Correction: Nam et al. Identification of Thiazolo[5,4-b]pyridine Derivatives as c-KIT Inhibitors for Overcoming Imatinib Resistance. Cancers 2023, 15, 143.

The authors would like to make a correction to the previous article [...].

Environmental-Driven Approach towards Level 5 Self-Driving.

As technology advances in almost all areas of life, many companies and researchers are working to develop fully autonomous vehicles. Such level 5 autonomous driving, unlike levels 0 to 4, is a driverless vehicle stage and so the leap from level 4 to level 5 autonomous driving requires much more research and experimentation. For autonomous vehicles to safely drive in complex environments, autonomous cars should ensure end-to-end delay deadlines of sensor systems and car-controlling algorithms including machine learning modules, which are known to be very computationally intensive. To address this issue, we propose a new framework, i.e., an environment-driven approach for autonomous cars. Specifically, we identify environmental factors that we cannot control at all, and controllable internal factors such as sensing frequency, image resolution, prediction rate, car speed, and so on. Then, we design an admission control module that allows us to control internal factors such as image resolution and detection period to determine whether given parameters are acceptable or not for supporting end-to-end deadlines in the current environmental scenario while maintaining the accuracy of autonomous driving. The proposed framework has been verified with an RC car and a simulator.

Corrected QTc interval combined with troponin value and mortality in acute ischemic stroke.

Background and Purpose: Cardiac biomarkers including, elevated troponin (ET) and prolonged heart rate-corrected QT (PQTc) interval on electrocardiography are known to frequent and have a prognostic significance in patients with acute ischemic stroke (AIS). However, it is still challenging to practically apply the results for appropriate risk stratification. This study evaluate whether combining ET and PQTc interval can better assess the long-term prognosis in AIS patients. Methods: In this prospectively registered observational study between May 2007 and December 2011, ET was defined as serum troponin-I ≥ 0.04 ng/ml and PQTc interval was defined as the highest tertile of sex-specific QTc interval (men ≥ 469 ms or women ≥ 487 ms). Results: Among the 1,668 patients [1018 (61.0%) men; mean age 66.0 ± 12.4 years], patients were stratified into four groups according to the combination of ET and PQTc intervals. During a median follow-up of 33 months, ET (hazard ratio [HR]: 4.38, 95% confidence interval [CI]: 2.94-6.53) or PQTc interval (HR: 1.53, 95% CI: 1.16-2.01) alone or both (HR: 1.77, 95% CI: 1.16-2.71) was associated with increased all-cause mortality. Furthermore, ET, PQTc interval alone or both was associated with vascular death, whereas only ET alone was associated with non-vascular death. Comorbidity burden, especially atrial fibrillation and congestive heart failure, and stroke severity gradually increased both with troponin value and QTc-interval. Conclusions: In patients with AIS, combining ET and PQTc interval on ECG enhances risk stratification for long-term mortality while facilitating the discerning ability for the burden of comorbidities and stroke severity.

Determinants of COVID-19 vaccine Hesitancy: 2020 California Health Interview Survey.

Although the COVID-19 vaccine is a key intervention against the ongoing COVID-19 pandemic, vaccine hesitancy is a barrier to vaccination coverage, leading to a higher risk of COVID-19-related morbidity and mortality. To reduce vaccine hesitancy, the factors affecting it must be addressed. Based on the determinants of health approach, this study aimed to investigate whether the distribution of determinants of health differed between the vaccine hesitancy group and the vaccine acceptance group and to identify determinants of participants' hesitancy to receive the COVID-19 vaccine if it was available. This study utilized the 2020 California Health Interview Survey Data collected between May and December 2020. Data were collected using a population-based web and telephone health survey. Data from 21,949 participants in California were included, and 4,183 (23.4 %) showed vaccine hesitancy. The following determinants were positively associated with vaccine hesitancy: female sex, Black and American Indian/Alaskan Native ethnicity, smoking, poverty, U.S.-born citizen, frequent use of social media, food insecurity, and limited healthcare access. Older age, not having severe psychological distress, not having diabetes, and high perceived safety in the neighborhood were negatively associated with COVID-19 vaccine hesitancy. This study also found that higher use of social media potentially threatened vaccine uptake, whereas frequent internet use was negatively associated with vaccine hesitancy. Public health and other relevant service providers should address the determinants of vaccine hesitancy and develop effective strategies and interventions for vaccine-hesitant groups.

Explanatory Power and Prognostic Implications of Factors Associated with Troponin Elevation in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: We investigated the impact of comorbidity burden on troponin elevation, with separate consideration of neurological conditions, in patients with acute ischemic stroke (AIS). METHODS: This prospective, observational cohort study consecutively enrolled patients with AIS for 2 years. Serum cardiac troponin I was repeatedly measured, and disease-related biomarkers were collected for diagnosis of preassigned comorbidities, including atrial fibrillation (AF), ischemic heart disease (IHD), myocardial hypertrophy (MH), heart failure (HF), renal insufficiency (RI), and active cancer. The severity of neurological deficits and insular cortical ischemic lesions were assessed as neurological conditions. Adjusted associations between these factors and troponin elevation were determined using a multivariate ordinal logistic regression model and area under the receiver operating characteristic curve (AUC). Cox proportional hazards model was used to determine the prognostic significance of comorbidity beyond neurological conditions. RESULTS: Among 1,092 patients (66.5±12.4 years, 63.3% male), 145 (13.3%) and 335 (30.7%) had elevated (≥0.040 ng/mL) and minimally-elevated (0.040-0.010 ng/mL) troponin, respectively. In the adjusted analysis, AF, MH, HF, RI, active cancer, and neurological deficits were associated with troponin elevation. The multivariate model with six comorbidities and two neurological conditions exhibited an AUC of 0.729 (95% confidence interval [CI], 0.698-0.759). In Cox regression, AF, IHD, and HF were associated with adverse cardio-cerebrovascular events, whereas HF and active cancer were associated with mortality. CONCLUSION: Troponin elevation in patients with AIS can be explained by the burden of comorbidities in combination with neurological status, which explains the prognostic significance of troponin assay.

Moderating Effects of Physical Activity on the Relationship between Adverse Childhood Experiences and Health-Related Quality of Life.

The effects of adverse childhood experiences (ACEs) on health-related quality of life (HRQOL) and their associations with physical activities (PA) are well-documented. However, the specific effects of different types of ACEs (e.g., child abuse and household dysfunction) on HRQOL and the role of PA are inconclusive. The purpose of this study is to find the buffering role of PA as a moderator that may reduce the negative impact of ACEs in general and the specific effects of different types of ACEs on HRQOL, perceived physical health, and mental health over time. The 2019 Behavioral Risk Fact Surveillance System (BRFSS), a state-based surveillance system supported by the CDC in the U.S., was used for this study. A total of 127,370 respondents from 17 states were selected for this study. First, descriptive statistics were generated and correlation analyses were conducted to find the association among variables and examine the possible predictors of HRQOL. Moderation models were then tested using Structural Equation Modeling (SEM). HRQOL in adults is negatively associated with ACEs, but is positively associated with PA. We found buffering effects of physical activity in the following relationships: (1) child abuse and HRQOL, (2) child abuse and perceived physical health, (3) ACEs and perceived mental health, (4) child abuse and perceived mental health, and (5) household dysfunction and perceived mental health. Our findings suggest that improvement of PA level is a significant predictor of improved HRQOL of adults with ACEs.

Identification of Thiazolo[5,4-b]pyridine Derivatives as c-KIT Inhibitors for Overcoming Imatinib Resistance.

c-KIT is a promising therapeutic target against gastrointestinal stromal tumor (GIST). In order to identify novel c-KIT inhibitors capable of overcoming imatinib resistance, we synthesized 31 novel thiazolo[5,4-b]pyridine derivatives and performed SAR studies. We observed that, among these substances, 6r is capable of inhibiting significantly c-KIT and suppressing substantially proliferation of GIST-T1 cancer cells. It is of note that 6r is potent against a c-KIT V560G/D816V double mutant resistant to imatinib. Compared with sunitinib, 6r possesses higher differential cytotoxicity on c-KIT D816V Ba/F3 cells relative to parental Ba/F3 cells. In addition, kinase panel profiling reveals that 6r has reasonable kinase selectivity. It was found that 6r remarkably attenuates proliferation of cancer cells via blockade of c-KIT downstream signaling, and induction of apoptosis and cell cycle arrest. Furthermore, 6r notably suppresses migration and invasion, as well as anchorage-independent growth of GIST-T1 cells. This study provides useful SAR information for the design of novel c-KIT inhibitors overcoming imatinib-resistance.

Smart Search System of Autonomous Flight UAVs for Disaster Rescue.

UAVs (Unmanned Aerial Vehicles) have been developed and adopted for various fields including military, IT, agriculture, construction, and so on. In particular, UAVs are being heavily used in the field of disaster relief thanks to the fact that UAVs are becoming smaller and more intelligent. Search for a person in a disaster site can be difficult if the mobile communication network is not available, and if the person is in the GPS shadow area. Recently, the search for survivors using unmanned aerial vehicles has been studied, but there are several problems as the search is mainly using images taken with cameras (including thermal imaging cameras). For example, it is difficult to distinguish a distressed person from a long distance especially in the presence of cover. Considering these challenges, we proposed an autonomous UAV smart search system that can complete their missions without interference in search and tracking of castaways even in disaster areas where communication with base stations is likely to be lost. To achieve this goal, we first make UAVs perform autonomous flight with locating and approaching the distressed people without the help of the ground control server (GCS). Second, to locate a survivor accurately, we developed a genetic-based localization algorithm by detecting changes in the signal strength between distress and drones inside the search system. Specifically, we modeled our target platform with a genetic algorithm and we re-defined the genetic algorithm customized to the disaster site's environment for tracking accuracy. Finally, we verified the proposed search system in several real-world sites and found that it successfully located targets with autonomous flight.

Prognostic Significance of Prolonged Corrected QT Interval in Acute Ischemic Stroke.

Background and Purpose: The aim of this study was to determine the relationship between the heart rate-corrected QT (QTc) interval and the risk of incident long-term mortality in patients with acute ischemic stroke (AIS), considering the impact of sex differences on clinical characteristics, outcomes, and QTc intervals. Methods: We analyzed prospectively registered data included patients with AIS who visited the emergency room within 24 h of stroke onset and underwent routine cardiac testing, such as measurements of cardiac enzymes and 12-lead ECG. QTc interval was corrected for heart rate using Fridericia's formula and was stratified by sex-specific quartiles. Cox proportional hazards models were used to examine the association between baseline QTc interval and incident all-cause death. Results: A total of 1,668 patients with 1,018 (61.0%) men and mean age 66.0 ± 12.4 years were deemed eligible. Based on the categorized quartiles of the QTc interval, cardiovascular risk profile, and stroke severity increased with prolonged QTc interval, and the risk of long-term mortality increased over a median follow-up of 33 months. Cox proportional hazard model analysis showed that the highest quartile of QTc interval (≥479 msec in men and ≥498 msec in women; hazard ratio [HR]: 1.49, 95% confidence interval [CI]: 1.07-2.08) was associated with all-cause death. Furthermore, dichotomized QTc interval prolongation, defined by the highest septile of the QTc interval (≥501 ms in men and ≥517 m in women: HR: 1.33, 95% CI: 1.00-1.80) was significantly associated with all-cause mortality after adjusting for all clinically relevant variables, such as stroke severity. Conclusions: Prolonged QTc interval was associated with increased risk of long-term mortality, in parallel with the increasing trend of prevalence of cardiovascular risk profiles and stroke severity, across sex differences in AIS patients.

Fisheye-Based Smart Control System for Autonomous UAV Operation.

Recently, as UAVs (unmanned aerial vehicles) have become smaller and higher-performance, they play a very important role in the Internet of Things (IoT). Especially, UAVs are currently used not only in military fields but also in various private sectors such as IT, agriculture, logistics, construction, etc. The range is further expected to increase. Drone-related techniques need to evolve along with this change. In particular, there is a need for the development of an autonomous system in which a drone can determine and accomplish its mission even in the absence of remote control from a GCS (Ground Control Station). Responding to such requirements, there have been various studies and algorithms developed for autonomous flight systems. Especially, many ML-based (Machine-Learning-based) methods have been proposed for autonomous path finding. Unlike other studies, the proposed mechanism could enable autonomous drone path finding over a large target area without size limitations, one of the challenges of ML-based autonomous flight or driving in the real world. Specifically, we devised Multi-Layer HVIN (Hierarchical VIN) methods that increase the area applicable to autonomous flight by overlaying multiple layers. To further improve this, we developed Fisheye HVIN, which applied an adaptive map compression ratio according to the drone's location. We also built an autonomous flight training and verification platform. Through the proposed simulation platform, it is possible to train ML-based path planning algorithms in a realistic environment that takes into account the physical characteristics of UAV movements.

Security-Enhanced Push Button Configuration for Home Smart Control.

With the emergence of smart and converged home services, the need for the secure and easy interplay of various devices has been increased. Push Button Configuration (PBC) is one of the technologies proposed for easy set-up of a secure session between IT and consumer devices. Although the Wi-Fi Direct specification explicitly states that all devices must support the PBC method, its applicability is very limited. This is because the security vulnerability of PBC can be maliciously exploited so that attackers can make illegitimate sessions with consumer devices. To address this problem, this paper proposes a novel Security-enhanced PBC (SePBC) scheme with which we can uncover suspicious or malicious devices. The proposed mechanism has several unique features. First, we develop a secure handshake distance measurement protocol by preventing an adversary sitting outside the region from maliciously manipulating its distance to be fake. Second, it is compatible with the original Wi-Fi PBC without introducing a brand-new methodology. Finally, SePBC uses lightweight operations without CPU-intensive cryptography computation and employs inexpensive H/W. Moreover, it needs to incur little overhead when there is no attack. This paper also designs and implements the proposed SePBC in the real world. Our experimental results and analysis show that the proposed SePBC scheme effectively defeats attacks on PBC while minimizing the modification of the original PBC equipment.

Primary Caregivers' Support for Female Family Members With Breast or Gynecologic Cancer.

BACKGROUND: Female patients with cancer depend on loved ones; thus, family support is pivotal to assist patients in successfully adjusting to life with treatment routines. OBJECTIVE: Our study explored the experiences of primary caregivers who provide care and support for female family members with cancer. METHODS: This study used a qualitative phenomenological research approach. Interviews and journaling about the caregiving experience were conducted with the family members of female cancer patients-6 spouses, 11 daughters, 1 son, and 1 younger sister. Data analysis involved Giorgi's 3-step phenomenological analysis method. RESULTS: The central theme of the primary caregivers' supportive care for their female family member with cancer was "being with" her. This was composed of the following themes: "being there for her via efforts," "living through feelings of guilt and anxiety," and "lessons learned from cancer in the family." CONCLUSIONS: This study reveals an integrated picture of family caregivers' supportive caring experiences. By providing both positive and negative aspects of the caregiving experience, the findings in this study will provide a theoretical foundation to develop more successful support programs for family caregivers of female patients with cancer. IMPLICATIONS FOR PRACTICE: Family-oriented education programs need to be developed to include both the family and the patient in the long journey of cancer. The family caregivers' feelings of guilt regarding the cause of the illness and feelings of anxiety about the uncertainty of the illness should be assessed and managed during the course of the patients' treatment and care.

Palliative and end-of-life care in prisons: a content analysis of the literature.

PURPOSE: The growing numbers of terminally ill and dying in prison has high economic and moral costs as global correctional systems and the society at large. However, to date little is known about the extent to which palliative and end-of-life care is infused within global prison health care systems. The purpose of this paper is to fill a gap in the literature by reviewing and critically appraising the methods and major findings of the international peer-reviewed literature on palliative and end-of-life care in prison, identify the common elements of promising palliative and end-of-life services in prison, and what factors facilitate or create barrier to implementation. DESIGN/METHODOLOGY/APPROACH: A content analysis was conducted of the existing peer-reviewed literature on palliative and end-of-life care in prison. English-language articles were located through a comprehensive search of peer-reviewed journals, such as Academic Search Premier Literature databases using differing combinations of key word search terms, "prison," "palliative care," and "end-of-life care." A total of 49 studies published between 1991 and 2013 met criteria for sample inclusion. Deductive and inductive analysis techniques were used to generate frequency counts and common themes related to the methods and major findings. FINDINGS: The majority (n=39) of studies were published between 2001-2013 in the USA (n=40) and the UK (n=7). Most were about US prison hospice programs (n=16) or barriers to providing palliative and end of life care in prisons (n=10). The results of the inductive analysis identified common elements of promising practices, which included the use of peer volunteers, multi-disciplinary teams, staff training, and partnerships with community hospices. Obstacles identified for infusing palliative and end-of-life care in prison included ethical dilemmas based on custody vs care, mistrust between staff and prisoners, safety concerns, concern over prisoners' potential misuse of pain medication, and institutional, staff, and public apathy toward terminally ill prisoners and their human rights to health in the form of compassionate and palliative care, including the use of compassionate release laws. RESEARCH LIMITATIONS/IMPLICATIONS: Implications for future research that foster human rights and public awareness of the economic and moral costs of housing the sick and dying in prisons. More research is needed to document human rights violations as well as best practices and evidence-based practices in palliative and end-of-life care in prisons. Future studies should incorporate data from the terminally ill in prison, peer supports, and family members. Future studies also should employ more rigorous research designs to evaluate human rights violations, staff and public attitudes, laws and policies, and best practices. Quantitative studies that use experimental designs, longitudinal data, and multiple informants are needed. Qualitative data would allow for thick descriptions of key stakeholders experiences, especially of the facilitators and barriers for implementing policy reform efforts and palliative care in prisons. Practical implications - This review provides a foundation on which to build on about what is known thus far about the human right to health, especially parole policy reform and infusing palliative and end-of-life care for the terminally ill and dying in prisons. This information can be used to develop or improve a new generation research, practice, policy, and advocacy efforts for that target terminally ill and dying in prison and their families and communities. SOCIAL IMPLICATIONS: There are significant social implications to this review. From a human rights perspective, the right to freedom from torture and cruel and unusual punishment is a fundamental human right along with prisoners' rights for an appropriate level of health care. These rights should be guaranteed regardless of the nature of their crime or whether they are in a prison placement. The information provided in this review can be used to educate and possible transform individual's and society's views toward the terminally ill and dying who are involved in the criminal justice system. ORIGINALITY/VALUE: This paper extends the extant literature by using both quantitative and qualitative analysis methods to organize, summarize, and critically analyze the international literature on palliative care and end of life care in prison. This review is designed to increase awareness among the international community of the pain and suffering of the terminally ill in prison and the facilitators and barriers to providing them compassionate care while in custody.

Hypoglycemic effects of Welsh onion in an animal model of diabetes mellitus.

Tight control of blood glucose is the most important strategy for the treatment of diabetes mellitus. Here, we investigated the beneficial effects of Welsh onion on fasting and postprandial hyperglycemia. Inhibitory activities of hot water extracts from the green stalk and white bulb, which are the edible portions of the Welsh onion, and the fibrous root extract against yeast α-glucosidase were measured in vitro. To study the effects of Welsh onion on postprandial hyperglycemia, a starch solution (1 g/kg) with and without Welsh onion fibrous root extract (500 mg/kg) or acarbose (50 mg/kg) was administered to streptozotocin-induced diabetic rats after an overnight fast. Postprandial plasma glucose levels were measured and incremental areas under the response curve were calculated. To study the hypoglycemic effects of chronic feeding of Welsh onion, five-week-old db/db mice were fed an AIN-93G diet or a diet containing either Welsh onion fibrous root extract at 0.5% or acarbose at 0.05% for 7 weeks after 1 week of adaptation. Fasting plasma glucose and blood glycated hemoglobin were measured. Compared to the extract from the edible portions of Welsh onion, the fibrous root extract showed stronger inhibition against yeast α-glucosidase, with an IC(50) of 239 µg/mL. Oral administration of Welsh onion fibrous root extract (500 mg/kg) and acarbose (50 mg/kg) significantly decreased incremental plasma glucose levels 30-120 min after oral ingestion of starch as well as the area under the postprandial glucose response curve, compared to the control group (P < 0.01). The plasma glucose and blood glycated hemoglobin levels of the Welsh onion group were significantly lower than those of the control group (P < 0.01), and were not significantly different from those fed acarbose. Thus, we conclude that the fibrous root of Welsh onion is effective in controlling hyperglycemia in animal models of diabetes mellitus.

An application of a service-oriented system to support array annotation in custom chip design for epigenomic analysis.

We present the implementation of an application using caGrid, which is the service-oriented Grid software infrastructure of the NCI cancer Biomedical Informatics Grid (caBIG), to support design and analysis of custom microarray experiments in the study of epigenetic alterations in cancer. The design and execution of these experiments requires synthesis of information from multiple data types and datasets. In our implementation, each data source is implemented as a caGrid Data Service, and analytical resources are wrapped as caGrid Analytical Services. This service-based implementation has several advantages. A backend resource can be modified or upgraded, without needing to change other components in the application. A remote resource can be added easily, since resources are not required to be collected in a centralized infrastructure.

Mutation analysis of the KAL gene in female patients with gonadotropin-releasing hormone deficiency.

Isolated gonadotropin-releasing hormone (GnRH) deficiency, including Kallmann's syndrome (KS) and idiopathic hypogonadotropic hypogonadism (IHH), is a congenital disorder, which is characterized by a functional deficit in hypothalamic GnRH secretion. Despite recent advances in the understanding of the pathogenesis of the X-linked form of KS as the identification of the KAL gene (Xp22.3), the genetic basis of the sporadic form in female patients remains unclear. Although most searches for mutations in X chromosome have been reported in males, the newly recognized phenomenon of inheritance, such as genomic imprinting and uniparental disomy, raises the possibility of a female phenotype in the X- linked genetic defect. Here, the molecular study of the coding region of the KAL gene (exon 5 to 14) in 10 unrelated females with KS (n=6) or IHH (n=4) is reported. None of the subjects had familial histories of delayed puberty or hypogonadism. Samples from 4 healthy, unrelated female volunteers were used for identification of polymorphisms. PCR of the 10 exons of the KAL gene was performed on genomic DNA. The PCR products of the 10 exons were subject to single strand conformation polymorphism (SSCP) analysis to identify possible mutations. In an SSCP analysis of the amplified fragments (fragment size: 147 to 302 bp), no mutations or polymorphisms were found in any of the 10 patients and 4 controls. In conclusion, it is unlikely that KAL gene mutations are a clinically significant cause of sporadic GnRH deficiency in female patients, indicating the existence of defects in unidentified genes that result in the expression of the phenotypes in females.

Effects of prenatal exposure to the environmental pollutant 2-bromopropane on embryo-fetal development in rats.

2-Bromopropane (2-BP), a halogenated propane analogue, is a substitute for chlorofluorocarbones. The present study was carried out to investigate the potential adverse effects of 2-BP on pregnant dams and embryo-fetal development after maternal exposure on gestational days (GD) 6 through 19 in Sprague-Dawley rats. The test chemical was administered subcutaneously to pregnant rats at dose levels of 0, 250, 500, and 1000 mg/kg per day. All dams were subjected to caesarean section on GD 20 and their fetuses were examined for external, visceral and skeletal abnormalities. In the 1000 mg/kg group, maternal toxicity included an increase in the incidence of abnormal clinical signs, a suppression in the body weight and body weight gain, and a decrease in the food intake. Developmental toxicity included an increase in the fetal deaths, a decrease in the litter size, and a reduction in the fetal body weight. In addition, an increase in the incidence of fetal external, visceral, and skeletal abnormalities was seen. In the 500 mg/kg group, minimal developmental toxicity including decreased fetal body weight and increased fetal ossification delay was observed. There were no adverse effects on either pregnant dams or embryo-fetal development in the 250 mg/kg group. These findings suggest that a 14-day subcutaneous dose of 2-BP is embryotoxic and teratogenic at a maternally toxic dose (i.e., 1000 mg/kg per day) and is minimally embryotoxic at a nonmaternally toxic dose (i.e., 500 mg/kg per day) in Sprague-Dawley rats. In the present experimental conditions, the no-observed-adverse-effect level (NOAEL) of 2-BP is considered to be 500 mg/kg per day for dams and 250 mg/kg per day for embryo-fetal development.

Subacute toxicity and toxicokinetics of CJ-10882, a type IV phosphodiesterase inhibitor, after 4-week repeated oral administration in dogs.

The subacute toxicity and toxicokinetics of a type IV phosphodiesterase inhibitor, CJ-10882, were evaluated after single (on the 1st day) and 4-week (on the 27th day) oral administration of the drug, in doses of 0 (to serve as a control), 2, 10 and 50 mg/kg/day, to male and female dogs (n=3 for male and female dogs for each dose). During the test period, clinical signs, mortality, body weight, food consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, organ weight and histopathology were examined. The 4-week repeated oral doses of CJ-10882 resulted in salivation, vomiting, and atrophy of the thymus. The absolute toxic dose was 50 mg/kg/day and the level at which no adverse effects were observed was 2 mg/kg/day for male and female dogs. There were no significant gender differences in the pharmacokinetic parameters of CJ-10882 for each dose after both single and 4-week oral administration. The pharmacokinetic parameters of CJ-10882 were dose independent after a single oral administration; the time to reach a peak plasma concentration (T(max)) and the dose-normalized area under the plasma concentration-time curve from time zero to 8 h in plasma (AUC(0-8 h)) were not significantly different among three doses. The accumulation of CJ-10882 after 4-week oral administration was not notable at the toxic dose of 50 mg/kg/day. For example, after 4-week administration, the dose-normalized AUC(0-8 h) value at 50 mg/kg/day (0.132 microg h/ml) was not significantly greater than that at 10 mg/kg/day (0.131 microg h/ml). After 4-week oral administration, the dose-normalized C(max) and AUC(0-8 h) at 50 mg/kg/day were not significantly higher and greater, respectively, than those after the single oral administration.

Subacute toxicity and toxicokinetics of a new antibiotic, DW-224a, after single and 4-week repeated oral administration in dogs.

The subacute toxicity and toxicokinetics of a new fluoroquinolone antibiotic, DW-224a, were evaluated after single (on the 1st day) and 4-week (on the 28th day) oral administration of the drug at doses of 0 (to serve as a control), 10, 30, and 90 mg/kg/d, to male and female dogs (n=3 for male and female dogs for each dose). During the test period, clinical signs, mortality, body weight, food consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, organ weight and histopathology were examined. The 4-week repeated oral dose of DW-224a resulted in vomiting, salivation, increased serum cholesterol level, and atrophy of thymus and testes. The target organ was determined to be the thymus and testes. The absolute toxic dose of DW-224a was 30 mg/kg and the level at which no adverse effects were observed was 10 mg/kg for both sexes. There were no significant gender differences in the pharmacokinetic parameters of DW-224a for each dose after both single and 4-week oral administration. The pharmacokinetic parameters of DW-224a were dose independent after a single oral administration; the time to reach the peak plasma concentration (T(max)) and the dose-normalized area under the plasma concentration-time curve from time zero to 24 h in plasma (AUC(0-24 h)) were not significantly different among the three doses. The accumulation of DW-224a after 4-week oral administration was not notable at the toxic dose of 90 mg/kg/d. For example, after 4-week administration, the dose-normalized AUC(0-24 h) value at 90 mg/kg/d (7.69, 7.05 microg h/ml) was not significantly greater than that at 10 mg/kg/d. After 4-week oral administration, the dose-normalized C(max) and AUC(0-24 h) at 90 mg/kg/d were not significantly higher and greater, respectively, than those after a single oral administration.