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Aims: Information on breastfeeding and safety of biologics in infants is lacking due to difficulties in case collection. We evaluated methods for determining the concentration of biologics in breast milk using a dry filter method that can simplify the collection, storage and transport of breast milk. Methods: To generate dried filter paper (DFP) samples, approximately 30 μL of breast milk was placed onto a Whatman 903 card and punched out. After extraction, the supernatant was measured using an enzyme‐linked immunosorbent assay. Three concentrations of each drug were prepared in liquid breast milk (LBM) and DFP samples to determine their stability up to 28 days after storage at 2–8°C or −20°C for LBM and 25 ± 5°C for DFP. LBM and DFP samples were also provided by nursing mothers using biologics during lactation, and drug concentrations in both samples were compared. The agreement between the two measurement methods was confirmed by Bland–Altman analysis. Results: Breast milk was provided by 12 mothers who used biologics (tocilizumab, abatacept, etanercept, golimumab, sarilumab and belimumab). The coefficients of variation for within‐run and between‐run precision for the six drugs were within 15% for both LBM and DFP, and accuracy was within 90%–110% of the quality controls. After 28 days, concentrations remained at more than 90%. The difference between the values obtained by each method was within the acceptable range of error (−12.1 to +16.6 ng/mL). Conclusions: A method for determining the concentration of biologics using DFP is expected to help improve pharmacotherapy for lactating women. [ABSTRACT FROM AUTHOR]

The quality-assured preparation of crushed and diluted preparations for children is a challenge. In this study, a multicenter study was conducted to validate the preparation method for the quality assurance of baclofen powder, clonidine powder, and hydrocortisone powder prepared from tablets according to a previously established method. In-hospital preparations were prepared at five medical facilities under different crushing and mixing conditions. After storage in closed bottles, in-use bottles, and laminated paper for 120 days, ingredients stability, drug elution, and content uniformity after packaging were evaluated. All three ingredients were maintained at between 90% and 110% of their initial content for 120 days under packaging conditions of 25 ± 2 °C and 60 ± 5% relative humidity, with no change in dissolution in all formulations made at all five facilities. The content uniformity was also acceptable. The established method may contribute to quality-assured pediatric dosage form modification. [ABSTRACT FROM AUTHOR]

Sulfamethoxazole trimethoprim (ST) combinations are used to prevent infection in immunocompromised patients. In pediatric patients, conventional ST combination tablets (cTab) are large and granules are not preferred due to their rough and bitter taste in the mouth. Since a new formulation of smaller tablets (sTab, 1 cTab = 1-gram granules = 4 sTab) was approved, a study regarding the usability of sTab in pediatric patients was conducted. Children who started taking sTab of the ST combination at our hospital between August 2021 and August 2022 were included. Using an anonymous questionnaire, the dosage of ST combinations, the child's response (3-point visual scale: positive, neutral, or negative), preparation and administration time, and method of taking the drug were asked. Twenty-two patients (median age: 11.0 years) receiving cTab. Median (range) number of tablets per dose was 1 (0.5–1.5) tablet, and was 4 tablets (1.0–4.0) after switching to sTab. Twenty patients (median age: 5.0 years) receiving granules. Median (range) single dose was 0.75 (0.2–2.0) gram, and was 2.0 (1.0–4.0) tablets after switching to sTab. Post-dose reactions were positive in 5, neutral in 7, and negative in 10 cases for cTab, and positive in 1, neutral in 7, and negative in 12 cases for granules. After switching to sTab, 9, 13 and 0 cases, and 10, 9 and 1 cases were positive, neutral, and negative, respectively. Median preparation and administration times were decreased after switching to sTab in both cTab and granules groups. The frequency of dosage manipulations was also decreased. The switch to sTab improved acceptability, and decreased burden of administration, suggesting that sTab is a user-friendly formulation in pediatric medications. [ABSTRACT FROM AUTHOR]

Baclofen is used as a skeletal muscle relaxant for multiple sclerosis patients and pediatric patients with cerebral palsy and is prescribed to pediatric patients at 0.3 to 1.0 mg/kg/dose. Baclofen tablets, an oral drug, are usually administered as a powder in pediatric wards after a formulation change by the pharmacist. However, there is no information about stability and assurance of quality for compounded products. The purpose of this study was to design a 10 mg/g oral powder of baclofen and to investigate the stability and changes in the physical properties of this compounded product. A 10 mg/g baclofen powder was prepared by adding extra-fine crystal lactose hydrate to crushed and filtrated baclofen tablets and was stored in a polycarbonate amber bottle with desiccant or in a coated paper laminated with cellophane and polyethylene. The stability of baclofen at 25 ± 2 °C/60 ± 5%RH was tested for 120 days in 'bottle (closed)', 'bottle (in use)', and 'laminated' storage conditions. Baclofen concentrations ranged from 90.0% to 110.0% of the initial concentration under all storage conditions. No crystallographic or dissolution changes were observed after storage. This information can help with the management of baclofen compounded powder in pharmacies. [ABSTRACT FROM AUTHOR]

A neonatal patient with Herpes simplex virus type-2 meningoencephalitis was treated by high-dose intravenous acyclovir therapy. Serum and cerebrospinal fluid (CSF) concentrations were measured retrospectively, showing that the CSF-to-serum concentration ratio was 0.67–0.71, which was higher than the previously reported values in other age groups. [ABSTRACT FROM AUTHOR]

Introduction: Areas displaying reduced bipolar voltage are defined as low‐voltage areas (LVAs). Moreover, left atrial (LA) LVAs after pulmonary vein isolation (PVI) have been reported as a predictor of recurrent atrial fibrillation (AF). In this study, we compared grid mapping catheter (GMC) with PentaRay catheter (PC) for LA voltage mapping on Ensite Precision mapping system. Methods: Twenty‐six consecutive patients with LVAs and border zone within the LA were enrolled. After achieving PVI, voltage mapping under high right atrial pacing for 600 ms was performed twice using each catheter type (GMC first, PC next). Furthermore, LVA was defined as a region with a bipolar voltage of <0.50, and border zone was defined as a region with a bipolar voltage of <1.0, or <1.5 mV. Results: Compared with PC, using GMC, voltage mapping contained more mapping points (20 242 [15 859, 26 013] vs. 5589 [4088, 7649]; p <.0001), and more mapping points per minute(1428 [1275, 1803] vs. 558 [372, 783]; p <.0001). In addition, LVA and border zone size using GMC was significantly less than that reported using PC: <1.0 mV (5.9 cm2 [2.9, 20.2] vs. 13.9 cm2 [6.3, 24.1], p =.018) and <1.5 mV voltage cutoff (10.6 cm2 [6.6, 27.2] vs. 21.6 cm2 [12.6, 35.0], p =.005). Conclusion: Bipolar voltage amplitude estimated by GMC was significantly larger than that estimated by PC on Ensite Precision mapping system. GMC may be able to find highly selective identification of LVAs with lower prevalence and smaller LVA and border zone size. [ABSTRACT FROM AUTHOR]

What is known and objective: Statins are associated with improved pregnancy outcomes in patients with preeclamptic antiphospholipid syndrome (APS) and intrauterine foetal death. Several studies showed that statins are not teratogenic. However, data characterizing placental transfer and excretion of pravastatin into breast milk are limited. Case summary: We experienced two patients diagnosed with APS received 10 mg of pravastatin from the first trimester until delivery to prevent pre‐eclampsia. Pravastatin concentrations in maternal serum, infant serum and cord blood were evaluated. The estimated maternal‐foetal transfer ratios of pravastatin in the two patients were 25.5% and 23.8% respectively. Pravastatin was eliminated from neonatal serum within 2 days. Both infants developed normally with no drug‐related adverse effects. Pravastatin was not detected in either patient's breast milk at 3 days after the last dose. What is new and conclusion: The infants delivered from the mothers who were treated with pravastatin during pregnancy had no apparent adverse effects. [ABSTRACT FROM AUTHOR]

Introduction: Remdesivir was originally developed to treat Ebola hemorrhagic fever, and its efficacy in treating coronavirus disease 2019 was detected during a preliminary analysis of a randomized controlled trial. It is known that Severe Acute Respiratory Syndrome Coronavirus 2 is not transmitted through human milk, but data about the presence of remdesivir in human milk have been lacking. Main issue: In this case study, we determined the human milk-to-serum drug concentration ratio and the relative dose of Remdesivir in one participant. Management: The participant, a 28-year-old primipara, was found to have Coronavirus 2 infection in 2019, 2 days after delivery. She was given Remdesivir. The Remdesivir concentration in maternal serum and human milk was measured, and the milk-to-serum drug concentration ratio was found to be low (0.089), as was the relative infant dose (0.0070). The participant could not breastfeed her infant during her Coronavirus 2 infection treatment because in Japan anyone with COVID-19 was completely quarantined. However, she was able to resume breastfeeding after discharge and breastfed her infant for 6 months with supplements. Conclusion: Given the low amount of Remdesivir in the participant's milk, the inclusion of antibodies to Severe Acute Respiratory Syndrome Coronavirus 2, which can be expected to protect the infant from infection, and various other benefits of human milk, suggests that breastfeeding is safe during treatment with Remdesivir. [ABSTRACT FROM AUTHOR]

A major hurdle in pediatric formulation development is the lack of safety and toxicity data on some of the commonly used excipients. While the maximum oral safe dose for several kinds of excipients is known in the adult population, the doses in pediatric patients, including preterm neonates, are not established yet due to the lack of evidence-based data. This paper consists of four parts: (1) country-specific perspectives in different parts of the world (current state, challenges in excipients, and ongoing efforts) for ensuring the use of safe excipients, (2) comparing and contrasting the country-specific perspectives, (3) past and ongoing collaborative efforts, and (4) future perspectives on excipients for pediatric formulation. The regulatory process for pharmaceutical excipients has been developed. However, there are gaps between each region where a lack of information and an insufficient regulation process was found. Ongoing efforts include raising issues on excipient exposure, building a region-specific database, and improving excipient regulation; however, there is a lack of evidence-based information on safety for the pediatric population. More progress on clear safety limits, quantitative information on excipients of concern in the pediatric population, and international harmonization of excipients' regulatory processes for the pediatric population are required. [ABSTRACT FROM AUTHOR]

A venous aneurysm is characterized by a localized dilated lesion in most major veins. Popliteal venous aneurysms (PVAs) are rare; however, they are one of the causes of deep vein thrombosis (DVT) and pulmonary thromboembolism (PTE), which can be critical due to the high mortality risk. We present a 21-year-old woman without prior medical history, who arrived by ambulance after having a transient cardio-pulmonary arrest. Contrast computed tomography revealed a massive PTE and a right PVA with a thrombus. Laboratory data suggested that she had no thrombotic predisposition. Therefore, we diagnosed her condition as a massive PTE that derived from a thrombus, which arose from the right PVA. After successful intravenous thrombolysis of the PTE and DVT, surgical plication of the right PVA was performed to prevent the recurrence of PTE. She has had no recurrence of PTE or DVT two years after surgical treatment. This case suggests that surgical plication might be an effective way of preventing recurrence in patients with PVA. Popliteal venous aneurysm (PVA) occurrence is rare, but it can result in deep vein thrombosis (DVT) and pulmonary thromboembolism (PTE). To treat our patient who suffered transient cardiac-pulmonary arrest caused by a massive PTE, we first used a recombinant tissue plasminogen activator and anticoagulant therapy. After the condition was stabilized, surgical plication of the right PVA was performed to prevent DVT recurrence. The present case suggests that surgical plication might be beneficial. [ABSTRACT FROM AUTHOR]

Safety information on diazoxide for pregnant and lactating women with hypoglycemia is limited. In this case report, we assessed diazoxide concentrations in maternal and infant blood, cord blood, and breast milk. We described a 30-year-old pregnant woman diagnosed with hypoglycemia due to nesidioblastosis at 4 months of age. Before becoming pregnant, she was treated with oral diazoxide (75–375 mg). All medications were discontinued after she was discovered to be pregnant. During gestational week 25, diazoxide treatment was resumed at 150–175 mg daily for repeated hypoglycemic episodes. Diazoxide administration was continued in combination with diet treatment until delivery. Glucose levels were well controlled. During gestational week 40, a male infant weighing 3069 g was delivered via spontaneous vaginal delivery with no pregnancy or neonatal complications. Diazoxide concentrations detected in maternal serum at 2.5–11.6 h after oral treatment ranged from 12.4 to 32.7 µg/mL. In cord blood, the diazoxide concentration was 18.5 µg/mL at 7.2 h after the last dose. During lactation, no hypoglycemia or hyperglycemia was observed. The approximate calculated ratio of diazoxide in breast milk and maternal serum was 0.09. The calculated daily infant dose was 0.47 mg/kg/day. The relative infant dose via breast milk ranged from 3.1% to 5.9%. Diazoxide transferred from maternal blood to the fetus across the placenta. It also transferred into breast milk, but there were no harmful effects on the infant. [ABSTRACT FROM AUTHOR]

Compounding of medications, such as crushing tablets and dispersing the contents of capsules, is a common practice in pharmacies and hospitals worldwide and is often done to provide age-appropriate formulations for oral use in pediatric patients. In the present study, a retrospective, descriptive, questionnaire-based survey was conducted to clarify the current status of drug compounding for pediatric patients in Japan. An electronic questionnaire was distributed to 740 hospitals in Japan with pediatric beds, and 208 (28.1%) of these hospitals responded. The total instances of compounding numbered 14,864 (9.6% of the total pediatric oral prescriptions) and comprised 266 active pharmaceutical ingredients (APIs), one-third of which (98 APIs) were compounded even though flexible dosage forms were available. The three most frequently compounded drugs were dantrolene sodium capsules (1152 prescriptions), ramelteon tablets (726 prescriptions), and hydrocortisone tablets (652 prescriptions), all of which were prescribed and administered in powder form. Although compounding of medications frequently varied by the patients' age, steroids such as prednisolone, dexamethasone, and hydrocortisone were commonly compounded in all age groups. To ensure the quality and safety of these compounded medications, developing a standard protocol for compounding methods is urgently needed in Japan. [ABSTRACT FROM AUTHOR]

Aims: Our purpose was to investigate the association between the B‐type natriuretic peptide (BNP) level at discharge, the occurrence of worsening renal function (WRF), and long‐term outcomes in patients with heart failure (HF). Methods and results: We enrolled hospitalized acute HF patients. We divided patients into four groups on the basis of BNP <250 pg/mL (BNP−) or BNP ≥250 pg/mL (BNP+) at discharge and the occurrence of WRF during admission: BNP−/WRF−, BNP−/WRF+, BNP+/WRF−, and BNP+/WRF+. We evaluated the association between BNP at discharge, WRF, and cardiovascular/all‐cause mortality/hospitalization due to HF. Clinical follow‐up was completed in 301 patients. At discharge, percentages of the patients with clinical signs of HF were low and similar among four groups. The median follow‐up period was 1206 days (interquartile range, 733–1825 days). The composite endpoint of cardiovascular mortality and HF hospitalization was significantly different between the four groups [12.9% (BNP−/WRF−), 22.7% (BNP−/WRF+), 35.8% (BNP+/WRF−), and 55.4% (BNP+/WRF+), P < 0.0001]. All‐cause mortality was also different etween the four groups (15.1%, 38.6%, 28.7%, and 39.3%, respectively, P = 0.003). In the multivariate Cox proportional hazards model, the combination of BNP ≥250 pg/mL and WRF showed the highest hazard ratio (HR) for composite endpoint (HR, 5.201; 95% confidence interval, 2.582–11.11; P < 0.0001), and BNP−/WRF+ was associated with increased all‐cause mortality (HR, 2.286; 95% confidence interval, 1.089–4.875; P = 0.03). Patients in BNP+/WRF+ had a higher cardiovascular mortality (28.6%), and those in BNP−/WRF+ had a high non‐cardiovascular mortality (29.5%). Conclusions: Heart failure patients with BNP ≥250 pg/mL at discharge and in‐hospital occurrence of WRF had the highest risk for the composite endpoint (cardiovascular mortality and HF hospitalization) among groups. [ABSTRACT FROM AUTHOR]

The demand for tocilizumab is increasing in women who wish to bear children and who have active rheumatoid arthritis. Described here is a woman with rheumatoid arthritis who discontinued her tocilizumab therapy at the end of the first trimester and resumed it after delivery and where tocilizumab levels in maternal serum, infant serum, and the breast milk were measured. Tocilizumab was not detected in maternal serum just before delivery, or in umbilical cord blood or infant serum after birth. Tocilizumab levels in colostrum after intravenous injection were 0.57% of those in serum. Tocilizumab treatment in the first trimester was not associated with a significant drug level in the fetus at delivery and no fetal complications were noted. [ABSTRACT FROM AUTHOR]

Background: The need for a large volume of serum sample significantly reduces the feasibility of neonatal pharmacokinetic studies in daily practice, which must often rely on scavenged or opportunistic sampling. This problem is most apparent in preterm newborns, where ethical and practical considerations prohibit the collection of large sample volumes. Most of the fluconazole analysis assays published thus far required a minimum serum sample of 50 to 100 μL for a single assay. The purpose of the present study was to develop and validate a sensitive method requiring a smaller sample volume (10 μL) to satisfy clinically relevant research requirements. Methods: Following simple protein precipitation and centrifugation, the filtrated supernatant was injected into a liquid chromatography system and separated with a C18 reverse-phase column. Fluconazole and the internal standard (IS, fluconazole-d4) were detected and quantified using tandem mass spectrometry. The method was validated with reference to the Food and Drug Administration's Guidance for Industry. Accuracy and precision were evaluated at six quality control concentration levels (ranging from 0.01 to 100 μg/mL). Results: Investigated calibration curves were linear in the 0.01–100 μg/mL range. Intra- and inter-day accuracy (− 7.7 to 7.4%) and precision (0.3 to 6.0%) were below 15%. The calculated limit of detection and the lower limit of quantification (LLOQ) was 0.0019 μg/mL and 0.0031 μg/mL, respectively. Fluconazole in the prepared samples was stable for at least 4 months at − 20 °C and − 80 °C. This method was applied to analyze 234 serum samples from ten neonates who received fosfluconazole, a water-soluble phosphate prodrug of fluconazole which converts to fluconazole in the body, as part of a pharmacokinetic study using daily scavenged laboratory samples. The median (range) concentration up to 72 h after fosfluconazole administration was 2.9 (0.02 to 26.8 μg/mL) μg/mL, which was within the range of the calibration curve. Conclusion: Fluconazole was able to be detected in an extremely small volume (10 μL) of serum from neonates receiving fosfluconazole. The method presented here can be used to quantify fluconazole concentrations for pharmacokinetic studies of the neonatal population by using scavenged samples. [ABSTRACT FROM AUTHOR]

Background: Neonatal hemochromatosis (NH) is a rare but serious disease causing fulminant hepatic failure. The recurrence rate of NH in a subsequent infant of a mother with an affected infant is 70-90%. Recently, antenatal maternal high-dose intravenous immunoglobulin (IVIG) treatment has been reported to be effective for preventing NH recurrence. However, data on the IgG concentrations during this treatment are limited.Objective: We report a Japanese experience and present a pharmacokinetic simulation model of IgG during IVIG treatment.Methods: Women with histories of pregnancy diagnosed with NH were treated with IVIG weekly from the second trimester until the end of gestation. Serum IgG levels during treatment were collected frequently and pharmacokinetics were simulated by a two-compartment model.Results: Six women were included during eight pregnancies. None experienced severe adverse events. Three out of eight infants showed temporary liver dysfunction, but none required any treatment. A simulation study showed that the estimated trough and peak levels of IgG concentrations during IVIG were 2000-3000 and 4000-5000 mg/dl, respectively.Conclusion: This treatment prevented the recurrence of NH in siblings in Japanese women. We examined the details of serum IgG concentrations and introduced a new pharmacokinetic simulation model of IgG concentrations during IVIG treatment. [ABSTRACT FROM AUTHOR]

We report on an 8‐year‐old girl with Wilson disease who developed three episodes of peritonitis due to extended‐spectrum beta‐lactamase‐producing Escherichia coli after liver transplantation. Massive ascites were thought to account for low meropenem concentrations with standard dosing. Extending the infusion achieved higher troughs, greater time above minimum inhibitory concentration. [ABSTRACT FROM AUTHOR]

Objectives: In the absence of consensus, the present meta-analysis was performed to determine an optimal dosing regimen of vancomycin for neonates.Methods: A 'meta-model' with 4894 concentrations from 1631 neonates was built using NONMEM, and Monte Carlo simulations were performed to design an optimal intermittent infusion, aiming to reach a target AUC0-24 of 400 mg·h/L at steady-state in at least 80% of neonates.Results: A two-compartment model best fitted the data. Current weight, postmenstrual age (PMA) and serum creatinine were the significant covariates for CL. After model validation, simulations showed that a loading dose (25 mg/kg) and a maintenance dose (15 mg/kg q12h if <35 weeks PMA and 15 mg/kg q8h if ≥35 weeks PMA) achieved the AUC0-24 target earlier than a standard 'Blue Book' dosage regimen in >89% of the treated patients.Conclusions: The results of a population meta-analysis of vancomycin data have been used to develop a new dosing regimen for neonatal use and to assist in the design of the model-based, multinational European trial, NeoVanc. [ABSTRACT FROM AUTHOR]

Aims: Tocilizumab (TCZ), a humanized anti‐interleukin‐6 receptor monoclonal antibody, is used to treat rheumatic diseases. There is limited information about the administration of TCZ during lactation. The dried spot method, a simple technique for processing biological samples which involves placement of a drop of specimen onto filter paper, has been used in clinical pharmacology to determine various drug concentrations. This study examined the feasibility of sample collection using the dried milk spot (DMS) method for obtaining data about the transfer of TCZ into breast milk. Methods: Concentrations of TCZ determined using DMSs prepared by patients were compared with those using liquid breast milk. Results: In an enzyme‐linked immunosorbent assay of TCZ in DMSs, the accuracy ranged from 93.0% to 113.8% and the precision ranged from 0.3% to 8.4%. All concentrations of TCZ were within 15% of the reference value when analyzed on separate days. TCZ in DMSs at room temperature, 4°C, and −20°C were stable for 28 days. Extracted TCZ concentrations from patient‐prepared DMSs were strongly correlated with those of liquid samples (r = 0.996). In a pharmacokinetic study, the median (range) maximum and minimum concentrations were 113 ng/mL (68‐205) and 8.5 ng/mL (4.8‐13.4), respectively. The milk‐to‐serum ratio at the trough TCZ concentration of 3 lactating mothers were 0.0015, 0.00082 and 0.0014. Conclusions: The DMS method for measuring TCZ transfer into breast milk may be reliable and feasible, and should contribute to evaluating the safety of breast‐fed infants whose mothers receive TCZ during lactation. [ABSTRACT FROM AUTHOR]

We used a paclitaxel-coated drug-eluting balloon (DEB) for pulmonary vein stenosis (PVS) after repair of total anomalous pulmonary venous return with asplenia. No adverse effect of paclitaxel was revealed and plasma concentration of paclitaxel was not elevated after intervention. Although progression of PVS slowed after dilatation with the DEB, stenosis recurred relentlessly, resulting in patient demise. This strategy may be safe for infantile cases, but requires further effective strategy, such as usage of larger sizes of DEBs. < Learning objective: Paclitaxel-coated drug-eluting balloons may be safely used for pulmonary vein stenosis after total anomalous pulmonary venous return repair in an infant with asplenia. However, their effectiveness is still limited.> [ABSTRACT FROM AUTHOR]