A first-in-human phase 1 study of simnotrelvir, a 3CL-like protease inhibitor for treatment of COVID-19, in healthy adult subjects.

Safe and efficacious antiviral therapeutics are in urgent need for the treatment of coronavirus disease 2019. Simnotrelvir is a selective 3C-like protease inhibitor that can effectively inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We evaluated the safety, tolerability, and pharmacokinetics of dose escalations of simnotrelvir alone or with ritonavir (simnotrelvir or simnotrelvir/ritonavir) in healthy subjects, as well as the food effect (ClinicalTrials.gov Identifier: NCT05339646). The overall incidence of adverse events (AEs) was 22.2% (17/72) and 6.3% (1/16) in intervention and placebo groups, respectively. The simnotrelvir apparent clearance was 135-369 L/h with simnotrelvir alone, and decreased significantly to 19.5-29.8 L/h with simnotrelvir/ritonavir. The simnotrelvir exposure increased in an approximately dose-proportional manner between 250 and 750 mg when co-administered with ritonavir. After consecutive twice daily dosing of simnotrelvir/ritonavir, simnotrelvir had a low accumulation index ranging from 1.39 to 1.51. The area under the curve of simnotrelvir increased 44.0 % and 47.3 % respectively, after high fat and normal diet compared with fasted status. In conclusion, simnotrelvir has adequate safety and tolerability. Its pharmacokinetics indicated a trough concentration above the level required for 90 % inhibition of SARS-CoV-2 in vitro at 750 mg/100 mg simnotrelvir/ritonavir twice daily under fasted condition, supporting further development using this dosage as the clinically recommended dose regimen.

A first-in-human phase I study of SHR-1906, a humanized monoclonal antibody against connective tissue growth factor, in healthy participants.

New therapeutic targets and drugs are urgently needed to halt the fibrosing process in idiopathic pulmonary fibrosis (IPF). SHR-1906 is a novel fully humanized monoclonal antibody against the connective tissue growth factor, which plays an essential role in the genesis of IPF. We assessed the safety, tolerability, pharmacokinetics (PKs), and immunogenicity of single dose SHR-1906 in healthy participants. This was a randomized, double-blind, placebo-controlled, dose-escalation, phase I study. Twelve healthy participants for each dose level were enrolled to receive single ascending doses of SHR-1906 intravenously (1.5, 6, 12, 20, 30, and 45 mg/kg) or placebo and followed for 71 days. The primary end points were safety and tolerability. Treatment-related treatment-emergent adverse events occurred in 25 participants (46.3%) in the SHR-1906 group and 11 (61.1%) in the placebo group. No serious adverse events occurred. Over the dose range investigated, the geometric mean clearance was 0.14-0.63 mL/h/kg, the geometric mean volume of distribution at steady-state was 47.4-75.5 mL/kg, and the terminal elimination half-life was 51.9-349 h. SHR-1906 showed nonlinear PKs. The peak concentration increased in a dose-proportional manner, whereas the area under the concentration-time curve showed a greater than dose-proportional increase. Anti-drug antibodies of SHR-1906 were detected in nine of 54 participants (16.7%). A single dose of SHR-1906 up to 45 mg/kg demonstrated a favorable tolerability profile in healthy participants. The PKs and immunogenicity of SHR-1906 were evaluated, supporting further clinical development.

Population pharmacokinetics and pharmacogenetics of apatinib in adult cancer patients.

AIMS: Apatinib is widely used in Chinese cancer patients. As the in vivo drug disposition of apatinib has large individual differences, adverse events are prone to occur. Cytochrome P450 (CYP)3A5 and cancer types maybe the main factors affecting this individual differences. The objective of our study was to establish a population pharmacokinetics (PK) model of apatinib in adult cancer patients, and to explore optimal dosage regimens for individualized treatment. METHODS: Adult patients with various types of cancer treated with apatinib were enrolled. The concentration of apatinib in plasma was determined by high-performance liquid chromatography-tandem mass spectrometry. CYP3A5 genotype was determined using TaqMan allelic discrimination technique. The population PK model was developed by NONMEM V7.4. The dosing regimen was optimized based on Monte Carlo simulations. RESULTS: A population PK model of apatinib in adult cancer patient was established. CYP3A5 genotype and systemic cancer type (digestive system cancers, nondigestive system cancers) were the most significant covariates for PK parameters. Patients with CYP3A5*1 expressers (CYP3A5*1/*1 and CYP3A5*1/*3) had lower apparent clearance and apparent volume of distribution than patients who do not express CYP3A5*1 (CYP3A5*3/*3). Patients with nondigestive system cancer had higher apparent volume of distribution and absorption rate constant than digestive system cancer. The results of dose simulation suggest that the apatinib dose in patients who do not express CYP3A5*1 should be 33.33-50.00% higher than that in CYP3A5*1 expressers. CONCLUSIONS: A population PK model of apatinib in adult cancer patients was established. CYP3A5 genotype and systemic cancer type had concurrent effects on PK parameters. CYP3A5 patients who do not express CYP3A5*1 required higher doses.

Pharmacokinetics and bioavailability of a new long-acting insulin analog in healthy Chinese volunteers: an open, randomized, single-dose, two-period and two-sequence cross-over study.

Objectives: INS068 is a novel, soluble, and long-acting insulin analog. In this study, we evaluated the pharmacokinetics and relative bioavailability of two formulations of INS068 in healthy Chinese subjects: a reference formulation packaged in vials and administered via syringe (R), and a test formulation packaged and administered via pen injector (T). Methods: A randomized, open-label, two-period, two-sequence crossover study was conducted with 24 healthy Chinese subjects. Subjects were randomized and administered subcutaneously in the abdomen at 0.4 U/kg of test or reference INS068 injection according to an open crossover design. INS068 concentrations in the serum were measured using LC-MS/MS, and the pharmacokinetic parameters of maximum concentration (Cmax) and area under the concentration-time curve (AUC0-t and AUC0-∞) were used to evaluate relative bioavailability. Results: After a single dose at 0.4 U/kg, the median Tmax of INS068 was 12 h for both formulations, and the mean t1/2 for T and R was 13.0 h and 12.6 h, respectively. The geometric means of Cmax and AUC0-∞ were 3.99 nmol/L and 120 h·nmol/L for the T, and 4.05 nmol/L and 117 h·nmol/L for the R, respectively. The geometric mean ratios of Cmax, AUC0-t and AUC0-∞ of T over R were 98.7% (90% CI: 92.7%-105.2%), 102.6% (90% CI: 100.0%-105.3%) and 102.8% (90% CI: 100.1%-105.5%). Conclusion: The overall PK profile of the two formulations of INS068 injection was comparable in healthy subjects, and the pen injector of INS068 had adequate safety and tolerability, supporting it as a new formulation in a phase III study and bridging PK data from early phase clinical trials. Clinical Trial Registration: clinicaltrials.gov, identifier: NCT05336071.

Preparation and characterization of a novel colorimetric indicator film based on gelatin/polyvinyl alcohol incorporating mulberry anthocyanin extracts for monitoring fish freshness.

This work aimed to develop a novel colorimetric indicator film for monitoring of food freshness based on gelatin/polyvinyl alcohol matrix incorporated with anthocyanin extracts from mulberry. The color of anthocyanin extracts solutions obviously changed from bright red to dark green in the pH range of 2.0-11.0. FTIR spectra and isothermal titration calorimetry showed that the anthocyanin extracts were successfully combined with gelatin/polyvinyl alcohol matrix by hydrogen binding and electrostatic interaction, which enhanced the stability of anthocyanin. The scanning electric microscopy showed that the compatibility between polyvinyl alcohol and gelatin were improved owing to the addition of anthocyanin extracts. With the anthocyanin extracts addition from 0 to 45 mg/100 mL mixed solution, the tensile strength decreased from 30.80 to 21.01 MPa and the elongation at break increased from 589.22% to 905.86%. The color response of film in buffer solution of different pH were in accordance with anthocyanin extracts solutions, and its color changes were clearly visible with naked eye. Finally, the film was evaluated by a test on monitoring fish spoilage, which presented visible color changes due to volatile nitrogenous compounds formed over time. These results showed that this developed film could be used as an effective method for the monitoring of food freshness.

Protective effects of Momordica grosvenori extract against lipid and protein oxidation-induced damage in dried minced pork slices.

The experiment was conducted to assess the protective effects of Momordica grosvenori extract (MGE) against lipid and protein oxidation-induced damage in vacuum-packed dried minced pork slices stored at room temperature for 21days. Antioxidant activity of MGE was evaluated by measuring its radical scavenging activities and reducing power with progressive concentrations from 40 to 200g/L. MGE was added to the dried minced pork slices at 7, 10 or 15g/100g. Results showed that inclusion of MGE in dried minced pork slice significantly delayed the formation of hexanal, thiobarbituric acid-reactive substances and carbonyls and reduced the sulfhydryl loss in a dose-dependent manner (P<0.05), indicating that MGE exerted a protective effect against lipids and protein oxidation. Concomitantly, an intense increase of redness and loss of lightness and yellowness was found to take place (P<0.05), though it exhibited little negative effects on the sensory properties of slices. Mogrosides, the main bioactive components in M. grosvenori, decreased primarily during processing while they were relatively stable during storage under vacuum condition, room temperature. All these results demonstrated MGE had great potential as a natural antioxidant used in meat products.

Mulberry anthocyanin biotransformation by intestinal probiotics.

This study was designed to evaluate mulberry anthocyanins bioconversion traits for intestinal probiotics. Five intestinal beneficial bacteria were incubated with mulberry anthocyanins under anaerobic conditions at 37°C, and bacterial ß-glucosidase activity and anthocyanin level were determined. Results demonstrated that all strains could convert mulberry anthocyanins to some extent. With high ß-glucosidase production capacity, Streptococcus thermophiles GIM 1.321 and Lactobacillus plantarum GIM 1.35 degraded mulberry anthocyanins by 46.17% and 43.62%, respectively. Mulberry anthocyanins were mainly biotransformed to chlorogenic acid, crypto-chlorogenic acid, caffeic acid, and ferulic acid during the anaerobic process. Non-enzymatic deglycosylation of anthocyanins also occurred and approximately 19.42% of the anthocyanins were degraded within 48h by this method.

A Novel Mesophilic Anaerobic Digestion System for Biogas Production and In Situ Methane Enrichment from Coconut Shell Pyroligneous.

A novel mesophilic anaerobic digestion process with detoxification-treated coconut shell pyroligneous was established, exhibiting an effective advantage in biogas production. The pyroligneous collected contained 166.2 g l(-1) acetic acid, indicating great potential for biogas production. Detoxification was an effective way of simultaneously enriching biodegradable ingredients and removing inhibitors (mainly as phenols and organic acids) for digestion process. The digestion process lasted 96 h and fermentation characteristics (chemical oxygen demand (COD) removal ratio, volatile fatty acid (VFA) consumptions, pH, total gas, methane yield, and phenol removal efficiency) were measured. The experiments successfully explored the optimum detoxification parameters, oxidized with 10 % H2O2 followed by overliming, and demonstrated 89.3 % COD removal, 91.4 % methane content, 0.305 LCH4/g COD removed CH4 yield, and 88.81 % phenol removal ratio. This study provided clues to overcome the negative effects of inhibitors in pyroligneous on biogas production. The findings could contribute to significant process in detoxified pretreatment of pyroligneous and develop an economically feasible technology for treating pyroligneous after producing charcoal.

[Analysis of tobacco site features using near-infrared spectroscopy and projection model].

In this paper, total of 5170 flue-cured tobacco samples collected from 2003 to 2012 in the domestic and foreign origin by Shanghai Tobacco Group Technical Center were tested by near infrared spectroscopy, including the typical upper leaves 1394, central 2550, the lower part of 1226. Using projection model of based on principal component and Fisher criterion (PPF), follow the projected results to get no statistically significant differences at adjacent principal components, and the number of principal components as little as possible, in this paper, four main components to build projection analysis model, the model results show that: the near-infrared spectral characteristics of the upper and lower leaves have a significant difference that can be achieved almost entirely distinguished; while the middle leaves with upper and lower have a certain degree of overlap, which is consistent to the actual situation of the continuity of tobacco leaf. At the same time, Euclidean distance between the predicted sample projection values and the mean projection values of each class in the model, a description is given for the prediction samples to quantify the extent of the site features, and its first and second close categories. Using the dispersion of projected values in model and the given threshold value, prediction results can be refined into typically upper, upper to central, central to upper, typical central, central to the lower, the lower to central, typically the lower, or super-model range. The model was validated by 34 tobacco samples obtained from the re-drying process in 2012 with different origins and parts. This kind of analysis methods, not only can achieve discriminant analysis, and get richer feature attribute information, can provide guidance on the raw tobacco processing and formulations.

[Discrimination of different aging methods of grape wine based on ATR infrared spectroscopy].

A total of 96 red wines aged with 3 kinds of methods were included in this study, including 44 wines aged in oak barrel, 26 wines aged in stainless steel tank added with oak chips and 26 wines aged in stainless steel tanks. The infrared spectra of the wines were scanned by Fourier transform infrared spectrometer with attenuated total reflection (ATR) accessories. To classify the 96 different aged wines, discriminant partial least squares (DPLS) method and support vector machine (SVM) method were used to establish models respectively. In order to examine the stability of the discriminant model, modeling was repeated 10 times with two-thirds of samples randomly selected as cross-validation. All the models had high discriminating power with the classification accuracy of the cross-validation and the validation all higher than 90%. These results suggest that the infrared ATR spectroscopy combined with pattern recognition method is a promising tool for discriminating different aging wines.

[Research on characteristic of tobaccos from different ecological environments base on near infrared spectroscopy].

Four hundred ninety five samples from 3 parts of tobacco were collected from 11 different ecological environments in 2010 to analyze the characteristics of tobaccos in different ecological environments with near infrared spectroscopy. The results indicate that the differences are remarkable both between lower and upper parts and between lower and middle parts of tobacco, while negligible between upper and middle parts of tobacco under the same ecological environment. Good stability and consistency were showed by the similarity of characteristics of tobaccos under different ecological environments, and the projection correlation coefficient of analysis set and validation set is over 98%. This article also proposes a method of measuring the similarity between characteristics of tobaccos from different ecological environments. The results can provide reference data to quantify tobacco's planting programming, production processing and quality management.

[Tobacco plant parts similarity analysis based on near-infrared spectroscopy and SIMCA algorithm].

The appearance features of tobacco reflect its inner quality. Many factors, such as different plant parts, variety and maturity, provide standard and foundation for tobacco production processing. According to the different position of tobacco plant parts, tobacco plants leaves can be divided into five parts as tip, upper-middle, middle, lower-middle and priming leaf respectively. Five hundred tobacco leaf samples (100 each for one of five tobacco plant parts) from Yunnan province in 2008 were collected using near infrared spectroscopy, which all belong to tobacco varieties of K326. The similarity analysis of tobacco plant parts was carried out using mathematical model of SIMCA similarity analysis. The conclusion showed that the tobacco plant parts similarity results based on near-infrared spectroscopy corresponded to the relative tobacco plant parts in Yunnan province. The farther two tobacco plant parts were away from each other, the lower the similarity of corresponding parts was. And the similarity results of adjacent tobacco plant parts were different. The study discussed a method of confirming PC numbers and realized the quantitative similarity analysis between classes. It is instructive in replacement or adjustment of tobacco leaf blending and evaluation of tobacco industrial grading.

[The application of near-infrared diffuse reflection spectra based on the principle of linear additive in tobacco redrying formula].

In the process of analyzing and designing tobacco redrying formula using near infrared spectroscopy, a great deal of spectra for different ratio mixed samples are badly needed. However these sample spectra are very hard to obtain in the actual production process. Furthermore, for the samples of different grades it is difficult to achieve the goal of even mixing, in consequence of introducing inevitable errors. In order to solve the above problems, the present paper proposes to use "theory of even mixed spectrum" produced by linear additive near infrared spectroscopy in place of the spectra of actual mixed samples. This way can not only eliminate the errors caused by uneven mixture, but also leave out the course of mixing samples and measuring spectra and save time, effort, and material simultaneously. This article analyzes the comparison between linear additive spectra and the spectra of actual mixed samples from the following four aspects: original spectra, derivative spectra, principal components, and the data of PPF projection, accordingly verifing the feasibility and superiority of the linear additive spectra.

Formation of amyloid fibrils from kidney bean 7S globulin (Phaseolin) at pH 2.0.

The amyloid fibrils formed by heating 1.0% (w/v) kidney bean phaseolin (7S globulin) solution at pH 2.0 with an ionic strength of 20 mM at 85 degrees C were characterized using transmission electron microscopy (TEM), atomic force microscopy (AFM), binding of thioflavin T (Th T) and Congo Red dyes, and circular dichroism spectroscopy. The morphology of the formed fibrils was closely dependent upon heating time from 15 to 720 min. The diameters of the fibrils formed at various times were similar, but the mean contour length progressively increased with heating time. The Th T maximum fluorescence also progressively increased with heating time. The heating process caused remarkable changes in secondary, tertiary, and quaternary conformations of the phaseolin, but the extents of the changes were closely related to the heating time. With a short heating time (e.g., 15 min), the beta-strand content decreased from 38.7 to 22.9%, but further heating resulted in recovery of beta-strand structure. The tertiary and quaternary conformations gradually became flexible and unfolded upon heating. Gel electrophoresis analysis indicated that heating disrupted the polypeptides of phaseolin, leading to the formation of fragments with lower molecular mass (e.g., <10 kDa after 360 min). The results suggest that the amyloid fibril formation of phaseolin (7S globulin) involved the disruption of its polypeptides, as well as conformational changes at secondary, tertiary, and quaternary structural levels. This appears to be the first direct observation of amyloid fibrils from legume 7S storage globulin.

[Research on calibration transfer of NIR filter spectrophotometer].

Calibration transfer is an important issue to building up universal and comparable performance of spectrometer data in near infrared spectral analysis technology. Methods of slope/bias correction, direct standardization (DS), and target factor analysis (TFA) were used for the calibration transfer among five NIR filter spectrophotometers using maize as the samples. The effects of three calibration transfer methods were compared. The DS method has the best performance. The average calibration transfer difference of DS is 7.01%. This study also relates to the dependence of calibration transfer on the number of standardization samples. It was proven by experiment that the results of calibration transfer will be better as the number of samples is increased and will be generally stable when there are twenty standardization samples. However, the effect of calibration transfer attained by DS is degraded sharply when the number of standardization samples decreases to be below twenty. Moreover, slope/bias and TFA are not sensitive to the number of standardization samples.

[NIR spectrometer for non-destruction measurement of oil contents in a corn seed].

NIR spectromneter for non-destruction measurement of oil contents in an integrated kernel of corn was manufactured. Using LED (light emitting diode) as the light source and six filters as the monochromator, the specifications of the instrument are compared with those of the commercial instruments. The regression coefficient, the standard error, and the relative error of measuring oil contents in an integrated kernel of corn are 0.9688, 0.72 and 0.062 respectively. The results meet the demand of high-oil corn breeding.