Use of Japanese Herbal Kampo Medicine in Patients With Acute Cardiovascular Disease　- A 12-Year Nationwide Cohort Analysis.

BACKGROUND: Kampo, a Japanese herbal medicine, is approved for the treatment of various symptoms/conditions under national medical insurance coverage in Japan. However, the contemporary nationwide status of Kampo use among patients with acute cardiovascular diseases remains unknown. METHODS AND RESULTS: Using the Japanese Diagnosis Procedure Combination database, we retrospectively identified 2,547,559 patients hospitalized for acute cardiovascular disease (acute myocardial infarction, heart failure, pulmonary embolism, or aortic dissection) at 1,798 hospitals during the fiscal years 2010-2021. Kampo medicines were used in 227,008 (8.9%) patients, with a 3-fold increase from 2010 (4.3%) to 2021 (12.4%), regardless of age, sex, disease severity, and primary diagnosis. The top 5 medicines used were Daikenchuto (29.4%), Yokukansan (26.1%), Shakuyakukanzoto (15.8%), Rikkunshito (7.3%), and Goreisan (5.5%). From 2010 to 2021, Kampo medicines were initiated earlier during hospitalization (from a median of Day 7 to Day 3), and were used on a greater proportion of hospital days (median 16.7% vs. 21.4%). However, the percentage of patients continuing Kampo medicines after discharge declined from 57.9% in 2010 to 39.4% in 2021, indicating their temporary use. The frequency of Kampo use varied across hospitals, with the median percentage of patients prescribed Kampo medications increasing from 7.7% in 2010 to 11.5% in 2021. CONCLUSIONS: This nationwide study demonstrates increasing Kampo use in the management of acute cardiovascular diseases, warranting further pharmacoepidemiological studies on its effectiveness.

Machine Learning-based Models for Outpatient Prescription of Kampo Formulations: An Analysis of a Health Insurance Claims Database.

BACKGROUND: Despite the widespread practice of Japanese traditional Kampo medicine, the characteristics of patients receiving various Kampo formulations have not been documented in detail. We applied a machine learning model to a health insurance claims database to identify the factors associated with the use of Kampo formulations. METHODS: A 10% sample of enrollees of the JMDC Claims Database in 2018 and 2019 was used to create the training and testing sets, respectively. Logistic regression analyses with lasso regularization were performed in the training set to construct models with prescriptions of 10 commonly used Kampo formulations in 1 year as the dependent variable and data of the preceding year as independent variables. Models were applied to the testing set to calculate the C-statistics. Additionally, the performance of simplified scores using 10 or 5 variables were evaluated. RESULTS: There were 338,924 and 399,174 enrollees in the training and testing sets, respectively. The commonly prescribed Kampo formulations included kakkonto, bakumondoto, and shoseityuto. Based on the lasso models, the C-statistics ranged from 0.643 (maoto) to 0.888 (tokishakuyakusan). The models identified both the common determinants of different Kampo formulations and the specific characteristics associated with particular Kampo formulations. The simplified scores were slightly inferior to full models. CONCLUSION: Lasso regression models showed good performance for explaining various Kampo prescriptions from claims data. The models identified the characteristics associated with Kampo formulation use.

Individualization of the infusion rate of a soybean oil-based intravenous lipid emulsion for inpatients, based on baseline triglyceride concentrations: A population pharmacokinetic approach.

BACKGROUND: A rapid infusion rate for intravenous lipid emulsion (ILE) can cause adverse effects; therefore, safe and efficient infusion rates are desired. This study aimed to develop a triglyceride (TG) kinetic model after soybean oil-based ILE (SO-ILE) administration and individualize the infusion rate via a population pharmacokinetic approach. METHODS: Eighty-three inpatients were enrolled in this prospective observational study. A TG kinetic model was applied to the observations based on population pharmacokinetics using a nonlinear mixed-effect model. The patients' characteristics and laboratory parameters were evaluated to identify predictors of TG kinetics, and the maximum acceptable infusion rate was defined as that for which the maximum TG concentration did not exceed 400 mg/dl in 90% of patients. RESULTS: No adverse events associated with SO-ILE administration were observed. The developed TG kinetic model explained the observed TG concentrations and identified the baseline TG concentration and body weight as predictors of TG kinetics. The estimated maximum acceptable infusion rates greatly varied among individuals, ranging from <0.01 to 0.3 g/kg/h. CONCLUSION: The present study suggested the necessity and demonstrated the feasibility of individualizing the infusion rates of SO-ILE, using a population pharmacokinetic approach.

Population Semiphysiologic Kinetic Modeling and Simulation of Plasma Triglyceride Levels After Soybean Oil-Based Intravenous Lipid Emulsion Administration in Rats.

BACKGROUND: Soybean oil-based intravenous lipid emulsion (SO-ILE) has clinical utility as an energy source and in lipid rescue therapy. However, an excessive infusion rate of SO-ILE in routine use and in lipid rescue therapy may cause serious side effects. There is little information about plasma triglyceride (TG) kinetics following SO-ILE administration. The present study aimed to develop a population semiphysiologic kinetic model of TG and to predict the TG kinetics even at extremely high concentrations in rats. MATERIALS AND METHODS: TG concentration profiles after intravenous bolus (0.1, 0.25, 0.5, 1.0, 1.5, and 2.0 g/kg) or infusion (3.0 g/kg/h for 1 hour) of SO-ILE to rats were analyzed by a kinetic model constructed with 4 pathways: apolipoprotein acquisitions, zero-order catabolism, first-order uptake to storage sites, and zero-order secretion from storage sites. The developed model was subjected to internal and external validation. RESULTS: Plasma TG concentrations appeared to decline in a biphasic manner with nonlinear TG kinetics. The developed kinetic model was well validated and found to accurately predict the external validation data. CONCLUSIONS: The proposed kinetic model accurately described TG concentrations after SO-ILE administration at various infusion rates, including a lipid rescue regimen. The maximum acceptable infusion rate of SO-ILE in routine use should correspond to the maximum velocity of the apolipoprotein acquisition: 0.619 g/kg/h in rats. The prediction of TG kinetics at extremely high concentrations will provide useful information for lipid rescue therapy.

Laparoscopically assisted anorectoplasty using perineal ultrasonographic guide: a preliminary report.

BACKGROUND/PURPOSE: As minimal invasive surgery, laparoscopically assisted anorectal pull-through has been reported with new devices. However, it is not easy to create an accurate pull-through canal (PTC) because of the narrow space between the urethra and puborectal sling. The authors describe a new method using perineal ultrasonography. METHODS: The rectourethral prostatic fistula was dissected laparoscopically. Externally, electrostimulation identified the center of the muscle contraction, over which a 1.2-cm skin incision was made, and the lower part of PTC was created by hemostat forceps guided by electrostimulation. An ultrasonographic probe applied to the perineum demonstrated the urethra, and the forceps was advanced behind the urethra into the pelvic cavity using the ultrasonographic guide. Anorectal pull-through was performed after dilatation of the PTC with dilators. RESULTS: The authors applied this procedure in 5 cases of male high and intermediate anomalies. Surgical damages to the urethra and the levator and vertical muscles were not encountered. Postoperative fluoroscopic study demonstrated good anterior angulation and intact contraction and relaxation of those muscles. CONCLUSION: The combination of laparoscopic dissection, pinpointing the center of anal sphincter by electrostimulation, and identification of the urethra by ultrasonographic images from the perineum facilitated creation of appropriate PTC in the muscle complex.

Cow's milk allergy presenting Hirschsprung's disease-mimicking symptoms.

The authors present a neonatal case of allergic colitis, which manifested the difficulty of spontaneous defecation and irregular narrowing of distal rectum in contrast enema. Rectal suction biopsy showed positive acetylcholinesterase activity. These clinical, radiological and histological findings were indistinguishable from Hirschsprung's disease. Gastrointestinal symptoms were improved by the cessation of cow's milk formula. The present findings may impact on the less recognizable gastrointestinal manifestation of allergic colitis.

Alanyl-glutamine-supplemented parenteral nutrition prevents intestinal ischemia-reperfusion injury in rats.

BACKGROUND: Intestinal ischemia-reperfusion (I/R) injury plays an important role in the pathogenesis of systemic inflammation and multiple-organ failure. We studied whether glutamine, the primary fuel of the small intestine, prevents intestinal mucosal damage after intestinal I/R in rats. METHODS: Rats were randomly divided into 4 groups: a sham-standard amino acid (SAA) group (n = 8); a sham-glutamine (Gln) group (n = 8); an I/R-SAA group (n = 10); and an I/R-Gln group (n = 9). Alanyl-glutamine solution was produced by replacing 36% of the total amino acid nitrogen with Gln. The superior mesenteric artery was ligated. After 60 minutes of ischemia, reperfusion was initiated and infusion was started. After 24-hour reperfusion, the intestinal segment was removed for morphological and biochemical analysis, and blood samples were drawn from the portal vein. Fluorescein isothiocyanate-conjugated dextran 70,000 (FITC-dextran) was infused into the duodenum 2 hours before animal death. RESULTS: In the I/R-SAA group, extensive epithelial sloughing and mucosal ulceration of villous tips were observed, whereas these findings did not occur in the I/R-Gln group. Mucosal wet weight, DNA, and protein content decreased significantly in the I/R-SAA group compared with the sham-SAA group and increased significantly in the I/R-Gln group compared with the I/R-SAA group. Plasma FITC-dextran significantly increased in the I/R-SAA group compared with the sham-SAA group, but the plasma level in the I/R-Gln group was comparable with that of each sham group. Mucosal glutaminase activity significantly increased in both the I/R-SAA and I/R-Gln groups compared with the sham-SAA and sham-Gln groups, respectively. CONCLUSIONS: Alanyl-glutamine protects against morphologic and functional mucosal injury after intestinal I/R in rats.

Follow-up studies of anorectal malformations after posterior sagittal anorectoplasty.

BACKGROUND/PURPOSE: There are few follow-up studies comparing posterior sagittal anorectoplasty (PSARP) with conventional procedures for patients with anorectal malformations (ARM). The authors have examined retrospectively postoperative anorectal function of patients with ARM treated with PSARP compared with those treated with conventional methods. METHODS: Anorectal function in 23 patients with high and intermediate type anorectal malformations (PSARP group), who underwent PSARP more than 4 years previously, were assessed by Kelly's clinical scoring system and objective studies. These results were compared with those in 14 cases (5 high and 9 intermediate type cases; control group), who underwent other conventional surgical procedures. RESULTS: Using Kelly's clinical scoring system, scores of the PSARP group compared with the control group were good in 48% versus 21%, fair in 48% versus 58%, and poor in 4% versus 21%, respectively. Barium enema studies suggested better anorectal sphincteric function in patients with high anorectal malformation in the PSARP group. Magnetic resonance imaging (MRI) studies showed more correct placement of the rectum through the striated muscle complex in the PSARP group at the I-line level. Manometric studies showed no difference in maximum resting pressure, anal canal length, and the incidence of anorectal reflex between the two groups. CONCLUSIONS: The favorable results of MRI and barium enema studies can be explained by direct visualization of the striated muscle complex with the aid of electrical stimulation as well as no harmful effects of amputation of the sphincter muscle in PSARP. However, manometric studies suggest anorectal function in patients with high and intermediate anorectal malformations is limited even after PSARP. Long-term postoperative follow-up with adequate bowel management is required for all patients with high or intermediate anorectal malformation.

Gut glutamine metabolism at different stages of sepsis in rats.

PURPOSE: To investigate gut glutamine metabolism and determine the effects of glutamine supplementation in different stages of sepsis in a rat model. METHODS: Sepsis was induced by cecal ligation and puncture (CLP), and control rats underwent a sham operation. In the first experiment, a continuous infusion of normal saline was started at the end of the operation. Intestinal blood flow, glutamine concentrations of the abdominal aorta and superior mesenteric vein (SMV) were measured, and gut glutamine extraction and flux were calculated 5 h after the sham operation, and 5 and 20 h after CLP, being groups Ia ( n = 9), Ib ( n = 8), and Ic ( n = 8), respectively. In the second experiment, animals received a continuous infusion of alanyl-glutamine instead of normal saline and were divided into groups IIa ( n = 8), IIb ( n = 8), and IIc ( n = 6). The same parameters were measured in each group and compared with those of the corresponding group in the first experiment. RESULTS: In the first experiment, no significant difference in SMV blood flow was seen among the groups. The arterial glutamine concentration was increased in group Ic ( P < 0.05) compared with that in groups Ia and Ib. Gut glutamine extraction was significantly increased in group Ib ( P < 0.01) and significantly decreased in group Ic ( P < 0.05) compared with that in group Ia. In the second experiment, gut glutamine flux was significantly increased in group Ilb ( P < 0.01) compared with that in group Ib, but the increase did not reach statistical significance between groups Ia and IIa or between groups Ic and IIc. CONCLUSION: These results indicate that intestinal glutamine uptake is increased and glutamine utilization is enhanced by glutamine supplementation in early sepsis.