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Tilmicosin, as an effective broad-spectrum antibacterial drug, has incomplete absorption and low bioavailability due to its low water solubility, which limits its veterinary clinical applications. As a non-polymeric drug carrier, γ-cyclodextrin was complexed with tilmicosin through supercritical carbon dioxide assistance for the first time, and confirmed by FTIR, X-ray diffraction, proton NMR and scanning electron microscopy. The water solubility of tilmicosin was increased 57-fold through complexation with γ-cyclodextrin, and the release and bioavailability of tilmicosin in the complex were significantly improved. The tilmicosin in complex showed better anti-Streptococcus agalactiae activity than that of tilmicosin alone in MIC, MBC and drug susceptibility studies.

Abstract: Transformations of the difunctionalizated cyclodextrin derivatives is a daunting task due to the challenging purification and unambiguous characterization of the final compounds. Lactose has the ability to recognize the liver cells, and the folate receptor (alpha subunit) is overexpressed in multiple tumors, including liver cancer. Therefore, cyclodextrin conjugated with lactose and folic acid should have the liver cell targeting capability, and its inclusion complex with liver cancer drug such as Sorafenib, not only can increase drug ‘s water solubility but also increase the drug’s targeting ability. Fondaparinux as a synthetic heparin may improve the survival of cancer patients, so lactose and Fondaparinux conjugated cyclodextrin derivative can increase drug’s solubility and drug’s anti-tumor efficacy. Accordingly, Fondaparinux, folic acid and lactose conjugated 6A,6D-bifunctionlized -cyclodextrin derivatives are designed and synthesized as potential liver cancer drug carriers in order to increase cancer drug’s targeting ability, solubility and stability.

GST-HG131, a novel dihydroquinolizinone (DHQ) compound, has been shown to reduce circulating levels of HBsAg in animals. This first-in-human trial evaluated the safety, tolerability, and pharmacokinetic profile of GST-HG131 in healthy Chinese subjects. This was a double-blind, randomized, placebo-controlled phase Ia clinical trial that was conducted in two parts. Part A was a single-ascending-dose (SAD; GST-HG131 10 30, 60, 100, 150, 200, 250 or 300 mg or placebo) study, which also assessed the food effect of GST-HG131 100 mg. Part B was a multiple-ascending-dose (MAD; GST-HG131 30, 60 or 100 mg or placebo BID) study. Tolerability assessments included adverse events, vital signs, 12-lead electrocardiogram, physical examination, and clinical laboratory tests. PK analyses were conducted in blood, urine, and fecal samples. Single doses of GST-HG131 ≤ 300 mg and multiple doses of GST-HG131 ≤ 60 mg were generally safe and well tolerated; however, multiple dosing was stopped at GST-HG131 100 mg, as pre-defined stopping rules specified in the protocol were met (Grade II drug related AEs of nausea and dizziness in >50% of subjects). In the SAD study, median t(max) of GST-HG131 was 1-6 h, and t(1/2) ranged from 3.88 h to 14.3 h. PK parameters were proportional to dose. Exposure was reduced after food intake. In the MAD study, steady-state was attained on day 4, and there was no apparent plasma accumulation of GST-HG131 on day 7 (R(acc) < 1.5). In conclusion, GST-HG131 exhibited an acceptable safety profile in healthy subjects at single doses ranging from 10-300 mg and multiple doses (BID) ranging from 30-60 mg, and the MAD doses (30 mg and 60 mg BID) that potentially meet the therapeutic AUC requirements. These findings imply GST-HG131 has potential as a therapeutic option for CHB infection. (This study has been registered at ClinicalTrials.gov under identifier NCT04499443.).

Breast cancer (BC) has recently surpassed lung cancer to become the most commonly diagnosed cancer in women worldwide. Approximately 70% of BC was ER+, in which estrogen receptor α (ERα, encoded by ESR1 gene) drives dysregulated cell proliferation. In clinic, ER+ BC has been effectively treated by endocrine therapy targeting estrogen or ER. As the first approved ERα degrader, fulvestrant has proven to be effective for locally advanced or metastatic BC. However, its clinical utilization is hampered by inconvenience of intramuscular injection, as well as its poor PK/PD profile and limited efficacy, especially in the patient population that developed ESR1 mutation-conferring drug resistance after the earlier line of treatment with an aromatase inhibitor. Thus, developing an oral and more effective therapy for ER+ BC remains an unmet medical need. We report herein discovery and preclinical investigation of a novel orally bioavailable SERD TFX06. TFX06 demonstrated potent binding affinity to ERα with a Ki of 0.10 nM and preferably antagonized ERα to ERβ with an IC50 value of 0.086 nM and 2.83 nM, respectively. TFX06 potently induced ERα degradation in ER+ BC cells and substantially inhibited cell proliferation in BC cell lines with ER wild type (WT), and MCF-7 cells expressing Y537S or D538G mutants. Oral administration of TFX06 demonstrated impressive antitumor efficacy in ER WT (TGI = 101%) and ER D538G-expressing (TGI = 99%) MCF-7 cell line-derived xenograft (CDX) models in mice. Similarly, in an ER+ BC patient-derived xenograft (PDX) model (HCI-013) with ER Y537S mutation, TFX06 also exerted excellent antitumor activity (TGI = 99%). Furthermore, TFX06 in combination with palbociclib achieved synergistic activity in MCF-7 CDX model. Moreover, TFX06 exhibited an excellent correlation between systemic/local drug exposure, pharmacodynamic modulation (i.e., ERα downregulation) and antitumor activity. Collectively, these findings demonstrate that TFX06 is a novel, orally bioavailable SERD. TFX06 demonstrates substantial antitumor activity in both in vitro and in vivo preclinical tumor models, including those expressing ESR1 mutations, through downregulation of ERα. The preclinical data warranted the clinical evaluation of TFX06 in human with an IND application submitted to the China NPMA. Citation Format: Jinping Wu, Ke An, Douglas D. Fang, Jianyu Lu, Lihong Hu, Jing Wang, Kaili Zhang, Yuanfeng Xia, Charles Ding, Shuhui Chen, Sha Wei. Preclinical development of an oral selective estrogen receptor degrader (SERD) TFX06 for the treatment of ER+HER2− breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 474.

Galactosyl and lactosyl conjugated 6A,6D-bifunctionlized β cyclodextrin derivatives were designed and synthesized as the potential liver cancer drug carriers through SN2 replacement and click reactions in order to increase liver cancer drug's targeting ability, solubility and stability. The synthetic methods and strategies to obtain the designed compounds were discussed.

National emission inventories (NEIs) take years to assemble, but they can become outdated quickly, especially for time-sensitive applications such as air quality forecasting. This study compares multi-year NO x trends derived from satellite and ground observations and uses these data to evaluate the updates of NO x emission data by the US National Air Quality Forecast Capability (NAQFC) for next-day ozone prediction during the 2008 Global Economic Recession. Over the eight large US cities examined here, both the Ozone Monitoring Instrument (OMI) and the Air Quality System (AQS) detect substantial downward trends from 2005 to 2012, with a seven-year total of −35% according to OMI and −38% according to AQS. The NO x emission projection adopted by NAQFC tends to be in the right direction, but at a slower reduction rate (−25% from 2005 to 2012), due likely to the unaccounted effects of the 2008 economic recession. Both OMI and AQS datasets display distinct emission reduction rates before, during, and after the 2008 global recession in some cities, but the detailed changing rates are not consistent across the OMI and AQS data. Our findings demonstrate the feasibility of using space and ground observations to evaluate major updates of emission inventories objectively. The combination of satellite, ground observations, and in-situ measurements (such as emission monitoring in power plants) is likely to provide more reliable estimates of NO x emission and its trend, which is an issue of increasing importance as many urban areas in the US are transitioning to NO x -sensitive chemical regimes by continuous emission reductions.

The U. S. National Air Quality Forecasting Capability (NAQFC) provides air quality forecast for the nation by disseminating numerical model predicted surface concentration of O3 and PM2.5 to the public. However, the fidelity of NAQFC is dependent on the accuracies of the emission projection factors employed to estimate the various emissions. This study focuses on comparing variability of surface NOx and O3 concentrations for two emission modeling scenarios for July of 2011: the Base Case and a New Emission Case. The Base Case used the U.S. EPA 2005 National Emission Inventory (NEI2005), its projection procedures adhered to a standard practice used by NAQFC since its inception in 2003. The New Emission Case adopted a scaling procedure based on more recent EPA data demonstrated a significant reduction of the mobile source’s share of NOx emission among the major contributors. It reduced from 33.6 % in the Base Case to 25.2 % in the New Emission Case. This is even more significant if one takes into account the large increase in vehicle miles traveled since 2005. The NOx SIP Call had achieved significant reduction of NOx emission from power plants, but still lagged behind that achieved by the reduction in the on-road vehicular (mobile) exhausts. Geographically population change trends in the last decade do not necessarily translates into proportional changes in NOx emission.