Pharmacokinetics of L-theanine and the effect on amino acid composition in mice administered with L-theanine.

L-theanine, an amino acid component of the tea leaves of Camellia sinensis, is sold in Japan as a supplement for good sleep. Although several studies in humans and mice have reported the effects of L-theanine on brain function, only a few reports have comprehensively clarified the disposition of theanine administered to mice and its effects on concentrations of other blood amino acids. In this study, we aimed to determine the changes in the blood levels of L-theanine administered to mice and amino acid composition of the serum. L-theanine were administered to four-week-old Std-ddY male mice orally or via tail vein injection. L-theanine and other amino acids in serum prepared from blood collected at different time points post-dose were labeled with phenylisothiocyanate and quantified. The serum concentration of orally administered L-theanine peaked 15 min after administration. The area under the curve for tail vein injection revealed the bioavailability of L- theanine to be approximately 70%. L-theanine administration did not affect any amino acid levels in the serum, but a significant increase in the peak area overlapping the Glycine (Gly) peak was observed 30 min after administration. L-theanine administered to mice was rapidly absorbed and eliminated, suggesting that taking L-theanine as a supplement is safe without affecting its own levels or serum levels of other amino acids. However, considering that Gly, similar to L-theanine, is used as a dietary supplement for its anxiolytic effects and to improve sleep, determining the effects of L-theanine administration on Gly is important and needs further research.

Proposal for the development of biologics in pediatric rheumatology.

In order to assess the development, approval and early introduction into clinical practice of biologics in the pediatric field, we herein describe the current status of the development to approval of biologics as anti-rheumatic agents for children in Japan, discuss the present problems and provide a proposal for the future. It has become apparent that the duration of the review period required for the preparation of clinical trials and Pharmaceuticals and Medical Devices Agency approval is clearly reduced compared with the past. Thus, it was speculated that a rate-limiting step in the process from development to approval was the duration of clinical trials from start to end. Hence, we focused on the following key words with regard to promotion of the development of biologics and their early practical use: "registry", "centralization", and "global cooperation", all of which are related to the reduction of duration of a clinical trial. In conclusion, to reduce the duration of a clinical trial, it is essential to complete a world-scale registry system by developing the registry system established by the Pediatric Rheumatology Association of Japan. The next step is then to carefully plan to participate in the international network using the world-scale registry system, and develop global cooperative trials in which we can ensure a sufficient number of entries from Japan.

Pharmacist perceptions of a "good death" and differences in perception between patients with cancer, oncologists, and oncology nurses: a questionnaire survey.

BACKGROUND: For pharmacists expected to encounter the deaths of many of their patients in the near future, it is important to understand the perception of a "good death" for patients with cancer who are likely to be aware of the circumstances of their poor prognosis. In this study, we clarified pharmacists' perceptions of a "good death" and considered the differences in perception among patients with cancer, oncologists, and oncology nurses. METHODS: From April to June 2022, an anonymous questionnaire survey was conducted on pharmacists working in hospitals and pharmacies and on members of the Japanese Society for Pharmaceutical Palliative Care and Sciences. The questionnaire consisted of 57 questions, called attributes, developed by Miyashita et al. to investigate the perception of "good death" in Japanese cancer medicine. The importance of those attributes was investigated using a 7-point Likert scale. RESULTS: Three thousand four hundred thirty-two pharmacists were made aware of this survey, and 207 participated in the survey. The responses of pharmacists to the 57 questions were very similar to those of the oncologists. Among them, "Fighting against disease until one's last moment" and "Not making trouble for others" had very low importance, which was the most significantly different from the responses of patients with cancer. "Fighting against disease until one's last moment" tended to be significantly underestimated by pharmacists engaged in patient guidance and interview compared to that by pharmacists not engaged in the duty (p = 0.02). Also, when we compared pharmacists with or without qualifications related to cancer and palliative care, there was no significant difference in the importance of "Fighting against disease until one's last moment." However, the importance of "Not making trouble for others" for qualified pharmacists was significantly underestimated (p = 0.04). CONCLUSION: Since pharmacists understand the limits of chemotherapy, they may want to be close to the patient but may not strongly agree with the "Fighting against cancer" component that patients with cancer prefer. It may be necessary to reconsider better ways of approaching the wishes and satisfaction of patients with cancer under the care of medical professionals in the field of oncology.

iPAPP: study protocol for a multicentre randomised controlled trial comparing safety and efficacy of intravenous paracetamol and indomethacin for the treatment of patent ductus arteriosus in preterm infants.

INTRODUCTION: Patent ductus arteriosus (PDA) causes severe morbidity in premature infants. Although the use of indomethacin is the standard therapy for PDA, it is sometimes not applicable because of its adverse effects, such as renal and platelet dysfunctions. Paracetamol has emerged as an alternative to indomethacin owing to its excellent safety profile in infants. Of the recently reported case series and clinical trials on the use of paracetamol for PDA, there are few reports in Japan on paracetamol use in preterm infants. Furthermore, indications for the use of paracetamol for PDA have not been approved for use in PDA. While the safety of intravenous paracetamol therapy in case series of preterm infants treated for haemodynamically significant PDA (hsPDA) has been reported, studies which were conducted to compare paracetamol to indomethacin are limited. We, therefore, intend to investigate the hypothesis that intravenous administration of paracetamol has superior safety over indomethacin. METHODS AND ANALYSIS: Multicentre open-label randomised controlled trial for intravenous administration of paracetamol for PDA in preterm infants. The inclusion criteria are (1) hsPDA, (2) gestational age from 24 to 34 weeks and birth weight (BW) from 500 to 2000 g, (3) enrolment between 24 hours and 7 days from birth and (4) obtaining parental consent. The primary outcome is renal dysfunction within 48 hours from the last dose of the study drug. Enrolled patients fulfilling all the inclusion criteria are randomly allocated to either intravenous paracetamol or intravenous indomethacin. This trial requires 110 patients. ETHICS AND DISSEMINATION: The clinical trial would follow Japan's Clinical Trials Act. The trial protocol was approved by the Clinical Research Review Board of Saitama Medical University (approval number: 222001). A written informed consent would be obtained from one of the parents. The results are expected to be published in a scientific journal. TRIAL REGISTRATION NUMBER: jRCTs031220386. PROTOCOL VERSION: 31 March 2022, version 1.0.

The Trajectory of Expressed Colostrum Volume in the First 48 Hours Postpartum: An Observational Study.

Objective: Colostrum, the first form of human milk, is strongly encouraged for infants due to its benefits. During the early postpartum (PP) period, the secreted colostrum volume can be minimal, causing concerns among mothers about sufficient milk supply. Few studies have examined temporal changes in the colostrum. This study aimed to elucidate the trajectory of expressed colostrum volume in the first 48 hours after delivery. Materials and Methods: This was a cross-sectional observational study performed at Kagawa National Children's Hospital. One hundred five mothers who did not directly breastfeed in the first 48 hours after delivery were enrolled in the study. Well-trained midwives instructed the mothers on how to express human milk, and mothers started to express as soon as possible after delivery. Mothers were advised to express human milk every 3 hours, and the milk volume was measured. Results: Within 3 hours PP, 60% of mothers expressed milk, and the median frequency of expression was 14 (interquartile range, 11-16) times in the first 48 hours. At 0-3 and 3-6 hours PP, the volume of initially expressed milk was 0.4 (0.0-2.0) mL and 1.0 (0.0-6.0) mL, respectively. Subsequently, milk volume decreased. The volume remained low until 30 hours PP and increased dramatically; this phenomenon is termed secretory activation, which began later in primiparous women than in multiparous women. Conclusion: The decline in expressed milk volume during the early PP period caused concern among mothers. Therefore, mothers should be informed of the PP trajectory of human milk volume.

Relationship between cerebral oxygenation and phosphorylation potential during secondary energy failure in hypoxic-ischemic newborn piglets.

The aim of this study was to evaluate the hypothesis that cerebral hemoglobin (Hb) oxygenation is related to phosphorylation potential during primary and secondary cerebral energy failure in newborn infants who have experienced birth asphyxia. We subjected newborn piglets to severe transient cerebral hypoxic-ischemia followed by resuscitation and examined cerebral energy metabolism by 31P-magnetic resonance spectroscopy and evaluated changes in cerebral Hb oxygen saturation (ScO2) using full-spectrum near-infrared spectroscopy before, during, and up to 54 h after the hypoxic-ischemic insult. ScO2 was significantly decreased during the hypoxic-ischemic insult compared with baseline values. During secondary energy failure, piglets were separated based on the relationship between the ratio of phosphocreatine to inorganic phosphate and ScO2; those with a negative correlation were less injured than those with a positive correlation. These results indicate that changes in ScO2 as measured by near-infrared spectroscopy are related to phosphorylation potential during secondary energy failure in asphyxiated infants.

Extrauterine environment affects the cortical responses to verbal stimulation in preterm infants.

Using optical topography, changes in the cerebral oxygenation were compared in the parieto-temporal lobe of preterm and term infants of equal postconceptional age in response to verbal stimulation. Eight preterm infants of gestational age 23-34 weeks were studied at postconceptional term age (38-46 weeks). Ten term infants were studied at 2-11 days after birth. Twenty-four-channel near-infrared optical topography (NIOT) was used to measure changes in concentration of oxyhemoglobin ([oxyHb]), deoxyhemoglobin ([deoxyHb]) and total hemoglobin ([totalHb]) in the bilateral temporal cortices. Verbal stimulation was provided by a recording of a Japanese fairy tale. The latency in response to verbal stimulation was significantly shorter in the preterm infants than in the term infants. This time is thought to reflect brain development, particularly the development of the neuro-vascular coupling mechanisms in the cerebral cortex. The present results indicate that the number of days after birth is more closely related to development of auditory system and neuro-vascular coupling than is postconceptional age. Thus, this suggests that early extrauterine environment affects the cortical responses to verbal stimulation in preterm infants.

Effects of bilirubin photoisomers on the measurement of direct bilirubin by the bilirubin oxidase method.

Background We occasionally encounter increases in direct bilirubin value on reanalysis of the surplus serum collected in the past from a neonate with indirect hyperbilirubinemia. But the details of this phenomenon are unclear. We evaluated the change of direct bilirubin and the relation of bilirubin photoisomer of the serum exposed to room light. Methods Surplus serum samples from neonates with indirect hyperbilirubinemia were exposed to room light for 24 h. The bilirubin fraction assay of samples was performed by the bilirubin oxidase method (Nescauto and Aqua-auto Kainos reagent) and high-performance liquid chromatography. Results Direct bilirubin increased significantly from 0.61 to 2.36 mg/dL. The respective ratios of bilirubin photoisomers before and after exposure were as follows: cyclobilirubin (0.007 to 0.29) and (EZ)-bilirubin (0.018 to 0.041) increased significantly, (ZZ)-bilirubin decreased 0.84 to 0.55 significantly. The difference of the cyclobilirubin concentration was most closely associated with those of the direct bilirubin concentration. Conclusion Direct bilirubin value was increased after exposure to the room light, and increase in direct bilirubin was significantly correlated by cyclobilirubin increase in the serum samples from neonates with indirect hyperbilirubinemia.

Risk factors associated with respiratory disorders in late preterm infants.

OBJECTIVE: Late preterm infants are still high risk for respiratory problems. The aim of this study was to identify risk factors associated with respiratory problems in Japanese late preterm infants. METHODS: In this retrospective multicenter study, we included singleton late preterm deliveries at 34+(0/7)-36+(6/7) weeks of gestation. We excluded cases with congenital anomalies. We defined neonatal respiratory disorders (NRD) as the combination of the need for mechanical ventilation or the use of nasal continuous positive airway pressure. We examined the perinatal risk factors associated with NRD. RESULTS: We included 683 late preterm infants. We found that 13.7%, 6.8% and 2.6% of the infants with NRD were born at 34, 35 and 36 weeks of gestation, respectively. In a multivariate logistic regression analysis adjusting for confounders, the gestational age (GA) at birth (adjusted odds ratio 0.40 per week [95% confidence interval, 0.25-0.61]), cesarean birth (4.18 [2.11-8.84]), and a low Apgar score (33.3 [9.93-121.3]) were independent risk factors associated with NRD. CONCLUSIONS: An earlier GA, cesarean delivery, and a low Apgar score are independent risk factors associated with NRD in singleton late preterm infants. Patients with late preterm deliveries exhibiting these risk factors should be managed in the intensive delivery setting.

Quantification of cerebral hemoglobin as a function of oxygenation using near-infrared time-resolved spectroscopy in a piglet model of hypoxia.

Near-infrared spectroscopy (NIRS) has been used for measurement of cerebral hemoglobin (Hb) concentrations in neonates to study cerebral oxygenation and hemodynamics. We perform measurements by portable three-wavelength NIR time-resolved spectroscopy (TRS) in a piglet hypoxia model with various degrees of oxygenation to estimate the absorption coefficient (mu(a)) and reduced scattering coefficient (mu(s)') of the head. Measurements of absolute values of mu(a) at three wavelengths enable estimation of Hb concentration and Hb oxygen saturation in the head (SO2). However, there is a problem concerning which background absorption should be used to estimate Hb concentration in the head derived from mu(a) at three wavelengths because it is different from a simple in vitro model. Therefore, we use two different background absorption values with the assumption that background absorption is due only to 85% (by volume) water or that background absorption is equal to absorption of the piglet head with blood exchange transfusion by fluorocarbon (FC), and we compared SO2 measured by TRS with arterial Hb oxygen saturation (SaO2) and sagittal sinus venous Hb oxygen saturation (SvO2) measured by a co-oximeter at several inspired fractional O2(FI(O2)) concentrations. We find that SO2 values using the absorption (abs) of the piglet head with blood exchange transfusion (BET) by FC are not significantly different from SO2 values using the water-only background at FI(O2) in the range of 15 to 100%, but that the values using abs of the head with BET by FC are lower than the values using the water-only background at FI(O2) in the range of 12 to 4%. The SO2 values calculated from the water-only background are higher than those of SaO2 at FI(O2) in the range of 10 to 4%. However, SO2 values using the abs of the head with BET by FC are between those of SaO2 and SvO2 over the whole range of FI(O2). Therefore, abs of the head with BET by FC is more useful for estimation of the absolute values of oxyHb and deoxyHb of the piglet head.

Developmental changes in serum half-life of (EZ)-cyclobilirubin.

BACKGROUND: Phototherapy has been a standard treatment for neonatal hyperbilirubinemia for more than 40 years, but it has remained sub-optimal. AIMS: To clarify the developmental changes in parameters of (4E, 15Z)-cyclobilirubin ((EZ)-C) elimination in order to obtain basic data for establishing optimal phototherapy. STUDY DESIGN: Blood samples were taken at regular intervals after stopping phototherapy, and bilirubin fractions were analyzed by high-performance liquid chromatography. SUBJECTS AND METHODS: The subjects were 46 infants with hyperbilirubinemia who underwent phototherapy. The gestational age and birth weight of the subjects ranged from 25.0 to 41.0 weeks and from 656 to 3810 g, respectively, and the age at cessation of phototherapy was a median of 5 days. A kinetic model of (EZ)-C elimination was established, and the serum half-life of (EZ)-C was calculated on the basis of the determined model. Relationships of the half-life of (EZ)-C with birth weight and gestational age were investigated. RESULTS: Serum (EZ)-C elimination followed a first-order kinetic model in 43 infants and a zero-order kinetic model in three extremely low birth weight infants. The half-life of (EZ)-C calculated on the basis of a first-order elimination model in serum ranged from 68 to 274 min and showed weak negative correlations with birth weight and gestational age. CONCLUSIONS: Serum (EZ)-C excretion followed a first-order kinetic model in most of the neonates. The half-life of (EZ)-C becomes more prolonged in the very low birth weight infant and early gestational age.

Influence of glucuronosyl bilirubin and (EZ)-cyclobilirubin on determination of serum unbound bilirubin by UB-analyser.

BACKGROUND: In the enzyme reaction for the determination of the unbound (free) bilirubin concentration by glucose oxidase and peroxidase, materials with low affinity for serum protein are reactive. The influence of these materials on the determination of serum unbound bilirubin was investigated. METHODS Serum samples from patients with neonatal hyperbilirubinaemia were analysed by high-performance liquid chromatography for total glucuronosyl bilirubin concentration (TGC) and (EZ)-cyclobilirubin concentration [(EZ)-C]. Based on these measurements, the samples were classified into three groups: group I [13 samples, TGC <2 micromol/L and (EZ)-C < 2.5 micromol/L]; group II [four samples, TGC < 2 micromol/L and (EZ)-C > or = 2.5 micromol/L]; and group III (five samples, TGC > or = 2 micromol/L). The concentrations of total bilirubin and unbound bilirubin were measured in these same samples with a UB-analyser. When the absorbance at 460nm was monitored, the decrease in absorbance was non-linear (concave curve). The degree of concavity was estimated (D15 value) as the deviation from linearity at 15s. RESULTS: The D15 value was significantly higher in groups II and III than in group I. D15 value correlated significantly with TGC, (EZ)-C and unbound bilirubin concentration, and the unbound bilirubin concentration correlated significantly with TGC and (EZ)-C. CONCLUSION: These results indicated that determination of serum unbound bilirubin concentration using the UB-analyser could be positively skewed by high concentrations of TGC and (EZ)-C.

Pharmacokinetics of zonisamide in perinatal period.

Zonisamide is widely used for intractable epilepsy and the effects of this drug on fetuses and neonates through the mother taking it for epilepsy need to be clarified. We measured the zonisamide concentration in plasma and breast milk using high-performance liquid chromatography to investigate the transfer of zonisamide through the placenta and breast milk, as well as its pharmacokinetics, in two neonates born to epileptic mothers receiving zonisamide. The transfer rates were 92% via the placenta and 41-57% through the breast milk. The first-order kinetics of zonisamide in the two infants was elimination half-lives of 109 and 61h, respectively.

Henoch-Schönlein purpura with intracerebral hemorrhage.

We describe a case of Henoch-Schönlein purpura (HSP) with massive intracerebral hemorrhage (ICH) in a 7-year-old-girl. A cranial CT scan revealed extensive ICH in the left parietal region and right parieto-temporal through occipital regions. At the time of ICH onset, hypertension and coagulation abnormality were not observed, but factor XIII activity was markedly reduced 9%. ICH was thought to have resulted from a marked decrease in factor XIII. Factor XIII preparation was administered immediately after the onset of ICH, and enlargement of the hemorrhagic region was not seen. The present case is the only reported case of HSP complicated by ICH in which factor XIII level was measured.

Ethosuximide induced agranulocytosis.

Agranulocytosis caused by ethosuximide is extremely rare in children. Drug-induced agranulocytosis is an unexpected side effect of a drug, and delay in diagnosis of agranulocytosis can result in a fatal outcome. We experienced a case of a 16-month-old male infant with Down syndrome in whom fever appeared 16 days after the start of administration of ethosuximide and then severe pneumonia developed. Results of a blood test on admission showed a decreased leukocyte count of 1700/microl, and a hemogram showed that there were no granulocytes. The erythrocyte and thrombocyte counts were within normal ranges. The results of a bone marrow aspiration test showed that there was no production of any types of granulocytes. The patient required mechanical ventilation due to deterioration in his pneumonia and complication with disseminated intravascular coagulation, but the neutrophilic leukocytes began to increase from the 8th day after discontinuation of ethosuximide administration and start of treatment with granulocyte colony-stimulating factor, and the patient survived. The mechanism of onset in this case is thought to have been immunologic. Careful attention should be given to this type of agranulocytosis because of its sudden onset at 1-2 weeks after the start of administration of the causal drug. A drug-induced lymphocyte stimulation test was useful for diagnosis in this case, showing a positive reaction only for ethosuximide.

Pharmacokinetics of prophylactic micafungin in very-low-birth-weight infants.

We evaluated the use of micafungin as a prophylaxis in very-low-birth-weight infants. Micafungin was first administered to 25 very-low-birth-weight infants 12 to 24 hours after birth at a dose of 1 mg/kg/d. the apparent volume of distribution, the apparent elimination rate constant, the elimination half-life, and the total body clearance (mean +/- SD) were 0.76 +/- 0.28 L/kg, 0.12 +/- 0.041 1/h, 6.7 +/- 2.2 h, and 0.089 +/- 0.047 L/kg/h, respectively.

In vitro production of bilirubin photoisomers by light irradiation using neoBLUE.

BACKGROUND: The light-emitting diode is used as one of the new light sources for phototherapy. NeoBLUE (Atom Medical, Tokyo, Japan) incorporates blue light-emitting diodes for the treatment of neonatal hyperbilirubinemia. The authors compared the in vitro efficacy of neoBLUE with conventional phototherapy devices. METHODS: The three light devices used included neoBLUE and two conventional phototherapy devices with six blue-white (BW) or six green (GR) fluorescent tubes. A bilirubin/human serum albumin solution (15 mg/dL) in 200 x 300 mm elliptical bag was irradiated with each three light device. The average light intensity of neoBLUE, BW and GR was 22.5, 10.2 and 2.6 microW/cm(2) per nm, respectively, for the irradiated area. Bilirubin photoisomers and native bilirubin were measured by high-performance liquid chromatography. RESULTS: In neoBLUE, BW and GR, the respective production rate of cyclobilirubin was 6.0, 3.7 and 3.9 x 10(-2) mg/dL/min, and the respective (4Z, 15E)-bilirubin/(4Z, 15Z)-bilirubin ratio after irradiation was 0.44, 0.33 and 0.12; the (4Z, 15Z)-bilirubin reduction rate at 20 min after irradiation was 60, 68 and 82%, respectively. The reduction rate of (4Z, 15Z)-bilirubin correlated with the (4Z, 15E)-bilirubin/(4Z, 15Z)-bilirubin ratio. CONCLUSION: Phototherapy using the neoBLUE under high level may be clinically more effective than therapy using the conventional light source from the results of the production rate of cyclobilirubin.

Cortisol levels in umbilical vein and umbilical artery with or without antenatal corticosteroids.

BACKGROUND: The developmental changes of the umbilical cortisol levels in neonates at gestational age of 23-41 weeks were studied and the effect of antenatal steroid administration on the umbilical cortisol levels were examined. METHODS: Cortisol levels in the umbilical vein (UV) and the umbilical artery (UA) were studied in 35 neonates at the gestational age (GA) of 23-41 weeks with or without antenatal administration of corticosteroids. Serum cortisol concentrations were measured by the high performance liquid chromatography method. RESULTS: The correlation between cortisol levels in UV and birthweight (BW) was weak and negative in premature infants. UV cortisol levels in the neonates with antenatal corticosteroid were lower than those in the neonates without antenatal corticosteroid, but the relation was not significant. The developmental changes of UV cortisol levels were the same as those in Murphy's study (spontaneous-onset labor). The cortisol levels in UV and UA had a significantly positive correlation and both had almost equal concentrations. There were no correlations between cortisol levels in UV and placental weight, Apgar Score at 1 and 5 min. CONCLUSIONS: In the neonates whose birthweight was less than 2000 g without antenatal corticosteroid, there was a negative correlation between cortisol levels in UV and BW but there was no correlation between cortisol levels in UV and GA. That the neonates with antenatal corticosteroid would have a suppressed adrenocortical function after birth could not be proved.