• Toxicological Research
• /
• v.18 no.2
• /
• pp.195-203
• /
• 2002

This study was performed to evaluate single and repeated-dose toxicities oj a new cophalosporin antibiotic agent IDC-7l81 in Sprague-Dawley rats. IDC-7181 was injected intravenously to rats at dose levels of 0, 3.2, 16, 80, 400 and 2,000 mg/kg/day for single-dose toxicity study and at dose levels of 0, 10, 50 and 250 mg/kg/day for 4-week repeated-dose toxicity study. In both studies, there were no dose-related changes in mortality clinical signs, body weight changes, food and water consumption, opthalmoscopy, organ weights, urine analysis, biochemical examination, and hematological findings of all animals treated with IDC-7l8l. Gross and histopathological findings revealed no evidence of specific toxicity related to IDC-7181. These results suggest that the intravenous maximum tolerated dose value of IDC-7181 may be over 250 mg/kg and $LD_{50}$ value may be over 2,000 mg/kg in rats.

• Journal of the Korean Statistical Society
• /
• v.32 no.1
• /
• pp.33-46
• /
• 2003

The continual reassessment method (CRM) provides a Bayesian estimation of the maximum tolerated dose (MTD) in phase I clinical trials. The CRM has been proposed as an alternative design of the standard design. The CRM has been modified to improve practical feasibility and, recently, the likelihood approach CRM has been proposed. In this paper we investigate the consistency and asymptotic normality of the modified likelihood approach CRM in which the maximum likelihood estimate is used instead of the posterior mean. Small-sample properties of the consistency is examined using complete enumeration. Both the asymptotic results and their small-sample properties show that the modified CRML outperforms the standard design.

• Biomolecules & Therapeutics
• /
• v.1 no.2
• /
• pp.251-261
• /
• 1993

The subacute toxicity of combined antibiotics, SP-102 (Sulbactam.Piperacilline), was examined in S.D.rats. Four groups of rats were administered intraperitoneally with 0, 512, 1280 and 3200 mg/kg/day of SP-102 for 30 days. Hain clinical sign related to the compound was soft stool. The body weight gain was slightly decreased in male rats treated with 1280, 3200 mg/kg and in female rats treated with 1280 mg/kg of SP-102. Water consumption was significantly increased in rats administered with SP-102. There were no dose-related changes of urinalysis, biochemical examination and hematological findings in all the groups treated with SP-102. Gross necropsy and histopathology revealed no evidence of specific toxicity related to SP-102. Our data indicate that no-observed effect level of SP-102 is below 512 mg/kg in male and female rats. Maximum tolerated dose of SP-102 was estimated to be above 3200 ma/kg in this study.

• Environmental Mutagens and Carcinogens
• /
• v.22 no.4
• /
• pp.255-258
• /
• 2002

In order to determine the safety of chemicals and pharmaceutical products, various methods can be used to evaluate the toxicity. In this study the genotoxic effect of the widely used industrial chemical, cadmium chloride, was assessed using the micronucleus test in peripheral blood of mice. The presence of micronucleated reticulocytes by microscopic observation following acridine orange staining indicated a potential genotoxic effect. The genotoxicity of intraperitoneally (i.p.) administered cadmium chloride (0.5, 1, 2 mg/kg) appeared to be dose dependent, with the maximum tolerated dose (MTD) found to be 2 mg/kg. Compared to the negative control (saline), cadmium chloride (2 mg/kg) exhibited statistically significant genotoxic potential (P<0.05) but was found to be less than the positive control of mitomycin C (0.5 mg/kg) and was not statistically significant compared to historical negative controls (P>0.05).

• Proceedings of the Korean Society of Toxicology Conference
• /
• 2001.10a
• /
• pp.170-170
• /
• 2001

This study was designed to evaluate a repeated intravenous dose toxicity of a new anticancer agent, SB extracted from Pulsatilla korean Nakai in Beagle dogs. Animals were intravenously injected with dosages of 0, 0.062, 0.25, and 1 mg/kg of SB everyday for 13 weeks, respectively. There were no dose-related changes in clinical signs, body weight changes, food and water consumptions, opthalmoscopy, and urine analysis. There were somewhat significant differences compared with control group in organ weight, biochemical examination, and hematology findings of animals treated with SB. However, these changes were not dose-related changes. Gross and histopathological findings revealed no evidence of specific toxicity related to SB. These indicate that intraveous maximum tolerated dose value of SB may be over 1mg/kg in rats.

• Journal of Oriental Neuropsychiatry
• /
• v.24 no.1
• /
• pp.131-144
• /
• 2013

Objectives : To provide information on the safety of ACM, we carried out a single oral dose-increasing toxicity and 4-weeks repeated oral dose determining test of ACM in beagle dogs. Methods : In a single oral dose-increasing toxicity test, beagles were treated with ACM orally increasing dose level (1,000, 2,000, 5,000 mg/㎏) at interval of 3 days. After administration, signs of toxicity were observed for two weeks. In 4-weeks repeated oral dose determinating test, beagles were treated with ACM with oral dose 500, 1,000, 2,000 mg/kg for 4 weeks. Mortality, clinical signs, body weight changes, food consumption, urinalysis, hematological and biochemical parameters, organ weights, necropsy findings, and histological findings were monitored during the study period. Results : In a single oral dose-increasing toxicity test, we found no mortality, abnormalities in clinical signs, body weight, and necropsy findings during the study period. In 4-weeks repeated oral dose determinating test, we found no mortality, abnormalities in clinical signs, body weight, food consumption, urinalysis, hematological and biological parameters, gross findings, organ weights, necropsy findings, and histopathological findings in any of the beagles tested. Conclusions : The results obtained in these studies suggest that maximum tolerated dose (MTD) of ACM in male and female beagle dogs was supposed to be over 5,000 mg/kg. For the future studies of toxicity, it is advisable that high dose and low dose are set at 2000 mg/kg and 500 mg/kg, respectively.

• Communications for Statistical Applications and Methods
• /
• v.29 no.4
• /
• pp.421-439
• /
• 2022

Phase I dose-finding trials are essential in drug development. By finding the maximum tolerated dose (MTD) of a new drug or treatment, a Phase I trial establishes the recommended doses for later-phase testing. The primary toxicity endpoint of interest is often a binary variable, which describes an event of a patient who experiences dose-limiting toxicity. However, there is a growing interest in dose-finding studies regarding non-binary outcomes, defined by either the weighted sum of rates of various toxicity grades or a continuous outcome. Although several novel methods have been proposed in the literature, accessible software is still lacking to implement these methods. This study introduces a newly developed R package, UnifiedDoseFinding, which implements three phase I dose-finding methods with non-binary outcomes (Quasi- and Robust Quasi-CRM designs by Yuan et al. (2007) and Pan et al. (2014), gBOIN design by Mu et al. (2019), and by a method by Ivanova and Kim (2009)). For each of the methods, UnifiedDoseFinding provides corresponding functions that begin with next that determines the dose for the next cohort of patients, select, which selects the MTD defined by the non-binary toxicity endpoint when the trial is completed, and get oc, which obtains the operating characteristics. Three real examples are provided to help practitioners use these methods. The R package UnifiedDoseFinding, which is accessible in R CRAN, provides a user-friendly tool to facilitate the implementation of innovative dose-finding studies with nonbinary outcomes.

• Radiation Oncology Journal
• /
• v.35 no.2
• /
• pp.121-128
• /
• 2017

Purpose: To report the results of a correlation analysis of skin dose assessed by in vivo dosimetry and the incidence of acute toxicity. This is a phase 2 trial evaluating the feasibility of intraoperative radiotherapy (IORT) as a boost for breast cancer patients. Materials and Methods: Eligible patients were treated with IORT of 20 Gy followed by whole breast irradiation (WBI) of 46 Gy. A total of 55 patients with a minimum follow-up of 1 month after WBI were evaluated. Optically stimulated luminescence dosimeter (OSLD) detected radiation dose delivered to the skin during IORT. Acute toxicity was recorded according to the Common Terminology Criteria for Adverse Events v4.0. Clinical parameters were correlated with seroma formation and maximum skin dose. Results: Median follow-up after IORT was 25.9 weeks (range, 12.7 to 50.3 weeks). Prior to WBI, only one patient developed acute toxicity. Following WBI, 30 patients experienced grade 1 skin toxicity and three patients had grade 2 skin toxicity. Skin dose during IORT exceeded 5 Gy in two patients: with grade 2 complications around the surgical scar in one patient who received 8.42 Gy. Breast volume on preoperative images (p = 0.001), ratio of applicator diameter and breast volume (p = 0.002), and distance between skin and tumor (p = 0.003) showed significant correlations with maximum skin dose. Conclusions: IORT as a boost was well-tolerated among Korean women without severe acute complication. In vivo dosimetry with OSLD can help ensure safe delivery of IORT as a boost.

• Psychiatry investigation
• /
• v.15 no.12
• /
• pp.1188-1202
• /
• 2018

Objective This study protocol aims to determine, using a rigorous approach in patients with bipolar disorder (BD) and non-seasonal major depressive episode (MDE), the characteristics of bright light therapy (BLT) administration (duration, escalation, morning and mid-day exposures) depending on the tolerance (hypomanic symptoms). Methods Patients with BD I or II and treated by a mood stabilizer are eligible. After 1 week of placebo, patients are randomized between either morning or mid-day exposure for 10 weeks of active BLT with glasses using a dose escalation at 7.5, 10, 15, 30 and 45 minutes/day. A further follow-up visit is planned 6 months after inclusion. Patients will be included by cohorts of 3, with at least 3 days of delay between them, and 1 week between cohorts. If none meet a dose limiting toxicity (DLT; i.e hypomanic symptoms), the initiation dose of the next cohort will be increased. If one patient meet a DLT, an additionnal cohort will start at the same dose. If 2 or 3 patients meet a DLT, from the same cohort or from two cohorts at the same dose initiation, the maximum tolerated dose is defined. This dose escalation will also take into account DLTs observed during the intra-subject escalation on previous cohorts, with a "Target Ceiling Dose" defined if 2 DLTs occured at a dose. Discussion Using an innovative and more ergonomic device in the form of glasses, this study aims to better codify the use of BLT in BD to ensure a good initiation and tolerance.

• Journal of Gastric Cancer
• /
• v.21 no.4
• /
• pp.418-425
• /
• 2021

Purpose: We designed a new regimen by combining intraperitoneal (IP) paclitaxel (PTX) with systemic S-1 plus oxaliplatin (SOX) for the treatment of advanced gastric cancer with peritoneal metastasis. This dose-escalation study aimed to determine the maximum tolerated dose (MTD) and recommended dose (RD) of IP PTX administered weekly to patients. Materials and Methods: Eight cycles of IP PTX plus SOX regimen were administered to the patients. S-1 was administered orally twice daily at a dose of 80 mg/m²/day for 14 consecutive days, followed by 7 days of rest. Intravenous oxaliplatin was administered at a fixed dose of 100 mg/m² on day 1, while IP PTX was administered on days 1 and 8. The initial dose of IP PTX was 40 mg/m², and the dose escalation was set in units of 20 mg/m² up to 80 mg/m². Dose-limiting toxicities (DLTs) were defined as grade 3 non-hematologic toxicities, grade 4 leukopenia, grade 3 febrile neutropenia, and grade 3 thrombocytopenia. Results: Nine patients were included in the study. No DLTs were observed in any of the enrolled patients. Therefore, the MTD was not reached, and the RD of IP PTX was determined to be 80 mg/m². Four patients (44%) showed a decreased peritoneal cancer index score on second-look laparoscopic examination. Conclusions: The present study determined the dose for further clinical trials of IP PTX to be 80 mg/m², when combined with a systemic SOX regimen.