Overview of regulatory frameworks on the national lot release of plasma-derived medicinal products in Korea.

Plasma-derived medicinal products (PDMPs) are essential in the treatment of acute and chronic life-threatening diseases. The Korea Ministry of Food and Drug Safety has conducted a national lot release (NLR) of PDMPs since 2012 based on a summary protocol review system and lot release testing. However, few studies have investigated the performance or characteristics of the NLR framework. Over the past decade, the NLR of PDMPs was approximately 1000 per year, including mainly albumins, immunoglobulins, fibrin sealant kits, and coagulation factors, among others. The NLR system for PDMPs is similar to that for vaccines, except that PDMPs are manufactured using human plasma, which requires strict safety management. This study describes the status of NLR procedures for PDMPs and outlines the regulatory requirements needed to safely manage plasma for fractionation in Korea. This study can aid national control laboratories and marketing authorization holders in developing regulatory systems that assure the availability of safe and effective PDMPs.

Mdivi-1: Effective but complex mitochondrial fission inhibitor.

Mdivi-1, Mitochondrial DIVIsion inhibitor 1, has been widely employed in research under the assumption that it exclusively influences mitochondrial fusion, but effects other than mitochondrial dynamics have been underinvestigated. This paper provides transcriptome and DNA methylome-wide analysis for Mdivi-1 treated SH-SY5Y human neuroblastoma cells using RNA sequencing (RNA-seq) and methyl capture sequencing (MC-seq) methods. Gene ontology analysis of RNA sequences revealed that p53 transcriptional gene network and DNA replication initiation-related genes were significantly up and down-regulated, respectively, showing the correlation with the arrest cell cycle in the G1 phase. MC-seq, a powerful sequencing method for capturing DNA methylation status in CpG sites, revealed that although Mdivi-1 does not induce dramatic DNA methylation change, the subtle alterations were concentrated within the CpG island. Integrative analysis of both sequencing data disclosed that the p53 transcriptional network was activated while the Parkinson's disease pathway was halted. Next, we investigated several changes in mitochondria in response to Mdivi-1. Copy number and transcription of mitochondrial DNA were suppressed. ROS levels increased, and elevated ROS triggered mitochondrial retrograde signaling rather than inducing direct DNA damage. In this study, we could better understand the molecular network of Mdivi-1 by analyzing DNA methylation and mRNA transcription in the nucleus and further investigating various changes in mitochondria, providing inspiration for studying nuclear-mitochondrial communications.

Epigenetic landscape analysis reveals the significance of early reduced chromatin accessibility in osteoclastogenesis.

Recently improved techniques could provide snapshots of chromatin structure generated based on chromatin accessibility. Since chromatin accessibility determines transcriptional potential, it has been attempted in a variety of cell systems. However, there has been no genome-wide analysis of chromatin accessibility for the entire murine osteoclast (OC) differentiation process. We performed an Assay for Transposase-Accessible Chromatin (ATAC)-sequencing (seq) during RANKL-induced OC differentiation and found that global chromatin accessibility decreased, especially early in OC differentiation. The global histone H3K27Ac level, an active histone modification mark, was diminished during OC differentiation by western blot and histone extract experiments. Its genomic enrichment was also reduced based on publicly available H3K27Ac chromatin immunoprecipitation (ChIP)-seq data. ATAC-seq and H3K27Ac ChIP-seq data demonstrated that RANKL induced a less accessible chromatin state during OC differentiation. Restoration of reduced H3K27Ac, presumably representing accessible states upon acetate treatment, suppresses OC differentiation by provoking immune-related gene expression. Subsequential integrative analysis of ATAC-seq, RNA-seq after acetate treatment, and H3K27Ac ChIP-seq reveals that Irf8 and its downstream targets are the most vulnerable to chromatin accessibility changes and acetate supplementation. Taken together, our study generated chromatin accessibility maps during the whole OC differentiation and suggested perturbation of chromatin accessibility might be a potential therapeutic strategy for excessive OC diseases.

Preperitoneal Pelvic Packing versus Angioembolization for Patients with Hemodynamically Unstable Pelvic Fractures with Pelvic Bleeding: A Single-Centered Retrospective Study.

The aim of this study was to compare the outcomes of preperitoneal pelvic packing (PPP) and angioembolization (AE) for patients with equivocal vital signs after initial resuscitation. This single-centered retrospective study included information from the database of a regional trauma center from April 2014 to December 2022 for patients with pelvic fractures with a systolic blood pressure of 80-100 mmHg after initial fluid resuscitation. The patients' characteristics, outcomes, and details of AE after resuscitative endovascular balloon occlusion of the aorta (REBOA) placed in zone III were collected. The follow-up duration was from hospital admission to discharge. A total of 65 patients were enrolled in this study. Their mean age was 59.2 ± 18.1 years, and 40 were males. We divided the enrolled patients into PPP (n = 43) and AE (n = 22) groups. The median time from emergency department (ED) to procedure and the median duration of ED stay were significantly longer in the AE group than in the PPP group (p ≤ 0.001 for both). The median mechanical ventilation (MV) duration was significantly shorter (p = 0.046) in the AE group. The number of patients with complications, overall mortality, and mortality due to hemorrhage did not differ between the two groups. Three patients (13.6%) were successfully treated with AE after REBOA. AE may be beneficial for patients with hemodynamically unstable pelvic fractures who show equivocal vital signs after initial fluid resuscitation in terms of reducing the MV duration and incidence of infectious complications.

Effect of Antithrombin III Administration on the Prognosis of Severe Trauma Patients with Disseminated Intravascular Coagulation.

BACKGROUND: We aimed to investigate the effects of antithrombin III administration on the prognosis of severe trauma patients with disseminated intravascular coagulation (DIC). METHODS: Medical records of a total of 4023 patients who were admitted to the intensive care unit (ICU) at the single regional trauma center from January 2016 to December 2020 were retrospectively analyzed. After the exclusion of young patients (<15 years old), mild trauma (ISS < 16), non DIC, etc., a total of 140 patients were included in the study. These patients were classified into antithrombin III-administered and non-antithrombin III-administered groups. Clinical data, including laboratory findings, trauma- and ICU-related severity scores, prognosis (including length of hospital stay), and need for organ support, were retrospectively collected. We evaluated the characteristics of the two groups, and compared and analyzed the vital signs, laboratory findings, prognosis, and clinical outcomes of each group. With this, we analyzed the effect of antithrombin III administration in severe trauma patients with DIC. RESULTS: Of the 140 patients, 61 were treated with antithrombin III. No significant difference was observed in the baseline characteristics between the two groups for initial laboratory results, initial vital signs, or trauma-related severity scores. The improvement of the sequential organ failure assessment (SOFA) score, a prognostic marker, was significantly greater in the administered group (p = 0.009). Additionally, the antithrombin-administered group showed a larger improvement in the SOFA score than the non-administered group (p = 0.002). However, there was no statistical difference between the two groups for the frequency or duration of organ support treatments (renal replacement therapy, mechanical ventilation), mortality, or length of hospital stay. CONCLUSION: Antithrombin III administration in severe trauma patients with DIC improved SOFA scores and aided in multi-organ dysfunction recovery. Appropriate indications should be studied to maximize the drug's improvement effect in patients with severe trauma in the future.

Comparison of mortality among hemorrhage-control methods performed for hemodynamically unstable patients with traumatic pelvic fractures: A multi-center study.

BACKGROUND: /Objective: We aimed to analyze the effects of hemorrhage control methods on the mortality of patients with hemodynamic instability due to pelvic fracture and investigate independent mortality risk factors in these patients. METHODS: Ninety-seven pelvic bone fracture patients with hemodynamic instability who visited the emergency departments of two university hospitals over 5 years were enrolled. These patients were categorized based on 28-day mortality (survival group) and acute hemorrhage mortality (non-survival group). Forty-seven patients (48.5%) underwent pelvic angiography; 45 (46.4%), pre-peritoneal pelvic packing; and 19 (19.6%), external fixation. RESULTS: Differences in hemorrhage control methods did not significantly affect mortality. However, there was a significant difference in mortality between the groups with and without hemorrhage control methods. Multivariate logistic regression analysis revealed that patient age, trauma and injury severity score (probability of survival), and blood transfusion amount within 24 h were independent risk factors for 28-day mortality. Meanwhile, patient age, Glasgow coma scale (GCS) score, systolic blood pressure (SBP), and blood transfusion amount within 24 h were independent risk factors for mortality due to acute hemorrhage. CONCLUSION: Rapid and appropriate application of hemorrhage control methods can reduce acute hemorrhage-related mortality in hemodynamically unstable patients with pelvic fractures. Moreover, none of the hemorrhage control methods were superior for the decreasing mortality rate in these patients.

Outcomes improvement despite continuous visits of severely injured patients during the COVID-19 outbreak: experience at a regional trauma centre in South Korea.

BACKGROUND: Understanding the changes in characteristics of patients who visited trauma centres during the coronavirus disease 2019 (COVID-19) pandemic is important to facilitate aneffective response. This retrospective study was conducted to analyse differences in the characteristics and outcomes of patients who visited our trauma centre between pre-COVID-19 and COVID-19 eras. METHODS: Medical data of trauma patients enrolled in the Korean trauma database from 1 January 2018 to 31 August 2021 were collected. The number of trauma centre visits, patient characteristics, factors associated with in-hospital intervention, and outcomes werecompared between patients in the two time periods. Propensity score matching was performed to analyse the outcomes in patients with similar characteristics and severitybetween patients in the two time periods. RESULTS: The number of emergency department (ED) trauma service visits reduced in the COVID-19 era. Based on the mean age, the patients were older in the COVID-19 era. Abbreviated injury scale (AIS) 1, AIS3, AIS5, and injury severity score (ISS) were higher in the COVID-19 era. The proportion of motor vehicle collisions decreased, whereas falls increased during the COVID-19 era. Ambulance transportation, admission to the general ward, and time from injury to ED visit significantly increased. Patient outcomes, such as hospital length of stay (LOS), intensive care unit (ICU) LOS, and duration of mechanical ventilation improved, while injury severity worsened during the COVID-19 era. After adjusting for patient characteristics and severity, similar findings were observed. CONCLUSION: The small reduction in the number of trauma patients and visits by patients who hadhigher ISS during the COVID-19 pandemic highlights the importance of maintaining trauma service capacity and capability during the pandemic. A nationwide or nationalmulticentre study will be more meaningful to examine the impact of the COVID-19 outbreak on the changes in trauma patterns, volume, and patient outcomes.

Determination of risk factors associated with surgical site infection in patients undergoing preperitoneal pelvic packing for unstable pelvic fracture.

BACKGROUND: Several recent studies have shown that preperitoneal pelvic packing (PPP) effectively produces hemostasis in patients with unstable pelvic fractures. However, few studies have examined the rate of surgical site infections (SSIs) in patients undergoing PPP following an unstable pelvic fracture. The purpose of the present study was to evaluate factors associated with SSI in such patients. METHODS: We retrospectively reviewed the medical charts of 188 patients who developed hemorrhagic shock due to pelvic fracture between April 2012 and May 2021. Forty-four patients were enrolled in this study. RESULTS: SSI occurred in 15 of 44 patients (34.1%). The SSIs occurred more frequently in cases of repacking during the second-look surgery (0 vs. 4 [26.7%], P=0.010) and combined bladder-urethra injury (1 [3.4%] vs. 4 [26.7%], P=0.039). The incidence of SSIs was not significantly different between patients undergoing depacking within or after 48 hours (12 [41.4%] vs. 5 [33.3%], P=0.603). The mean time to diagnosis of SSI was 8.1±3.9 days from PPP. The most isolated organism was Staphylococcus epidermidis. CONCLUSIONS: Repacking and combined bladder-urethra injury are potential risk factors for SSI in patients with unstable pelvic fracture. Close observation is recommended for up to 8 days in patients with these risk factors. Further, 48 hours after PPP, removing the packed gauze on cessation of bleeding and not performing repacking can help prevent SSI. Additional analyses are necessary with a larger number of patients with the potential risk factors identified in this study.

Senescence and impaired DNA damage responses in alpha-synucleinopathy models.

α-Synuclein is a crucial element in the pathogenesis of Parkinson's disease (PD) and related neurological diseases. Although numerous studies have presented potential mechanisms underlying its pathogenesis, the understanding of α-synuclein-mediated neurodegeneration remains far from complete. Here, we show that overexpression of α-synuclein leads to impaired DNA repair and cellular senescence. Transcriptome analysis showed that α-synuclein overexpression led to cellular senescence with activation of the p53 pathway and DNA damage responses (DDRs). Chromatin immunoprecipitation analyses using p53 and γH2AX, chromosomal markers of DNA damage, revealed that these proteins bind to promoters and regulate the expression of DDR and cellular senescence genes. Cellular marker analyses confirmed cellular senescence and the accumulation of DNA double-strand breaks. The non-homologous end joining (NHEJ) DNA repair pathway was activated in α-synuclein-overexpressing cells. However, the expression of MRE11, a key component of the DSB repair system, was reduced, suggesting that the repair pathway induction was incomplete. Neuropathological examination of α-synuclein transgenic mice showed increased levels of phospho-α-synuclein and DNA double-strand breaks, as well as markers of cellular senescence, at an early, presymptomatic stage. These results suggest that the accumulation of DNA double-strand breaks (DSBs) and cellular senescence are intermediaries of α-synuclein-induced pathogenesis in PD.

Correlation between the Injury Site and Trauma Mechanism in Severely Injured Patients with Blunt Trauma.

Background: In patients with severe injury, predicting the injury site without using advanced diagnostic modalities can help formulate a diagnosis and treatment plan based on the suspected injury site. Objectives: This study aimed to determine the correlation between the injury site and trauma mechanism in severely injured patients with blunt trauma. Methods: We retrospectively analyzed the clinical characteristics-including age, sex, date of emergency room (ER) visit, time of injury, trauma mechanism (car accident, motorcycle accident, bicycle accident, pedestrian accident, fall, slipping and rolling down, crush injury, assault, and others), final diagnosis, injury severity score, abbreviated injury scale (AIS) score, and injury site-of 1,245 patients in a tertiary trauma center. Results: There was a strong correlation between certain injury sites and specific trauma mechanisms. In particular, most trauma mechanisms were associated with injury to the head and neck, as well as the chest, with a combined frequency of >40.0%. Moreover, when using one-way analysis of variance and Bonferroni's post hoc tests, there were significant differences in AIS scores 1, 3, 4, and 5 for each trauma mechanism. Conclusion: Generally, when patients with severe injury present to the ER, the injury site can be predicted upon initial assessment based on the trauma mechanism. Based on our study, the injury site predicted by a specific mechanism should be checked repeatedly and additionally through physical examination and imaging tools. This can reduce misdiagnosis and help with accurate diagnosis and treatment.

Hexosamine Biosynthetic Pathway-Derived O-GlcNAcylation Is Critical for RANKL-Mediated Osteoclast Differentiation.

O-linked-N-acetylglucosaminylation (O-GlcNAcylation) performed by O-GlcNAc transferase (OGT) is a nutrient-responsive post-translational modification (PTM) via the hexosamine biosynthetic pathway (HBP). Various transcription factors (TFs) are O-GlcNAcylated, affecting their activities and significantly contributing to cellular processes ranging from survival to cellular differentiation. Given the pleiotropic functions of O-GlcNAc modification, it has been studied in various fields; however, the role of O-GlcNAcylation during osteoclast differentiation remains to be explored. Kinetic transcriptome analysis during receptor activator of nuclear factor-kappaB (NF-κB) ligand (RANKL)-mediated osteoclast differentiation revealed that the nexus of major nutrient metabolism, HBP was critical for this process. We observed that the critical genes related to HBP activation, including Nagk, Gfpt1, and Ogt, were upregulated, while the global O-GlcNAcylation was increased concomitantly during osteoclast differentiation. The O-GlcNAcylation inhibition by the small-molecule inhibitor OSMI-1 reduced osteoclast differentiation in vitro and in vivo by disrupting the translocation of NF-κB p65 and nuclear factor of activated T cells c1 (NFATc1) into the nucleus by controlling their PTM O-GlcNAcylation. Furthermore, OSMI-1 had a synergistic effect with bone target therapy on osteoclastogenesis. Lastly, knocking down Ogt with shRNA (shOgt) mimicked OSMI-1's effect on osteoclastogenesis. Targeting O-GlcNAcylation during osteoclast differentiation may be a valuable therapeutic approach for osteoclast-activated bone diseases.

A nomogram to predict arterial bleeding in patients with pelvic fractures after blunt trauma: a retrospective cohort study.

BACKGROUND: Pelvic bone fractures are one of the biggest challenges faced by trauma surgeons. Especially, the presence of bleeding and hemodynamic instability features is associated with high morbidity and mortality in patients with pelvic fractures. However, prediction of the occurrence of arterial bleeding causing massive hemorrhage in patients with pelvic fractures is difficult. Therefore, the aim of this study was to develop a nomogram to predict arterial bleeding in patients with pelvic bone fractures after blunt trauma. METHODS: The medical records of 1404 trauma patients treated between January 2013 and August 2017 were retrospectively reviewed. Patients older than 15 years with a pelvic fracture due to blunt trauma were enrolled (n = 148). The pelvic fracture pattern on anteroposterior radiography was classified according to the Orthopedic Trauma Association/Arbeitsgemeinschaft fur Osteosynthesefragen (OTA/AO) system. Multivariable logistic regression modeling was used to determine the independent risk factors for arterial bleeding. A nomogram was constructed based on the identified risk factors. RESULTS: The most common pelvic fracture pattern was type A (58.8%), followed by types B (34.5%) and C (6.7%). Of the 148 patients, 28 (18.9%) showed pelvic arterial bleeding on contrast-enhanced computed tomography or angiography, or in the operative findings. The independent risk factors for arterial bleeding were a type B or C pelvic fracture pattern, body temperature < 36 °C, and serum lactate level > 3.4 mmol/L. A nomogram was developed using these three parameters, along with a systolic blood pressure < 90 mmHg. The area under the receiver operating characteristic curve of the predictive model for discrimination was 0.8579. The maximal Youden index was 0.1527, corresponding to a cutoff value of 68.65 points, which was considered the optimal cutoff value for predicting the occurrence of arterial bleeding in patients with pelvic bone fractures. CONCLUSIONS: The developed nomogram, which was based on the initial clinical findings identifying risk factors for arterial bleeding, is expected to be helpful in rapidly establishing a treatment plan and improving the prognosis for patients with pelvic bone fractures.

Glutamine metabolite α-ketoglutarate acts as an epigenetic co-factor to interfere with osteoclast differentiation.

Osteoclasts (OCs) have been well-known involved in the exacerbation of bone-related diseases. However, the role of metabolites on osteoclastogenesis has not been well characterized. Herein, we found osteoclastogenesis was negatively regulated by α-ketoglutarate (αKG) in vitro and in vivo (C57BL/6 mouse). Kinetic transcriptome analysis revealed the upregulation of solute carrier family 7 member 11 (Slc7a11), a subunit of the cysteine/glutamate antiporter, as well as the downregulation of typical OC maker genes through αKG treatment. Given that Slc7a11 could control ROS level through glutathione import, we measured intracellular ROS, then RANKL-induced ROS production was inhibited by αKG. Notably, we highlight that αKG plays an epigenetic co-factor at the Slc7a11 promoter by demethylating repressive histone H3K9 methylation and simultaneously increasing the nuclear factor erythroid 2-related factor (Nrf2) binding, a critical transcription factor through chromatin immunoprecipitation (ChIP) analysis. Together, we suggested that αKG could be a therapeutic strategy for OC activated diseases.

SMARCB1 Acts as a Quiescent Gatekeeper for Cell Cycle and Immune Response in Human Cells.

Switch/sucrose non-fermentable (SWI/SNF)-related matrix-associated actin-dependent regulator of chromatin (SMARC) subfamily B member 1 (SMARCB1) is a core subunit of the switch/sucrose non-fermentable (SWI/SNF) complex, one of the adenosine triphosphate (ATP)-dependent chromatin remodeler complexes. The unique role of SMARCB1 has been reported in various cellular contexts. Here, we focused on the general role of the ubiquitous expression of SMARCB1 in a normal cell state. We selected ARPE19 (human primary retinal pigment epithelium) and IMR90 (from human fetal lung fibroblasts) cell lines as they have completely different contexts. Furthermore, although these cell lines have been immortalized, they are relatively close to normal human cells. The loss of SMARCB1 in ARPE19 and IMR90 cells reduced cell cycle progression via the upregulation of P21. Transcriptome analysis followed by SMARCB1 knockdown in both cell lines revealed that SMARCB1 was not only involved in cell maintenance but also conferred immunomodulation. Of note, SMARCB1 bound to interleukin (IL) 6 promoter in a steady state and dissociated in an active immune response state, suggesting that SMARCB1 was a direct repressor of IL6, which was further confirmed via loss- and gain-of-function studies. Taken together, we demonstrated that SMARCB1 is a critical gatekeeper molecule of the cell cycle and immune response.

Factors predicting the need for hemorrhage control intervention in patients with blunt pelvic trauma: a retrospective study.

BACKGROUND: Blunt pelvic injuries are often associated with pelvic fractures and injuries to the rectum and genitourinary tract. Pelvic fractures can lead to life-threatening hemorrhage, which is a common cause of morbidity and mortality in trauma. Thus, early identification of patients with pelvic fractures at risk severe bleeding requiring urgent hemorrhage control is crucial. This study aimed to investigate early factors predicting the need for hemorrhage control in blunt pelvic trauma. METHODS: The medical records of 1760 trauma patients were reviewed retrospectively between January 2013 and June 2018. We enrolled 187 patients with pelvic fracture due to blunt trauma who were older than 15 years. The pelvic fracture pattern was classified according to the Orthopedic Trauma Association/Arbeitsgemeinschaft fur Osteosynthesefragen (OTA/AO) classification. A multivariate logistic regression model was used to determine independent predictors of the need for pelvic hemorrhage control intervention. RESULTS: The most common pelvic fracture pattern was type A (54.5%), followed by types B (36.9%) and C (8.6%). Of 187 patients, 48 (25.7%) required pelvic hemorrhage control intervention. Hemorrhage control interventions were most frequently performed in patients with type B fractures (54.2%). Multivariate logistic regression analysis revealed that type B (odds ratio [OR] = 4.024, 95% confidence interval [CI] = 1.666-9.720, p = 0.002) and C (OR = 7.077, 95% CI = 1.781-28.129, p = 0.005) fracture patterns, decreased body temperature (OR = 2.275, 95% CI = 0.134-0.567, p < 0.001), and elevated serum lactate level (OR = 1.234, 95% CI = 1.061-1.435, p = 0.006) were factors predicting the need for hemorrhage control intervention in patients with blunt pelvic trauma. CONCLUSION: Patients with type B and C fracture patterns on the OTA/AO classification, hypothermia, or an elevated serum lactate level are at risk for bleeding and require pelvic hemorrhage control intervention.

Oncogenic IL7R is downregulated by histone deacetylase inhibitor in esophageal squamous cell carcinoma via modulation of acetylated FOXO1.

The interleukin-7 receptor (IL7R) is generally expressed in immune cells and is critical in survival, development and homeostasis in the immune system. Advanced genome-wide cancer studies have reported that IL7R is genetically amplified in human esophageal squamous cell carcinoma (ESCC), however, the exact role of IL7R in ESCC has not been investigated. In the present study, it was found that IL7R was overexpressed in ESCC cohorts and the loss of IL7R induced anti-oncogenic effects in ESCC cell lines. A small panel of epigenetic drugs were screened for their ability to downregulate the expression of IL7R. Unexpectedly, apicidin, a histone deacetylase (HDAC) inhibitor, effectively downregulated the expression of IL7R in a dose-dependent manner at an early time-point, as determined by quantitative polymerase chain reaction and IL7R immunostaining, and did not require de novo protein synthesis. Of note, apicidin induced the acetylation of Forkhead box-containing protein, O subfamily 1, which acts as a repressor at the IL7R promoter, accompanied with depleted active histone modifications based on chromatin immunoprecipitation assay. Taken together, these results demonstrated that targeting oncogenic IL7R in ESCC by HDAC inhibitors may be a valuable therapeutic approach.

A thirteen-week oral toxicity study of So-ochim-tang-gami-bang, a traditional Korean medicine, in Sprague-Dawley rats.

ETHNOPHARMACOLOGICAL RELEVANCE: So-ochim-tang-gamibang (SOCG) is a traditional Korean medicine formulated to control internal energy flow (Qi) and has been prescribed to improve stress-induced depressive disorders. AIM OF THE STUDY: SOCG has been used in clinical practice for the last two decades and its efficacy against stress-induced thoracic pain has been suggested. Although SOCG has been used as an herbal formula in Korean medicine, its toxicity has not yet been evaluated. In this study, we evaluated the safety of SOCG through a 13-week general toxicity study in rats. MATERIAL AND METHODS: SOCG was administered by oral gavage to rats at doses of 0 (control), 800, 2000, and 5000mg/kg/day over a 13-week period. Toxicity testing was conducted by evaluating mortality, clinical signs, body weight, food consumption, urinalysis, hematology, serum biochemistry, organ weight, necropsy, and histopathology compared with the concurrent control. RESULTS: SOCG-related changes were noted in clinical signs and urinalysis. The observed clinical signs were compound-colored stool and salivation. Urinalysis results revealed brown or amber colored urine and elevated levels of protein. However, these changes were not considered to be adverse. CONCLUSIONS: The no-observed-adverse-effect-level of SOCG was determined to be above 5000mg/kg in both male and female rats. The result of this study can lay the foundation for the application of SOCG in humans and prove useful for detailed investigations on the toxicity or pharmacological effects of SOCG.

Subchronic Oral Toxicity Study of Acanthopanax divaricatus var. albeofructus in Rats.

Acanthopanax divaricatus (Siebold & Zucc.) Seem. var. albeofructus (ADA), a traditional medical herb, has been used to treat arthritis and muscular injury, to strengthen muscle and bone, and to get vital energy. However, information regarding its toxicity is limited. ADA was administered by oral gavage to groups of rats at doses of 0 (control), 1,000, 1,500, 2,000, 2,500, and 3,000 mg/kg five times per week for 13 weeks. Mortality, clinical signs, body weights, food consumption, hematology, serum chemistry, urinalysis, organ weights, necropsy, histopathological finding, vaginal cytology, and sperm morphology were compared between control and ADA-treated groups. Salivation was intermittently observed in both sexes receiving 2,500 and 3,000 mg/kg directly after dosing. Absolute liver weights increased in females receiving 2,000, 2,500, and 3,000 mg/kg ADA (P < 0.05, P < 0.01, and P < 0.01, respectively) and so did the relative liver weights (P < 0.001). Salivation and increased liver weight were ADA-related changes but not considered to be adverse effects. Salivation was intermittent and transient, and the liver weight increase was minor and not accompanied by other changes such as hepatic morphological or functional alterations. The no-observed-adverse-effect-level was determined to be at least 3,000 mg/kg in both sexes of rats.

Subchronic toxicity of Acorus gramineus rhizoma in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Acorus gramineus rhizoma (AGR) is the dry rhizome of Acorus gramineus Solander from the family Araceae that has been used as sedative, analgesic, diuretic, digestive and antifungal agent. AIM OF THE STUDY: To evaluate the no-observed-adverse-effect level (NOAEL) and the toxicity of AGR, following repeated oral administration to rats for 13 weeks. MATERIALS AND METHODS: AGR was administered by oral gavage to groups of rats (10 per group, each sex) at doses of 0 (control), 25, 74, 222, 667, or 2,000mg/kg/day, 5 times per week for 13 weeks. Mortality, clinical signs, body weights, food consumption, hematology, serum chemistry, urinalysis, vaginal cytology, sperm motility, sperm morphology, organ weights, gross and histopathological findings were compared between control and AGR groups. RESULTS: No mortality or remarkable clinical signs were observed during this 13-week study. No adverse effects on body weight, food consumption, urinalysis, hematology, serum chemistry, organ weights, gross lesion, histopathology, vaginal cytology, sperm motility or deformity were observed in any of the male or female rats treated with AGR. CONCLUSIONS: On the basis of these results, the NOAEL of AGR is determined to be 2,000mg/kg/day for male and female rats.

Single- and Repeat-dose Oral Toxicity Studies of Lithospermum erythrorhizon Extract in Dogs.

Lithospermum erythrorhizon has long been used in traditional Asian medicine for the treatment of diseases, including skin cancer. The oral toxicity of a hexane extract of Lithospermum erythrorhizon root (LEH) was investigated in Beagle dogs by using single escalating doses, two-week dose range-finding, and 4-week oral repeat dosing. In the single dose-escalating oral toxicity study, no animal died, showed adverse clinical signs, or changes in body weight gain at LEH doses of up to 2,000 mg/kg. In a 2 week dose range-finding study, no treatment-related adverse effects were detected by urinalysis, hematology, blood biochemistry, organ weights, or gross and histopathological examinations at doses of up to 500 mg LEH/kg/day. In the 4 week repeat-dose toxicity study, a weight loss or decreased weight gain was observed at 300 mg/kg/day. Although levels of serum triglyceride and total bilirubin were increased in a dose dependent manner, there were no related morphological changes. Based on these findings, the sub-acute no observable adverse effect level for 4-week oral administration of LEH in Beagles was 100 mg/kg/day.