Challenges of pediatric pharmacotherapy: A narrative review of pharmacokinetics, pharmacodynamics, and pharmacogenetics.

PURPOSE: Personalized pharmacotherapy, including for the pediatric population, provides optimal treatment and has emerged as a major trend owing to advanced drug therapeutics and diversified drug selection. However, it is essential to understand the growth and developmental characteristics of this population to provide appropriate drug therapy. In recent years, clinical pharmacogenetics has accumulated knowledge in pediatric pharmacotherapy, and guidelines from professional organizations, such as the Clinical Pharmacogenetics Implementation Consortium, can be consulted to determine the efficacy of specific drugs and the risk of adverse effects. However, the existence of a large knowledge gap hinders the use of these findings in clinical practice. METHODS: We provide a narrative review of the knowledge gaps in pharmacokinetics (PK) and pharmacodynamics (PD) in the pediatric population, focusing on the differences from the perspective of growth and developmental characteristics. In addition, we explored PK/PD in relation to pediatric clinical pharmacogenetics. RESULTS: The lack of direct and indirect biomarkers for more accurate assessment of the effects of drug administration limits the current knowledge of PD. In addition, incorporating pharmacogenetic insights as pivotal covariates is indispensable in this comprehensive synthesis for precision therapy; therefore, we have provided recommendations regarding the current status and challenges of personalized pediatric pharmacotherapy. The integration of clinical pharmacogenetics with the health care system and institution of educational programs for health care providers is necessary for its safe and effective implementation. A comprehensive understanding of the physiological and genetic complexities of the pediatric population will facilitate the development of effective and personalized pharmacotherapeutic strategies.

Normal reference values for left atrial strains and strain rates in school children assessed using two-dimensional speckle-tracking echocardiography.

Left atrium (LA) function is a known predictive marker of heart failure in adults. Few reports of LA function analyses using LA strain (ɛ) and strain rate (SR) measurements in children exist. Thus, this study aimed to determine normal reference values for LA ɛ and SR in healthy school children and to investigate methods of interpreting LA function data based on maturational changes using two-dimensional speckle-tracking echocardiography (2DSTE). We recruited 112 healthy school children (median age 12.0 years; range 6-16 years). LA ɛ and SR were investigated using 2DSTE multi-vendor analysis software (TomTec Imaging Systems, Germany) and compared to Doppler parameters and LA volumes measured by the conventional method. The onset of the P wave was selected as the reference point for the LA ɛ analysis. Normal ranges of LA ɛ [reservoir (ɛRS), conduit (ɛCD), or contractile (ɛCT)] and positive SR (SRPOS), early negative SR (SREN), and late negative SR (SRLN) were obtained using Z-score models via the lambda-mu-sigma method. According to the Z-score curves, all ɛ showed slight falling or continuous flat lines against age, body surface area (BSA), or heart rate (HR); however, ɛ CT showed modestly positive associations with HR. As for SR, the Z-score curves showed falling lines against age and BSA. In contrast, Z-score curves for SREN and SRLN showed rising lines against HR. SREN was independent of E/e' and was negatively correlated with LA volume indexed against BSA. This study demonstrated the normal reference values for LA ɛ and SR using 2DSTE in school children. The present results recommended that LA ɛ should be evaluated together with changes in LA SR for accurate assessment, considering maturational changes including age, BSA, and HR in school children.

Recent updates on echocardiography and ultrasound for Kawasaki disease: beyond the coronary artery.

Kawasaki disease (KD) is a systemic vasculitis with a predilection for damage to the coronary arteries. In the acute phase, clinical decision making for KD relies on the measurements of the coronary z-score obtained by 2-dimensional echocardiography (2DE). In the convalescent phase, KD patients with coronary artery abnormalities (CAAs) eventually show arteriosclerotic vascular remodeling characterized by marked intimal proliferation and neoangiogenesis after KD vasculitis, which often induces myocardial ischemia. To date, several well-established surrogate markers including dobutamine stress echocardiography (DSE), the carotid intima-media thickness (CIMT) and flow-mediated dilatation (FMD), have been made available for risk assessment and the prediction of cardiovascular disease (CVD) in KD patients. Additionally, the use of carotid contrast-enhanced ultrasonography (CEUS), has enabled the visualization and quantification of the adventitial vasa vasorum (VV) network, assessing active vascular remodeling at remote arterial sites in KD patients with CAAs. However, there was no evidence of major vascular structural changes in KD patients in whom CAAs had never been detected. Thus, assessment of multiple modalities using 2DE may provide direct information not only on the vascular health but also on the stratification of the risk of CVD in KD patients with CAAs.

Impact of persistent left ventricular regional wall motion abnormalities in childhood cancer survivors after anthracycline therapy: Assessment of global left ventricular myocardial performance by 3D speckle-tracking echocardiography.

AIMS: To identify left ventricular (LV) mechanical impairment by 3D speckle-tracking echocardiography (3DSTE) in long-term childhood cancer survivors after anthracycline therapy with or without persistent LV regional diastolic wall motion abnormalities (WMA) and a preserved LV ejection fraction (EF >53%). METHODS AND RESULTS: Thirty-two patients (median: 14.6 years) and 12 age-matched controls were studied. The patients were divided into two groups according to the existence of WMA: Group 1 (with WMA: n=14), Group 2 (without WMA: n=18). 3DSTE was performed to assess LV global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS), global area strain (GAS), LV torsion, LV end-diastolic volume (LVEDV), and LV end-systolic volume (LVESV). LV systolic dyssynchrony index (SDI) was calculated as the percentage of the standard deviation of time to peak strain of the 16 segments divided by the RR interval. There was no significant difference in LVEDV, LVESV, GLS, torsion, or SDI derived from LS, CS, or AS among the 3 groups. In contrast, there were significant differences in GRS, GCS, and GAS, and SDI derived from RS among the 3 groups. Compared with group 2, group 1 had significantly reduced GRS (p<0.001), GCS (p<0.01), GAS (p<0.01), and greater SDI derived from GRS (p<0.01). Moreover, the existence of WMA was correlated with GRS (p<0.001), SDI derived from GRS (p<0.001), and LVEF (p=0.036). Multiple linear regression analysis identified GRS as a significant determinant of the existence of WMA (ß=0.751, p=0.001). CONCLUSION: Childhood cancer survivors with persistent LV regional WMA show a reduced LV myocardial performance compared with those without WMA, despite a preserved LVEF.

Reassessment of carotid intima-media thickness by standard deviation score in children and adolescents after Kawasaki disease.

Previous studies that used carotid ultrasound have been largely conflicting in regards to whether or not patients after Kawasaki disease (KD) have a greater carotid intima-media thickness (CIMT) than controls. To test the hypothesis that there are significant differences between the values of CIMT expressed as absolute values and standard deviation scores (SDS) in children and adolescents after KD and controls, we reviewed 12 published articles regarding CIMT on KD patients and controls. The mean ± SD of absolute CIMT (mm) in the KD patients and controls obtained from each article was transformed to SDS (CIMT-SDS) using age-specific reference values established by Jourdan et al. (J: n = 247) and our own data (N: n = 175), and the results among these 12 articles were compared between the two groups and the references for comparison of racial disparities. There were no significant differences in mean absolute CIMT and mean CIMT-SDS for J between KD patients and controls (0.46 ± 0.06 mm vs. 0.44 ± 0.04 mm, p = 0.133, and 1.80 ± 0.84 vs. 1.25 ± 0.12, p = 0.159, respectively). However, there were significant differences in mean CIMT-SDS for N between KD patients and controls (0.60 ± 0.71 vs. 0.01 ± 0.65, p = 0.042). When we assessed the nine articles on Asian subjects, the difference of CIMT-SDS between the two groups was invariably significant only for N (p = 0.015). Compared with the reference values, CIMT-SDS of controls was within the normal range at a rate of 41.6 % for J and 91.6 % for N. These results indicate that age- and race-specific reference values for CIMT are mandatory for performing accurate assessment of the vascular status in healthy children and adolescents, particularly in those after KD considered at increased long-term cardiovascular risk.

Long-term prognostic impact of dobutamine stress echocardiography in patients with Kawasaki disease and coronary artery lesions: a 15-year follow-up study.

OBJECTIVES: This study sought to determine the prognostic value of dobutamine stress echocardiography (DSE) over a 15-year follow-up for predicting cardiac events in adolescent Kawasaki disease (KD) patients with coronary artery lesions (CALs). BACKGROUND: Although DSE is an established technique for the detection of coronary artery disease, its prognostic value to predict cardiac events in adolescent KD patients with CALs is unknown. METHODS: Fifty-eight adolescent KD patients, including 36 patients with CALs documented by coronary angiography, and 22 patients with normal coronary arteries documented by echocardiography who underwent DSE were reviewed at initial testing (mean age: 13.6 years) and at 15 years' follow-up. Follow-up events were tabulated as major adverse cardiac events (MACEs) that included cardiac death, nonfatal myocardial infarction, and revascularization. RESULTS: During a mean follow-up of 14.7 years, there were 16 patients with MACEs (acute myocardial infarction: n = 1; old myocardial infarction: n = 7; coronary artery bypass grafting: n = 4; percutaneous coronary intervention: n = 4). Significant coronary artery disease (CAD) (>70% coronary stenosis) was detected in 31.0% of patients at initial testing and 42.1% at follow-up. However, there were no significant differences in wall motion score indices (WMSI) at peak DSE between initial testing and follow-up (p = 0.762). Five of 6 patients (85%) with false-positive DSE results (WMSI: ≥1.25) at initial testing, who had giant aneurysms without CAD, developed CAD with MACEs during follow-up. Cumulative event-free survival rate to 15 years was 25.0% in patients with WMSI ≥1.25 and 91.7% in patients with WMSI <1.25. Cox regression analysis showed the grade of peak WMSI at initial testing to be the only independent predictor of MACEs (relative risk: 3.28; 95% confidence interval: 1.73 to 6.20). CONCLUSIONS: DSE provided independent prognostic information up to 15 years in adolescent KD survivors.

Characteristics of earlier atherosclerotic involvement in adolescent patients with Kawasaki disease and coronary artery lesions: significance of gray scale median on B-mode ultrasound.

OBJECTIVE: To test the hypothesis that textural changes in the carotid intima-media complex (IMC) detected by B-mode ultrasound are associated with the difference of remodeling process in earlier atherosclerotic involvement in patients with Kawasaki disease (KD) and coronary artery lesions (CALs). METHODS: Eighteen patients with KD and CALs (mean age 17.2 years), 17 patients with heterozygous familial hypercholesterolemia (FH) (mean age 16.9 years) and 15 age-matched healthy controls (Cont) were assessed and compared for carotid intima-media thickness (CIMT), elastic property (E(p)), and first- and second-order statistics. RESULTS: KD showed significantly higher gray scale median (GSM) than FH and Cont. KD and FH showed significantly higher CIMT, entropy and lower angular second moment than Cont, but no significant difference was found between KD and FH. CONCLUSION: Higher GSM in KD may indicate alteration of tissue components and heterogeneity of IMC, suggesting the development of arteriosclerotic vascular remodeling after vasculitis. This is distinct from that of atherosclerosis with lower GSM often observed in FH.

Changes in the textural characteristics of intima-media complex in young patients with familial hypercholesterolemia: implication for visual inspection on B-mode ultrasound.

BACKGROUND: To test the hypothesis that textural changes in the carotid intima-media complex (IMC) on visual inspection by B-mode ultrasound are associated with early atherosclerotic involvement in patients with heterozygous familial hypercholesterolemia (FH). METHODS: 55 patients (mean age 13.4 years) were categorized into three groups according to the degree of thickness in IMC (intima-media thickness [IMT]) (groups I-III) and 15 healthy controls within the same age range as the patients were assessed for first- and second-order statistics and visual scoring of textural changes in IMC (1, normal; 2, proximal interface disruption; 3, granulation). RESULTS: There was no significant difference in first-order statistics among the four groups. As for second-order statistics, groups II (moderately increased IMT) and III (markedly increased IMT) had significantly higher entropy and lower angular second moment than group I (normal IMT) and control. Likewise, groups II and III received significantly higher visual scoring than group I. Visual scoring correlated with entropy (r = 0.57) and angular second moment (r = -0.50). Multiple regression analysis identified entropy (beta = 0.52) and visual scoring (beta = 0.42) as significant determinants of IMT. CONCLUSIONS: These findings demonstrate that higher visual scoring may indicate dishomogeneity of IMC, suggesting early medial infiltration. This seems to be a simple visual marker to more effectively identify high-risk young patients with FH.

Age-related acceleration of endothelial dysfunction and subclinical atherosclerosis in subjects with coronary artery lesions after Kawasaki disease.

The objective of this study was to test the hypothesis that accelerated endothelial dysfunction and the development of premature atherosclerosis are associated with age in subjects with coronary artery lesions after Kawasaki disease (KD). A case-control study was performed at a university hospital that included 35 post-KD subjects across a wide age range (range, 8-42 years) without traditional cardiovascular risk factors and 35 age- and sex-matched healthy control subjects (Cont). Flow-mediated dilatation (FMD) of the brachial artery-induced by reactive hyperemia, intima media thickness (IMT), and elastic modulus (Ep) of the common carotid artery were compared between KD and Cont subjects assessed against age. KD subjects had slightly higher levels of body mass index, lipid profile, and HbA1c than Cont subjects, but the differences were not significant. The mean IMT (p < 0.001), age-adjusted percentage normal IMT (%N IMT; p < 0.0001), and Ep (p < 0.001) were significantly higher in KD than Cont subjects, and the peak FMD% (p < 0.01) was significantly lower in KD than Cont subjects. There were significant correlations between FMD% and age (r = -0.51 p < 0.0001), IMT and age (r = 0.68, p < 0.001), and Ep and age (r = 0.58, p < 0.01) in KD but not Cont subjects. When the difference in FMD% between KD and matched Cont subjects (DeltaFMD%) was plotted against age, no significant relationship was found, although significant correlations between DeltaIMT and age (r = 0.52, p < 0.01) as well as between DeltaEp and age (r = 0.46, p < 0.05) were observed. When we defined values that were +2.0 SD over the mean control values (i.e., %N IMT >or= 120% and/or Ep >or= 50 kPa) as markers of subclinical atherosclerosis, 15 subjects met the criteria. Subjects over the age of 22 years were more likely to have (OR = 16.54, p = 0.0001) subclinical atherosclerosis in this cohort. Our results suggest that endothelial dysfunction and the development of premature atherosclerosis were accelerated in adult post-KD compared to Cont subjects.

B-flow sonographic demonstration for assessing carotid atherosclerosis in young patients with heterozygous familial hypercholesterolemia.

PURPOSE: To determine whether bloodstream swirls detected with B-mode flow (B-flow) sonography at the region of the carotid bifurcation can predict the early progression of atherosclerosis, we prospectively examined the relationships between the size of bloodstream swirls as identified with B-flow sonography, the local mechanical behavior of the common carotid artery (CCA), and some cardiovascular risk factors in young patients with heterozygous familial hypercholesterolemia (FH). METHODS: Thirty-eight young patients (mean age 25.8 +/- 14.1 years) with FH were evaluated for the following parameters: age, sex, body mass index, degree of dyslipidemia, presence of a plaque, intima-media thickness (IMT), elastic modulus (Ep) and internal diameter of the CCA via duplex scan, wall shear stress, maximal diameter of the bloodstream swirl (Sm) at bifurcation, maximal diameter of the CCA (Cm) at the level of the swirl's center, and diameter ratio (Sm/Cm) via B-flow sonography. RESULTS: Bloodstream swirls of varying size at the site of bifurcation were observed in all patients. Six (15.7%) out of 38 patients exhibited plaques at bifurcation. All plaques were located at the far wall and were in contact with the distal portion of the bloodstream swirl as observed with B-flow sonography. Univariate analysis revealed that Sm/Cm and Sm were positively correlated with age, presence of a plaque, IMT, and Ep and were negatively correlated with shear stress. Multivariate analysis revealed that Sm was significantly correlated with age (P < 0.01) and Ep (P < 0.05). CONCLUSIONS: Our results suggest that a bloodstream swirl visualized at the carotid bifurcation with B-flow sonography may be an indicator of a local mechanism for the age-related progression of atherosclerosis in young patients with FH.

Adult Kawasaki disease unrelated to epstein-barr virus and group A Streptococcus.

A 23-year-old Japanese woman with a fever and generalized skin eruptions was referred to our hospital in July 1999. At admission, her temperature was 38.9 degrees C, and she had fluctuating symptoms including erythema of the extremities, conjunctival hyperemia, strawberry tongue, and generalized skin eruptions, but lymphadenopathy was not verified. An initially elevated urine leukocyte count (more than 100 per high power field) later returned to normal range without antibiotic therapy. Adult Kawasaki disease was diagnosed on the basis of the above symptomology. Echocardiograph showed transient effusion in the pericardium. Using the Harada scoring system for treatment of Kawasaki disease, we gave the patient aspirin and did not administer intravenous immunoglobulin. The clinical course was uneventful, and on the day of discharge (day 22 after onset), the laboratory test results were nearly normal. Laboratory test results were negative for both Epstein-Barr virus and group A Streptococcus.

Detection of myocardial contractile reserve by low-dose dobutamine quantitative gated single-photon emission computed tomography in patients with Kawasaki disease and severe coronary artery lesions.

We studied 24 patients with severe coronary artery lesions to assess myocardial perfusion and left ventricular contractile reserve simultaneously using low-dose dobutamine quantitative electrocardiographically gated single-photon emission computed tomography in patients with Kawasaki disease. Low-dose dobutamine infusion was started after an injection of technetium-99m tetrofosmin at rest. Myocardial contractile reserve was evaluated using the post-stress and low-dose dobutamine images, and myocardial perfusion was evaluated using the stress and rest images. Quantitative electrocardiographically gated single-photon emission computed tomography during low-dose dobutamine infusion is a useful and safe method for the combined evaluation of myocardial contractile reserve and myocardial perfusion.

Familial combined hyperlipidemia (FCHL) in children: the significance of early development of hyperapoB lipoproteinemia, obesity and aging.

It is not easy to make diagnose FCHL in children, since a clear expression of lipoprotein abnormality is unlikely and standard criteria have not yet been established. We investigated eight cases of childhood FCHL and their families with respect to familial history, anthropometric parameters and serum lipoprotein levels, to explore the characteristics of childhood FCHL. To diagnose childhood FCHL it is necessary to clarify both the family history and lipid profiles of the parents. In this study, two prominent features were suggested; that serum TG level is affected by both obesity and age, and also in particular, that a significantly elevated level of serum apoB is a predominant feature of FCHL in childhood. It was found that hyperapoB may be revealed antecedently without other lipid abnormalities at an early age. Regardless of other lipoprotein abnormality, it was suggested that hyperapoB might be added to the early diagnostic criteria for FCHL.