[Translation] Safety, pharmacokinetics and pharmacodynamics of continuous administration of ethaselen dispersible tablets in patients with advanced malignant solid tumors with high TrxR expression

主要目的： 1.观察乙烷硒啉分散片连续给药在TrxR阳性肿瘤患者中的安全性 2. 研究乙烷硒啉分散片在肿瘤患者体内药代动力学 3. 研究乙烷硒啉在肿瘤患者中的药代/药效关系次要目的： 1. 观察乙烷硒啉在TrxR阳性肿瘤患者中的疗效。

[Translation]

Main objectives: 1. To observe the safety of continuous administration of ethaselen dispersible tablets in patients with TrxR-positive tumors 2. To study the pharmacokinetics of ethaselen dispersible tablets in tumor patients 3. To study the pharmacokinetic/pharmacodynamic relationship of ethaselen in tumor patients Secondary objectives: 1. To observe the efficacy of ethaselen in patients with TrxR-positive tumors.

Start Date29 Aug 2014

Sponsor / Collaborator

Peking University

[+1]

NCT02166242 / CompletedPhase 1IIT

Phase 1c Single Arm Study of Thioredoxin Reductase Inhibitor Ethaselen, for the Treatment of Thioredoxin Reductase High Expressed Advanced Non-small Cell Lung Cancers Who Have Received More Than Two Lines Standard Treatment.

Thioredoxin reductase plays an critical role in lung cancer patients, in vitro study showed that, ethaselen, specific inhibitor of thioredoxin reductase, could inhibit lung cancer cell growth and induce apoptosis. In China, phase 1 clinical trials of ethaselen showed that 1200 mg dose ethaselen could be well tolerated, in pre-clinical study we found that, approximately 50% non-small cell lung cancers harbored high thioredoxin reductase expression(IHC result ++ or +++), phase 1a/b of ethaselen had finished in 2008, the result showed that 1200mg ethaselen per day was safety and tolerated by Chinese malignant tumor patients.In pre-clinical research, our group found that, elevated of thioredoxin reductase activity was associated with the expression of thioredoxin reductase tested by immunohistochemistry, which means high expression of this enzyme may be a favourite predicted factor of ethaselen, the specific inhibitor of thioredoxin reductase.

Start Date01 Jun 2014

Sponsor / Collaborator

Hunan Cancer Hospital

100 Clinical Results associated with Ethaselen

100 Translational Medicine associated with Ethaselen

100 Patents (Medical) associated with Ethaselen

1,788

Literatures (Medical) associated with Ethaselen

01 Oct 2024·Journal of Applied Animal Welfare Science

Hormonal-Induced Cervical Relaxation During Diestrus in Ewes: Cervical Transposing Feasibility and Use of hCG for Rescuing Disrupted Luteal Function

Article

Author: Ferreira Fonseca, Jeferson ; Vergani, Gabriel Brun ; Arrais, Aline Matos ; Garcia, Alexandre Rossetto ; Schinaider Do Amaral Pereira, Verônica ; Bastos, Rosemary ; Rios Coelho Alves, Bruna ; Oliveira, Maria Emilia Franco ; Roberto Bourg Melo, Marco ; Novita Esteves, Sergio

Cervical relaxation (CR) was performed in ewes during diestrus, to prospect a feasible protocol for non-surgical embryo transfer (NSET). In Trial 1, naturally mated ewes (n=13) received CR protocols with estradiol benzoate (EB, 1 mg on D6) and oxytocin (OT, 50 IU on D7) only (G-EB+OT) or associated with human chorionic gonadotropin (hCG, 300 IU on D7, G-EB+OT+hCG) and were compared to non-hormonally treated (G-control) ewes. Estradiol concentration increased (P<0.05) from D6 to D7 in G-EB+OT and G-EB+OT+hCG, then decreased (P<0.05) on D8. The G-EB+OT had reduced (P<0.05) progesterone on D8, and 0% (0/5) pregnancy, while G-control had 100% (3/3) conception rate. The treatment with hCG mitigated the progesterone drop on D8 and resulted in 50% (2/4) conception rate. In Trial 2, cervical transposing success after treatment with EB, OT, and hCG on D6 and D7 was assessed in nulliparous (n=25) and multiparous (n=30) ewes. The EB+OT+hCG protocol allowed efficient cervical transposition (~78% of cervical transposition success into ~5 min) in nulliparous and multiparous females and did not alter total and blood perfusion areas of corpora lutea (CL). The use of EB+OT+hCG was efficient to ensure effective cervical transposing in nulliparous and multiparous ewes, with no apparent deleterious effect on CL function, and may contribute to animal welfare, allowing a less invasive NSET procedure.

17 Jul 2024·mBio

Edeine B ₁ produced by Brevibacillus brevis reduces the virulence of a plant pathogenic fungus by inhibiting mitochondrial respiration

Article

Author: Park, Jiyeun ; Kim, Bomin ; Kim, Yeong Seok ; Choi, Gyung Ja ; Son, Hokyoung ; Han, Jae Woo ; Nguyen, Minh Van ; Kim, Hun ; Jeon, Junhyun ; Lee, Joo-Youn

ABSTRACT Plant pathogenic fungi cause serious diseases, which result in the loss of crop yields and reduce the quality of crops worldwide. To counteract the escalating risks of chemical fungicides, interest in biological control agents to manage plant diseases has significantly increased. In this study, we comprehensively screened microbial culture filtrates using a yeast screening system to find microbes exhibiting respiratory inhibition activity. Consequently, we found a soil-borne microbe Brevibacillus brevis HK544 strain exhibiting a respiration inhibitory activity and identified edeine B 1 (EB 1 ) from the culture filtrate of HK544 as the active compound of the respiration inhibition activity. Furthermore, against a plant pathogenic fungus Fusarium graminearum , our results showed that EB 1 has effects on multiple aspects of respiration with the downregulation of most of the mitochondrial-related genes based on transcriptome analysis, differential EB 1 -sensitivity from targeted mutagenesis, and the synergistic effects of EB 1 with electron transport chain complex inhibitors. With the promising plant disease control efficacy of B. brevis HK544 producing EB 1 , our results suggest that B. brevis HK544 has potential as a biocontrol agent for Fusarium head blight. IMPORTANCE As a necrotrophic fungus, Fusarium graminearum is a highly destructive pathogen causing severe diseases in cereal crops and mycotoxin contamination in grains. Although chemical control is considered the primary approach to control plant disease caused by F. graminearum , fungicide-resistant strains have been detected in the field after long-term continuous application of fungicides. Moreover, applying chemical fungicides that trigger mycotoxin biosynthesis is a great concern for many researchers. Biocontrol of Fusarium head blight (FHB) by biological control agents (BCAs) represents an alternative approach and could be used as part of the integrated management of FHB and mycotoxin production. The most extensive studies on bacterial BCAs-fungal communications in agroecosystems have focused on antibiosis. Although many BCAs in agricultural ecology have already been used for fungal disease control, the molecular mechanisms of antibiotics produced by BCAs remain to be elucidated. Here, we found a potential BCA ( Brevibacillus brevis HK544) with a strong antifungal activity based on the respiration inhibition activity with its active compound edeine B 1 (EB 1 ). Furthermore, our results showed that EB 1 secreted by HK544 suppresses the expression of the mitochondria-related genes of F. graminearum , subsequently suppressing fungal development and the virulence of F. graminearum . In addition, EB 1 exhibited a synergism with complex I inhibitors such as rotenone and fenazaquin. Our work extends our understanding of how B. brevis HK544 exhibits antifungal activity and suggests that the B. brevis HK544 strain could be a valuable source for developing new crop protectants to control F. graminearum .

01 Jul 2024·Journal of Dairy Science

Comparison of gonadotropin-releasing hormone and estradiol benzoate plus gonadotropin-releasing hormone to initiate a progesterone-based timed artificial insemination resynchronization protocol in lactating dairy cows

Article

Author: Alves, Rodrigo L O R ; Wiltbank, Milo C ; Motta, Jessica C L ; Sartori, Roberto ; E Silva, Lucas O ; Gonzales, Bruno ; Consentini, Carlos E C ; Abadia, Tattiany ; Melo, Leonardo F

The present study compared 2 strategies to initiate a progesterone (P4)-based timed artificial insemination (TAI) protocol for lactating dairy cows: only GnRH or estradiol benzoate (EB) plus GnRH (EB+GnRH). Lactating Holstein cows (n = 487; 184 primiparous and 303 multiparous) from 2 commercial dairy herds were used for their second or greater services postpartum. Each week, cows that were nonpregnant at the pregnancy diagnosis 32 d after a previous AI were randomly assigned to 1 of 2 experimental groups that differed only in the strategy to initiate (d 0) the TAI protocol. On d 0, every cow received a 2.0-g P4 implant; in the EB+GnRH group, cows were treated with 2.0 mg i.m. of EB and 16.8 µg i.m. of the GnRH analog buserelin acetate, whereas in the GnRH group, cows received only 16.8 µg i.m. of GnRH. On d 7 after the initial treatment, 0.530 mg i.m. of cloprostenol sodium (PGF) was administered in all cows, followed by a second dose on d 8, concomitant with 1.0 mg i.m. of estradiol cypionate and P4 implant withdrawal. The TAI was performed on d 10 (48 h after P4 device withdrawal) in both experimental groups. Only conventional Holstein semen was used throughout the study. The percentage of cows with corpus luteum (CL) on d 0 (73%) and overall ovulation rate after d 0 (54%) did not differ between groups. The CL regression between d 0 and the first PGF treatment was greater in the EB+GnRH group than the GnRH group (42% vs. 31%). Consequently, the proportion of cows with CL at PGF was greater when only GnRH was used on d 0 compared with EB+GnRH (86% vs. 82%), and the mean number of CL at PGF was greater (1.23 vs. 1.11). The expression of estrus near TAI was greater in GnRH group (84% vs. 77%), and cows showing estrus had greater (44% vs. 10%) pregnancy per AI (P/AI) on d 32 for both treatments. We found no effect of the presence of CL on d 0 or at PGF, nor of ovulation after d 0 or CL regression between d 0 and d 7 on fertility. However, fertility was critically impaired when cows did not have CL at both times, d 0 and at PGF treatment. We did not observe any interaction between treatment and other variables, and the P/AI was similar in cows receiving EB+GnRH or only GnRH on d 0 (37.8% vs. 36.6%). In summary, although there was no detectable difference in P/AI between treatments, this study demonstrated potential negative physiological outcomes caused by EB treatment on d 0 (greater incidence of luteolysis after d 0 and fewer cows with CL at PGF treatment). Overall, we found no benefit of adding EB at the initiation of a P4-based TAI protocol on fertility compared with using GnRH alone, despite differences in ovarian dynamics and expression of estrus.

100 Deals associated with Ethaselen

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Hematologic Neoplasms	Phase 2	CN	Peking University	-
Hematologic Neoplasms	Phase 2	CN	Kaixi Pharmaceutical (Wuhan) Co., Ltd.	-
Advanced Malignant Solid Neoplasm	Phase 1	CN	Peking University	29 Aug 2014
Advanced Malignant Solid Neoplasm	Phase 1	CN	Tibet Cheezheng Tibetan Medicine Co., Ltd.	29 Aug 2014
Advanced Lung Non-Small Cell Carcinoma	Preclinical	CN	Hunan Cancer Hospital	01 Jun 2014

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