Regular Dose Research Articles

Dietary Supplementation of 25-Hydroxyvitamin D3 Improves Growth Performance, Antioxidant Capacity and Immune Function in Weaned Piglets.

This study was conducted to evaluate the effects of 25-hydroxyvitamin D3 (25(OH)VD3) and Vitamin D3 (VD3) supplemented in the diet of weaned piglets on their growth performance, bone quality, intestinal integrity, immune function and antioxidant capacity. A total of 192 weaned piglets were allocated into four groups and they were fed a control diet containing 2000 IU VD3 (negative control, NC), NC + 100 ppm colistin sulfate (positive control, PC), NC + 2000 IU VD3 (VD3) and NC + 2000 IU 25(OH)VD3 (25(OH)VD3). The results showed that 25(OH)VD3 improved the growth performance, bone quality and antioxidase activity of piglets compared with the other groups. Meanwhile, 25(OH)VD3 up-regulated ileal mRNA expressions of tight junction proteins and host defense peptides. The VD3 group had an increased intestinal sIgA content and mRNA expression of pBD-1 compared with the NC group. Both groups of VD3 and 25(OH)VD3 altered the microbial β-diversity compared with the NC group, and 25(OH)VD3 increased ileal concentrations of acetate and butyrate. In conclusion, our findings indicated that a regular dosage of 2000 IU VD3 in the weaned piglets’ diet did not achieve optimal antioxidant capacity and immune function. 25(OH)VD3 had better growth performance than VD3 at the same inclusion level, which is associated with the improved intestinal integrity and antioxidant capacity.

Effect of Acupressure at P6 on Nausea and Vomiting in Women with Hyperemesis Gravidarum: A Randomized Controlled Trial.

Hyperemesis gravidarum is characterized by severe nausea and vomiting. This study aims to illustrate the efficacy of acupressure at P6 in treating nausea and vomiting in hyperemesis gravidarum. This parallel randomized controlled trial was conducted from 2016–2017 in a tertiary hospital. Hospitalized women with ≤16 weeks of gestation and moderate to severe nausea and vomiting classified using a modified PUQE score were randomly assigned in a 1:1 ratio to either apply an acupressure wristband at the P6 point three times daily or to receive regular doses of intravenous antiemetics. The primary outcome was differences in modified PUQE scores among the groups. The secondary outcomes were differences in the rate of urine ketone clearance and the frequency of requiring rescue antiemetics. Ninety women were equally randomized into two groups, with no dropout. There was a statistically significant difference in the degrees of nausea and vomiting between the groups at 8, 16, and 24 hours post-admission (p8hours= 0.001, p16hours = 0.006, and p24hours = 0.001). The requirement of antiemetics and the rate of urine ketone clearance between the two groups were also statistically significant, at p = 0.001 and p = 0.02 respectively. There were no side effects in either group. The P6 acupressure was efficacious in alleviating nausea and vomiting among hyperemesis gravidarum women. The trial was retrospectively registered on ClinicalTrials.gov (NCT05175079).

Effects of missed dose and delayed dose quetiapine on its pharmacokinetics and pharmacodynamics

Nonadherence to the prescribed medication can result in a poor treatment outcome. This study determined the impacts of multiple missed dose or delayed dose scenarios on quetiapine (QTP) pharmacokinetics and pharmacodynamics. QTP concentration-time profiles and Brief Psychiatric Rating Scale (BPRS) scores under multiple missed doses and delayed dose scenarios were simulated using Monte Carlo simulations and compared with those of the full adherence scenario using the Mann-Whitney U test. The simulations were performed using the model structure and parameter estimates obtained from Kimko et al's study. Missing one, two and three consecutive QTP doses significantly decreased trough concentration (Ctrough) by 71.4, 103, and 128ng/mL. However, Ctrough rapidly increased to values close to those of the full adherence scenario when the regular dose was resumed. Further, all missed dose scenarios did not significantly impact the maximum percent reduction of BPRS score from baseline, but significant impacts on the minimum percent reduction of BPRS score from baseline were observed. However, the change in BPRS score from the full adherence scenario rapidly resumed when the regular dose was taken. Moreover, this study identified that a delayed dose as late as 6 hours did not significantly impact the maximum concentrations when the regular dose was resumed. Based on the simulations, a missed dose can be taken as late as 6 hours before the next scheduled dose, otherwise it should be skipped. For multiple missed doses scenarios, QTP pharmacokinetics and pharmacodynamics rapidly returned to the stage close to the full adherence scenario when a single regular dose was resumed.

The Temperature Effect of Madeira Vine (Anredera Cordifolia) Leaf Oil Extraction and Its Characterization as An Additive in Health Supplement Product

The immune system is one of the most important things that need to be preserved in the midst of the Corona Virus Disease 2019 (Covid-19) pandemic. Consuming the components of the compounds contained in Madeira vine (Binahong) leaf oil in the right and regular doses can be one way to enhance the immune system. This oil can be obtained by carrying out the extraction process with the reflux method on Madeira vine leaf. This study aimed to determine the optimal time and temperature of Madeira vine leaf oil extraction process. The extraction process was carried out at 40, 50, and 60 °C for 90, 100, and 110 minutes. Madeira vine leaf oil obtained was analyzed for its density, solubility in ethanol, and chemical compounds. The results showed that the highest yield (62.45% w/w) was achieved using optimal temperature of 60 °C and time of 110 minutes. The density of the oil obtained ranges from 0.786-0.812 gr/ml. Analysis using Gas Chromatography-Mass Spectrophotometry (GCMS) showed that the resulting extract contained several components namely Neophytadiene; 2-Hexadecen-1-ol, 3,7,11,15-tetramethyl (phytol); Hexadecanoic Acid, methyl ester (methyl palmitate); 9,12-Octadecadienoic acid (Z,Z), methyl ester (methyl linoleate); 9-Octadecenoic acid (Z), methyl ester (methyl oleate); 9-Octadecenoic acid, methyl ester;and Octadecanoic acid, methyl ester (Stearic acid).

Early [18]FDG PET/CT scan predicts tumor response in head and neck squamous cell cancer patients treated with erlotinib adjusted per smoking status.

Translational RelevanceEvaluation of targeted therapies is urgently needed for the majority of patients with metastatic/recurrent head and neck squamous cell carcinoma (HNSCC) who progress after immunochemotherapy. Erlotinib, a targeted inhibitor of epidermal growth factor receptor pathway, lacks FDA approval in HNSCC due to inadequate tumor response. This study identifies two potential avenues to improve tumor response to erlotinib among patients with HNSCC. For the first time, this study shows that an increased erlotinib dose of 300 mg in smokers is well-tolerated and produces similar plasma drug concentration as the regular dose of 150 mg in non-smokers, with increased study-specific defined tumor response. The study also highlights the opportunity for improved patient selection for erlotinib treatment by demonstrating that early in-treatment [18]FDG PET/CT is a potential predictor of tumor response, with robust statistical correlations between metabolic changes on early in-treatment PET (4-7 days through treatment) and anatomic response measured by end-of-treatment CT.PurposePatients with advanced HNSCC failing immunochemotherapy have no standard treatment options. Accelerating the investigation of targeted drug therapies is imperative. Treatment with erlotinib produced low response rates in HNSCC. This study investigates the possibility of improved treatment response through patient smoking status-based erlotinib dose optimization, and through early in-treatment [18]FDG PET evaluation to differentiate responders from non-responders.Experimental designIn this window-of-opportunity study, patients with operable HNSCC received neoadjuvant erlotinib with dose determined by smoking status: 150 mg (E150) for non-smokers and 300 mg (E300) for active smokers. Plasma erlotinib levels were measured using mass spectrometry. Patients underwent PET/CT before treatment, between days 4-7 of treatment, and before surgery (post-treatment). Response was measured by diagnostic CT and was defined as decrease in maximum tumor diameter by ≥ 20% (responders), 10-19% (minimum-responders), and < 10% (non-responders).ResultsNineteen patients completed treatment, ten of whom were smokers. There were eleven responders, five minimum-responders, and three non-responders. Tumor response and plasma erlotinib levels were similar between the E150 and E300 patient groups. The percentage change on early PET/CT and post-treatment PET/CT compared to pre-treatment PET/CT were significantly correlated with the radiologic response on post-treatment CTs: R=0.63, p=0.0041 and R=0.71, p=0.00094, respectively.ConclusionThis pilot study suggests that early in-treatment PET/CT can predict response to erlotinib, and treatment with erlotinib dose adjusted according to smoking status is well-tolerated and may improve treatment response in HNSCC. These findings could help optimize erlotinib treatment in HNSCC and should be further investigated.Clinical Trial Registration https://clinicaltrials.gov/ct2/show/NCT00601913, identifier NCT00601913.

Next-Generation Personalized Medicine: Implementation of Variability Patterns for Overcoming Drug Resistance in Chronic Diseases

Chronic diseases are a significant healthcare problem. Partial or complete non-responsiveness to chronic therapies is a significant obstacle to maintaining the long-term effect of drugs in these patients. A high degree of intra- and inter-patient variability defines pharmacodynamics, drug metabolism, and medication response. This variability is associated with partial or complete loss of drug effectiveness. Regular drug dosing schedules do not comply with physiological variability and contribute to resistance to chronic therapies. In this review, we describe a three-phase platform for overcoming drug resistance: introducing irregularity for improving drug response; establishing a deep learning, closed-loop algorithm for generating a personalized pattern of irregularity for overcoming drug resistance; and upscaling the algorithm by implementing quantified personal variability patterns along with other individualized genetic and proteomic-based ways. The closed-loop, dynamic, subject-tailored variability-based machinery can improve the efficacy of existing therapies in patients with chronic diseases.

Patients' and physicians’ perspectives on the burden and management of asthma: Results from the APPaRENT 2 study

BackgroundThe 2021 Global Initiative for Asthma (GINA) report recommends 2 treatment tracks depending on choice of reliever therapy: either inhaled corticosteroid (ICS)/formoterol, or short-acting β2-agonist (SABA) with ICS to be used whenever a SABA is taken. ObjectiveThe Asthma Patients' and Physicians’ Perspectives on the Burden and Management of Asthma (APPaRENT) 2 study aimed to understand current real-world treatment approaches and their alignment with GINA recommendations. MethodsPatients and physicians were recruited for the online survey from online panels from August–November 2021. Inclusion criteria: adults, physician diagnosis of asthma, ≥6 months prescribed inhaler use (patients); primary care, ≥4 patients with asthma per month, ≥3 years clinical practice (physicians). Results1650 patients and 1080 physicians were included. For patients with moderate to severe asthma, physicians prescribed proactive regular dosing (PRD) with ICS/long-acting β2-agonist (LABA) combination with (47%) or without (15%) SABA as initial therapy. Most pulmonologists (75%) and general practitioners (57%) selected a PRD approach. The majority of patients, 85% (79–91%), considered to be using maintenance and reliever therapy (MART), were also prescribed non-ICS rescue inhaler. ConclusionsPhysicians preferred a preventive regular dosing approach to achieve symptom control for patients with moderate to severe asthma, which is more aligned with GINA 2021 Track 2 recommendations than Track 1. Many patients on MART request additional rescue inhalers, suggesting that MART is being misapplied in most instances and that patients may perceive their asthma as inadequately controlled with MART therapy.

Local Adverse Drug Reactions in Ambulatory Asthma Patients Treated With Inhaled Corticosteroids: An Experience from a South Indian Teaching Hospital

Background:Inhaled corticosteroids (ICS) have an essential and established role in the treatment of asthma. Both systemic and local adverse effects may accompany the long-term use of ICS. Systemic adverse drug reactions (ADRs) of ICS are well established. However, there is a pau-city of information on local ADRs, especially in the Indian population.Objectives:This study aimed to determine the prevalence, severity, predictability, and preventabil-ity of local ADRs to ICS and their associated risk factors.Methods:Patients with asthma who need ICS were enrolled. Study patients were interviewed with open-ended questions to assess local ADRs to ICS at baseline and each follow-up visit, once a month for three months. Causality (Naranjo’s algorithm and WHO scale), severity (Hartwig SC scale), predictability (based on the frequency of occurrence of ADR and history of drug exposure), and preventability (Schumock and Thornton criteria) of local ADRs were assessed. Bivariate analy-sis and subsequently multivariate logistic regression were used to identify the risk factors for local ADRs to ICS.Results:A total of 243 patients (134 female) were included in the study. A total of 74 local ADRs were observed in 59 patients (a prevalence of 24.3%). The most common local ADRs included the feeling of thirst (14.8%), followed by cough during inhalation (8.6%) and taste disturbance (4.5%). All ADRs were predictable and mild in severity. Preventability assessment found 85.1% of local ADRs as ‘probably preventable’. Two out of five patients who had ADRs reduced or skipped doses because of the discomfort, despite their physician’s recommendation to continue their regular dose of ICS. Age &gt;41 years, use of MDI without spacer, and use of budesonide were identified as the risk factors for developing ADRs to ICS.Conclusion:Local ADRs to ICS were observed in approximately one in four patients with asthma. Two out of five patients who had ADRs reduced or skipped doses. Strategies to prevent local ADRs to ICS should focus on patients aged &gt;41 years, receiving budesonide, and using MDI without a spacer. We need to establish standards on the best practices for preventing ADRs, such as identify-ing the most suited device or ICS that is best tolerated by the individual patient and identifying the least ICS dose that maintains ideal asthma control.

Lithium replacement dose recommendations using Monte Carlo simulations.

Missed medication doses are a common clinical problem, and cause consternation when prescribing lithium because its plasma levels must be kept within a narrow therapeutic window. Therefore, this study set out to determine the potential impact of missed lithium doses on its pharmacokinetics, and to explore the optimal compensatory dosing scheme. This is difficult to determine clinically and in research because of ethical constraints and therefore we modelled the effects using simulations. Monte Carlo simulations were used to simulate lithium concentrations under different missed dose scenarios. For patients with normal renal function, the optimal replacement dosing scheme was selected based on the lowest percentage of deviation from the full adherence scenario. However, for patients with renal impairment the appropriate dosing schedule was selected based on the lowest number of simulated concentrations above the upper range of 1.2mEq/L. The impact of a missed lithium dose depended on its daily dose. The higher the daily dose, the higher the deviation from full adherence. In patients with normal renal function, replacement with a regular dose was most appropriate. But in patients with renal impairment, replacement with a partial dose appeared to be most suitable. This study has enabled insights into the optimal suitable lithium replacement dosing schemes for patients with normal renal function and renal impairment. These proposed schemes can be used cautiously in clinical practice in conjunction with clinician judgment and can also be used as a basis for future clinical research.

Pharmacotherapy for pulmonary embolism: new anticoagulants

Background: Pulmonary embolism is associated with reduced survival and considerable economic burden worldwide. In Korea, the incidence of pulmonary embolism has been gradually increasing. Older individuals are at an increased risk for pulmonary embolism and anticoagulation-related bleeding events. Typically, heparin and vitamin K antagonists are employed to treat pulmonary embolism; however, these agents present numerous limitations. Hence, novel anticoagulants with improved safety and efficacy profiles are urgently needed.Current Concepts: Direct oral anticoagulants (DOACs), including direct thrombin (coagulation factor II) inhibitors and selective inhibitors of coagulation factor Xa, have emerged as alternative agents. Phase III, large-scale clinical trials have revealed that DOACs are non-inferior to standard therapy during initial and long-term treatment of pulmonary embolism, considering the safety profile. Evidence-based clinical guidelines recommend that primary care clinicians employ DOACs over warfarin to achieve anticoagulation.Discussion and Conclusion: For over 70 years, the standard therapy for most patients with pulmonary embolism has involved heparin administration, overlapped and followed by a vitamin K antagonist. Recently developed DOACs against coagulation factor Xa or thrombin might overcome limitations of standard therapy, including the need for injection and regular dose adjustment with laboratory monitoring. These limitations hinder the management of patients with pulmonary embolism and negatively impact the patient’s quality of life. Four DOACs, including apixaban, dabigatran, edoxaban, and rivaroxaban, are currently available for treating pulmonary embolism in Korea, which could simplify the therapeutic strategy.

Vitamin D and SARS-CoV2 infection, severity and mortality: A systematic review and meta-analysis.

To assess the evidence on SARS-CoV2 infection and Covid-19 in relation to deficiency and supplementation of vitamin D, we conducted a systematic review up to April 2021. We summarised data from 38 eligible studies, which presented risk estimates for at least one endpoint, including two RCT and 27 cohort-studies: 205565 patients with information on 25OHD status and 2022 taking vitamin D supplementation with a total of 1197 admitted to the ICU or who needed invasive mechanical ventilation or intubation and hospital stay, and more than 910 Covid-19 deaths. Primary outcomes were severity and mortality and the main aim was to evaluate the association with vitamin D supplementation. Random effects models showed that supplementation was associated with a significant lower risk of both Covid-19 severe disease (SRR 0.38, 95% CI 0.20-0.72, 6 studies) and mortality (SRR 0.35, 95% CI 0.17-0.70, 8 studies). There were no statistically significant dose differences between studies: summary estimates with regular doses remain statistically significant, suggesting that higher doses are not necessary. For patients on vitamin D supplementation, a greater reduction in mortality risk emerged in older individuals and at higher latitudes. Regarding the quality of studies, assessed using the New Castle-Ottawa quality scale, the analysis revealed in most cases no statistically significant differences between low, medium or high quality studies. We found significant associations of vitamin D supplementation with Covid-19, encompassing risks of disease worsening and mortality, especially in seasons characterized by 25OHD deficiency and with not severe patients. Dedicated randomized clinical studies are encouraged to confirm these results.

The Skin of Our Teeth, PlayMakers Repertory Company, Chapel Hill, North Carolina

<i>The Skin of Our Teeth</i>, PlayMakers Repertory Company, Chapel Hill, North Carolina

Effect of Nonadherence on Levetiracetam Pharmacokinetics and Remedial Dose Recommendations Using Monte Carlo Simulations.

Nonadherence to levetiracetam (LEV) use can result in subtherapeutic concentrations and increase the risk of the occurrence of seizures. The impact of missing LEV doses on its pharmacokinetics and evidence of the appropriate remedial dose is lacking. This study has determined the influence of missed LEV doses on its pharmacokinetics and has explored the appropriate remedial dosage regimens. Monte Carlo simulation was used to assess the impacts of different remedial dosage regimens on LEV concentrations. Simulated LEV concentrations outside the individual therapeutic range were calculated for the compliance scenario and for each of the remedial dosage regimens. The percentage of deviation from the full compliance scenario was alsocalculated. The regimen with the lowest percentage of deviation was considered the most appropriate. The suitable LEV remedial dose varied across the delay times. For one missed dose, a remedial regimen with a regular dose followed by the usual dose was suitable for a delay time of less than 6 h, while areplacement with a regular dose followed by a partial dose appeared to be appropriate for a delay time of 6 h and longer. This was justified based on the concerns of LEV toxicity when the remedial dose is close to the next scheduled dose. For two consecutive missed doses, a remedial dose with one and a half of the regular dose was suitable if the gap between that and the next dose was greater than 6 h. The appropriate remedial dosage regimen for one and two consecutive missed doses of LEV have been proposed. These remedial regimens, however, should be applied with clinicians' judgment based on the clinical status of the patients.

P809: MODULATION OF ARACHIDONIC ACID PATHWAY BY IBUPROFEN RESULTS IN COMPLETE HEMATOLOGICAL RESPONSE IN GHOSAL HEMATODIAPHYSEAL DYSPLASIA WITHOUT NEED FOR CORTICOSTEROID

Background: Ghosal hematodiaphyseal dysplasia (GHDD) is a rare autosomal recessive disorder characterized by pancytopenia and increased bone density of the long bones. First described in families of Indian and Middle Eastern descent, subsequent studies identified the genetic lesion in this disease as due to loss of function mutations in the TBXAS1 gene encoding thromboxane synthase, a key component of the arachidonic acid pathway responsible for the formation of thromboxane A2 from prostaglandin H2. As well as pancytopenia, laboratory features include platelet aggregation defects and increase in osteoblastic activity, the latter being the basis of increased bone density in patients with Ghosal syndrome. Simultaneously, loss of thromboxane synthase activity may be associated with shunting of prostaglandin precursors away from production of thromboxane into production of pro-inflammatory prostaglandins. This may be the mechanism responsible for the observed marrow suppression seen in these patients. We describe a 3 year old female of non-consanguineous parents of Filipino origin who presented with marked pancytopenia. Next Generation Sequencing bone marrow failure gene panel revealed a novel homozygous mutation in TBXAS1. Subsequent DXA scanning revealed increased bone mineral density consistent with the diagnosis (Z -score +2.4 for lumbar spine (L1-4)) although clinical sequelae of bony disease were not apparent. Aims: While multiple case reports document that these patients have hematological response to long term corticosteroid therapy, we hypothesized that inhibition of cyclooxygenase (COX) upstream of thromboxane synthase in the arachidonic acid pathway may be effective in this condition. Methods: Patient was treated with ibuprofen at regular therapeutic doses (approximately 30 mg/kg/24 hours daily initially) and serial full blood counts were monitored. Results: The patient exhibited a rapid and complete response to ibuprofen with normalization of full blood counts. The dose of ibuprofen was reduced to 10 mg/kg/day, and hematologic response is maintained on low dose after one year.The treatment is well tolerated with no side effects. Image:Summary/Conclusion: Treatment of GHDD with ibuprofen is a novel approach that offers clear potential benefits in comparison to the known adverse effects profile of long term corticosteroids. Bone density scan and markers are in process to ascertain the impact of this treatment on bone density, although this may take longer to show beneficial effects. The treatment was easily tolerated and well managed by the patient and family at home with minimum disruption to her quality of life.

PB2097: ZANUBRUTINIB PLUS RITUXIMAB FOR THE TREATMENT OF ELDERLY UNFIT PATIENTS WITH PREVIOUSLY UNTREATED DIFFUSE LARGE-B CELL LYMPHOMA

Background: Diffuse Large B-cell lymphoma (DLBCL) is common in the elderly patients, Some elderly patients can not tolerate the standard dose of R-CHOP due to age, poor physical condition, and severe complications. The overall response rate of elderly unfit DLBCL patients who received a reduced dose R-CHOP regimen was only 60%. It is extremely important to explore new therapeutic options. Zanubrutinib is a Bruton tyrosine kinase (BTK) inhibitor which was still in an exploratory phase in patients with DLBCL.The efficacy of Zanubrutinib plus Rituximab in elderly unfit Patients with DLBCL is still unknown. Aims: This study was conducted to investigate the efficacy and safety of Zanubrutinib plus Rituximab in elderly unfit Patients With Previously Untreated Diffuse large-B cell Lymphoma in China. Methods: In the present study, a prospective, single-arm,single-center study was conducted (CHiCTR-2000039342). patients who fulfil the inclusion criteria were enrolled. Inclusion criteria: patients aged ≥65 years, pathologically confirmed DLBCL,and assessed unfit by Comprehensive Geriatric Assessment(IACA). Unfit patients defined as follows: i.e. IADL score ≤7, or age >75 years, or CCI score ≥3, or serum albumin <3.4 g/ml. Patients enrolled were planed to treat with Zanubrutinib combined with rituximab (Zanubrutinib 160 mg orally twice daily and rituximab 375 mg/m2 day1 iv, every 28 days, ZR regimen), for a total of eight courses. After induction therapy, maintenance treatment with Zanubrutinib 160mg orally twice daily was given until disease progression or unacceptable toxicity. Efficacy was evaluated by PET/CT or enhanced Computed Tomography scan every two months, treatment-related adverse effects were evaluated in every one month. This study was approved by the Ethics Committee of Beijing Hospital, National Center of Gerontology, Beijing, China. Results: From July 2020 to December 2021, a total of eight elderly unfit DLBCL patients were enrolled. one patient was 72 years old with IADL score of 6, CCI score of 4. the other seven patients were aged over 80 years. the most common comorbidities were cardiovascular disease, hypertension, diabetes.The female to male ratio was 6:2. four patients were classified as GCB pathological subtype, six patients were diagnosed with stage III-IV. At a median follow up of 8 months (2-19months). two patients achieved complete response(CR), and remained in CR at months 8. four patients achieved partial response(PR), with one patient disease progression(PFS 8 months), one patient achieved stable disease (SD) after 2 cycles and have disease progression after 4cycles, with a progression-free survival (PFS) of 4 months. one patient was refractory to treatment and withdrew after 2 cycles. One patients died due to disease progression, with overall survival(OS) of 11 months, ZR regimen was well-tolerated, with grade 2 urinary tract infections in 4/7 patients, grade 2 respiratory infections in 2/7, grade 1 Petechial hemorrhages in 3/7, grade 2 skin rash in 2/7, and grade 2 deep vein thrombosis in 1/7. No grade 4 or higher adverse events were observed. Seven patients had a dose reduction due to toxicity. The regular doses of Zanubrutinib can be tolerated was 160 mg qdA1-80mg qdP1. Two patients had discontinued Zanubrutinib due to adverse events for one to three weeks. Image:Summary/Conclusion: Zanubrutinib in combination with Rituximab may be a well-tolerated and effective regimen in elderly unfit DLBCL patients. Dose reduction may be required for some patients to improve tolerability. A large sample size clinical trial is needed to further validate this conclusion in the future.

The effect of nonadherence on phenobarbital concentrations and recommendations on the replacement dose using Monte Carlo simulation.

To determine the impacts of missed phenobarbital (PB) doses on its pharmacokinetics and to investigate the appropriate replacement dosing scheme for various PB missed dose scenarios. Monte Carlo simulations were performed using parameters from the selected population pharmacokinetic study. The impacts of missed PB dose and the proper replacement dosing scheme were assessed based on the percent deviation of simulated concentrations outside the reference range from the full adherence scenario. The impact of missed PB dose on its concentrations depended on the daily dose. The replacement with a respective regular dose and one and a half regular dose was appropriate for the one and two missed doses scenarios for patients receiving PB monotherapy. For patients receiving PB with valproic acid or phenytoin, the same replacement scheme was still appropriate. The results also indicated that weight did not influence the proper replacement dosing scheme. The impacts of missed PB doses on its pharmacokinetics were identified and the proper replacement dosing schemes for different missed dose scenarios were proposed. These schemes should be implemented based on the clinician's justification of the patient's seizure control.

The effect of nonadherence on phenobarbital concentrations and recommendations on the replacement dose using Monte Carlo simulation.

To determine the impacts of missed phenobarbital (PB) doses on its pharmacokinetics and to investigate the appropriate replacement dosing scheme for various PB missed dose scenarios. Monte Carlo simulations were performed using parameters from the selected population pharmacokinetic study. The impacts of missed PB dose and the proper replacement dosing scheme were assessed based on the percent deviation of simulated concentrations outside the reference range from the full adherence scenario. The impact of missed PB dose on its concentrations depended on the daily dose. The replacement with a respective regular dose and one and a half regular dose was appropriate for the one and two missed doses scenarios for patients receiving PB monotherapy. For patients receiving PB with valproic acid or phenytoin, the same replacement scheme was still appropriate. The results also indicated that weight did not influence the proper replacement dosing scheme. The impacts of missed PB doses on its pharmacokinetics were identified and the proper replacement dosing schemes for different missed dose scenarios were proposed. These schemes should be implemented based on the clinician's justification of the patient's seizure control.

Therapeutically dosed low molecular weight heparins in renal impairment: a nationwide survey

PurposeInternational guidelines vary in their recommendations whether or not to reduce the therapeutic dose of low molecular weight heparins (LMWHs) in renal impairment. The use of anti-Xa monitoring as a basis of dose adjustments is also a matter of debate. As this may lead to variations in treatment policies, we aimed to study the treatment policies of therapeutically dosed LMWHs in renal impairment in Dutch hospitals.MethodsAn 11-item survey was distributed between June 2020 and March 2021 to hospital pharmacists, representing Dutch hospital organisations. Primary outcomes were the dosing regimens of therapeutically dosed LMWHs in renally impaired patients. Secondary outcomes were the proportion of hospitals that used anti-Xa monitoring and the anti-Xa target range used.ResultsThere was a response from 56 of 69 (81%) Dutch hospital organisations where in each case a hospital pharmacist completed the survey. In these hospitals, 77 LMWH regimens were in use. In 76 of 77 (99%) regimens, a regular dose reduction was used at the start of treatment. Fifty-five of these hospitals used a dose reduction if estimated glomerular filtration rate (eGFR) < 50 ml/min and 17 used a dose reduction if eGFR < 30 ml/min. Anti-Xa levels were not routinely monitored in 40% of regimens, while 22% monitored anti-Xa if eGFR < 50 ml/min, 27% if eGFR < 30 ml/min and 10% in other eGFR cutoff values. Target ranges of 1.0–2.0 IU/ml (once daily) and 0.5/0.6–1.0 IU/ml (twice daily) were used in 69% of regimens that included monitoring of anti-Xa.ConclusionTreatment policies show substantial diversity in therapeutically dosed LMWHs in renally impaired patients. The most commonly used treatment regimen was a regular dose reduction if eGFR is < 50 ml/min, without anti-Xa monitoring.

Hypersensitivity and Induced Radioresistance in Chinese Hamster Cells Exposed to Radiations with Different LET Values.

We study the impact of radiation LET on manifestation of HRS/IRR response in Chinese hamster cells ovary cells exposed to radiations used in radiotherapy. Earlier we have investigated this response to carbon ions (455 MeV/amu) in the pristine Bragg curve plateau and behind the Bragg peak, 60Co γ-rays, and 14.5 MeV neutrons. Now we present results of cytogenetic metaphase analysis in plateau-phase CHO-K1 cells irradiated with scanning beam protons (83 MeV) at doses < 1 Gy and additional data for 14.5 MeV neutrons. Dose curves for frequency of total chromosome aberrations (CA, protons), paired fragments (protons, neutrons), aberrant cells (neutrons) had typical HRS/IRR structure: HRS region (up to 0.1 and 0.15 Gy), IRR region (0.1–0.6 Gy and 0.15–0.35 Gy) for protons and neutrons, respectively, and regular dose dependence. Taken together with previous results, the data show that LET increase shifts the HRS upper border (from 0.08–0.1 Gy for γ-rays, protons and plateau carbons to 0.12–0.15 Gy for “tail” carbons and neutrons). The IRR regions shortens (0.52–0.4 γ-rays and protons, 0.25 plateau carbons, 0.2 Gy “tail” carbons and neutrons). CA level of IRR increases by 1.5–2.5 times for carbons as compared to γ-rays and protons. Outside HRS/IRR the yield of CA also enhanced with LET increase. The results obtained for different LET radiations suggest that CHO-K1 cells with G1-like CA manifested the general feature of the HRS/IRR phenomena.

Comparison of Power of Trend Tests for Toxicological Application Based on Dose-Response Profiles Enumerated Using a Nonparametric Algorithm.

Tests for dose-response trend may be used to support conclusions on the toxicity of a substance in a range of doses evaluated in a comparative experiment. Criteria are proposed for evaluating and comparing alternative tests, and are applied in a comparison of certain tests applicable with continuous responses, namely, a multiplicity-adjusted pairwise comparison procedure, a trend test based on a single contrast, and four multiple-contrast trend tests. Methods considered treat dose as ordinal information. A particular focus was comparison of the simple test of a single contrast, with coefficients proportional to dose rank, with the multiple-contrast methods available with modern computing. To explore the role of the dose-response curve shape, regular dose-response shapes (or profiles), defined by the mean response for each dose level, using a simple grid-based algorithm were generated. Power for individual profiles may be used to illustrate the effect of curve shape on the power of alternative tests. To facilitate selection of tests, we report average power over profiles, averaging at different levels of granularity, first separately for each of several curve shape categories, and then over all profiles, weighting shape categories equally. Power results for the six tests evaluated at least provide clear distinctions between some procedures that are more-preferred, versus less-preferred. Our analyses expand the comparisons of tests available and contribute a methodology for choice of statistical methods for toxicological data analysis. Environ Toxicol Chem 2022;41:1754-1764. Published 2022. This article is a U.S. Government work and is in the public domain in the USA.