Author: Xia, Menghang ; Huang, Ruili ; Raziuddin, Razi ; Houck, Keith A. ; Hsu, Chia-Wen ; Soni, Vikas ; Martin, Matt ; Sakamuru, Srilatha ; Zhao, Jinghua ; Paul-Friedman, Katie ; Crofton, Kevin M. ; Varticovski, Lyuba ; Stavreva, Diana A. ; Hager, Gordon L.

BACKGROUNDThyroid hormone receptors (TRs) are critical endocrine receptors that regulate a multitude of processes in adult and developing organisms, and thyroid hormone disruption is of high concern for neurodevelopmental and reproductive toxicities in particular. To date, only a small number of chemical classes have been identified as possible TR modulators, and the receptors appear highly selective with respect to the ligand structural diversity. Thus, the question of whether TRs are an important screening target for protection of human and wildlife health remains.OBJECTIVEOur goal was to evaluate the hypothesis that there is limited structural diversity among environmentally relevant chemicals capable of modulating TR activity via the collaborative interagency Tox21 project.METHODSWe screened the Tox21 chemical library (8,305 unique structures) in a quantitative high-throughput, cell-based reporter gene assay for TR agonist or antagonist activity. Active compounds were further characterized using additional orthogonal assays, including mammalian one-hybrid assays, coactivator recruitment assays, and a high-throughput, fluorescent imaging, nuclear receptor translocation assay.RESULTSKnown agonist reference chemicals were readily identified in the TR transactivation assay, but only a single novel, direct agonist was found, the pharmaceutical betamipron. Indirect activation of TR through activation of its heterodimer partner, the retinoid-X-receptor (RXR), was also readily detected by confirmation in an RXR agonist assay. Identifying antagonists with high confidence was a challenge with the presence of significant confounding cytotoxicity and other, non-TR-specific mechanisms common to the transactivation assays. Only three pharmaceuticals-mefenamic acid, diclazuril, and risarestat-were confirmed as antagonists.DISCUSSIONThe results support limited structural diversity for direct ligand effects on TR and imply that other potential target sites in the thyroid hormone axis should be a greater priority for bioactivity screening for thyroid axis disruptors. https://doi.org/10.1289/EHP5314.

01 Mar 2005·British Journal of OphthalmologyQ2 · MEDICINE

A randomised, placebo controlled clinical trial of the aldose reductase inhibitor CT-112 as management of corneal epithelial disorders in diabetic patients

Q2 · MEDICINE

Article

Author: Nejima, R ; Yamagami, S ; Miyata, K ; Miyai, T ; Otani, S ; Amano, S ; Nakahara, M

AIMTo evaluate the efficacy of topical aldose reductase inhibitor CT-112 (5-[3-ethoxy-4-pentyloxyphenyl]-2,4-thiazolidinedione) on corneal epithelial barrier function in diabetic patients.METHODSThis was a prospective, randomised, double masked placebo controlled study. 34 eyes of 34 diabetic patients were randomly assigned treatment with 0.25% eye drops of CT-112 (n = 22) or a placebo (n = 12) four times a day for 8 weeks. Corneal fluorescein staining and corneal sensation were examined before treatment as well as 4 and 8 weeks after administration. Corneal epithelial permeability to fluorescence was measured with an anterior fluorophotometer.RESULTSAverage scores of superficial punctate keratopathy and corneal sensitivity did not differ significantly between the two groups at any time. Whereas average fluorescein concentrations did not differ significantly for the CT-112 and placebo groups before treatment, they did differ significantly 4 and 8 weeks after treatment (4 weeks, p = 0.0327; 8 weeks, p = 0.0143).CONCLUSIONThe topical aldose reductase inhibitor, CT-112 improves the corneal epithelial barrier function in diabetic patients.

01 Dec 2004·Colloids and Surfaces B: BiointerfacesQ2 · ENGINEERING & TECHNOLOGY

Preparation of stable aqueous suspension of a hydrophobic drug with polymers

Q2 · ENGINEERING & TECHNOLOGY

Article

Author: Hideo Terayama ; Hisayuki Nakayama ; Kunio Esumi ; Katsuhiro Inada ; Shinichi Yasueda

Pharmaceutical preparation of a hydrophobic aldose reductase inhibitor 5-(3-ethoxy-4-pentyloxyphenyl)-2,4-thiazolidinedione (CT112) was investigated. CT112 dissolved in a basic solution with different kinds of polymers was neutralized by acid to obtain a suspension preparation. In particular, the addition of a polymer, hydroxypropyl methyl cellulose (HPMC) provided a stable CT112 suspension with a homogeneous particle size, and there seemed to be an optimal concentration of HPMC for the stable suspension. The addition of polysorbate 80 brought higher CT112 solubility in water, but did not provide a stable suspension. X-ray diffraction, IR spectrum, and thermal analysis revealed that the particles in the suspension with HPMC had lower degree of crystallinity, less hydrophobic particle surface, and lower melting point and decreased fusion enthalpy than the suspension without HPMC. These results suggested that the highly stable CT112 suspension could be attained by the adsorption of the polymer.

100 Deals associated with Risarestat

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Complications	Phase 3	-	Senju Pharmaceutical Co., Ltd.	-
Diabetes Complications	Phase 3	-	Takeda Pharmaceutical Co., Ltd.	-

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