Comparison of pediatric lens scattered dose measurements between axial 40-mm and helical 160-mm detector width computed tomography scan modes.

BACKGROUND: Reports comparing field lens doses between helical scans with a 40-mm detector width and axial scans with a 160-mm detector width using different computed tomography (CT) scanners are currently scarce. OBJECTIVE: To compare scatter doses for lenses between a helical scan with a 40-mm detector width and an axial scan with a 160-mm detector width when using different CT scanners in the context of pediatric chest examinations. MATERIALS AND METHODS: Two different CT machines were used: Revolution CT (GE Healthcare, Waukesha, WI) with a 256-row, 0.625-mm multidetector; and Aquilion ONE GENESIS Edition (Canon Medical Systems, Otawara, Japan) with a 320-row, 0.5-mm multidetector. Three pediatric anthropomorphic phantoms were used, with optically stimulated luminescence dosimeters (OSLDs) placed on the left and right lenses. The scatter dose values measured by the OSLDs were compared between a helical scan with a 40-mm detector width and an axial scan with a 160-mm detector width during pediatric chest CT examinations. RESULTS: Median equivalent doses for the helical and axial scans were 0.12 and 0.12 mSv/mGy for the newborn, 0.17 and 0.16 mSv/mGy for the 1-year-old, and 0.18 and 0.15 mSv/mGy for the 5-year-old, respectively, when using the Revolution CT. With the Revolution CT, no significant differences were observed in the scatter doses between helical and axial scans in the newborn and 1-year-old phantoms. However, the lens scatter dose for the helical scan was approximately 20-35% higher than that for the axial scan in the 5-year-old phantom (P<0.01). The median equivalent doses of eye lenses for the helical and axial scans were 0.12 and 0.07 mSv/mGy for the newborn, 0.07 and 0.05 mSv/mGy for the 1-year-old, and 0.14 and 0.12 mSv/mGy for the 5-year-old, respectively, when using the Aquilion ONE. With the Aquilion ONE, lens scatter doses for the helical scan were approximately 70%, 40%, and 30% higher in the newborn, 1-year-old, and 5-year-old phantoms, respectively, than those for the axial scan (P<0.01). CONCLUSIONS: When using the Aquilion ONE, lens scatter doses for the helical scan were significantly higher in all three phantoms than those for the axial scan. In contrast, when using the Revolution CT, the lens scatter dose for the helical scan was significantly higher in the 5-year-old phantom than that for the axial scan. These results suggest that although scattered doses may vary with respect to the CT scanner and body size, they are generally lower in the case of axial scans.

Impact of beam collimation of z-overscanning on dose to the lens and thyroid gland in paediatric thoracic computed tomography imaging.

BACKGROUND: Adaptive collimation reduces the dose deposited outside the imaged volume along the z-axis. An increase in the dose deposited outside the imaged volume (to the lens and thyroid) in the z-axis direction is a concern in paediatric computed tomography (CT). OBJECTIVE: To compare the dose deposited outside the imaged volume (to the lens and thyroid) between 40-mm and 80-mm collimation during thoracic paediatric helical CT. MATERIALS AND METHODS: We used anthropomorphic phantoms of newborns and 5-year-olds with 40-mm and 80-mm collimation during helical CT. We compared the measured dose deposited outside the imaged volume using optically stimulated luminescence dosimeters (OSLD) at the surfaces of the lens and thyroid and the image noise between the 40-mm and 80-mm collimations. RESULTS: There were significant differences in the dose deposited outside the imaged volume (to the lens and thyroid) between the 40-mm and 80-mm collimations for both phantoms (P < 0.01). CONCLUSION: Compared with that observed for 80-mm collimation in helical CT scans of the paediatric thorax, the dose deposited outside the imaged volume (to the lens and thyroid) was significantly lower in newborns and 5-year-olds with 40-mm collimation.

Cardiac computed tomography angiography with and without bolus tracking methods in infants with congenital heart disease.

The study investigated radiation dose, vascular computed tomography (CT) enhancement and image quality of cardiac computed tomography angiography (CCTA) with and without bolus tracking (BT) methods in infants with congenital heart disease (CHD). The volume CT dose index (CTDIvol) and dose length product (DLP) were recorded for all CT scans, and the effective dose was obtained using a conversion factors. The CT number for the ascending aorta (AO) and pulmonary artery (PA), image noise of muscle tissue and contrast-to-noise ratio (CNR) were measured and calculated. The median values in the groups with and without BT were 2.20 mGy versus 0.44 mGy for CTDIvol, 8.10 mGy·cm versus 6.20 mGy·cm for DLP, and 0.66 mSv versus 0.51 mSv for effective dose (p < 0.001). There were no statistical differences in vascular CT enhancement, image noise, and CNR. CCTA without BT methods can reduce the radiation dose while maintaining vascular CT enhancement and image quality compared to CCTA with BT methods.

Effectiveness of low tube voltage scan in the exposure dose for lenses during paediatric thoracic CT examination: anthropomorphic phantoms study.

To determine whether using lower-tube voltage reduces the scattered dose for the lens during paediatric thoracic computed tomography (CT). Two paediatric anthropomorphic phantoms (ATOM Phantom, CIRS, Norfolk, Virginia, USA) representing a newborn and 5-year-old were placed on the gantry of CT scanner, and optically stimulated luminescence dosemeters were placed on the left and right lenses, in front of the left and right thyroid glands, in front of the left and right mammary glands, and in front of and behind the mammary gland level and we measured scattered dose of the optically stimulated luminescence dosemeter was compared for each phantom between 80 and 120 kVp. Significant differences were observed in the scatter doses for the lens between 80 and 120 kVp (p < 0.01). Compared with the 120 kVp scan, the scatter doses for the lens were ~15-40% lower in newborn and 5-year-olds using the 80 kVp scan during paediatric CT.

PATIENT DOSIMETRY SURVEY OF PEDIATRIC DIAGNOSTIC AND THERAPEUTIC CARDIAC CATHETERISATION IN JAPAN.

To propose reference values for air-kerma at the reference point (Ka,r), air-kerma area product (PKA), fluoroscopy time (FT) and number of cine images (CI) for four age groups in Japan, a nationwide questionnaire was posted to 132 pediatric catheterisation of certified facility in Japan, using the conventional post system, to which 43 facilities responded. For diagnostic cardiac angiography, reference values were as follows: Ka,r: 86, 102, 165 and 264 mGy; PKA: 9.3, 9.5, 16 and 34 Gy.cm2; FT: 33, 29, 26 and 30 min and CI: 1904, 1966, 2405 and 1871 images. For therapeutic cardiac angiography, reference values were as follows: Ka,r: 107, 163, 103 and 202 mGy; PKA: 7.5, 18, 7 and 24 Gy.cm2; FT: 56, 52, 42 and 30 min and CI: 3886, 3232, 2212 and 4316 images for less than 1, 1-5, 6-10 and 11-15 y, respectively. To optimal patient exposure from diagnostic and therapeutic cardiac catheterisation, it is therefore necessary to establish reference values for pediatric cardiac catheterisation examinations for four age groups.

NATIONWIDE SURVEY OF RADIATION EXPOSURE FOR RADIOFREQUENCY CATHETER ABLATION FOR PULMONARY VEIN ISOLATION AND NONPULMONARY VEIN ISOLATION IN JAPAN.

To propose typical values for the arrhythmia region between pulmonary vein isolation (PVI) and nonpulmonary vein isolation (non-PVI) in Japan. A nationwide questionnaire was posted to 343 facilities, to which 125 facilities (36.4%) responded. Results is the median for PVI and non-PVI were in terms of Ka,r (317 and 196 mGy), PKA (40.8 and 26.3 Gy.cm2), FT (43.0 and 27.3 min), and CI (326 and 102 images). When comparing PVI and non-PVI procedures, there were significant differences in Ka, r, PKA, FT, and CI (p < 0.05). In other words, by classifying into two types, PVI and non-PVI, we contributed to the establishment of typical values in Japan's RFCA.

Pharmacokinetic and pharmacodynamic analysis of baloxavir marboxil, a novel cap-dependent endonuclease inhibitor, in a murine model of influenza virus infection.

BACKGROUND: Baloxavir acid, the active form of the orally available prodrug baloxavir marboxil, is a novel cap-dependent endonuclease inhibitor of influenza virus. Baloxavir marboxil has been shown to rapidly reduce virus titres compared with oseltamivir in clinical studies. OBJECTIVES: We investigated the relationship between pharmacokinetic (PK) parameters and antiviral activity of baloxavir acid based on virus titre reduction in lungs of infected mice. METHODS: BALB/c mice infected with a sub-lethal dose of influenza A(H1N1), A(H1N1)pdm09, A(H3N2) or type B virus were treated on day 5 with oral baloxavir marboxil (0.5-50 mg/kg q12h), subcutaneous baloxavir acid (0.25-8 mg/kg/day), oseltamivir phosphate (5 or 50 eq mg/kg q12h) or other antivirals for 1 day. Lung virus titres were assessed 24 h after initial antiviral dosing. PK testing was performed at up to 24 h post-dosing of baloxavir marboxil or baloxavir acid in A/WSN/33-infected mice and the PK/pharmacodynamic (PD) relationship was evaluated for baloxavir acid. RESULTS: Oral baloxavir marboxil administration showed dose-dependent virus titre reductions in lungs of mice infected with the different types/subtypes of influenza viruses 24 h post-dosing. Baloxavir marboxil at 15 mg/kg q12h resulted in ≥100-fold and ≥10-fold reductions in influenza A and B virus titres, respectively, compared with oseltamivir phosphate. PK/PD analysis showed that the plasma concentration at the end of the dosing interval (Cτ) or the plasma concentration at 24 h after initial dosing (C24) was the PK parameter predicting the virus titres at 24 h post-dosing of baloxavir acid. CONCLUSIONS: PK/PD analysis of baloxavir acid based on virus titre reduction in this mouse model could be helpful in predicting and maximizing virological outcomes in clinical settings.

Baloxavir Treatment in Adolescents With Acute Influenza: Subgroup Analysis From the CAPSTONE-1 Trial.

BACKGROUND: Baloxavir marboxil has demonstrated safety and efficacy in treating adult and adolescent outpatients with acute influenza (CAPSTONE-1 trial). Here, we report a subgroup analysis of outcomes in adolescents from the trial. METHODS: CAPSTONE-1 was a randomized, double-blind, placebo-controlled study. Eligible adolescent outpatients (aged 12-17 years of age) were randomized in a ratio of 2:1 to a single dose of baloxavir 40/80 mg if less than/greater than or equal to 80 kg or placebo. The main outcomes were the time to alleviation of symptoms (TTAS), duration of infectious virus detection, and incidence of adverse events (AEs). RESULTS: Among 117 adolescent patients, 90 (77%) comprised the intent-to-treat infected population (63 baloxavir and 27 placebo; 88.9% A(H3N2)). The median TTAS was 38.6 hours shorter (95% confidence interval: -2.6, 68.4) in the baloxavir group compared with placebo (median TTAS, 54.1 hours vs 92.7 hours, P = .0055). The median time to sustained cessation of infectious virus detection was 72.0 hours for baloxavir compared with 120.0 hours for placebo recipients (P < .0001). Treatment-emergent PA/I38X-substituted viruses were detected in 5 of the 51 (9.8%) baloxavir recipients. In the safety population (76 baloxavir and 41 placebo), AEs were less common in baloxavir than placebo recipients (17.1% vs 34.1%; P = .0421). In the baloxavir group, no AEs except for diarrhea were reported in 2 or more patients. CONCLUSIONS: Baloxavir demonstrated clinical and virologic efficacy in the otherwise healthy adolescents with acute influenza compared with placebo. There were no safety concerns identified. These results were similar to the adult population in CAPSTONE-1 and support baloxavir as a treatment option in adolescents.

Peripheral endothelial function can be improved by daily consumption of water containing over 7 ppm of dissolved hydrogen: A randomized controlled trial.

BACKGROUND: Measurement of the reactive hyperemia index (RHI) using peripheral arterial tonometry (PAT) has shown benefits in the evaluation of vascular endothelial function and prediction of cardiovascular disease prognosis. Thus, it is important to examine the factors that promote the RHI. In this study, we aimed to investigate the effect of molecular hydrogen (H2) on reactive hyperemia-PAT of the small arteries of fingers in healthy people. METHODS: To determine the efficacy of H2 for improving peripheral vascular endothelial function, water containing high H2 concentrations was administered to participants, and the Ln_RHI was measured in the finger vasculature. Sixty-eight volunteers were randomly divided into two groups: a placebo group (n = 34) that drank molecular nitrogen (N2)-containing water and a high H2 group (n = 34) that drank high H2 water (containing 7 ppm of H2: 3.5 mg H2 in 500-mL water). The Ln_RHI was measured before ingesting the placebo or high H2 water, 1 h and 24 h after the first ingestion, and 14 days after daily ingestion of high H2 water or the placebo. The mixed effects model for repeated measures was used in data analysis. RESULTS: The high H2 group had a significantly greater improvement in Ln_RHI than the placebo group. Ln_RHI improved by 22.2% (p<0.05) at 24 h after the first ingestion of high H2 water and by 25.4% (p<0.05) after the daily consumption of high H2 water for 2 weeks. CONCLUSIONS: Daily consumption of high H2 water improved the endothelial function of the arteries or arterioles assessed by the PAT test. The results suggest that the continuous consumption of high H2 water contributes to improved cardiovascular health.

Baloxavir Marboxil 2% Granules in Japanese Children With Influenza: An Open-label Phase 3 Study.

BACKGROUND: A granule formulation of baloxavir marboxil, a selective inhibitor of influenza cap-dependent endonuclease, was newly developed for children with difficulty swallowing tablets. METHODS: A multicenter open-label study was conducted during the 2017-2018 influenza season to assess the safety, pharmacokinetics and clinical/virologic outcomes of single, oral, weight-based doses of baloxavir granules in Japanese children infected with influenza virus. The primary clinical endpoint was the time to illness alleviation of influenza. RESULTS: All 33 enrolled children completed the study and received baloxavir (1 mg/kg for 12 children weighing <10 kg, 10 mg for 21 children weighing 10 to <20 kg). Detected viruses were influenza B (36.4%), A(H1N1)pdm09 (33.3%) and A(H3N2) (27.3%). Adverse events (AEs) were reported in 54.5% of children. No deaths, serious AEs or AEs leading to discontinuation were reported. The mean (SD) plasma concentrations of baloxavir acid at 24 hours post-dose were 72.8 (24.0) and 51.3 (19.3) ng/mL in the 1-mg/kg and 10-mg dose groups, respectively. The median time to illness alleviation (95% confidence interval) was 45.3 (28.5-64.1) hours. A >4-log decrease in infectious viral titer occurred on day 2 and a temporary 2-log increase on day 4. Polymerase acidic protein/I38T/M-substituted viruses were detected in 5 children infected with influenza A, but none with influenza B. CONCLUSIONS: Baloxavir granules and the weight-based dose regimen were considered to be well tolerated in children, with rapid influenza virus reduction and associated symptom alleviation. Evidence of baloxavir activity against influenza B was observed, but further data are required for confirmation.

Population Pharmacokinetics and Exposure-Response Relationships of Baloxavir Marboxil in Influenza Patients at High Risk of Complications.

Baloxavir marboxil, a prodrug of cap-dependent endonuclease inhibitor baloxavir acid, reduces the time to improvement of influenza symptoms in patients infected with type A or B influenza virus. To characterize its pharmacokinetics, a population pharmacokinetic model for baloxavir acid was developed using 11,846 plasma concentration data items from 1,827 subjects, including 2,341 plasma concentration data items from 664 patients at high risk of influenza complications. A three-compartment model with first-order elimination and first-order absorption with lag time well described the plasma concentration data. Body weight and race were found to be the most important factors influencing clearance and volume of distribution. The exposures in high-risk patients were similar to those in otherwise healthy patients, and no pharmacokinetic difference was identified regarding any risk factors for influenza complications. Exposure-response analyses were performed regarding the time to improvement of symptoms and the reduction in the influenza virus titer in high-risk patients. The analyses suggested that body weight-based dosage, 40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg, can shorten the time to improvement of influenza symptoms and reduce virus titer for both type A and B influenza virus regardless of the exposure levels of the high-risk patients as well as for the otherwise healthy influenza patients. The results of our population pharmacokinetic and exposure-response analyses in patients with risk factors of influenza complications should provide useful information on the pharmacokinetic and pharmacodynamic characteristics of baloxavir marboxil and also for the optimization of dose regimens.

Clinical Drug-Drug Interaction Studies to Evaluate the Effects of a P-Glycoprotein Inhibitor, CYP3A Inhibitors, and a CYP3A Inducer on the Pharmacokinetics of Naldemedine in Healthy Subjects.

BACKGROUND: Naldemedine is a peripherally acting µ-opioid receptor antagonist that is indicated to treat opioid-induced constipation. OBJECTIVES: To assess the potential for drug-drug interactions between a single oral dose of naldemedine and the oral P-glycoprotein inhibitor cyclosporine, cytochrome P450 (CYP) 3A inhibitors itraconazole and fluconazole, and CYP3A inducer rifampin. METHODS: Three Phase 1, open-label studies were conducted in healthy subjects. In the P-glycoprotein inhibitor study, subjects received naldemedine 0.4 mg alone or coadministered with cyclosporine 600 mg. In the CYP3A inhibitors study, subjects in separate cohorts received naldemedine 0.2 mg alone or with itraconazole or fluconazole. In the CYP3A inducer study, subjects received naldemedine 0.2 mg alone or with rifampin 600 mg. Geometric mean ratios and 90 % confidence intervals were used to evaluate the effects of coadministered drugs on naldemedine maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC). Safety assessments included occurrence of adverse events (AEs), laboratory parameters, vital signs, and electrocardiography results. RESULTS: A total of 56 subjects were enrolled (n = 14 in each cohort). Cyclosporine increased naldemedine AUC0-inf 1.78-fold and Cmax 1.45-fold. Itraconazole and fluconazole increased naldemedine AUC0-inf 2.91-fold and 1.90-fold, and Cmax 1.12-fold and 1.38-fold, respectively. Rifampin decreased naldemedine AUC0-inf by 83% and Cmax by 38%. Across studies, AEs were generally mild. Laboratory, vital sign, or electrocardiogram assessments produced no clinically significant findings. CONCLUSIONS: Coadministration of naldemedine with a P-glycoprotein inhibitor or a strong/moderate CYP3A inhibitor increases naldemedine exposure; coadministration with a strong CYP3A inducer decreases its exposure. Coadministration of naldemedine with cyclosporine, itraconazole, fluconazole, or rifampin was generally safe and well tolerated.

Naldemedine is a targeted medication approved in the USA, Europe, and Japan for the treatment of opioid-induced constipation. Symptoms of constipation may include passing fewer stools than usual, having lumpy or hard stools, and/or straining to have bowel movements. In some cases, these symptoms are side effects of regular opioid use, which is often medically necessary for the management of moderate-to-severe pain. For naldemedine to be prescribed safely, doctors must know what other medications a patient is taking and how these medications may affect one another. This is commonly known as drug-drug interactions. Some drug-drug interactions may decrease how well a medication works, while other drug-drug interactions may increase the side effects experienced by a patient. In this paper, researchers report the results of three Phase 1 studies in healthy subjects examining how naldemedine interacts with other drugs. The drugs chosen for investigation are commonly evaluated in DDI studies and may affect the transport or metabolic pathway of naldemedine, including the P-glycoprotein inhibitor cyclosporine, the CYP3A inhibitors itraconazole and fluconazole, and the CYP3A inducer rifampin. These studies demonstrate that co-administration of naldemedine with each of these drugs impacted the pharmacokinetics of naldemedine. Cyclosporine, itraconazole, or fluconazole all increased naldemedine exposure, while rifampin decreased naldemedine exposure. For all drug combinations, observed side effects were generally mild and well tolerated. Additional testing, including vital signs and heart monitoring, did not reveal any other safety concerns. In conclusion, these findings support the cautious use of naldemedine in combination with cyclosporine, itraconazole or fluconazole. Concomitant use with rifampin should be avoided.

Carryover effects of baloxavir acid in human nasopharyngeal/pharyngeal swabs on infectious titer testing of influenza virus.

Baloxavir marboxil (BXM) demonstrated a rapid and profound decline in infectious viral titer 1 day after BXM administration. Rapid reduction in virus titer is a characteristic of BXM. There may be a possibility that drug carryover effects have impacts on the observed antiviral effects due to the poor correlation that was observed between viral titer reduction and alleviation of influenza symptoms. Here, we report possible carryover effects of baloxavir acid (BXA), an active form of BXM, on infectious titer testing. Our findings indicate that there is little impact of BXA carryover on the infectious titer testing.

Baloxavir Marboxil in Japanese Pediatric Patients With Influenza: Safety and Clinical and Virologic Outcomes.

BACKGROUND: We assessed the safety and effectiveness of baloxavir marboxil administration in Japanese children with influenza. METHODS: This open-label study administered 1 weight-adjusted dose of baloxavir to 107 children aged 1-11 years with laboratory-confirmed, febrile influenza virus infection of ≤48 hours duration. RESULTS: Adverse events (AEs) were reported in 34.6% of patients, most commonly vomiting (7.5%); no serious AEs or AEs causing discontinuation occurred. The median time to alleviation of influenza illness was 44.6 hours (95% confidence interval, 38.9-62.5 hours), to resolution of fever was 21.4 hours, and to sustained cessation of infectious viral shedding was 24.0 hours. However, viruses with amino acid substitutions in the viral polymerase acidic protein at position I38 (PA/I38T/M) emerged in 18 of 77 (23.4%) patients. Emergence was associated with longer infectious virus detectability (median time, 180.0 hours) and time to illness alleviation (median, 79.6 vs 42.8 hours in patients without PA/I38T/M-substituted viruses). Among patients with PA/I38T/M-substituted virus emergence, those with baseline hemagglutinin inhibition (HAI) antibody titer <40 experienced delay in time to illness alleviation (median, 85.4 vs 56.0 hours in patients with higher baseline HAI antibody titer). CONCLUSIONS: A single, oral dose of baloxavir marboxil was well tolerated and rapidly reduced viral titers, but the common emergence of PA/I38T/M-substituted viruses warrants consideration of alternative dosing regimens in young children. CLINICAL TRIALS REGISTRATION: Japan Pharmaceutical Information Center Clinical Trials Information (Japic CTI-163417).

Molecular hydrogen suppresses superoxide generation in the mitochondrial complex I and reduced mitochondrial membrane potential.

Molecular hydrogen (H2) is recognized as a medical gas applicable to numerous diseases including neurodegenerative diseases, metabolic disorders, and rheumatoid arthritis. Although the efficacy of H2 is reportedly attributed to its scavenging capability against the hydroxyl radical, the mechanisms underlying its therapeutic efficacy are not fully understood. Herein, we estimated the role of H2 in the energy converting system of the mitochondria, the source of reactive oxygen species. To investigate the effects of H2 on mitochondrial function, direction of electron flow, superoxide generation, and mitochondrial membrane potential were investigated. Forward electron transport (FET) or reverse electron transport (RET) was assessed by monitoring the decrease or increase of ß-nicotinamide adenine dinucleotide hydrate (NADH, - or +, µM, respectively) in the presence of ß-nicotinamide adenine dinucleotide (NAD+) and/or succinate in the isolated mitochondria. H2O2 converted from superoxide by superoxide dismutase (SOD) was measured to estimate electron leakage in the mitochondria. The effects of H2 on mitochondrial membrane potential were observed by staining cells with the fluorescence probe, teramethylrhodamine ethyl ester (TMRE). Despite the absence of succinate, a distinct RET was observed (from +0.0313 ± 0.0106 µM to +1.20 ± 0.302 µM) by adding 25 µM H2. In the presence of 5 µM NADH, RET by succinate inverted to FET from +1.62 ± 0.358 µM to -1.83 ± 0.191 µM, accompanied by a suppression of superoxide generated predominantly from complex I by 51.1%. H2 solely reduced mitochondrial membrane potential of the cultured cells by 11.3% as assessed by TMRE. The direction of electron flow was altered by H2 depending on the NAD+/NADH ratio, accompanied by suppression of superoxide generation H2 could suppress superoxide generation in complex I in vitro and reduce membrane potential in vivo. H2 may also neutralize semiquinone radicals to reduce superoxide produced in complex III. H2 may function as a rectifier of the electron flow affecting the mitochondrial membrane potential to suppress oxidative damage in mitochondria.

Therapeutic Efficacy of Molecular Hydrogen: A New Mechanistic Insight.

BACKGROUND: Molecular hydrogen (H2) is now recognized as a therapeutic gas for the treatment of numerous diseases including neurodegenerative diseases, metabolic disorders, and inflammatory diseases. Nonpolar, neutral H2 is assumed to have health benefits facilitated by its passive diffusion across the human body immediately after administration and is considered a safe therapeutic inert gas that does not interfere with physiological enzymatic reactions. The effects of H2 on mammalian cells are assumed to be based on non-enzymatic reactions with reactive oxygen species (ROS) exhibiting extremely high reactivity. However, many reports on therapeutic applications of H2 have the limitation to regard H2 only as a scavenger for the hydroxyl radical and peroxynitrite. METHODS: Apart from this proposed principle, a new possible mechanism of H2 activation and consumption in mammalian cells is considered in this review, which is specifically focused on the mitochondrial complex I that has a close evolutionary relationship with energy-converting, membrane-bound [NiFe]-hydrogenases (MBH). Notably, the possibility that H2 may function as both electron and proton donor in the ubiquinone-binding chamber of complex I is discussed. RESULTS: H2 is proposed to act as the rectifier of the mitochondrial electron flow in the disordered or pathological state when the accumulation of electrons leads to ROS production, specifically during the re-supply of O2 after hypoxia in the mitochondria. CONCLUSION: Furthermore, H2 is proposed to convert the quinone intermediates to the fully reduced ubiquinol, thereby increasing the antioxidant capacity of the quinone pool as well as preventing the generation of ROS.

Population Pharmacokinetics of Doripenem in Pediatric Patients and Monte-Carlo Pharmacokinetic-Pharmacodynamic Simulations for Dosing Regimen Assessment.

The aims of this study were to evaluate the pharmacokinetics of doripenem (Finibax®, Doribax®, S-4661), a parenteral carbapenem antibiotic, in pediatric patients based on concentrations of doripenem in plasma after administration of 20 mg/kg 2 or 3 times daily and to evaluate the dosing regimens by using Monte-Carlo pharmacokinetic-pharmacodynamic simulations. Population pharmacokinetic analysis was performed by using 190 plasma concentrations of doripenem from 99 patients (2 months-13 years old). The two-compartment model well described the doripenem plasma concentrations in pediatric patients. Body weight was found to be the most significant influential factor. Gender was also found to be a significant covariate although the effect was relatively small. Monte-Carlo simulations indicated that 20 mg/kg over 1 h infusion would give 90% probability of target attainment for 40% of time above minimum inhibitory concentration against Haemophilus influenzae and Streptococcus pneumoniae, major causative pathogens in pediatric infections, and that 40 mg/kg, the highest approved dose for Japanese pediatric patients, administered over 3 h infusion achieved 98.6% against 8 µg/mL. The developed population pharmacokinetic model of doripenem and Monte-Carlo simulations for pediatric patients should provide useful information for understanding the pharmacokinetic and pharmacokinetic-pharmacodynamic characteristics of doripenem and for optimal treatment of pediatric patients.

Population Pharmacokinetics of Baloxavir Marboxil in Japanese Pediatric Influenza Patients.

Baloxavir marboxil is a prodrug of baloxavir acid, an inhibitor of cap-dependent endonuclease, and suppresses the replication of influenza virus. The aim of this study was to investigate its pharmacokinetic characteristics in Japanese pediatrics. Population pharmacokinetic analysis was conducted for baloxavir acid with 328 plasma concentration data points in a clinical study of 107 Japanese pediatric influenza patients. The plasma baloxavir acid concentration profiles were well captured by a 2-compartment model including first-order absorption and lag time. Body weight was considered to be the most crucial covariate, which affects clearance and volume of distribution. The body weight-based dose regimen (10 mg for 10 kg to less than 20 kg pediatrics, 20 mg for 20 kg to less than 40 kg pediatrics, and 40 mg for at least 40 kg pediatrics) for Japanese pediatrics can provide comparable exposure to baloxavir acid to that for adults. In conclusion, the population pharmacokinetic model would be useful to comprehend the characteristics of baloxavir acid pharmacokinetics in pediatric patients.

Baloxavir marboxil in Japanese patients with seasonal influenza: Dose response and virus type/subtype outcomes from a randomized phase 2 study.

BACKGROUND: Baloxavir marboxil (baloxavir) is an antiviral drug that inhibits the viral "cap-snatching" step in virus RNA transcription initiation. In Phase 2 study, baloxavir significantly shortend the time to alleviation of symptoms (TTAS) and showed significantly greater reduction in influenza virus titer compared with placebo. This provides additional outcomes including efficacy against virus types/subtypes and pharmacokinetic/pharmacodynamic (PK/PD) analysis. METHODS: Subgroup analyses by virus types/subtype were conducted for the primary and key secondary endpoints. Blood samples were collected totally at 2 to 5 points including Day 2 after baloxavir dosing. PK/PD analyses were conducted for TTAS and change in virus titer using the liner model and the Emax model, respectively. RESULTS: The median TTAS in each baloxavir dose group was significantly shorter than in the placebo group for patients with A/H1N1pdm virus, and was numerically shorter than the placebo group for patients with A/H3N2 and type B virus. Baloxavir significantly reduced virus titer within 1 day after treatment: for A/H1N1pdm, A/H3N2, and B virus, all 3 doses of baloxavir marboxil reduced virus titer on Day 2 to a greater extent than placebo. No clear PK/PD relationships were found for the TTAS, but the larger reduction in virus titer was observed in increasing C24. CONCLUSION: These results support that baloxavir marboxil will be effective against a range of virus types/subtypes.