Therapeutic drug monitoring in pregnancy: Levetiracetam.

OBJECTIVE: Levetiracetam (LEV) is an antiseizure medication that is mainly excreted by the kidneys. Due to its low teratogenic risk, LEV is frequently prescribed for women with epilepsy (WWE). Physiological changes during gestation affect the pharmacokinetic characteristics of LEV. The goal of our study was to characterize the changes in LEV clearance during pregnancy and the postpartum period, to better plan an LEV dosing paradigm for pregnant women. METHODS: This retrospective observational study incorporated a cohort of women who were followed up at the epilepsy in pregnancy clinic at Tel Aviv Sourasky Medical Center during the years 2020-2023. Individualized target concentrations of LEV and an empirical postpartum taper were used for seizure control and to reduce toxicity likelihood. Patient visits took place every 1-2 months and included a review of medication dosage, trough LEV blood levels, week of gestation and LEV dose at the time of level measurement, and seizure diaries. Total LEV concentration/dose was calculated based on LEV levels and dose as an estimation of LEV clearance. RESULTS: A total of 263 samples were collected from 38 pregnant patients. We observed a decrease in LEV concentration/dose (C/D) as the pregnancy progressed, followed by an abrupt postpartum increase. Compared to the 3rd trimester, the most significant C/D decrease was observed at the 1st trimester (slope = .85), with no significant change in the 2nd trimester (slope = .11). A significant increase in C/D occurred postpartum (slope = 5.23). LEV dose was gradually increased by 75% during pregnancy compared to preconception. Average serum levels (µg/mL) decreased during pregnancy. During the postpartum period, serum levels increased, whereas the LEV dose was decreased by 24%, compared to the 3rd trimester. SIGNIFICANCE: LEV serum level monitoring is essential for WWE prior to and during pregnancy as well as postpartum. Our data contribute to determining a rational treatment and dosing paradigm for LEV use during both pregnancy and the postpartum period.

A Case Series of 11 Patients With Subacute Serotonin Syndrome.

BACKGROUND: Serotonin syndrome is an acute, life-threatening illness characterized by mental status changes, neuromuscular symptoms, and autonomic instability. Some patients taking serotonergic antidepressants have been noted to have unexplained mental status changes and/or neuromuscular changes without autonomic instability raising the possibility of a more chronic or attenuated form of serotonin syndrome. OBJECTIVE: Assessment of antidepressant blood levels to support the diagnosis of a subacute serotonin syndrome. METHODS: At a tertiary psychiatric outpatient clinic, patients with unexplained mental status and/or neuromuscular changes without autonomic instability had antidepressant blood levels assessed. RESULTS: Eleven patients were identified with signs and symptoms partially consistent with serotonin syndrome. Nine patients had cognitive changes, while four patients had motor changes, and three patients had psychosis. All patients had elevated blood levels of a single serotonergic antidepressant. Limited follow-up suggests that symptoms improve with reduction of antidepressant medication. CONCLUSIONS: These cases suggest that a more chronic, attenuated form of serotonin syndrome exists. Diagnostic criteria are proposed for a distinct clinical entity: subacute serotonin syndrome (SSS). Further research is required to validate these criteria. Clinicians should consider drawing antidepressant levels for patients with symptoms and signs suggestive of SSS-especially those at increased vulnerability for excessive serotonergic agonism. Given the high prevalence of antidepressant medication use, the awareness of SSS could lead to improved patient outcomes and public health.

The Clearance of Midazolam and Metabolites during Continuous Renal Replacement Therapy in Critically Ill Patients with COVID-19.

INTRODUCTION: Midazolam-based continuous intravenous sedation in patients admitted to the intensive care unit (ICU) was a necessity during the COVID-19 pandemic. However, benzodiazepine-based sedation is associated with a high incidence of benzodiazepine-related delirium and additional days on mechanical ventilation. Due to the requirement of high midazolam doses in combination with the impaired renal clearance (CL) of the pharmacological active metabolite 1-OH-midazolam-glucuronide (10% compared to midazolam), ICU patients with COVID-19 and continuous renal replacement therapy (CRRT) were at risk of unintended prolonged sedation. Several CRRT-related factors may have influenced the delivered CL of midazolam and its metabolites. Therefore, the aim of the study was to identify and describe these CRRT-related factors. METHODS: Pre-filter blood samples and ultrafiltrate samples were collected simultaneously. Midazolam, 1-OH-midazolam, and 1-OH-midazolam-glucuronide plasma samples were analyzed using an UPLC-MS/MS method. The prescribed CRRT dose was corrected for downtime and filter integrity using the urea ratio (urea concentration in effluent/urea concentration plasma). CL of midazolam and its metabolites were calculated with the delivered CRRT dose (corrected for downtime and saturation coefficient [SD]). RESULTS: Three patients on continuous venovenous hemodialysis (CVVHD) and 2 patients on continuous venovenous hemodiafiltration (CVVHDF) were included. Midazolam, 1-OH-midazolam, and 1-OH-midazolam-glucuronide concentrations were 2,849 (0-6,700) µg/L, 153 (0-295) µg/L, and 27,297 (1,727-39,000) µg/L, respectively. The SD was 0.03 (0.02-0.03) for midazolam, 0.05 (0.05-0.06) for 1-OH-midazolam, and 0.33 (0.23-0.43) for 1-OH-midazolam-glucuronide. The delivered CRRT CL was 1.4 (0-1.7) mL/min for midazolam, 2.7 (0-3.5) mL/min for 1-OH-midazolam, and 15.7 (4.0-27.7) mL/min for 1-OH-midazolam-glucuronide. CONCLUSIONS: Midazolam and 1-OH-midazolam were not removed during CVVHD and CVVHDF. However, 1-OH-midazolam-glucuronide was removed reasonably, approximately up to 43%. CRRT modality, filter integrity, and downtime affect this removal. These data imply a personalized titration of midazolam in critically ill patients with renal failure and awareness for the additional sedative effects of its active metabolites.

Maternal and umbilical cord blood levels of leptin in pre-eclamptic and healthy pregnant women: A comparative cross-sectional study.

BACKGROUND: Pre-eclampsia is a multi-systemic disease with its attendant increased maternal and perinatal morbidities and mortality. It has been hypothesized that leptin contributes immensely to the natural history of pre-eclampsia. However, there is considerable disagreement in the reports of existing research work on the link between fetomaternal serum leptin levels and pre-eclampsia. OBJECTIVE: To determine and compare the maternal and umbilical cord sera levels of leptin in women with pre-eclampsia and healthy pregnant women. STUDY DESIGN: This is an analytical cross-sectional study. METHODS: The study involved consenting 120 pregnant participants (60 on each arm). Pregnant women diagnosed with pre-eclampsia constituted the investigation group, while the controls were normotensive pregnant women. They were matched for maternal age and body mass index. Venous blood specimens were obtained from the participants for assessment of the serum leptin concentration while umbilical cord blood samples were obtained following delivery of the neonate in advance of the removal of the placenta. The collected blood samples were analysed for the levels of leptin in a blinded pattern. The primary outcome measures were maternal serum leptin levels and umbilical cord serum leptin levels. RESULTS: Mean maternal serum leptin concentration in the pre-eclampsia group was significantly higher than that in the control group (24.88 ± 3.92 vs. 15.03 ± 2.98ng/mL, p < 0.001). Similarly, maternal serum leptin concentration was significantly higher in participants with severe pre-eclampsia compared with those with mild pre-eclampsia (25.91 ± 3.5 vs. 22.83 ± 4.02ng/mL, p = 0.003). However, the mean umbilical cord serum leptin level in the pre-eclampsia group was significantly lower than in the control group (6.43 ± 2.08 vs. 7.27 ± 2.24; p = 0.034). There was a weak positive correlation between maternal serum leptin level and neonatal umbilical serum leptin level in the pre-eclamptic group (r = 0.21, p = 0.04). CONCLUSION: Maternal serum leptin concentration is significantly increased in women with pre-eclampsia, compared with their normotensive counterparts. This increase becomes even more pronounced as the severity of the disease progresses. Maternal serum leptin assessment has the potential to become a veritable tool in the diagnosis and monitoring of pregnancies complicated by pre-eclampsia.

Case Report: Case series: association between blood concentration and side effects of sotorasib.

Introduction: Sotorasib is a crucial therapeutic agent for patients with non-small cell lung cancer (NSCLC) harboring the KRAS p.G12C mutation. Despite its efficacy, the relationship between blood sotorasib concentrations and side effects remains largely unexplored. Methods: This study enrolled five patients with KRAS p.G12C-positive NSCLC treated with sotorasib (LUMAKRAS® Tablets, Amgen, Japan) between July 2022 and February 2023 at Asahikawa Medical University Hospital. Blood sotorasib levels were monitored, and their association with adverse events was examined, with no adjustments made to drug dosages based on these levels. Results: Variable blood sotorasib levels were observed among the participants. Notably, one patient developed interstitial pneumonitis, although a definitive attribution to sotorasib was uncertain due to prior pembrolizumab treatment. The study revealed no consistent association between blood sotorasib levels and adverse events or therapeutic outcomes, with some patients experiencing severe side effects at higher concentrations, while others did not. Conclusion: Preliminary findings suggested that monitoring blood sotorasib levels may aid in anticipating adverse events in this small cohort. However, future studies with larger sample sizes and extended follow-up periods are required to validate these initial observations. Such studies could potentially offer insights into personalized dosing strategies, thereby mitigating adverse effects and enhance patient care for individuals with KRAS p.G12C-positive NSCLC.

A case report-"When less is more": controlled inpatient reduction of anticholinergic burden in a patient with clozapine-resistant schizophrenia.

The functional status of an individual with schizophrenia is the defining factor in their quality of life and is closely associated with cognitive abilities, which are impaired in individuals with schizophrenia and considered to be the core symptom of the disorder. The use of psychopharmacotherapy can also have a significant impact on cognitive functioning. The relationship between clozapine treatment and cognitive impairment in individuals with schizophrenia is an intricate one. While some studies have reported a positive effect of clozapine on learning and memory, other studies have found that patients treated with clozapine experienced a decline in cognitive functioning in particular areas. In particular, attention and memory have been shown to deteriorate with rising plasma levels of clozapine. This effect may be attributed to its anticholinergic effect. A reduction in the medication related to anticholinergic burden has been previously found to improve cognitive abilities. In the presented case, we describe a psychotic relapse with delirium symptoms in a patient on clozapine treatment with potentially toxic clozapine blood level. The symptoms of delirium subsided after a clozapine dose adjustment. Gradually lowering the initially very high anticholinergic burden improved the patient's cognitive functioning.

Study of zeolite clinoptilolite d-glucose adsorption properties in vitro and in vivo.

Beneficial effects of a natural zeolite clinoptilolite in vivo on mammals, including humans, have been empirically observed and documented in literature. The positive biological activities have been associated to its detoxifying and antioxidative properties, and its immunostimulative and adsorption properties. Herein, we present the in vitro and in vivo study of clinoptilolite zeolite materials adsorption properties for d-glucose. In particular, we present data on the interaction of d-glucose on the tested zeolites' surface obtained by scanning electron microscope (SEM) and Energy-dispersive X-ray spectroscopy (EDS) and quantification by ultra high-performance liquid chromatography (UHPLC). We also present results on the reduction of blood glucose levels in mice pre-treated with clinoptilolite in vivo upon feeding with d-glucose. In vivo results were in line with the in vitro adsorption and/or interaction properties of tested zeolite materials for d-glucose and were quantified by UHPLC as well (11.34% for TMAZ; 10.82% for PMA and 8.76% for PMAO2). In vivo experiments in mice showed that PMA zeolite reduces blood glucose levels upon 15 min for 13% (at p < 0.05) up to 19.11% upon 120 min (without statistical significance) in clinoptilolite pre-treated mice fed by addition of d-glucose. Due to lack of explicit mechanistic knowledge on zeolite clinoptilolite interactions or adsorption with sugars in vitro and in vivo, presented study provides novel insights into these aspects for researchers in the field. The presented data merit further investigations as the material clearly shows a potential in management of hyperglycemia, such as for example in obese people, people with diabetes and people with metabolic syndrome where it could help regulate blood glucose levels.

Pursuing the Real Vancomycin Clearance during Continuous Renal Replacement Therapy in Intensive Care Unit Patients: Is There Adequate Target Attainment?

INTRODUCTION: Vancomycin is used in intensive care unit (ICU) patients for the treatment of infections caused by gram-positive bacteria. The vancomycin pharmacokinetic/pharmacodynamic index is a ratio of the area under the concentration to the minimum inhibitory concentration ≥400-600 h*mg/L. This target can generally be achieved by a plasma concentration of 20-25 mg/L. Together with the pathophysiological alterations and pharmacokinetic variability associated with critical illness, the use of continuous renal replacement therapy (CRRT) may complicate the attainment of adequate vancomycin concentrations. The primary objective was the prevalence of attainment of vancomycin concentrations 20-25 mg/L after 24 h in adult ICU patients receiving CRRT. Secondary outcomes were to evaluate target attainment at days 2 and 3 and to calculate vancomycin clearance (CL) by CRRT and residual diuresis. METHODS: We performed a prospective observational study in adult ICU patients on CRRT, which received at least 24 h continuous infusion of vancomycin. Between May 2020 and February 2021, daily vancomycin residual blood gas and dialysate samples were collected from 20 patients, every 6 h and if possible vancomycin urine samples. Vancomycin was analysed with an immunoassay method. The CL by CRRT was calculated by a different approach correcting for the downtime and providing insight into the degree of filter patency. RESULTS: The proportion of patients with vancomycin concentrations <20 mg/L was 50% 24 h after starting vancomycin (n = 10). No differences were observed in patient characteristics. The target vancomycin concentration 20-25 mg/L was only achieved in 30% of the patients. On days 2 and 3, despite the use of TDM and albeit in lower percentages, sub- and supratherapeutic levels were still observed. Taking downtime and filter patency into account resulted in lower vancomycin CL. CONCLUSIONS: 50% of the studied ICU patients on CRRT showed subtherapeutic vancomycin concentrations 24 h after starting therapy. The results reveal that optimization of vancomycin dosage during CRRT therapy is needed.

Patient with bipolar I disorder who presented with low blood lithium levels after receiving crushed tablets via a nasogastric tube: A case report.

In clinical psychiatric cases, the placement of a nasogastric tube is occasionally considered. If a patient who presents with mania or other psychiatric conditions refuses to take drugs, they are administered via the nasogastric tube. The tablet is crushed, suspended, passed via the nasogastric line, and reaches the stomach directly. However, the effects of these processes on blood drug concentrations remain unclear. Herein, we report a patient with bipolar I disorder who presented with low blood lithium carbonate (Li) concentrations after receiving the drug via the nasogastric tube. Case: A 26-year-old woman developed manic symptoms with grandeur delusion. She was admitted to a psychiatric hospital three times after diagnosis. Her manic symptoms with delusion improved with Li and aripiprazole (ARP). Her condition stabilized with Li 800 mg/day and ARP 9 mg/day. After the Li dose was reduced to 600 mg/day, she maintained remission, with the blood level range of Li being 0.31 ∼ 0.42 mEq/L. After 1 year, she was admitted to our hospital due to a jaw deformity. During the perioperative period, treatment with oral Li was discontinued by the surgeons, and her manic symptoms recurred. During therapy with olanzapine 20 mg and Li 800 mg, her blood Li concentration was 0.67 mEq/L. The symptoms remained. Hence, the Li dose increased to 1,000 mg/day. However, she refused to take the medication. Thus, a nasogastric tube was used to administer medicines. Thereafter, the blood Li concentration decreased to 0.43 mEq/L, which was lesser than 800 mg/day. Each blood sample was collected approximately 18 h after the administration. Her symptoms remained. Thereafter, she agreed to take the medication, and the Li concentration reached 0.78 mEq/L. Then, the symptoms partly improved. Conclusion: After the administration of Li via the nasogastric tube, the Li concentration decreased, which was lower than expected. This phenomenon could be attributed to the fact that the medication was crushed, suspended, and administered via the nasogastric tube. Therefore, pulverizing and administering Li tablets via the nasogastric tube can be applied for the management of mania, however, caution should be observed because of the risk of fluctuations in blood Li levels, as in this case.

Systematic review and meta-analysis on the therapeutic reference range for escitalopram: Blood concentrations, clinical effects and serotonin transporter occupancy.

Introduction: A titration within a certain therapeutic reference range presupposes a relationship between the blood concentration and the therapeutic effect of a drug. However, this has not been systematically investigated for escitalopram. Furthermore, the recommended reference range disagrees with mean steady state concentrations (11-21 ng/ml) that are expected under the approved dose range (10-20 mg/day). This work systematically investigated the relationships between escitalopram dose, blood levels, clinical effects, and serotonin transporter occupancy. Methods: Following our previously published methodology, relevant articles were systematically searched and reviewed for escitalopram. Results: Of 1,032 articles screened, a total of 30 studies met the eligibility criteria. The included studies investigated escitalopram blood levels in relationship to clinical effects (9 studies) or moderating factors on escitalopram metabolism (12 studies) or serotonin transporter occupancy (9 studies). Overall, the evidence for an escitalopram concentration/effect relationship is low (level C). Conclusion: Based on our findings, we propose a target range of 20-40 ng/ml for antidepressant efficacy of escitalopram. In maintenance treatment, therapeutic response is expected, when titrating patients above the lower limit. The lower concentration threshold is strongly supported by findings from neuroimaging studies. The upper limit for escitalopram's reference range rather reflects a therapeutic maximum than a tolerability threshold, since the incidence of side effects in general is low. Concentrations above 40 ng/ml should not necessarily result in dose reductions in case of good clinical efficacy and tolerability. Dose-related escitalopram concentrations in different trials were more than twice the expected concentrations from guideline reports. Systematic review registration: [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=215873], identifier [CRD42020215873].

Therapeutic Reference Range for Aripiprazole in Schizophrenia Revised: a Systematic Review and Metaanalysis.

RATIONALE: While one of the basic axioms of pharmacology postulates that there is a relationship between the concentration and effects of a drug, the value of measuring blood levels is questioned by many clinicians. This is due to the often-missing validation of therapeutic reference ranges. OBJECTIVES: Here, we present a prototypical meta-analysis of the relationships between blood levels of aripiprazole, its target engagement in the human brain, and clinical effects and side effects in patients with schizophrenia and related disorders. METHODS: The relevant literature was systematically searched and reviewed for aripiprazole oral and injectable formulations. Population-based concentration ranges were computed (N = 3,373) and pharmacokinetic influences investigated. RESULTS: Fifty-three study cohorts met the eligibility criteria. Twenty-nine studies report blood level after oral, 15 after injectable formulations, and nine were positron emission tomography studies. Conflicting evidence for a relationship between concentration, efficacy, and side effects exists (assigned level of evidence low, C; and absent, D). Population-based reference ranges are well in-line with findings from neuroimaging data and individual efficacy studies. We suggest a therapeutic reference range of 120-270 ng/ml and 180-380 ng/ml, respectively, for aripiprazole and its active moiety for the treatment of schizophrenia and related disorders. CONCLUSIONS: High interindividual variability and the influence of CYP2D6 genotypes gives a special indication for Therapeutic Drug Monitoring of oral and long-acting aripiprazole. A starting dose of 10 mg will in most patients result in effective concentrations in blood and brain. 5 mg will be sufficient for known poor metabolizers.

The effects of exercise on circulating endocannabinoid levels-a protocol for a systematic review and meta-analysis.

BACKGROUND: Increased circulating endocannabinoids levels are typically associated with aerobic exercise. This phenomenon is associated with a "runner's high," a state of euphoria and well-being experienced after a long exercise. We will provide in this review a transparent and standardized methodology following the PRISMA-P and Cochrane Handbook for Systematic Reviews of Interventions for conducting a systematic review and meta-analysis for synthesizing the available evidence about the effects of physical activity on the circulating levels of AEA and 2-AG endocannabinoids in healthy subjects. METHODS: A multi-disciplinary team with basic and clinical expertise in exercise science developed this protocol. PubMed, EMBASE, Web of Science, CINAHL, SPORTDiscus, and Scopus will be the databases. A health sciences librarian was consulted in the development of the research. Search strategies will combine MeSH terms and free text words, including "exercise," "exercise, physical," "exercise training," "physical activity," "endocannabinoids," "2-arachidonoyl-glycerol," "glyceryl 2-arachidonate," "2-AG," "anandamide," "AEA," "n-arachidonoylethanolamide," "adult," "young adult," and "middle-aged." We will select experimental or quasi-experimental studies published through December 2021. The selection of studies, data extraction, assessment of the risk of bias, and the quality of evidence will be carried out in a paired and independent manner, and the consistency will be assessed using the statistics of Cohen Kappa. Methodological quality will be assessed using the Revised Cochrane risk of bias tool for randomized trials (RoB 2) and the Risk Of Bias In Nonrandomized Studies of Interventions (ROBINS-I) risk tool. We will use the Grading of Recommendations Assessment, Development, and Evaluation to assess the quality of the evidence, χ2 and I2 tests for heterogeneity, funnel plots, and the Egger test for publication bias. A meta-analysis for each data comparison will be performed whenever possible to determine the effect of physical activity on endocannabinoids' circulating levels. DISCUSSION: This systematic review and meta-analysis will provide an overview of the evidence about physical activity over AEA and 2-AG endocannabinoids, including comparability of variables between studies, critical interpretation of results, and use of accurate statistical techniques. The endocannabinoid is molecules by which muscles communicate with other tissues and organs, mediating the beneficial effects of exercise on health and performance, including increased glucose uptake, improved insulin action, and mitochondrial biogenesis. They are essential to exercise. Thus, this study will review the acute effect of physical exercise on circulating levels of endocannabinoids in healthy individuals. The results of this study will potentially be transferred to doctors, health professionals, and legislators to guide their decision making, as well as will improve future research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020202886 .

Central Nervous System Complications in Cystinosis: The Role of Neuroimaging.

Despite improvement in the specific treatment, clinical and anatomo-functional central nervous system (CNS) abnormalities of various severities are still observed in cystinosis patients. Patients who develop CNS complications today have a worse compliance to cysteamine treatment. Radiological studies have shown that cortical or central (ventriculomegaly) atrophy is observed in more than two thirds of cystinosis patients' magnetic resonance imaging (MRI) and correlates with the intelligence quotient score. Half of cystinosis patients have marked aspecific white matter hyperintensities. The development of advanced neuroimaging techniques provides new tools to further investigate CNS complications. A recent neuroimaging study using a voxel-based morphometry approach showed that cystinosis patients present a decreased grey matter volume in the left middle frontal gyrus. Diffusion tensor imaging studies have shown white matter microstructure abnormalities in children and adults with cystinosis, respectively in areas of the dorsal visual pathway and within the corpus callosum's body. Finally, leucocyte cystine levels are associated with decreased resting cerebral blood flow, measured by arterial spin labelling, in the frontal cortex, which could be associated with the neurocognitive deficits described in these patients. These results reinforce the relevance of neuroimaging studies to further understand the mechanisms that underline CNS impairments.

Optimizing doxepin therapy in dermatology: introducing blood level monitoring and genotype testing.

Doxepin, a tricyclic antidepressant, is the most efficacious antipruritic available to dermatologists; however its use is often suboptimal because of significant interindividual variability in doxepin plasma levels and clinical response between patients taking the same dose. As result, the Food and Drug Administration approves a maximum dose of 300 mg of doxepin per day and a 10 mg per cc liquid doxepin concentrate. These allow patients to significantly increase or decrease their dose, due to either a lack of clinical efficacy or side effects at typical dermatologic doses (often 10-25 mg per day). This review initially discusses the unique advantages of doxepin in dermatology. Then, it explores internal and external reasons why doxepin plasma levels and clinical response vary so significantly between patients, including genetic polymorphisms, drug interactions, comorbidities, sex, and ethnicity. Blood level monitoring is introduced, a tool dermatologists can use to optimize doxepin dosing in patients responding subtherapeutically to typical dermatologic doses. Without blood level monitoring, patients initially unresponsive to treatment could be labeled treatment failures when in fact they may be cases of inadequate dosing. Blood level monitoring allows for safe dose adjustments in these individuals to maximize patients' chances of achieving therapeutic success with this agent.

Elevated blood favipiravir levels are inversely associated with ferritin levels and induce the elevation of uric acid levels in COVID-19 treatment: A retrospective single-center study.

INTRODUCTION: Measurement of blood Favipiravir (FPV) levels and accumulation of data in COVID-19 patients are critical for assessing FPV efficacy and safety. We performed a retrospective study based on measurements of blood levels of FPV and related factors in COVID-19 patients admitted to our hospital. Furthermore, we also investigated the association between blood FPV levels and uric acid level alterations before and after FPV administration. METHODS: We enrolled 27 COVID-19 patients who had received FPV treatment at Hokushin General Hospital from April 1 to December 31, 2020. Age, gender, COVID-19 severity, presence of comorbidities, and laboratory data for each subject were investigated to identify factors that correlate with blood FPV levels. Uric acid levels were measured before and after FPV administration and a difference between the levels (i.e., a change of uric acid level) was evaluated. RESULTS: When a significant univariate variable was input by the stepwise method and a combination of variables that maintained statistical superiority was searched, serum ferritin was the only factor that independently affected blood FPV level. Furthermore, in the high-FPV group (20 µg/mL or more), a significant increase in uric acid levels was observed after FPV administration. The increment value was significantly larger than that in the low-FPV group (less than 20 µg/mL). CONCLUSIONS: Ferritin level was an important independent factor inversely affecting blood FPV level. Furthermore, a high blood FPV level induced the elevation of uric acid levels in COVID-19 treatment.

Optimal dose of topical tranexamic acid considering efficacy and safety in total knee arthroplasty: a randomized controlled study.

PURPOSE: This study aimed to evaluate the optimal dosage of topical tranexamic acid (TXA) considering the efficacy and safety for controlling bleeding after total knee arthroplasty (TKA). METHODS: This prospective randomized double-blinded placebo-controlled comparative study included 325 patients scheduled to undergo TKA, who were randomly assigned to five groups based on the topical TXA injection (n = 65 per group): control; group 1, 0.5 g TXA; group 2, 1.0 g TXA; group 3, 2.0 g TXA; and group 4, 3.0 g TXA. The primary outcome was decrease in postoperative hemoglobin levels. The secondary outcomes were blood loss calculated using Good's method, drainage volume, frequency of transfusion, and range of motion (ROM). Plasma TXA levels and complications were also evaluated. RESULTS: Significant differences were noted in the decrease in hemoglobin levels between the control group and groups 2 (p = 0.0027), 3 (p = 0.005), and 4 (p = 0.001). No significant differences were shown among the experimental groups. Significant differences in total blood loss and frequency of transfusion were noted between the control group and groups 2 (p = 0.004, 0.002, respectively), 3 (p = 0.007, 0.001, respectively), and 4 (p = 0.001, 0.009, respectively) without showing significant differences among the experimental groups. With respect to drainage volume, no significant differences were observed among the groups. The serum TXA levels increased proportionally with the applied dose of topical TXA immediately and at 3 and 6 h postoperatively. Symptomatic deep vein thrombosis or pulmonary embolism was not observed in any group. Other complications related to TXA administration were not detected. CONCLUSION: Topical application of 1.0 g or more of TXA shows significant bleeding control without a dose-response relationship. Blood TXA levels increase with the TXA dose following topical TXA application. Therefore, to prevent overdosing and reduce potential complications with ensuring the effectiveness, 1.0 g of TXA is recommended as a topical application. LEVEL OF EVIDENCE: I.

Differential Influence of Pueraria lobata Root Extract and Its Main Isoflavones on Ghrelin Levels in Alcohol-Treated Rats.

The study was carried out on alcohol-preferring male Wistar rats. The following drugs were repeatedly (28×) administered: acamprosate (500 mg/kg, p.o.), naltrexone (0.1 mg/kg, i.p), and Pueraria lobata (kudzu) root extract (KU) (500 mg/kg, p.o.) and its isoflavones: daidzin (40 mg/kg, p.o.) and puerarin (150 mg/kg, p.o.). Their effects on a voluntary alcohol intake were assessed. KU and alcohol were also given for 9 days in an experiment on alcohol tolerance development. Finally, total and active ghrelin levels in peripheral blood serum were measured by ELISA method. Acamprosate, naltrexone, daidzin, and puerarin, reducing the alcohol intake, caused an increase in both forms of ghrelin levels. On the contrary, though KU inhibited the alcohol intake and alcohol tolerance development, it reduced ghrelin levels in alcohol-preferring rats. The changes of ghrelin concentration could play a role as an indicator of the currently used drugs. The other effect on the KU-induced shift in ghrelin levels in the presence of alcohol requires further detailed study.

Clinical relationship between blood concentration and clinical symptoms in aconitine intoxication.

BACKGROUND: Aconitine is well-known for its potential analgesic, anti-inflammatory, and circulation promoting effects and has been widely used as a folk medicine in South Korea. Owing to its extremely toxic nature and relatively low safety margin, intoxication is sometimes fatal. The toxic compound mainly affects the central nervous system, heart, and muscle, resulting in cardiovascular complications. PURPOSE: To determine the exact relationship between blood concentration of aconitine and clinical manifestation. BASIC PROCEDURES: The National Forensic Service (NFS) was commissioned to assist in a quantitative analysis of highly toxic aconitine and corresponding blood concentrations by analyzing the body fluids of three patients who were suspected of aconitine poisoning. MAIN FINDINGS: Aconitine blood values tested by the NFS showed that patients with a blood concentration below a certain level developed symptoms slowly and showed a high severity of clinical manifestation. There was no correlation between blood concentration and symptoms or ECG results. CONCLUSIONS: In case of suspected aconitine poisoning, an emergency care department should be visited, even with symptomatic improvement, and the patient should be monitored for at least 24 h, depending on the level of recovery and changes in ECG results.

Fluctuation of peripheral blood levelamongapheresis platelet donors aged 56~60 in Guangzhou / 中国输血杂志

【Objective】 To study and analyze the fluctuation of peripheral blood of apheresis platelet donors aged 56~60, so as to provide data support for safe recruitment and retention of elderly donorsin China. 【Methods】 Elderly apheresisplatelet donors, aged 56~60, donated for 6 769 occasions from 2017 to 2019 in Guangzhou Blood Center were analyzed retrospectively and grouped by gender and age. The fluctuation of peripheral blood was analyzed byone way ANOVA.Further pairwise comparison was carried out by Turky if there were statistical differences. 【Results】 All the peripheral blood levels were statistically significant between men and women aged around 56 (P<0.05). The Plt(×109 / L), RBC(×1012 / L) and Hb(g/L) of women after and before 56 were (274.33±49.47) vs (296.61±44.89), (4.48±0.35) vs (4.4±0.3), and (125.87±9.08) vs (128.33±8.79), respectively, and the differences were statistically significant (P<0.05), while no differences was noticed between them inWBC(×109 / L) and Hct, (6.29±1.36) vs (6.26±1.46) and (0.39±0.05) vs (0.39±0.02), respectively(P>0.05). The RBC(1012 / L), Hb(g/L), WBC(×109 / L) and Hctof men after and before 56 were (4.94±0.39) vs (4.91±0.35), (137.15±12.83) vs (141.29±10.67), (5.77±1.23) vs (6.03±1.26) and (0.42±0.03) vs (0.42±0.03), respectively, and the differences were statistically significant (P<0.05), and no significant difference was noticed in Plt(×109 / L)(283.94±59.63) vs (283.5±62.7)(P>0.05). There was no significant difference in Plt between men and women after 56 (P>0.05). The RBC, Hb and Hct of men around 56 were higher than those of women (P<0.05). The deferral rate of pretransfusion blood testing increased as the platelet donors were older than 56, showing statistical significance(P<0.05). 【Conclusion】 Fluctuation of peripheral blood levelof platelet donors aged 56~60 occurred when they were around 56 years old, but within the normal range.Therefore, blood donation is generally safe under the current policy. As the physiological regulation function of these donors has decreased, the monitoring of peripheral blood routine before and after blood donation needs to be strengthened to ensure blood quality and the health of elderly platelet donors.

Central nervous system complications in adult cystinosis patients.

Little is known about the long-term progression of adult nephropathic cystinosis patients. Our objective was to study central nervous system complications in cystinosis patients in the era of early cysteamine treatment, using advanced neuroimaging techniques. Neurological examination and multimodal brain 3 Tesla MRI were performed in 21 adult cystinosis patients, including 18 infantile cystinosis patients, 20 controls matched for age and renal function, and 12 healthy controls. Differences in gray matter volume and rest cerebral blood flow (CBF) using arterial spin labeling sequence were investigated using whole-brain voxel-based approach. Median age was 33.8 years (18.7-65.8). Seven patients (38.9%) presented with at least one central nervous system clinical abnormality: two (11.1%) with seizures, three (16.7%) with memory defects, five (27.8%) with cognitive defect, and one (5.5%) with stroke-like episode. These patients had a worse compliance to treatment (compliance score 2 vs 1, P = .03) and received a lower median cysteamine dose (0.9 g/day vs 2.1 g/day, P = .02). Among patients with infantile cystinosis, 13 (72.2%) showed cortical atrophy, which was absent in controls, but it was not correlated with symptoms. Cystinosis patients showed a significant gray matter decrease in the middle frontal gyrus compared with healthy controls and a significant negative correlation between the cystine blood level and rest CBF was observed in the right superior frontal gyrus, a region associated with executive function. Compliance to cysteamine treatment is a major concern in these adult patients and could have an impact on the development of neurological and cognitive complications.