Discovery of HPG1860, a Structurally Novel Nonbile Acid FXR Agonist Currently in Clinical Development for the Treatment of Nonalcoholic Steatohepatitis.

The farnesoid X receptor (FXR) is a ligand-activated nuclear receptor. Activation of FXR significantly impacts the expressions of the pivotal genes involved in bile acid metabolism, inflammation, fibrosis, and homeostasis of lipid and glucose, leading to considerable interests in developing FXR agonists for the treatment of nonalcoholic steatohepatitis (NASH) or other FXR-relevant diseases. Herein, we describe the design, optimization, and characterization of a series of N-methylene-piperazinyl derivatives as the nonbile acid FXR agonists. Particularly, compound 23 (HPG1860), a potent full FXR agonist, shows high selectivity, favorable ADME and pharmacokinetics profile, along with favorable in vivo activities demonstrated in both rodent PD model and HFD-CCl4 model and is currently in clinical development in patients with NASH in phase II.

Effect of four plant oils on the stability of high internal phase Pickering emulsions stabilized by ovalbumin-tannic acid complex.

The poor interfacial stability of protein-stabilized high internal phase Pickering emulsions (HIPEs) is a major hurdle to realize their practical applications in food processing. The emulsifying stability is not only related to the protein itself, but also dependent upon the oil phases. In this study, four plant-based oils were studied to understand their respective effects on the interfacial stability of HIPEs prepared by ovalbumin (OVA) and ovalbumin-tannic acid complex (OVA-TA). Our findings revealed that the interfacial activities were closely related to the physicochemical properties of the oil phase, such as the number of carbon­carbon double bonds in the unsaturated fatty acids, melting point, and polarity. The emulsifying abilities were ranked as palm oil > soybean oil > olive oil > perilla oil. OVA-TA stabilized HIPEs exhibited excellent emulsifying stability compared with free OVA stabilized ones. This work provided a unique insight into understanding the interfacial stabilization mechanisms for protein-stabilized HIPEs with different kinds of oil phases.

The metabolism and excretion of the dipeptidyl peptidase 4 inhibitor [14C] cetagliptin in healthy volunteers.

The metabolism and excretion of cetagliptin were investigated in healthy male subjects after a single oral dose of 100mg/50µCi [14C] cetagliptin.The mean concentration-time profile of cetagliptin was similar to that of total radioactivity in plasma after oral administration of [14C] cetagliptin in healthy male subjects. Cetagliptin was rapidly absorbed after oral administration. Unchanged cetagliptin was the most abundant radioactive component in all matrices investigated. Approximately 53.13% of plasma AUC of total radioactivity was accounted for by cetagliptin. Each metabolite plasma AUC was not higher than 2.93% of plasma AUC of total radioactivity. By 336 h after administration, 91.68% of the administered radioactivity was excreted, and the cumulative excretion in the urine and faeces was 72.88% and 18.81%, respectively. The primary route of excretion of radioactivity was via the kidneys.Four metabolites were detected at trace levels, and it involved hydroxylated (M436-1 and M436-3), N- sulphate (M500), and N-carbamoyl glucuronic acid conjugates (M640B) of cetagliptin. These metabolites were detected also in plasma, urine, and faeces at low levels, except that metabolite M640B was not detected in faeces. All metabolites were observed with <10% of parent compound systemic exposure after oral administration.

Mass balance, pharmacokinetics and pharmacodynamics of intravenous HSK3486, a novel anaesthetic, administered to healthy subjects.

AIMS: This trial (NCT03751956) investigated the mass balance, pharmacokinetics and pharmacodynamics of HSK3486, a novel anaesthetic, in healthy subjects. METHODS: A single dose of 0.4 mg/kg [14 C]HSK3486 was administered to six healthy subjects. Blood, urine and faecal samples were collected, analysed for radioactivity, unchanged HSK3486 and profiled for metabolites. The Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale and vital signs were closely monitored during the study. RESULTS: The mean recovery of total radioactivity in excreta was 87.3% in 240 h, including 84.6% in urine and 2.65% in faeces. The exposure (AUC0-t ) of total radioactivity was much higher than that of unchanged HSK3486 in plasma, indicating there were circulating metabolites in plasma. The glucuronide conjugate of HSK3486 (M4) was found as the only major circulating metabolite in plasma (79.3%), while unchanged HSK3486 accounted for only 3.97% of the total radiation exposure. M4 also resulted in a longer estimated elimination half-life (t1/2 ) of total radioactivity than that of unchanged HSK3486 in plasma. Fortunately, the metabolite was detected to be not specific to red blood cells and was suggested to be nonhypnotic and nontoxic. All the subjects were quickly anaesthetized (2 min) after drug administration and woke up smoothly after a short time (5.5-14.1 min) with few residual effects. The only adverse event in the study was mild (grade 1) and consisted of hypotension. CONCLUSION: HSK3486 is a promising anaesthetic candidate with rapid onset of action and clear absorption, distribution, metabolism, excretion (ADME) processes. HSK3486 showed favourable pharmacokinetic characteristics, pharmacodynamic responses and safety at the study dose.

Comparative pharmacokinetics of amphotericin B after single- and multiple-dose administration of G-ABCD and conventional amphotericin B deoxycholate to rats.

OBJECTIVE: G-ABCD is a biosimilar product of amphotericin B colloidal dispersion (ABCD). This study was designed to systematically examine the plasma pharmacokinetics (PK) and tissue distribution of G-ABCD in rats, using amphotericin B deoxycholate (DAmB) as a positive control. METHODS: Male Sprague-Dawley rats received single dose or 14 doses of G-ABCD (1.0, 2.0 or 5.0 mg/kg) or the conventional micellar formulation DAmB) (1.0 mg/kg) via intravenous injection. Plasma and tissue samples were obtained for analysis of amphotericin B concentration by liquid chromatography-tandem mass spectrometry. RESULTS: After a single-dose administration of 1 mg/kg, G-ABCD resulted in a significantly lower plasma peak drug concentration (Cmax) (1536 vs. 5256 ng/mL) and area under the curve from time 0 to ∞ (AUC0-∞) (3972 vs. 7006 h ng/mL) of non-complexed amphotericin B than DAmB. G-ABCD was associated with quicker distribution but slower elimination of amphotericin B than DAmB. Amphotericin B concentration reached a steady state after seven doses of G-ABCD. After multiple doses of 1 mg/kg, G-ABCD showed a lower peak level and longer half-life of amphotericin B in plasma than DAmB. G-ABCD treatment in rats was associated with relatively higher distribution to liver and spleen, but reduced amphotericin B delivery to kidneys, the major target organ of toxicity. CONCLUSION: These results suggest that G-ABCD provides a flatter but more lasting plasma level of amphotericin B and lower kidney burden in rats than DAmB.

Absorption, Metabolism and Excretion of Surufatinib in Rats and Humans.

BACKGROUND: Surufatinib is a potent small-molecule tyrosine kinase inhibitor and exhibited significant efficacy in the treatment of neuroendocrine tumors in clinical trials. OBJECTIVE: The absorption, metabolism and excretion of surufatinib were investigated in rats and human volunteers following a single oral dose of [14C] surufatinib. METHODS: The radioactivity was measured in plasma, urine, feces and bile by liquid scintillation counting, and the metabolites were characterized by liquid chromatography coupled to mass spectrometry. RESULTS: Surufatinib was orally absorbed similarly in rats and human volunteers, with the median Tmax of 4 hours post-dose. The estimated t1/2 appeared longer in humans than in rats (mean t1/2: 3.12 hour for male rats, 6.48 hours for female rats and 23.3 hours for male human volunteers). The excretion of surufatinib was almost complete in rats and human volunteers in the studies, with the total radioactivity recovery of >90% of the dose. Similarly, in rats and humans, fecal excretion predominated (approximately 87% of the dose recovered in feces and only 5% in urine). The parent drug was the major radioactive component detected in the plasma extracts of rats and humans, and no single circulating metabolite accounted for >10% of the total radioactivity. Unchanged drug was a minor radioactive component in the excreta of rats and humans. CONCLUSION: Fecal excretion was the predominant way for the elimination of surufatinib and its metabolites in rats and humans. No disproportionate circulating metabolite was observed in humans.

[The Near Infrared Spectral Bands Optimal Selection in the Application of Liquor Fermented Grains Composition Analysis].

In order to improve the technical level of the rapid detection of liquor fermented grains, in this paper, use near infrared spectroscopy technology to quantitative analysis moisture, starch, acidity and alcohol of liquor fermented grains. Using CARS, iPLS and no information variable elimination method (UVE), realize the characteristics of spectral band selection. And use the multiple scattering correction (MSC), derivative and standard normal variable transformation (SNV) pretreatment method to optimize the models. Establish models of quantitative analysis of fermented grains by PLS, and in order to select the best modeling method, using R2, RMSEP and optimal number of main factors to evaluate models. The results showed that the band selection is vital to optimize the model and CARS is the best optimization of the most significant effect. The calculation results showed that R2 of moisture, starch, acidity and alcohol were 0.885, 0.915, 0.951, 0.885 respectively and RMSEP of moisture, starch, acidity and alcohol were 0.630, 0.519, 0.228, 0.234 respectively. After optimization, the model prediction effect is good, the models can satisfy the requirement of the rapid detection of liquor fermented grains, which has certain reference value in the practical.

Evaluation of mitochondrial toxicity in Marmota himalayana treated with metacavir, a novel 2',3'-dideoxyguanosine prodrug for treatment of hepatitis B Virus.

Metacavir (PNA) is a novel synthetic nucleoside analogue for the treatment of hepatitis B virus (HBV). Our recent studies showed that PNA, a prodrug of 2',3'-dideoxyguanosine (ddG), exhibited lower mitochondrial toxicity in long-term cultures of HepG2 cells. In the current study, we examined the long-term effects of PNA on mitochondrial toxicity in Marmota himalayana (Himalayan marmot). Himalayan marmots were treated daily with oral PNA (50 or 100 mg/kg), ziduvidine (AZT) (100 mg/kg), or water (control) for 90 days. PNA treatment did not alter the body weight or plasma lactate acid level. In livers from the animals treated with PNA at 100 mg/kg/day, histopathology showed mild steatosis or small focal liver cell necrosis. Electron microscopy also showed minor proliferation and partial mitochondrial swelling with crista reduction. Measurement of respiratory chain complex enzyme activity and mitochondrial DNA (mtDNA) content revealed no significant differences in skeletal muscle, liver, and kidney tissues between animals treated with PNA and controls. In contrast, in Himalayan marmots treated with AZT we observed delayed toxicity, including lactic acidosis, severe hepatic steatosis, obvious mitochondrial damage, and significant decreases in respiratory chain complex enzyme activity and mtDNA content. This is similar to the delayed toxicity syndrome observed previously in animals and humans. In summary, PNA treatment did not alter mitochondrial enzyme activity or mtDNA content. This suggests that PNA could pose a very low risk for adverse mitochondrion-related effects. However, long-term hepatotoxic effects of PNA were observed, and this indicates a need for continued monitoring of PNA-associated hepatotoxicity in clinical trials.

In vitro mitochondrial toxicity of metacavir, a new nucleoside reverse transcriptase inhibitor for treatment of hepatitis B virus.

Therapy with nucleoside reverse transcriptase inhibitors (NRTIs) can be associated with mitochondrial toxicity. In vitro studies have been used to predict the predisposition for and characterize the mechanisms causing mitochondrial toxicity. Metacavir (PNA) is a novel synthetic nucleoside analog for oral administration with potent and specific antiviral activity against hepatitis B virus (HBV). We assessed the potential for mitochondrial toxicity of PNA in long-term cultures of HepG2 hepatoma cells by measuring mitochondrial function (through lactate secretion), levels of mitochondrial DNA (mtDNA), and the activities of respiratory-chain complexes I to IV. Exposure of HepG2 cells to PNA at concentrations up to 50 µM for 15 days resulted in no deleterious effect on cell proliferation, levels of lactate or mtDNA, or enzyme activities of respiratory-chain complexes I to IV. In contrast, dideoxycytosine at 10 µM and zidovudine at 50 µM have significant effects on cell proliferation, levels of lactate and mtDNA, and enzyme activities of respiratory-chain complexes I to IV. However, PNA at a supratherapeutic concentration of 250 µM could result in significant alterations in the levels of mtDNA and the activities of respiratory-chain complex enzymes, revealing evidence of the potential mitochondrial toxicity of PNA. In summary, these in vitro results indicate that the potential for PNA to interfere with mitochondrial functions is low.

Sedative and hypnotic activities of the ethanol fraction from Fructus Schisandrae in mice and rats.

Fruits of Fructus Schisandrae have been used as medicine for the treatment for insomnia in traditional Chinese medicine. In the present research, the sedative and hypnotic activities of the ethanol fraction of Fructus Schisandrae fruit (SY3) were studied in mice and rats. In the open field test, SY3 (25, 50 and 100 mg/kg) significantly inhibited the motor activity of mice compared to the normal. Results also showed SY3 potentiated pentobarbital-induced sleep by not only increasing the number of falling asleep and prolonging sleeping time but also reducing sleep latency. Furthermore, sleep-wake stages of rats were evaluated by polytrophic recording for 3 h after treatment. The results demonstrated that SY3 at doses of 20, 40 and 80 mg/kg behaved remarkable action on sleep architecture of rats, which contain the increase of total sleeping time, the rate of deep slow wave sleep (SWS) and mean episode duration of deep SWS, and the decrease of the latency of deep SWS. Therefore, these results suggest that the ethanol fraction of Fructus Schisandrae fruit possesses potent sedative and hypnotic activity, which supported its therapeutic use for insomnia.