Causality Evaluation of Drug-Induced Liver Injury in Newborns and Children in the Intensive Care Unit Using the Updated Roussel Uclaf Causality Assessment Method

Purpose: Drug-induced liver injury (DILI) is a common adverse reaction in the clinic; however, there are relatively few reports of DILI in critically ill newborns and children. Making use of the Pediatric Intensive Care database (PIC), this study identifies which drugs are related to DILI in neonates and children in China.Methods: Using the PIC, we screened for patients whose liver was suspected of being injured by drugs during hospitalization. The medicine they used was then assessed by the Roussel Uclaf Causality Assessment Method (RUCAM). At the same time, we also collated drug combinations that may affect CYP (Cytochrome P) enzyme metabolism, which may cause DILI.Results: A total of 13,449 patients were assessed, of whom 77 newborns and 261 children were finally included. The main type of liver injury in neonates was mixed (83.1%), while the hepatic injury types of children were mostly distributed between hepatocellular (59.4%) and cholestatic (28.4%). In terms of the RUCAM assessment, the drugs that were most considered to cause or be associated with hepatic injury in newborns were medium and long chain fat emulsions (17%), sodium glycerophosphate (12%), and meropenem (9%); while omeprazole (11%), methylprednisolone sodium succinate (10%), and meropenem (8%) were the primary culprits of DILI in children. Drug combinations frequently seen in neonates that may affect CYP enzyme metabolism are omeprazole + budesonide (16.9%), dexamethasone + midazolam (10.4%), and midazolam + sildenafil (10.4%). In children, the commonly used drug combinations are fentanyl + midazolam (20.7%), ibuprofen + furosemide (18.4%), and diazepam + omeprazole (15.3%).Conclusions: In this study, medium and long chain fat emulsions and sodium glycerophosphate have been strongly associated with DILI in newborns, while omeprazole and methylprednisolone sodium succinate play an important role in the DILI of children. Also, attention should be paid to the effect on CYP enzymes when using multiple drugs at the same time. In future DILI cases, it is advisable to use the latest RUCAM for prospective study design so that complete case data and high RUCAM scores can be collected.

Optimization of Personalized Amlodipine Dosing Strategies for Children Based on Pharmacokinetic Data from Chinese Male Adults and PBPK Modeling

For children, a special population who are continuously developing, a reasonable dosing strategy is the key to clinical therapy. Accurate dose predictions can help maximize efficacy and minimize pain in pediatrics. Methods: This study collected amlodipine pharmacokinetics (PK) data from 236 Chinese male adults and established a physiological pharmacokinetic (PBPK) model for adults using GastroPlus™. A PBPK model of pediatrics is constructed based on hepatic-to-body size and enzyme metabolism, used similar to the AUC0-∞ to deduce the optimal dosage of amlodipine for children aged 1–16 years. A curve of continuous administration for 2-, 6-, 12-, 16-, and 25-year-olds and a personalized administration program for 6-year-olds were developed. Results: The results show that children could not establish uniform allometric amplification rules. The optimal doses were 0.10 mg·kg−1 for ages 2–6 years and −0.0028 × Age + 0.1148 (mg/kg) for ages 7–16 years, r = 0.9941. The trend for continuous administration was consistent among different groups. In a 6-year-old child, a maintenance dose of 2.30 mg was used to increase the initial dose by 2.00 mg and the treatment dose by 1.00 mg to maintain stable plasma concentrations. Conclusions: A PBPK model based on enzyme metabolism can accurately predict the changes in the pharmacokinetic parameters of amlodipine in pediatrics. It can be used to support the optimization of clinical treatment plans in pediatrics.

Drug-Induced Hepatic Injury in Newborns and Children in Intensive Care Unit: A Retrospective Study of China

Purpose Drug-induced liver injury (DILI) is a common adverse reaction in the clinic; however, there are relatively few reports of DILI in critically ill newborns and children. Making use of the Pediatric Intensive Care database (PIC), this study identifies which drugs are related to DILI in neonates and children in China. Methods Using the PIC, we screened for patients whose liver was suspected of being injured by drugs during hospitalization. The medicine they used was then assessed by the Roussel Uclaf Causality Assessment Method (RUCAM). We also collated drug combinations that may affect CYP enzyme metabolism, which may be one of the mechanisms that lead to DILI. Results A total of 13,449 patients were assessed, of whom 77 newborns and 261 children were finally included. The main type of liver injury in neonates was mixed (83.1%), while children’s hepatic injury types were mostly distributed between hepatocellular (59.4%) and cholestatic (28.4%). In terms of the assessment by the RUCAM, in newborns, the drugs that were most considered to cause or associated with hepatic injury comprised medium and long chain fat emulsion (17%), sodium glycerophosphate (12%) and meropenem (9%); while omeprazole (11%), methylprednisolone sodium succinate (10%) and meropenem (8%) are the primary culprit of DILI in children. Drug combinations that may affect CYP enzyme metabolism frequently seen in neonates are omeprazole + budesonide (16.9%), dexamethasone + midazolam (10.4%) and midazolam + sildenafil (10.4%). In children, the commonly used drug combinations are fentanyl + midazolam (20.7%), ibuprofen + furosemide (18.4%) and diazepam + omeprazole (15.3%). Conclusions The drugs that have been found to have hepatotoxicity (meropenem, medium and long chain fat emulsion, ibuprofen.etc.) are also related to DILI in newborns and children. When giving these drugs to newborns and children, physicians need to be more cautious. Also, pay attention to the effect on CYP 450 enzymes when using multiple drugs at the same time.

Impact of dietary calcium tetraborate supplementation on the mineral content of egg and eggshell of laying quails

Boron (B) is a trace element that plays an important role in the mineral, cell membrane, hormone, and enzyme metabolism of animals and humans. The aim of this study was to examine the effect of dietary calcium tetraborate (CaB4O7) supplementation on the mineral composition of egg content and eggshell of laying quails. For this purpose, a total of 20 male and 40 female quails, 6-week-old, were equally divided into 2 groups (control and additive groups) in 5 replicates (6 birds/replicate) and given CaB4O7 300 mg/kg feed in additive group. The experiment was conducted for 56 days. The eggs were collected and the mineral composition [B, calcium (Ca), magnesium (Mg), sodium (Na), iron (Fe), potassium (K), manganese (Mn), copper (Cu), zinc (Zn)] of egg content and eggshell samples were determined at the end of the experiment in randomly collected 6 eggs per group. Results of this study indicated dietary supplementation of CaB4O7 increased Mg (P<0.01), Na (P<0.01), and K (P<0.05) contents of edible parts of eggs compared to the control group, but B concentration were not determined in edible parts of eggs in both groups. Moreover, B (P<0.01), Mg (P<0.01), Na (P<0.01), Fe (P<0.01), K (P<0.05), Cu (P<0.05) and Zn (P<0.01) of eggshell were higher in the additive group than control. There were also significant correlations between examined minerals both edible and eggshell parts of the eggs. It may be concluded that supplementing diets with CaB4O7 could improve Ca metabolism, producing eggs enriched in minerals, promoting B, Mg, Na, Fe, K, Cu, and Zn deposition in eggshells, and improving eggshells quality. The effective B supplementation doses for functional egg production could be determined and B could be advantageous in terms of beneficial physiological effects.

IMAGERY IDENTIFICATION OF TOMATOES WHICH CONTAIN PESTICIDES USING LEARNING VECTOR QUANTIZATION

Tomatoes have a risk of carrying pesticides above the maximum residue limit (MRL) because the fruit is directly sprayed with pesticides during its production process. Pesticide residue in farmers’ produce pose indirect effects to the consumers, but in the long run, it may cause health problems such as neural disorders as well as enzyme metabolism. This research identifies the image of tomatoes containing pesticides by using two types of tomatoes were used as samples, namely tomatoes which contain pesticides, and those which do not contain pesticides. This research aims to develop an algorithm to identify tomatoes that contain pesticides and those which do not contain pesticides using Learning Vector Quantization (LVQ). The characteristics used to identify tomato images are average, variant, and standard deviation. This research consisted of two classes and used 40 training image data and 40 test image data for each class. During the training process using LVQ parameters, there were 98.75% best percentage at alpha 0.001 and decalpha 0.9 with the lowest iteration of 3. The final weight obtained from the parameters was then used to perform test data identification. In terms of the best performance on the test data, it was with alpha 0.001 and decalpha 0.9, which reached 97.5%.

In Vitro Assessment of Fluoropyrimidine-Metabolizing Enzymes: Dihydropyrimidine Dehydrogenase, Dihydropyrimidinase, and β-Ureidopropionase

Fluoropyrimidine drugs (FPs), including 5-fluorouracil, tegafur, capecitabine, and doxifluridine, are among the most widely used anticancer agents in the treatment of solid tumors. However, severe toxicity occurs in approximately 30% of patients following FP administration, emphasizing the importance of predicting the risk of acute toxicity before treatment. Three metabolic enzymes, dihydropyrimidine dehydrogenase (DPD), dihydropyrimidinase (DHP), and β-ureidopropionase (β-UP), degrade FPs; hence, deficiencies in these enzymes, arising from genetic polymorphisms, are involved in severe FP-related toxicity, although the effect of these polymorphisms on in vivo enzymatic activity has not been clarified. Furthermore, the clinical usefulness of current methods for predicting in vivo activity, such as pyrimidine concentrations in blood or urine, is unknown. In vitro tests have been established as advantageous for predicting the in vivo activity of enzyme variants. This is due to several studies that evaluated FP activities after enzyme metabolism using transient expression systems in Escherichia coli or mammalian cells; however, there are no comparative reports of these results. Thus, in this review, we summarized the results of in vitro analyses involving DPD, DHP, and β-UP in an attempt to encourage further comparative studies using these drug types and to aid in the elucidation of their underlying mechanisms.

Association of cytochrome P450 2A6 polymorphism, anxiety, and environmental factors with cigarette smoking by Thai adults

BackgroundThe effects and associations of genetic variation, psychological, and environment factors associated with cigarette smoking and nicotine dependence remain largely unknown.ObjectiveTo determine the influence and association of functional genetic polymorphisms of cytochrome P450 2A6 (CYP2A6), anxiety, and environmental factors on cigarette smoking and nicotine dependence.MethodA cross-sectional study was conducted at King Chulalongkorn Memorial Hospital, Thailand between October 2014 and June 2015. We recruited 127 Thai adult smokers when they visited for an annual physical check-up. Participants completed questionnaires regarding demographic characteristics, The Fagerstrom Test for Nicotine Dependence, and The Thai Hospital Anxiety and Depression Scale. Blood was collected for CYP2A6 genotyping to determine the enzyme metabolism level/group.ResultsFactors associated with significantly greater cigarette consumption were age and being ultrarapid/ extensive metabolizers (UM/EM). Anxiety and smoking by household family members were significantly associated with the degree of nicotine dependence. We observed associations between severe nicotine dependence and genotype (UM/EM) and age (b = 0.037; P = 0.005), intermediate metabolizers (IM) and age (b = 0.031; P = 0.43), UM/EM and anxiety (b = 0.258; P < 0.001), IM and anxiety (b = 0.285; P < 0.001), UM/EM and household smoking in the family members (b = 1.427; P = 0.003), and IM and smoking by household family members (b = 1.293; P = 0.024).ConclusionsInformation regarding the association between the gene encoding enzyme metabolism, anxiety, and their interactions may be beneficial for selecting treatment choices for smoking cessation for individual genotypic metabolizers.