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Purpose: The changes in the proportion of posterior cranial fossa structures during pediatric development remain unclear. This retrospective study aimed to investigate the growth patterns and ratios of these structures using CT scans. Methods: Head CT scans of pediatric patients with minor head trauma from Osaka Women's and Children's Hospital between March 2006 and May 2023 were analyzed. The study segmented the intracranial volume (ICV), posterior cranial fossa volume (PCFV), cerebellum volume (CBMV), and brainstem volume (BSV). Correlation coefficients were calculated among the parameters. Patients aged 0 to 10 years were divided into 15 age-related clusters, and mean and standard deviation values were measured. Growth curves were created by plotting mean values sequentially. Ratios such as PCFV/ICV and (CBMV + BSV)/PCFV were examined. Statistical analyses, including unpaired t tests and logarithmic curve fitting, were performed. Results: A total of 234 CT scans (97 from females, 115 from infants under 1 year of age) were analyzed. Positive correlations were observed among the parameters, with the strongest between PCFV and CBMV. The growth curves for ICV, PCFV, CBMV, and BSV exhibited a two-phase process, with rapid growth until approximately 4 years of age, followed by stabilization. The ratios PCFV/ICV and (CBMV + BSV)/PCFV showed increasing trends from birth onwards, stabilizing by 4 and 1 years of age, respectively. Conclusion: This study provides insights into the growth patterns and ratios of posterior cranial fossa structures in the pediatric population. The findings demonstrate a two-phase growth process and increasing trends in the examined ratios. [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]

Background: Powders for oral solutions and suspensions (POS) are commonly used as pediatric oral medicines worldwide, except for Japan. Although global pediatric formulation development accelerates POS importation to Japan without any formulation change, oral solid multiparticulates remain to be the preferred pediatric forms in the country. This study aimed to evaluate the acceptance situation of four typical POS form products (mycophenolate mofetil, sildenafil citrate, valganciclovir hydrochloride, and voriconazole) that were recently approved in Japan. Methods: A questionnaire on four products was completed by pharmacists in 29 children's hospitals with more than 100 beds each, between November and December of 2019. The questionnaire has six items on (#1) type of institution, (#2) formulary status, (#3) dispensing practice, (#4) reasons why POS form(s) were not selected as hospital formulary, (#5) advantages and disadvantages of POS form, and (#6) opinions for POS form. Results: Of the 29 institutions, 7 (24%), 9 (31%), 4 (13%), and 10 (34%) institutions used POS of mycophenolate mofetil, sildenafil citrate, valganciclovir hydrochloride, and voriconazole, respectively. Reasons for not using these products were dispensed drug loss, formulation issues, and management issues in the pharmaceutical department and pediatric ward. Pharmacists preferred drug compounding such as tablet crushing and capsule opening to POS form use. Conclusions: POS forms might be an unsuitable formulation for the current hospital settings in Japan. Thus, appropriate dosage forms that reflect the current clinical settings are necessary. [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]

Background: There are no reports on investigations of the characteristics of adverse drug reaction (ADR) reports for pediatric patients in the Japanese Adverse Drug Event Report database (JADER) and the utility of database for drug safety surveillance in these patients. Method: We aimed to evaluate ADR reports for pediatric patients in the JADER. We used spontaneous ADR reports included in the JADER since April 1, 2004, to December 31, 2017, which was downloaded in April 2018. In a total of 504,407 ADR reports, the number of spontaneous reports was 386,400 (76.6%), in which 37,534 (7.4%) were unknown age reports. After extraction of 27,800 ADR reports for children aged < 10 and 10–19 years, we excepted for ADR reports associated with a vaccine (n = 6355) and no-suspected drug reports (n = 86). A total of 21,359 (4.2%) reports were finally included in this analysis. Results: More than half of the ADR reports were for children aged < 10 years. Approximately 30% of ADR reports had multiple suspected drugs, which did not differ by age. The percentages of fatal outcomes of ADRs among patients aged < 10 and 10–19 years were 4.7 and 3.9%, respectively. The most frequently reported drug, reaction, and drug-reaction pair were oseltamivir, abnormal behavior, and oseltamivir and abnormal behavior, respectively. Conclusion: We clarified the characteristics of ADR reports for Japanese children by using the JADER. ADR report databases, especially those for pediatric patients, are valuable pharmacovigilance tools in Japan and other countries. Therefore, a proper understanding of the characteristics of the ADR reports in the JADER is important. Additionally, potential signals for ADRs in pediatric patients should be monitored continuously and carefully. [ABSTRACT FROM AUTHOR]

What is known and objective: Antiepileptic drugs (AEDs) are known to cause Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which are severe cutaneous disorders; however, real‐world data remain limited, especially on pediatric patients. The objective of this study was to investigate the association of AEDs with SJS and TEN in pediatric patients based on the Japanese Adverse Drug Event Report (JADER) database, which is a spontaneous reporting database. Methods: Adverse event reports submitted to the JADER database between 2004 and 2017 were analysed. We performed a retrospective pharmacovigilance disproportionality analysis, calculating the reporting odds ratio (ROR) with a 95% confidence interval (CI). Results and Discussion: A total of 159 605 adverse events were reported in pediatric patients. Significant SJS signals were detected for ethosuximide, phenytoin, phenobarbital, gabapentin, carbamazepine, zonisamide, clonazepam and lamotrigine. TEN signals were detected for ethosuximide, phenytoin, phenobarbital, gabapentin, carbamazepine and zonisamide, but the signal was strongest for gabapentin (ROR, 24.76; 95% CI, 11.4‐53.9). What is new and conclusion: Severe cutaneous disorders were associated with multiple AEDs, but individual AEDs were associated with variable signals. These results may be useful for minimizing the risk of SJS or TEN during treatment of children with AEDs. [ABSTRACT FROM AUTHOR]

Background: The lack of appropriate pediatric formulations is a global issue and information on acceptability is urgently needed to develop standard pediatric formulations. This study aimed to assess perceptions of acceptability of several oral dosage forms among pediatric patients at a community and a pediatric hospital in Japan and collected information about age-appropriate pediatric formulations, aiming to contribute to drug development promotion worldwide. Methods: A cross-sectional observational study was performed. A convenience sample of caregivers was recruited from available chain-owned retail pharmacies and inpatient pediatric units. The questionnaire was composed of 3 parts: (1) acceptability of the 5 dosage forms (tablets, capsules, powders, liquids, and orally disintegrating tablet) by age; (2) acceptability of dosage size, amount, and volume by age; and (3) the actual method of administration. Face-to-face interviews were conducted at 3 independent community pharmacies (324 parents) and tertiary care pediatric hospital wards (112 nursing staff). Acceptability scores and acceptable dosages were then determined. The survey was conducted from October 1 to December 1, 2017, for the hospital setting and November 1 to 30, 2017, for the outpatient setting. Results: The acceptability of oral dosage forms was roughly similar to the matrix drafted by the European Medical Agency. Differences in perception of the powder forms between communities and hospitals were also observed, with the nursing staff perceiving powder as being acceptable from the neonatal period. Conclusions: The difference in caregivers' perception of the acceptability of oral formulations between Japan and Europe was small. The powder form was found to be more acceptable in Japan. Further intervention studies are needed to assess the preferred pediatric formulation worldwide. [ABSTRACT FROM AUTHOR]

In Japan, four different types of hypotonic infusion fluids, namely, types 1-4, are available and used depending on the patient's condition. Although branded and generic products for each type of hypotonic infusion fluid are available, their physicochemical properties are unknown. For types 1 and 3 fluids, differences in the physicochemical properties of branded and generic products lead to different adverse events when administered. In the present study, we measured titration acidity, pH, and osmolality of branded and generic type 2 hypotonic infusion fluids, which have recently been recognized as useful for maintenance infusion among pediatric patients. We herein assessed their physicochemical information required while selecting a product in clinical practice. Experiments were performed using one branded and two generic products of type 2 hypotonic infusion fluids. Titration acidity was measured via neutralization titration, osmolality was measured via freezing point depression, and pH was measured via potentiometry using a glass electrode. Significant differences in titration acidity, which is a risk factor for metabolic acidosis, and pH, which is a risk factor for pH-dependent changes upon mixing, were observed between the branded and generic products. Our study indicates that titration acidity and pH should be evaluated appropriately to avoid adverse events in clinical practice while selecting a product of type 2 hypotonic infusion fluids. Our findings highlight the importance of evaluating the differences between branded and generic products, specifically when selecting it for pediatric patients with incompletely developed renal function and patients with impaired renal function.

The monitoring of the blood concentration at 2 h (C2) after the oral administration of a cyclosporine (CsA) microemulsion was reconfirmed to be useful for the prediction of systemic exposure, the area under the blood concentration–time curve from 0 to 4 h (AUC0–4), in a group of Japanese patients, consisting of 33 children aged 5–15 years and 19 young adults aged 16–27 years, with a greater correlation for C2 ( r = 0.927) than the trough concentration ( r = 0.488). The dose-normalized AUC0–4 was independent of gender or indications for CsA, while it depended on body size, i.e., the age ( P = 0.065) and total body weight ( P = 0.026). MDR1 C3435T had a weak, but insignificant effect ( P = 0.072); it was about 22–31% lower in the patients with TT3435. Co-administration of a steroid and further treatment with nifedipine had a more intensive effect ( P = 0.018); co-administration resulted in a 51% increase in the dose-normalized AUC0–4. A strong effect was also observed for the serum total cholesterol level ( P = 0.001). Collectively, the discrepancies in the results on MDR1 C3435T among investigators might be due to variability in the age/total body weight, co-administration drugs or serum lipid level. [ABSTRACT FROM AUTHOR]

Nagatoshi Y, Kawano Y, Okamura J. Comparison of the outcomes of allogeneic bone marrow transplantation from partially mismatched related donors, matched sibling donors, and matched unrelated donors in Japanese pediatric patients: A single center result. Pediatr Transplantation 2004: 8: 260–266. © 2004 Blackwell Munksgaard Human leukocyte antigen-disparity is an essential factor in selecting a suitable donor for allogeneic bone marrow transplantation (BMT), and selection criteria may differ between countries or races and between adults and children. We investigated the usefulness of partially mismatched related donors (PMRD) for Japanese children in comparison with matched sibling donors (MSD) and matched unrelated donors (MUD). Eighteen patients were transplanted from PMRD, who consisted of 12 parents, five siblings, and one cousin. Five of these 18 patient–donor pairs were serologically two-loci mismatched and 13 were one-locus mismatched. The probability of engraftment from PMRD was not different from that using BMT from MSD (n = 59) or MUD (n = 28). Severe acute graft-versus-host disease (GVHD) (≥grade III) developed more frequently in PMRD (25.5 ± 11.0%) than in MSD (0.0%), but was seen just as often as in MUD (21.9 ± 7.9%). The probabilities of chronic GVHD in PMRD (56.7 ± 14.3%) and MUD (41.7 ± 11.4%) were significantly higher than that in MSD (18.7 ± 5.7%, p = 0.01). However, there was no difference in the probability of event-free survival among the three groups. We conclude that PMRD (up to two-loci mismatch) could become suitable donors in BMT to the same extent as MUD for pediatric patients in Japan. [ABSTRACT FROM AUTHOR]

Objective: To investigate pediatric foreign body cases in the aerodigestive tract, and to elucidate the characteristic problems in Japan.Methods: A total of 310 pediatric patients (age 15 or below), gathered from two medical university hospitals (University of Tokyo and Jichi Medical School), were included in this study. Data were collected by retrospective chart review and were statistically analyzed.Results: Two-year-olds were the most common patients, and the range from age 1 to age 4 included 67.7% of all the patients. The most involved sites were the nose (39.4%) and the pharynx (38.4%), followed by the esophagus (12.9%) and the trachea-bronchi (6.5%). Fish bones and toys were the representative foreign bodies (30.7 and 13.6%, respectively). Other foreign bodies often encountered included coins, food, candy, peanuts and nuts, and batteries. The type of foreign body was closely related to the site in which foreign bodies were lodged: 77.3% of foreign bodies in the pharynx were fish bones, and toys were the most common impacted foreign body in the nose. In the esophagus, representative impacted foreign bodies were coins (35.7%), but disk-type battery ingestion has been increasing in recent years. Although most foreign bodies in the esophagus were safely removed, one case of a disk-type battery had a serious sequela. In the trachea-bronchi, peanuts, food, cotton, and coins were impacted. A rigid bronchoscope was basically used to remove foreign bodies, but in some cases, a fine flexible endoscope, with a channel for fiber forceps, was useful, because it could be inserted into narrow bronchi. Advance of a flexible endoscope will make it an excellent tool for diagnosis and management of the trachea-bronchial foreign body.Conclusions: Fish bones in the pharynx, which were closely related to Japanese eating habits, and toys in the nose, were the typical foreign bodies encountered in this study. In the esophagus, an increased incidence of disk-type battery ingestion has become a serious problem in recent years. Since prevention is the most essential way to manage foreign body cases, feedback from studies to public education should be encouraged. [ABSTRACT FROM AUTHOR]

In order to study the characteristics of pediatric patients ( ≤15 years at onset) with endolymphatic hydrops disorders, we selected 5 patients with Meniere's disease (MD) and 3 patients with delayed endolymphatic hydrops (DEH) from 7418 patients who had visited the Neurotological Clinic of the Toyama Medical and Pharmaceutical University Hospital between 1979 and 1999. Clinical features were characterized as follows: (i) pediatric MD patients were rare, comprising ≈1.5% of all the 337 MD patients in the sample; (ii) a fluctuating hearing loss, strong positive response in glycerol test, high SP/AP amplitude ratio in electrocochleography and moderate positive response in furosemide vestibulo-ocular reflex test were recorded; (iii) in 2 of the 5 pediatric MD patients, vertiginous attacks had persisted for a long period and they had undergone surgical procedures (sac operation and vestibular neurectomy); and (iv) the ipsilateral type of DEH was observed in 2/3 children, and contralateral DEH in 1/3. [ABSTRACT FROM AUTHOR]

Introduction: Certain drug characteristics, including dosage and form, are associated with either convenience or inconvenience for the patients taking them, and any inconvenience can be considered as a "cost" in disease treatment. Multiple antivirals are available for influenza in Japan, with various dosages and forms. This study evaluated the inconvenience costs associated with influenza antivirals for pediatric patients by using conjoint analysis on responses from their parents., Methods: An online survey (May 2021) was conducted for parents whose child took antivirals for influenza at 6-11 years during the 3 years until March 2021. Attributes of the conjoint analysis were administration routes and formulation (tablet, capsule, dry syrup, or inhalant), duration of administration, frequency of administration per day, and out-of-pocket expenses. We assumed the efficacy and safety to be equivalent among the antivirals. A logistic regression model was applied to the analysis. We also asked parents about their recent experiences with antiviral treatment for their child., Results: We collected responses from 3161 eligible individuals. The mean age (standard deviation) of the children when taking the antivirals and percentage of female children were 8.27 (1.63) years old and 53.2%, respectively. The tablet was the most preferred formulation; the inconvenience costs for each administration route and formulation, relative to the tablet as zero, were Japanese yen (JPY) 515 (US dollar 4.61, as of October 2021) for the inhalant, JPY 775 for the capsule, and JPY 804 for the dry syrup. The inconvenience costs for 5 days relative to 1 day and for twice a day relative to once a day were JPY 2150 and JPY 399, respectively., Conclusion: Based on the conjoint analysis, a single-dose tablet antiviral was suggested to have the lowest inconvenience cost for pediatric patients., Trial Registration: UMIN000044243., (© 2022. The Author(s).)

Children show a very wide range of physical development processes. These changes impact pharmacokinetic (PK) variability in pediatric patients. Most PK studies have been conducted on the Caucasian population. Therefore, whether current evidence of how developmental change affects PK and exposure-response relationships applies to Japanese pediatric patients remains unclear. This narrative review focuses on amikacin therapy in Japanese pediatric patients and shows the relationship between amikacin concentrations and efficacy/toxicity. Ten relevant articles were identified. Of these, nine articles were published in the 1980s. All studies reported a maximum concentration (Cmax) and minimum concentration (Cmin) of amikacin. Overall, articles reporting PK/pharmacodynamic (PD) indices and minimum inhibitory concentration (MIC) of isolated bacteria in Japanese pediatric patients is lacking, whereas all patients recovered from an infection state and showed negative cultures. Five of the included studies reported the association between Cmin and toxicity. The Cmin in three of four patients who developed toxicity was above 10 mg/L. This narrative review shows that further PK study of amikacin in Japanese pediatric patients is necessary. In particular, the pursuit of knowledge of Cmax/MIC ratio is vital. On the other hand, this review demonstrates that the optimal Cmin for Japanese pediatric patients is below 10 mg/L as a candidate concentration. However, it is noted that the number of patients who developed toxicity is very small.

Multiplex RT-PCR method using five sets of panel primers was developed for the detection of diarrheal viruses, including rotavirus A, B, and C, adenovirus, astrovirus, norovirus GI and GII, sapovirus, Aichi virus, parechovirus, enterovirus, cosavirus, bocavirus, and Saffold virus. The sensitivity of the method was evaluated and tested with 751 fecal specimens collected from Japanese children with acute diarrhea. Several kinds of viruses were detected in 528 out of 751 (70.3%) fecal specimens. Mixed-infection with different viruses in clinical specimens could also be effectively detected. The method proved to be reliable with highly sensitive and specific and useful for routine diagnosis. J. Med. Virol. 89:818-824, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Voriconazole is used for treating or preventing invasive aspergillosis and other invasive fungal infections. To minimize adverse reactions and to maximize treatment effects, therapeutic drug monitoring should be performed. However, it is challenging to optimize daily voriconazole dosing because limited data have been published so far on pediatric patients. We retrospectively analyzed voriconazole concentrations in patients aged 0-18 years. In addition, a literature review was conducted. In our study cohort, younger age and oral administration were significantly associated with lower plasma voriconazole concentrations (P < 0.01). An unfavorable outcome was associated with low concentrations of voriconazole (P = 0.01). Reports of voriconazole administration in pediatric patients show that higher doses are required in younger children and in patients receiving oral administration. Hence, the current data suggest that we should escalate both initial and maintenance doses of voriconazole in pediatric patients, particularly in patients of younger age receiving an oral administration of voriconazole., (Copyright © 2015. Published by Elsevier Ltd.)

The pharmacokinetic characteristics of liposomal amphotericin B (L-AMB; AmBisome(®)) in patients with invasive fungal infection were investigated. A population pharmacokinetic (PK) model in Japanese pediatric patients was developed based on 159 serum amphotericin B (AMPH-B) concentrations obtained in a post-marketing clinical study. The subjects were 39 patients with a mean age of 8.4 years (SD 4.5) and mean body weight of 27.1 kg (SD 14.1). A two-compartment PK model with zero-order input and first-order elimination was fitted to serum AMPH-B concentrations for L-AMB doses of 1.0, 2.5, and 5.0 mg/kg/day. Body weight showed significant correlations with PK parameters, such as clearance (CL) and distribution volume of the central compartment (Vc). The predicted Cmax/dose and AUC0-24/dose in Japanese pediatric patients were similar to those in non-Japanese pediatric patients and Japanese adult patients. Extremely large increases in Ctrough compared with predicted values were observed in some Japanese pediatric patients, but no relationships with demographic characteristics, clinical laboratory test values, or representative adverse drug reaction (decreased potassium) were found. The population PK parameters in this study are useful for simulating PK profiles of L-AMB and will be helpful for PK exposure comparisons among different populations and in investigations of pharmacokinetic-pharmacodynamic characteristics in patients., Chemical Compounds: Amphotericin B Deoxycholate (PubChem CID:23668620); amphotericin B (PubChem CID:5280965); 3-nitrophenol (PubChem CID:11137); methanol (PubChem CID:887)., (Copyright © 2015 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)