3 mg/L) on the first TDM occasion. The BestDose model performed slightly better than the model in Tucuxi (ME = −0.13 ± 5.16 vs. −1.90 ± 6.99 mg/L, p < 0.001), but overall results were in agreement between the two models. A significant proportion of patients exhibited underexposure or overexposure to daptomycin after the initial dosage, which supports TDM. The two models may be useful for model-informed precision dosing.


2021 ◽  
Vol 12 ◽  
Author(s):  
Bijun Wang ◽  
Wenxia Liu ◽  
Yi Liu ◽  
Wen Zhang ◽  
Chenchen Ren ◽  
...  

Unlike poor ovarian response, despite being predicted to be normal responders based on their ovarian reserve markers, many patients respond suboptimally to ovarian stimulation. Although we can improve the number of retrieved oocytes by increasing the recombinant FSH dose and adding LH, the effect of suboptimal ovarian response on cumulative live birth rate (CLBR) and offspring safety is unclear. This study focuses on the unexpected suboptimal response during ovulation induction, and its causes and outcomes are analysed for the first time with a large amount of data used to compare the cumulative pregnancy rate (CPR), CLBR and offspring safety of patients with one complete ART cycle with all embryos used. Our analysis included 5218 patients treated with the GnRH agonist long protocol for their first IVF–embryo transfer (ET) cycles. Patients were divided into two groups according to whether the ovarian response was suboptimal. Propensity score matching (PSM) was utilized for sampling at up to 1:1 nearest-neighbour matching with caliper 0.05 to balance the baseline and improve comparability between the groups. Results showed that age, BMI and basal FSH were independent risk factors for slow response; the initial dosage of Gn, FSH on the first day of Gn, and LH on the first day of Gn were independent protective factors for suboptimal response. Suboptimal responders were also more likely to have irregular menses. Regarding the clinical pregnancy rate of the fresh IVF/ICSI-ET cycles, the adjusted results of the two groups were not significantly different. There was no difference in the CPR, CLBR, or offspring safety-related data, such as gestational age, preterm delivery rate, birthweight, birth-height and Apgar Scores between the two groups after PSM. Age-related changes in the number of oocytes retrieved from women aged 20–40 years old between the two groups were different, indicating that suboptimal response in elderly patients suggests a decline in ovarian reserve. Although we can now improve the outcomes of suboptimal responders, it increases the cost to the patients and the time to live birth, which requires further attention.


2021 ◽  
Vol 8 (11) ◽  
pp. 271
Author(s):  
Rita Rebocho ◽  
Marina Domínguez-Ruiz ◽  
Ryane E. Englar ◽  
Carolina Arenas ◽  
Maria Dolores Pérez-Alenza ◽  
...  

This study aims to gather knowledge about the use of deoxycorticosterone pivalate (DOCP) by Western European Veterinarians (WEV) in dogs with typical hypoadrenocorticism. An observational cross-sectional study was conducted using an online survey, translated into four languages and disseminated to veterinary affiliates and mailing lists in six countries of Western Continental Europe. Respondents were tasked to share their therapeutic approach to hypoadrenocorticism, whether they preferred DOCP or fludrocortisone and the specific practical use of DOCP. One-hundred and eighty-four responses were included. Of these, 79.9% indicated that they preferred prescribing DOCP over fludrocortisone as a first-line treatment for mineralocorticoid supplementation. A total of 154 respondents had used DOCP at least once. Eighty percent of those who reported their initial dosage prescribed 2.2 mg/kg. After starting DOCP, 68.2% of the respondents assess electrolytes 10 and 25 days after administration following manufacturer instructions. In stable dogs, electrolytes are monitored quarterly, monthly, semi-annually, and annually by 44.2%, 34.4%, 16.9%, and 4.6% of respondents respectively. When treatment adjustment is required, 53% prefer to reduce dosage while 47% increase the interval between doses. Overall, DOCP is the preferred mineralocorticoid supplementation among WEV. Reported variability underlies the need to investigate the best strategies for DOCP use and therapeutic adjustments.


Author(s):  
Kathrine T. Isaksen ◽  
Maria Adele Mastroianni ◽  
Marit Rinde ◽  
Leiv Sindre Rusten ◽  
Dlawer Abdulla Batzenje ◽  
...  

Diffuse large B-cell lymphoma (DLBCL) patients have a median age of 70 years. Yet, empirical knowledge on treatment for older patients is limited as they are frequently excluded from clinical trials. We aimed to construct a simplified frailty score and examine survival and treatment-related mortality (TRM) according to frailty status and treatment intensity in an older, real-world DLBCL population. All patients ≥70 years diagnosed with DLBCL 2006-2016 in south-eastern Norway (n=784) were included retrospectively, and divided into a training (n=522) and validation cohort (n=262). We constructed and validated a frailty score based on geriatric assessment variables, and examined survival and TRM according to frailty status and treatment. The frailty score identified three frailty groups with distinct survival and TRM, independent of established prognostic factors (2-year overall survival (OS) fit 82%, unfit 47%, frail 14%, P&lt;0.001). For fit patients, full-dose R-CHOP (initial dosage&gt;80%) was associated with better survival than attenuated R-CHOP (2-year OS 86% vs 70%, P=0.012), also in adjusted analysis. For unfit and frail patients, full-dose R-CHOP was not superior to attenuated R-CHOP, while an anthracycline-free regimen was associated with poorer survival in adjusted analyses. A simplified frailty score identified unfit and frail patients with higher risk of death and TRM, which can aid treatment intensity decisions in older DLBCL patients. In this study, fit patients benefit from full-dose R-CHOP, while unfit and frail patients have no benefit of full-dose R-CHOP over R-miniCHOP. An online calculator for assessment of the frailty score is available at https://wide.shinyapps.io/app-frailty/.


2021 ◽  
Vol 10 (1) ◽  
pp. 89
Author(s):  
Melika Babaei ◽  
Sharareh R. Niakan Kalhori ◽  
Shima Sheybani ◽  
Hesam Karim

Introduction: Inadequate anesthetic, including under or over dosage, may lead to intraoperative awareness or prolonged recovery. Fuzzy expert systems can assist anesthesiologist to manage drug dosage in a right manner. Designing a fuzzy rule-based expert system to determine the Propofol anesthetic drug dosage was the main objective of this study.Material and Methods: This is a retrospective study. Fuzzy IF-THEN rules were defined based on evidences and experts’ linguistic rules for Propofol dose determination. Fuzzy toolbox in MATLAB software was used to design the system. Validation of system conducted with calculation of mean absolute error (MAE) and root mean squared error (RMSE). Also, difference mean between actual and predicted doses was tested with paired t-test in SPSS V.26 software. Data from 50 ENT (ears, nose, and throat) surgeries were used to validate the fuzzy system.Results: MAE for induction and maintenance doses was 0.128 and 1.95 respectively. RMSE for induction and maintenance doses was 0.228 and 3.383 respectively. Based on paired t-test result, there was no significant correlation between actual and predicted values (P>0.05).Conclusion: Obtained value from test and validation of system demonstrated a high performance and satisfying accuracy of the system. Therefore, this expert system can be used as a decision support system to determine initial dosage of anesthetic drugs. It can also be used for anesthesia students to learn drug administration.


2021 ◽  
Author(s):  
Yi-Chang Zhao ◽  
Yang Zou ◽  
Dan Tang ◽  
Chen-Lin Xiao ◽  
Yi-Wen Xiao ◽  
...  

Abstract Background: Voriconazole is a triazole antifungal agent and a commonly used first-line treatment for invasive aspergillosis (IA). The study was performed to explore the factors affecting voriconazole trough concentration and maintenance dose to optimize voriconazole dosage in pediatric patients. Method: The demographic information, concentration data, CYP2C19 genotypes, and clinical outcomes of eligible pediatric patients from January 1th, 2016 to December 31th, 2018 were collected retrospective . Result: The study finally included 145 voriconazole trough concentrations from 94 pediatric patients. Steady trough concentration ranged from 0.04 to 16.11 μg/mL. Morerover, the distinction between the maximum and the minimum corrected concentration of per kilogram maintenance dosage is as high as 907 folds and children ≤2 years old showed the minimum variation compared to other individuals (P<0.001). A high inter- and intra-individual variability of voriconazole in pediatric patients were observed. Only 54.5% of the pediatric patients achieved the target range (1.0 to 5.5 μg/mL) at unadjusted initial dosage, while 35.9% of children were subtherapeutic, only 9.6% of children were supratherapeutic at unadjusted initial dosing. The younger children (≤12 years) seem to have a lower trough concentration (P=0.0096) and lower percentage of target achievements (P=0.004). And 98.97% of the maintenance dosage was below 9.0 mg/kg. For pediatric patients of different ages, it was found that most of them was underdosed. While, to achieve targeted therapeutic level for different age groups of ≤2, 2-6, 6-12, and 12-18 years, the median voriconazole maintenance doses were 5.7, 6.7, 5.0, and 3.3 mg-1kg/12h, respectively had been required in order to achieve therapeutic level (P<0.001). Conclusion: Pediatric patients especially those ≤12 years old might need a higher dosage regime to achieve therapeutic trough concentration. Importantly, early and repeat monitoring of voriconazole is essential to ensure the effectiveness and safety of voriconazole in children.


2021 ◽  
Author(s):  
Moataz Dowaidar

Patients and clinicians worldwide seeking access to gene therapy, lentiviral vector or gene editing-mediated gene therapy may become feasible options. Several nations have built vectors, manufacturing and regulatory methods and either run separate clinical trials or participate in international trials in order to get access to and experience.Vector safety and effectiveness across habitats should be identical. The dilemma of whether to utilize larger or lower vector doses or whether to seek higher or lower steady-state factor levels remains unanswered. Multiple vector-specific factors (preclinical data, early trial data, threshold effect presence, interpatient dose-expression relationship variability, or dose and risk of transaminitis relationship, estimated expression duration) as well as cost-effectiveness analyzes for each setting are all relevant to the vector dose decision (including data on the healthcare system, economics, available alternative treatments, accepted goal for quality of life or contribution of patients to society). Because patients are unlikely to get a second vector dosage, the initial dosage should be delivered and monitored under optimum conditions, especially to avoid early expression loss due to uncontrolled transaminitis.In clinical research, haemophilia gene therapy is crucial to continuing safety and efficacy testing. Communicating and coordinating internationally is crucial to providing worldwide access to gene therapy, avoiding a new gap in haemophilia care, raising awareness, sharing knowledge and experience, and building suitable infrastructure and regulatory and financial platforms.


2021 ◽  
Author(s):  
Shan He ◽  
Xiaolin Ma ◽  
Jinghui Yang ◽  
Li Li

Abstract ObjectiveTo explore the appropriate dosage of levothyroxine treatment for congenital hypothyroidism patients based on thyroid function.Methods116 patients who were regularly followed up in our endocrine clinic during January 2010 to December 2020 were allocated in 4 groups in terms of their thyroid function (group A: TSH ≥ 100mIU/L, group B: 20mIU/L ≤ TSH<100mIU/L, group C: 4.6mIU/L<TSH<20mIU/L while free thyroxine (FT4)<6.6pmol/L, group D: 4.6<TSH<20mIU/ while FT4>6.6pmol/L). The initial dosage of levothyroxine was individualized given to each patient based upon their TSH level and adjusted according to their thyroid function at every follow-up time point. The levothyroxine dosage at each time point of groups was compared, the thyroid function after treatment, physical and neurological development of different groups were also assessed.ResultsExcept for the first month after initial levothyroxine treatment, there was a statistical difference in thyroid function between groups (p < 0.05), and some patients hadn’t reached the normal level, in the following time points, after individualized dosage adjustment, all patients achieved the normal thyroid function, moreover, the difference of levothyroxine dosage was significant between four groups (p < 0.05) and positively correlated with the severity of disease. Although there were statistical differences in neurological development between groups (p < 0.05), they were all within the normal range.ConclusionCompared to recommend dosage, individualized Levothyroxine dosage could also obtain the same therapeutic effect while may reduce the risk of drug overdose.


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