Infant Dose Research Articles

Cannabidiol Exposure Through Maternal Marijuana Use: Predictions in Breastfed Infants.

Knowledge about exposure to cannabidiol (CBD) in breastfed infants can provide an improved understanding of potential risk. The aim was to predict CBD exposure in breastfed infants from mothers taking CBD and CBD-containing products. Cannabidiol concentrations in milk previously attained from data collected through an existing human milk research biorepository were used to simulate infant doses and identify subgroups. A developed pediatric physiologically based pharmacokinetic model produced virtual breastfed infants administered the simulated CBD doses. Predicted breastfed infant exposures and upper area under the curve ratios were compared to the lowest therapeutic dose for approved indications in children. The existing human milk research biorepository contained 200 samples from 181 unique breastfeeding mothers for whom self-reported administration data and CBD concentrations had previously been measured. Samples that were above the lower limit of quantification with only one maternal administration typerevealed that administration type, i.e., joint/blunt or edible versus oil or pipe, resulted in significantly different subgroups in terms of milk concentrations. Resulting simulated infant doses (ng/kg) were described by lognormal distributions with geometric means and geometric standard deviations: 0.61 ± 2.41 all concentrations, 0.10 ± 0.37 joint/blunt or edible, and 2.23 ± 8.15 oil or pipe. Doses administered to breastfed infants had exposures magnitudes lower than exposures in children aged 4-11 years administered the lowest therapeutic dose for approved indications, and low upper area under the curve ratios. Based on real-world use, breastfeeding infants are predicted to receive very small exposures of CBD through milk. Studies examining adverse reactions will provide further insight into potential risk.

Radiation dose analysis of computed tomography coronary angiography in Children with Kawasaki disease.

There is evolving role of computed tomography coronary angiography (CTCA) in non-invasive evaluation of coronary artery abnormalities in children with Kawasaki disease (KD). Despite this, there is lack of data on radiation dose in this group of children undergoing CTCA. To audit the radiation dose of CTCA in children with KD. Study (December 2013-February 2018) was performed on dual source CT scanner using adaptive prospective electrocardiography-triggering. The dose length product (DLP in milligray-centimeters-mGy.cm) was recorded. Effective radiation dose (millisieverts-mSv) was calculated by applying appropriate age adjusted conversion factors as per recommendations of International Commission on Radiological Protection. Radiation dose was compared across the groups (0-1, 1-5, 5-10, and > 10 years). Eighty-five children (71 boys, 14 girls) with KD underwent CTCA. The median age was 5 years (range, 2 mo-11 years). Median DLP and effective dose was 21 mGy.cm, interquartile ranges (IQR) = 15 (13, 28) and 0.83 mSv, IQR = 0.33 (0.68, 1.01) respectively. Mean DLP increased significantly across the age groups. Mean effective dose in infants (0.63 mSv) was significantly lower than the other age groups (1-5 years 0.85 mSv, 5-10 years 1.04 mSv, and > 10 years 1.38 mSv) (P < 0.05). There was no significant difference in the effective dose between the other groups of children. All the CTCA studies were of diagnostic quality. No child required a repeat examination. CTCA is feasible with submillisievert radiation dose in most children with KD. Thus, CTCA has the potential to be an important adjunctive imaging modality in children with KD.

Anti-CD20 monoclonal antibody therapy in postpartum women with neurological conditions.

Postpartum, patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) have increased risk for disease activity. Anti-CD20 IgG1 monoclonal antibodies (mAb) are increasingly used as disease-modifying therapies (DMTs). Patients may wish to both breastfeed and resume DMT postpartum. This study aimed to determine the transfer of anti-CD20 IgG1 mAbs, ocrelizumab, and rituximab (OCR/RTX), into mature breastmilk and describe maternal and infant outcomes. Fifty-seven cis-women receiving OCR/RTX after 59 pregnancies and their infants were enrolled and followed up to 12M postpartum or 90 days post-infusion. Breastmilk was collected pre-infusion and serially up to 90 days and assayed for mAb concentration. Medical records and patients' questionnaire responses were obtained to assess neurologic, breastfeeding, and infant development outcomes. The median average concentration of mAb in breastmilk was low (OCR: 0.08 μg/mL, range 0.05-0.4; RTX: 0.03 μg/mL, range 0.005-0.3). Concentration peaked 1-7 days post-infusion in most (77%) and was nearly undetectable after 90 days. Median average relative infant dose was <1% (OCR: 0.1%, range 0.07-0.7; RTX: 0.04%, range 0.005-0.3). Forty-three participants continued to breastfeed post-infusion. At 8-12 months, the proportion of infants' growth between the 3rd and 97th World Health Organization percentiles did not differ for breastfed (36/40) and non-breastfed (14/16, p > 0.05) infants; neither did the proportion with normal development (breastfed: 37/41, non-breastfed: 11/13; p > 0.05). After postpartum infusion, two mothers experienced a clinical relapse. These confirm minimal transfer of mAb into breastmilk. Anti-CD20 mAb therapy stabilizes MS activity before conception to the postpartum period, and postpartum treatments appears to be safe and well-tolerated for both mother and infant.

Simultaneous Quantification of Psychotropic Drugs in Human Plasma and Breast Milk and Its Application in Therapeutic Drug Monitoring and Peripartum Treatment Optimization.

Therapeutic drug monitoring is recommended for several psychotropic drugs, particularly in sensitive situations such as the peripartum period. This study aimed to develop an ultra-high-performance liquid chromatography-tandem spectrometry method for the simultaneous quantification of 14 psychotropic drugs in human plasma and 4 in breast milk. The samples were precipitated with methanol containing the stable isotope-labeled analogs. Chromatographic separation was performed using a Phenomenex Luna Omega Polar C18 column. Detection was performed using a triple-quadrupole mass spectrometer equipped with an electrospray ionization interface. The method was fully validated in plasma according to the European Guidelines on Bioanalytical Method Validation and partially validated in breast milk by determining the intraday precision and accuracy, linearity, lower limit of quantification, and matrix effect. The correlation coefficients of the calibration curves were greater than 0.99. Coefficients of variation ranged from 3.05% to 14.66% and 0.62%-14.90% for internal standard-normalized matrix effect, 1.4%-14.1% and 2.1%-10.4% for intraday precision, and 3.2%-13.9% and 4.1%-9.6% for interday precision, in plasma and milk, respectively. The relative error in accuracy did not exceed ±15% for any analyte. The method was successfully applied clinically to measure the concentrations of psychotropic drugs in 952 plasma samples, among which 43% of the concentrations were out of the therapeutic range, and 13 breast milk samples, with calculated relative infant doses ranging from 0.32% to 8.18%. To the best of the authors' knowledge, this is the first routine technique validated for the quantification of psychotropic drugs in both plasma and breast milk, allowing for treatment optimization and prevention of adherence issues, including those in breastfeeding patients.

Simple and validated method to quantify lacosamide in human breast milk and plasma using UPLC/MS/MS and its application to estimate drug transfer into breast milk

BackgroundEpilepsy is a common neurological disorder. Lacosamide is a third-generation antiepileptic drug used to treat partial-onset seizures. Limited information is currently available on the transfer of lacosamide to breast milk. To facilitate studies on the safety of lacosamide use during breastfeeding, we aimed to develop a method to quantify lacosamide in human breast milk and plasma using ultra-performance liquid chromatography/tandem mass spectrometry.MethodsFifty microliters of breast milk or plasma was used, and samples were prepared by protein precipitation using methanol containing lacosamide-d3 as an internal standard (IS). Chromatography was performed using an ACQUITY HSS T3 column with an isocratic flow of 10 mM ammonium acetate solution/methanol (70:30, v/v). Lacosamide and IS were detected by multiple reaction monitoring in positive ion electrospray mode. The run time was 3.5 min.ResultsCalibration curves were linear and in the range of 0.5 to 100 ng/mL both in breast milk and plasma. The validation assessment indicated that precision, accuracy, matrix effects, selectivity, dilution integrity, and stability were acceptable. The developed method was successfully applied to quantify lacosamide in breast milk and plasma obtained from a volunteer who had been orally administered lacosamide twice a day (100 mg × 2). Relative infant dose of lacosamide was estimated to be 14.6% in breast milk at five time points.ConclusionsWe developed a simple and robust method to quantify of lacosamide in human breast milk and plasma. This method could be useful for in future studies investigating the safety of lacosamide use during breastfeeding.

Lemborexant levels in breast milk after single doses in healthy, lactating women.

The aim of this study is to determine the cumulative amount of lemborexant (a competitive dual orexin receptor antagonist approved to treat adults with insomnia) excreted in human breast milk and the relative infant dose (RID) as a proportion of daily maternal dose. E2006-A001-010 was a single-centre, open-label study that enrolled lactating women (≥18 years) who breastfed for ≥5 weeks postpartum. After overnight fasting, subjects received a single 10-mg oral dose of lemborexant. Using a standardized electric pump, milk was sampled before and ≤240 h (10 days) after dosing; combined and total volume were recorded. The cumulative total amount of lemborexant excreted, fraction of dose excreted, daily infant dose and RID were calculated. Lemborexant concentration in human milk was assessed by liquid chromatography with tandem mass spectrometry. Eight subjects completed the study. The mean cumulative total amount of lemborexant reached 0.0174 mg (coefficient of variation [CV] 54.5%; 0.174% of lemborexant 10 mg administered) in breast milk at 240 h (10 days); ~70% of excreted lemborexant accumulated in the first 24 h. For an infant weighing 6 kg, the daily infant dose was 0.00290 mg kg-1 (CV 54.5%) and the RID was 1.96% (CV 63.1%) of daily maternal dose. Mild treatment-emergent adverse events were reported in 4 subjects; these all resolved by end of study. Trace quantities of lemborexant were found in human breast milk. Lemborexant was well tolerated by healthy lactating women.

High accumulation of nivolumab in human breast milk: A case report

Nivolumab is an immunotherapeutic monoclonal antibody (mAb) that is used for the treatment of several types of cancer. The evidence on its use during lactation is lacking. Here, we report on a 39-year-old woman with metastasized melanoma who was treated with 480 mg nivolumab every four weeks during lactation. Breast milk samples were collected over the course of 34 days, including two cycles of nivolumab. The highest measured concentration of nivolumab during the first cycle was 503 ng/mL at day 13. The cumulative relative infant dose (RID) over the first cycle (28 days) was 9.8 %. The highest overall measured nivolumab concentration was 519 ng/mL at day 33, five days after administration of the second nivolumab cycle. Nivolumab seems to accumulate in breast milk over two consecutive cycles, hence the RIDs of consecutive cycles are expected to be higher. To draw further conclusions regarding safety of breastfeeding during nivolumab therapy, more information about the oral bioavailability of nivolumab in newborns, the nivolumab steady-state concentrations in breast milk and its pharmacodynamic effects are needed.

Evaluation of Intussusception Following Pentavalent Rotavirus Vaccine (RotaTeq) Administration in 5 African Countries.

A low-level risk of intussusception following rotavirus vaccination has been observed in some settings and may vary by vaccine type. We examined the association between RotaTeq vaccination and intussusception in low-income settings in a pooled analysis from 5 African countries that introduced RotaTeq into their national immunization program. Active surveillance was conducted at 20 hospitals to identify intussusception cases. A standard case report form was completed for each enrolled child, and vaccination status was determined by review of the child's vaccination card. The pseudo-likelihood adaptation of self-controlled case-series method was used to assess the association between RotaTeq administration and intussusception in the 1-7, 8-21, and 1-21 day periods after each vaccine dose in infants aged 28-245 days. Data from 318 infants with confirmed rotavirus vaccination status were analyzed. No clustering of cases occurred in any of the risk windows after any of the vaccine doses. Compared with the background risk of naturally occurring intussusception, no increased risk was observed after dose 1 in the 1-7 day (relative incidence = 2.71; 95% confidence interval [CI] = 0.47-8.03) or the 8-21 day window (relative incidence = 0.77; 95%CI = 0.0-2.69). Similarly, no increased risk of intussusception was observed in any risk window after dose 2 or 3. RotaTeq vaccination was not associated with increased risk of intussusception in this analysis from 5 African countries. This finding mirrors results from similar analyses with other rotavirus vaccines in low-income settings and highlights the need for vaccine-specific and setting-specific risk monitoring.

0895 Pharmacokinetics of pitolisant in breast milk and serum of healthy lactating women

Abstract Introduction Pitolisant is a potent and highly selective histamine-3-receptor antagonist/inverse agonist approved for the treatment of excessive daytime sleepiness or cataplexy in adult patients with narcolepsy. A phase 4, open-label study was conducted to evaluate the pharmacokinetics (PK) of pitolisant and its major metabolite, BP1.3484, in breast milk and serum following a single dose of pitolisant administered to healthy lactating women. Methods In this study, eight healthy lactating women (aged 22-42 years) who met eligibility criteria were enrolled and received a single oral dose of pitolisant (35.6 mg). Serial breast milk samples were collected at pre-dose on Day 1 and at various intervals through 24 hours post-dose. Serial blood samples for PK analyses were collected at pre-dose and through 120 hours post-dose. Since the total infant dosage calculated from single dose data may be under-estimated, steady-state serum concentrations were predicted using noncompartmental methods and then multiplied by the 24-hour breast milk:serum ratio (AUCBM/S) to estimate a more appropriate total infant dose. Results Pitolisant was excreted in breast milk, with mean CmaxBM/S and AUCBM/S ratios of 85.2% and 123%, respectively. Concentrations of pitolisant in breast milk were only slightly lower than concentrations in serum. However, since the volume of breast milk was low, the percentage of the maternal dose expressed in breast milk was very low. Steady state calculations for a 6-month-old infant resulted in a mean total infant dosage of 0.005 mg/kg/day (SD 0.002), which is 1.15% of the maternal dose. For BP1.3484, maternal exposure and the calculated mean daily infant exposure were much lower than pitolisant. All subjects completed the study as planned. Five subjects (62.5%) reported a total of 8 treatment-emergent adverse events, which were mild in severity and resolved by end of the study. Conclusion Pitolisant is present in human milk, but the mean daily infant dosage in a 6-month-old infant after steady-state dosing of pitolisant in healthy lactating women was estimated to be very low. Overall, a single oral dose of pitolisant 35.6 mg was well-tolerated in healthy lactating women. Support (if any) The study was sponsored by Harmony Biosciences LLC.

Preliminary Study on the Development of Caffeine Oral Solid Form 3D Printed by Semi-Solid Extrusion for Application in Neonates.

Apnea of prematurity can be treated with a body-weight-adjusted dosage of caffeine. Semi-solid extrusion (SSE) 3D printing represents an interesting approach to finely tailor personalized doses of active ingredients. To improve compliance and ensure the right dose in infants, drug delivery systems such as oral solid forms (orodispersible film, dispersive form, and mucoadhesive form) can be considered. The aim of this work was to obtain a flexible-dose system of caffeine by SSE 3D printing by testing different excipients and printing parameters. Gelling agents (sodium alginate (SA) and hydroxypropylmethyl cellulose (HPMC)) were used to obtain a drug-loaded hydrogel matrix. Disintegrants (sodium croscarmellose (SC) and crospovidone (CP)) were tested for get rapid release of caffeine. The 3D models were patterned by computer-aided design with variable thickness, diameter, infill densities, and infill patterns. The oral forms produced from the formulation containing 35% caffeine, 8.2% SA, 4.8% HPMC, and 52% SC (w/w) were found to have good printability, achieving doses approaching to those used in neonatology (between 3 and 10mg of caffeine for infants weighing approximately between 1 and 4kg). However, disintegrants, especially SC, acted more as binder/filler, showing interesting properties to maintain the shape after extrusion and enhance printability without a significant effect on caffeine release.

Pharmacokinetics of Ketamine Transfer Into Human Milk.

Ketamine is an N -methyl- d -aspartate-antagonistic dissociative anesthetic infused intermittently for off-label management of treatment-resistant depression, acute suicidality, and postpartum depression. Despite the prevalence of postpartum depression nearing upward of 15% of deliveries, almost no research has been done to evaluate its safety during lactation. In this study, human milk samples were released from the InfantRisk Center's Human Milk Biorepository of 4 participants treated with intermittent ketamine infusions (49-378 mg) to determine the levels of the drug and its active norketamine metabolite using liquid chromatography-mass spectrometry. The absolute infant dose of ketamine from human milk was 0.003 to 0.017 mg/kg per day, and norketamine was 0.005 to 0.018 mg/kg per day. The relative infant dose (RID) for ketamine ranged from 0.34% to 0.57%. The RID for norketamine ranged from 0.29% to 0.95%. There were no reported infant adverse effects. The findings of this study suggest that the transfer of ketamine, as well as its active metabolite, norketamine, into human milk is minimal, as estimated by RIDs less than 1% in all participants. These relative doses are well below standardly accepted safety thresholds.

Generic Workflow to Predict Medicine Concentrations in Human Milk Using Physiologically-Based Pharmacokinetic (PBPK) Modelling-A Contribution from the ConcePTION Project.

Women commonly take medication during lactation. Currently, there is little information about the exposure-related safety of maternal medicines for breastfed infants. The aim was to explore the performance of a generic physiologically-based pharmacokinetic (PBPK) model to predict concentrations in human milk for ten physiochemically diverse medicines. First, PBPK models were developed for "non-lactating" adult individuals in PK-Sim/MoBi v9.1 (Open Systems Pharmacology). The PBPK models predicted the area-under-the-curve (AUC) and maximum concentrations (Cmax) in plasma within a two-fold error. Next, the PBPK models were extended to include lactation physiology. Plasma and human milk concentrations were simulated for a three-months postpartum population, and the corresponding AUC-based milk-to-plasma (M/P) ratios and relative infant doses were calculated. The lactation PBPK models resulted in reasonable predictions for eight medicines, while an overprediction of human milk concentrations and M/P ratios (>2-fold) was observed for two medicines. From a safety perspective, none of the models resulted in underpredictions of observed human milk concentrations. The present effort resulted in a generic workflow to predict medicine concentrations in human milk. This generic PBPK model represents an important step towards an evidence-based safety assessment of maternal medication during lactation, applicable in an early drug development stage.

Predicting Chemotherapy Distribution into Breast Milk for Breastfeeding Women Using a Population Pharmacokinetic Approach.

Information on the distribution of chemotherapeutic drugs to breast milk is scarce, and reports are limited to small sample sizes. Anecdotal pharmacokinetic data have typically been acquired from lactating but non-breastfeeding patients who collect breast milk by means of an expression pump, which might not necessarily be representative for a breastfeeding population due to differences in milk production. Consequently, little is known about the variability of chemotherapy distribution to breast milk and the effect of milk production on the distribution of chemotherapy to breast milk. Our aim was to predict chemotherapy distribution to breast milk in a more realistic breastfeeding population and evaluate the effect of discarding breast milk on the potential chemotherapy exposure in infants. We developed a population pharmacokinetic model that described the breast milk production and the chemotherapy distribution to breast milk of a non-breastfeeding population, linked it to plasma pharmacokinetics, and extrapolated this to a breastfeeding population. We found that cumulative relative infant doses (RID) were higher than 10% for cyclophosphamide and doxorubicin and approximately 1% for paclitaxel. Simulations allowed us to predict the cumulative RID and its variability in the population for patients with different milk productions and the amount of breast milk that has to be discarded to reach cumulative RIDs below 1%, 0.1%, and 0.01%. Discarding 1-2, 3-6, and 0-1 days of breast milk (depending on the milk production of the patient) resulted in cumulative RID below 1% for cyclophosphamide, doxorubicin, and paclitaxel, respectively. Our results may help clinicians to derive the optimal breast milk discarding strategy for an individual patient that wants to breastfeed during chemotherapy and minimize chemotherapy exposure in their infants.

Annual effective dose associated with Ra-226 radioactivity in the water from several mining areas in Indonesia

This study aims to obtain data on estimated annual radiation doses for 3 age groups of the community residing in several mining locations and control areas to be used as consideration in the management of environmental radioactivity in mining areas in general. In this study, several mining areas have been selected, including: tin mining areas in the Bangka Belitung Islands, traditional gold mining in Kuantan and Pongkor, steam-electric power plant in Pacitan and Rembang as well as control areas which are Mamuju and Lampung. The radioactivity of Ra-226 in water on all study sites were used as secondary data for calculating the estimated annual effective dose for infants, children and adults. The results of the calculation of the estimated annual effective dose showed that the highest was received by the infant age group 1-2 years at the tin mining location, namely 6.55-18.3 E-04 Sv/y, the group of children aged 7-12 years at 4.52- 9.25.E-04 Sv /year and adults 0.35-18.3.E-04 Sv/year. While the lowest was in Mamuju area, respectively for infants = 6.65.E-07, children 3.36.E-07 and adults 1.30.E-07 Sv/year. There is a significant relationship between the activity of Ra-226 in water with the annual effective dose at each study site and the highest dose for infants aged 1-2 years compared to the children and adult groups. This needs attention in environmental management in the area, especially in the setting of public residential areas.

Maternal, fetal, neonatal and breastmilk flecainide concentration during maternal therapy and lactation: a case report

BackgroundMothers requiring the antiarrhythmic agent flecainide are often advised not to breastfeed, because of the lack of data concercing neonatal effects and flecainide plasma concentrations following maternal exposure as well as via lactation. This is the first report on combined maternal, fetal, neonatal and breastmilk flecainide concentrations in a breastfed infant of a mother requiring flecainide treatment.Case presentationA 35-year old Gravida 2 Para 1, known with ventricular arrhythmia, was referred to our tertiary center at 35 + 4 weeks of gestation. Because of an increase of ventricular ectopy, oral metoprolol 11.9 milligrams once daily was switched to oral flecainide 87.3 milligrams twice daily. Weekly collected maternal flecainide plasma trough concentrations fell within the therapeutic range of 0.2 to 1.0 mg/L and no further clinically significant arrhythmias occurred during the study period. A healthy son was born at 39 weeks of gestation and had a normal electrocardiogram. The fetal to maternal flecainide ratio was 0.72 and at three different timepoints, the flecainide concentration was higher in breastmilk than in maternal plasma. The relative infant dose received via breastmilk compared to maternal dose was 5.6%. Neonatal plasma concentrations were not detectable, despite the flecainide passage into breastmilk. All electrocardiograms to assess the neonatal antiarrhytmic effect were normal.ConclusionsOur results assume that flecainide can be prescribed safely to lactating mothers. Quantification of drug concentrations in neonatal blood in addition to measurements in maternal and fetal blood, and breastmilk, are helpful to evaluate the effects and safety of maternal medication use during pregnancy and lactation.

Infant Exposure to Antituberculosis Drugs via Breast Milk and Assessment of Potential Adverse Effects in Breastfed Infants: Critical Review of Data.

Infants of mothers treated for tuberculosis might be exposed to drugs via breast milk. The existing information on the exposure of breastfed infants lacks a critical review of the published data. We aimed to evaluate the quality of the existing data on antituberculosis (anti-TB) drug concentrations in the plasma and milk as a methodologically sound basis for the potential risk of breastfeeding under therapy. We performed a systematic search in PubMed for bedaquiline, clofazimine, cycloserine/terizidone, levofloxacin, linezolid, pretomanid/pa824, pyrazinamide, streptomycin, ethambutol, rifampicin and isoniazid, supplemented with update references found in LactMed®. We calculated the external infant exposure (EID) for each drug and compared it with the recommended WHO dose for infants (relative external infant dose) and assessed their potential to elicit adverse effects in the breastfed infant. Breast milk concentration data were mainly not satisfactory to properly estimate the EID. Most of the studies suffer from limitations in the sample collection, quantity, timing and study design. Infant plasma concentrations are extremely scarce and very little data exist documenting the clinical outcome in exposed infants. Concerns for potential adverse effects in breastfed infants could be ruled out for bedaquiline, cycloserine/terizidone, linezolid and pyrazinamide. Adequate studies should be performed covering the scenario in treated mothers, breast milk and infants.

Development and Validation of Physiologically Based Pharmacokinetic Model of Levetiracetam to Predict Exposure and Dose Optimization in Pediatrics

Levetiracetam (Lev) is an antiepileptic drug that has been increasingly used in the epilepsy pediatric population in recent years, but its pharmacokinetic behavior in pediatric population needs to be characterized clearly. Clinical trials for the pediatric drug remain difficult to conduct due to ethical and practical factors. The purpose of this study was to use the physiologically based pharmacokinetic (PBPK) model to predict changes in plasma exposure of Lev in pediatric patients and to provide recommendations for dose adjustment. A PBPK model of Lev in adults was developed using PK-Sim® software and extrapolated to the entire age range of the pediatric population. The model was evaluated using clinical pharmacokinetic data. The results showed the good fit between predictions and observations of the adult and pediatric models. The recommended doses for neonates, infants and children are 0.78, 1.67 and 1.22 times that of adults, respectively. Moreover, at the same dose, plasma exposure in adolescents was similar to that of adults. The PBPK models of Lev for adults and pediatrics were successfully developed and validated to provide a reference for the rational administration of drugs in the pediatric population.

Radionuclides in commercial children's food consumed in Croatia

This work presents first results of radioactivity measurements in selected early children's food (<year) which are commercially available, widespread, and typically consumed in Croatia. The samples are categorized according to growth of a child, from its first nourishment, adapted powdered milk, to its first solid food, cereal porridge powder, homogenized fruit porridge and finally mushed meals with vegetables and/or meat. Natural 4 K is detected and quantified in all of the samples (from 30 Bq/kg up to over 250 Bq/kg), with highest values in powdered milk (150–200 Bq/kg) and cereal porridge (maximum value 262 Bq/kg in the sample containing oats). 226 Ra was visible in all types of foods in the majority of the samples in small amounts, not exceeding 0.92 Bq/kg. 137 Cs was detected only in some of the powdered milk samples with maximum measured activities (0.65 ± 0.32 Bq/kg and 0.38 ± 0.14 Bq/kg) found in the samples where 4 K showed largest values, too. 90 Sr was detected in majority of samples of fruit, vegetable and meat meals, reaching up to 0.065 ± 0.025 Bq/kg in vegetable porridge containing potatoes and carrot. It was detected only in one sample of powdered milk, and in none of the cereal porridge samples. All of the presented results are within the values reported by other studies around the world. The results are used to estimate the ingestion doses to evaluate the radiological health risk, which is calculated to be 0.72 mSv/year. The contribution of 4 K prevails with about 72%. The biggest part comes from intake of fruit (34%), followed by intake of milk (24%) and cereals (20%). The contribution of radioactivity in water, taken from previous studies is also considered. Even the maximum possible value of the annual dose for infants still doesn't exceed the recommended limit of 1 mSv. • Results of radioactivity measurements results in baby food in Croatia are presented. • 4 K, 226 Ra, 90 Sr and 137 Cs are found and quantified in most of the samples. • The ingestion doses for infants are estimated to be 0.72 mSv/year. • Contribution of 4 K prevails with about 72% to the ingestion dose. • Highest contribution comes from intake of fruit (34%), milk (24%) and cereals (20%).

Toxicological testing of Fuganlin Oral Liquid on young Sprague Dawley rats

Purpose: To further evaluate the safety of Fuganlin Oral Liquid (FGLOL) for clinical application by conducting toxicological tests in young rats.&#x0D; Methods: Based on the clinical dose for infants aged less than 1 year, 4-day-old Sprague-Dawley (SD) rats were orally administered FGLOL3.88, 11.64 and 38.75 g crude drug/kg for 18 days, followed by a 3-week withdrawal. This was followed by evaluating the effect of FGLOL on various growth and development indicators, nerve reflex function and spontaneous behavior of the rats. Based on the clinical dose for children aged 1 - 6 years, 15-day-old rats were orally administered FGLOL3.88, 11.64 and 38.75 g crude drug/kg for 31 days, followed by a 3-week withdrawal in order to evaluate the impact of the FGLOL on the development of reproductive organs and nervous systems in young rats. The effects of FGLOL on the safety of young rats were judged based on ophthalmic examination, physical examination, spontaneous behavior and other developmental effects.&#x0D; Results: FGLOL did not cause animal death, and no significant toxicological changes were observed in the body weight, growth and development, and behavior of the young rats (p &lt; 0.05). No observed adverse effect level (NOAEL) even after administering the higher dose at each stage. However, the results at each stage showed that oral administration of a large amount of FGLOL had a greater effect on normal food consumption of the rats (p &lt; 0.05).&#x0D; Conclusion: The findings indicate that Fuganlin Oral Liquid, a traditional Chinese medicine formulation, is safe in rats. However, clinical trials are required to acertain its safety in humans.

Investigation of radioactivity level in drinking water resources and soil samples collected from the Hawraman villages, Iraq

In the present study, the RAD7 and NaI(Tl) techniques were utilized to determine the radon concentrations in drinking water resources and the natural primordial radionuclides in soil samples collected from Hawraman villages. The measured radon concentrations ranged from 1.7 ± 0.6 to 34.0 ± 2.8 Bq L−1 with an arithmetic mean of 14.8 ± 1.2 Bq L−1. This research demonstrates that roughly 54% of drinking water samples exceed the EPA-recommended level of 11.1 Bq L−1. For adults, children, and infants, the total annual effective doses for the three types (Ding, Dinh, and Ddi) vary from 7.6 to 149.2 μSv y−1 with an average of 65.0 μSv y−1, 8.1–160.0 μSv y−1 with an average of 69.7 μSv y−1, and 10.5–207.0 μSv y−1 with an average of 90.2 μSv y−1.18.2%, 22.7%, and 36.4%, respectively, of the annual effective dose for adults, children, and infants exceeds the 100 μSv y−1 level recommended by WHO and UNCEAR 2000.The activity concentrations of 226Ra, 232Th, and 4 K in soil samples varied from 10.9 ± 0.1 to 32.6 ± 0.2 Bq kg−1, 18.3 ± 0.4 to 52.1 ± 0.6 Bq kg−1, and 252.7 ± 2.5 to 585.6 ± 3.7 Bq kg−1. The arithmetic mean concentrations of 226Ra, 232Th, and 4 K were determined to be 19.4 ± 0.2 Bq kg−1, 36.2 ± 0.5 Bq kg−1and 426.6 ± 3.2 Bq kg−1, respectively.This research reveals that the average soil activity concentrations of 226Ra, 232Th, and 4 K are within the global average limits of 32, 45, and 420 Bq kg−1, respectively. Comparing the concentrations to global averages, some soil samples revealed significant amounts of radionuclides, with around 18% of 232Th and 41% of 4 K. The computed radiological hazard indices of 100% of Raeq., 82% of Dout, 82% of Eout, and 95.5% of ELCRout are all below the internationally recommended levels declared by Unscear 2000.