The efficacy of the leg swing and quadriceps strengthening exercises versus platelet-rich plasma and hyaluronic acid combination therapy for knee osteoarthritis: A retrospective comparative study.

The aim of this was to investigate the efficacy of physical exercise (leg swing and quadriceps strengthening exercises) versus platelet-rich plasma (PRP) and hyaluronic acid (HA) combination therapy. From January 2020 to August 2021, 106 patients with Kellgren-Lawrence Grade I-III knee osteoarthritis were divided into leg swing and quadriceps strengthening exercises (Group A) and intra-articular combination injections of PRP and HA (Group B) according to the treatment strategies. Patients in Group A received regular leg swing and quadriceps strengthening exercises for 3 months. Patients in Group B received 2 intra-articular combination injections of PRP (2 mL) and HA (2 mL) every 2 weeks. The primary outcome measures were the Visual Analogue Scale (VAS) and the Western Ontario and McMaster Universities (WOMAC) score. Secondary outcomes included single leg stance test and functional activity by 2-minute walk test and time up and go test. All outcomes were evaluated at baseline and again 1, 3, 6, and 12 months. The VAS and WOMAC scores were similar in both groups at 1 and 3 months after treatment (P > .05); however, Group A patients had significantly superior VAS and WOMAC scores than Group B patients at 6 and 12 months after treatment. For the single leg stance test, 2-minute walk test, and time up and go test, Group A patients were significantly superior to Group B throughout follow-up (P < .001). The leg swing and quadriceps strengthening exercises resulted in a significantly better clinical outcomes than the combined PRP and HA therapy, with a sustained lower pain score and improved quality of life, balance ability, and functional activity within 12 months.

Optimized approach for active peptides identification in Cerebrolysin by nanoLC-MS.

Cerebrolysin (CBL) is a peptide-rich preparation made by hydrolysis and purified extraction of porcine brain. CBL contains various neuroprotective peptides, such as neurotrophic factor, nerve growth factor and ciliary neurotrophic factor, which can be used to treat neurodegenerative diseases. However, the active peptides in CBL had not been studied in depth. In this study, the following was carried out in order to investigate the active peptides in CBL. First, CBL samples were treated using organic reagents (acetonitrile and acetone) to precipitate the proteins and different solid phase extraction methods (MCX mixed-mode cartridges, C18 SPE cartridge columns and HILIC sorbent). Then the samples were analyzed using nanoLC-MS, followed by the identification of peptides using different sequence analysis software (PEAKS, pNovo and novor). Finally, bioinformatics analysis was performed to predict peptides with potential neuroprotective functions in CBL, such as anti-inflammatory and antioxidant peptides. Results showed that the number of peptides obtained by the MCX method coupled with PEAKS was the highest and the method was the most stable. Bioinformatic analysis of the detected peptides showed that two anti-inflammatory peptides (LLNLQPPPR and LSPSLRLP) and an antioxidant peptide (WPFPR) might be neuroprotective peptides in CBL. In addition, this study found that some peptides in CBL were present in myelin basic protein and tubulin beta chain. The results of this study for the detection of active peptides in CBL laid the foundation for the subsequent study of its active ingredients.

Influence of thermal processing on the quality of hawthorn: Quality markers of heat-processed hawthorn.

Hawthorn and its derived products are used worldwide as foods as well as complementary medicine. During the preparation of hawthorn, heating and thermal processing are frequently reported. The thermal processing will change the medicinal purposes and modify the efficacy of hawthorn. However, details including the chemical profile shifting and quality markers of heat-processed hawthorn have not been well understood. In this study, we analyzed the hawthorn samples processed at different temperatures and different times by ultraviolet visible absorption spectrum and liquid-mass spectrometry technologies combined with multivariate statistical analysis. It was revealed for the first time that thermal processing could greatly change the ultraviolet-visible absorption spectra and chemical profiles of hawthorn even with heat treatment at 130°C for 10 min. And the ultraviolet visible absorption spectrum, especially the ratio value (RA500 nm/400 nm ), was a descriptive and qualitative indicator of heating degree for the thermal processing at the macroscopic level. Several components, such as hyperoside, chlorogenic acid, quercetin, and apigenin, decreased or increased in content during the processing, and they could be utilized as the chemical quality markers. The proposed quality markers for heat-processed hawthorn will be helpful for further optimizing the processing conditions of hawthorn.

Elucidating a Complicated Enantioselective Metabolic Profile: A Study From Rats to Humans Using Optically Pure Doxazosin.

Doxazosin (DOX) is prescribed as a racemic drug for the clinical treatment of benign prostatic hyperplasia and hypertension. Recent studies found that the two enantiomers of DOX exhibit differences in blood concentration and pharmacological effects. However, the stereoselective metabolic characteristics and mechanisms for DOX are not yet clear. Herein, we identified 34 metabolites of DOX in rats based on our comprehensive and effective strategy. The relationship among the metabolites and the most discriminative metabolites between (-)-DOX and (+)-DOX administration was analyzed according to the kinetic parameters using state-of-the-art multivariate statistical methods. To elucidate the enantioselective metabolic profile in vivo and in vitro, we carefully investigated the metabolic characteristics of metabolites after optically pure isomers administration in rat plasma, rat liver microsomes (RLMs) or human liver microsomes (HLMs), and recombinant human cytochrome P450 (CYP) enzymes. As a result, the differences of these metabolites were found based on their exposure and elimination rate, and the metabolic profile of (±)-DOX was more similar to that of (+)-DOX. Though the metabolites identified in RLMs and HLMs were the same, the metabolic profiles of the metabolites from (-)-DOX and (+)-DOX were greatly different. Furthermore, four human CYP enzymes could catalyze DOX to produce metabolites, but their preferences seemed different. For example, CYP3A4 highly specifically and selectively catalyzed the formation of the specific metabolite (M22) from (-)-DOX. In conclusion, we established a comprehensive metabolic system using pure optical isomers from in vivo to in vitro, and the complicated enantioselectivity of the metabolites of DOX was clearly shown. More importantly, the comprehensive metabolic system is also suitable to investigate other chiral drugs.

The efficacy and safety of roxadustat treatment for anemia in patients with kidney disease: a meta-analysis and systematic review.

BACKGROUND: Anemia is a common complication for patients with kidney disease. Roxadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (PHI), which is a newly approved oral drug for anemia. We performed this study to build evidence regarding efficacy and safety of roxadustat in kidney disease patients with or without dialysis. METHODS: We searched the databases of PubMed, Embase, Cochrane library and clinicaltrials.gov from the inception to July 20, 2020. The randomized controlled trials (RCTs) which compared roxadustat with placebo or other therapies in the treatment of anemia in kidney disease patients were included. Data were extracted from eligible studies and pooled in a meta-analysis model using RevMan5.3 and stata13.0 software. RESULTS: Eight RCTs with 1010 patients were included in our analysis. We found that roxadustat significantly increased hemoglobin (Hb) level (1.10 g/dL, 95% CI [0.52 g/dL, 1.67 g/dL], p = 0.0002), total iron-binding capacity (TIBC) (58.71 µg/dL, 95% CI [44.10 µg/dL, 73.32 µg/dL], p < 0.00001), iron level (9.28 µg/dL, 95% CI [0.11 µg/dL, 18.45 µg/dL], p = 0.05) compared with control group in kidney disease patients. In addition, our result showed that a significant reduction in hepcidin level (- 31.96 ng/mL, 95% CI [- 35.05 ng/mL, - 28.87 ng/mL], p < 0.00001), ferritin (- 44.82 ng/mL, 95% CI [- 64.42 ng/mL, - 25.23 ng/mL], p < 0.00001) was associated with roxadustat. No difference was found between roxadustat and control group in terms of oral iron supplementation, adverse events (AEs), serious adverse events (SAEs), infection, myocardial infraction, stroke, heart failure and death. CONCLUSIONS: Roxadustat has higher mean Hb level than placebo or EPO. Due to the short follow-up period and the lack of critical data, more RCTs are needed to prove long-term safety and effectiveness of roxadustat in the future.

The efficacy of panitumumab in refractory metastatic colorectal cancer: A meta-analysis.

PURPOSE: Panitumumab, an anti-epithelial growth factor receptor (EGFR) antibody, has been known to be effective treatments for wild-type KRAS metastatic colorectal cancer (mCRC). However, the efficacy of panitumumab for refractory mCRC remains controversial. Thus, we performed this meta-analysis to clarify and evaluate the effectiveness of panitumumab in patients with refractory mCRC. METHODS: PubMed, Cochrane and Embase were searched up to October 2018 using appropriate key words. Only randomized controlled trials (RCTs) were included in the qualified studies. Odds ratio (OR) along with 95% confidence interval (95% CI) were utilized for main outcome analysis. RESULTS: A total of 7 RCTs were included in this analysis. Overall survival (OS, OR=1.01, 95% CI 0.81-1.27; p=0.90) and progression free survival (PFS, OR =0.78, 95% CI 0.62-1.00; p=0.05) were not significantly different in mCRC patients pretreated with panitumumab, but the pooled OR for overall response rate (ORR) was 3.71 (95% CI 1.34-10.31;p=0.01), indicating that panitumumab improved the ORR. Moreover, subgroup analysis showed that patients treated with panitumumab plus irinotecan-based chemotherapy did not achieve any benefit in PFS (OR=0.91, 95% CI 0.68-1.22; p=0.53) or OS (OR=0.93, 95% CI 0.79-1.09; p=0.36) than controls. The results also indicated that the combination chemotherapy with either panitumumab or cetuximab was comparable in efficacy in terms of PFS (OR=0.80, 95% CI 0.62-1.04; p=0.10) and OS (OR=1.28, 95% CI 0.72-2.27, p=0.40). CONCLUSIONS: The current analysis indicates that panitumumab was not associated with survival benefit but ORR was improved among pre-treated mCRC patients. Future investigations are needed to identify relevant biomarkers in selected patients that would most likely benefit from panitumumab therapy for refractory mCRC.

LC-MS/MS determination and pharmacokinetic study of five flavone components after solvent extraction/acid hydrolysis in rat plasma after oral administration of Verbena officinalis L. extract.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine (TCM) has been used in clinical practice for several thousand years. TCM has played an indispensable role in the prevention and treatment of diseases, especially the complicated and chronic ones. Pharmacokinetic study on active constituents in herbal preparations is a good way for us to explain and predict a variety of events related to the efficacy and toxicity of TCM. AIM OF THE STUDY: A selective and sensitive HPLC-MS/MS method was first developed and validated for the determination of luteolin, kaempferol, apigenin, quercetol, and isorhamnetin in rat plasma. MATERIALS AND METHODS: The LC system consisted of an Agilent Technologies Series 1200 system (Agilent, USA) equipped with an automatic degasser, a quaternary pump, and an autosampler. Chromatographic separations were performed on a Waters SunFire™ C(18) column (150 mm × 4.6mm, 5 µm), and the column temperature was maintained at 25°C and the sample injection volume was 20 µL. The current LC-MS/MS assay was validated for linearity, intra-day and inter-day precisions, accuracy, extraction recovery and stability. RESULTS: The validated method was successfully applied to monitoring the concentrations and pharmacokinetic studies of five flavone compounds in rat plasma after a single oral administration of Verbena officinalis L. extract with a dosage of 8.0 mL/kg. The time to reach the maximum plasma concentration (T(max1)) was 0.48 ± 2.14 h for luteolin, 0.25 ± 0.13 h for kaempferol, 0.97 ± 1.08 h for apigenin, 1.04 ± 4.25 h for quercetol and 0.25 ± 0.16 h for isorhamnetin, and the maximum plasma concentration (T(max2)) was 3.97 ± 1.48 h, 4.05 ± 0.46 h, 4.33 ± 0.58 h, 2.99 ± 0.48 h and 4.02 ± 0.34 h. The elimination half-time (t(1/2)) of luteolin, kaempferol, apigenin, quercetol and isorhamnetin was 4.02 ± 0.81, 7.65 ± 0.71, 3.30 ± 0.83, 4.55 ± 0.49 and 5.56 ± 1.32 h, respectively. CONCLUSIONS: This paper described a simple, sensitive and validated LC-MS/MS method for simultaneous determination of luteolin, kaempferol, apigenin, quercetol and isorhamnetin in rat plasma after oral administration of V. officinalis L. extract, and investigated on their pharmacokinetic studies as well, with a short run time of 5 min.

Pharmacokinetic properties of paeoniflorin, albiflorin and oxypaeoniflorin after oral gavage of extracts of Radix Paeoniae Rubra and Radix Paeoniae Alba in rats.

AIM OF THE STUDY: To establish a HPLC-MS method and investigate the pharmacokinetic properties of paeoniflorin, albiflorin and oxypaeoniflorin and the pharmacokinetics difference of Radix Paeoniae Rubra and Radix Paeoniae Alba. MATERIALS AND METHODS: The extracts of Radix Paeoniae Rubra and Radix Paeoniae Alba were separately administrated to rats. The concentrations of paeoniflorin, albiflorin and oxypaeoniflorin in rat plasma were determined by HPLC-ESI-MS method. The plasma samples were pretreated by protein precipitation with methanol and chromatographic separation was performed on a C(18) column with a mobile phase consisted of 0.1% formic acid and methanol (67:33, v/v). The detection was accomplished by multiple-reaction monitoring (MRM) scanning via electrospray ionization (ESI) source operating in the negative ionization mode. Main pharmacokinetic parameters were estimated and the total AUC of the three components were compared. RESULTS: The pharmacokinetic parameters of paeoniflorin, albiflorin and oxypaeoniflorin were significantly different. There was significant difference between the pharmacokinetic characteristics of Radix Paeoniae Rubra and Radix Paeoniae Alba. CONCLUSIONS: A specific and sensitive HPLC-ESI-MS method was developed for simultaneous determination of paeoniflorin, albiflorin and oxypaeoniflorin in rat plasma and was successfully applied to pharmacokinetic study. The results might be helpful for the investigation of different effects of Radix Paeoniae Rubra and Radix Paeoniae Alba.

Capillary electrophoretic enantioseparation of m-nisoldipine using two different beta-cyclodextrins.

The methods for the enantioseparation of m-nisoldipine, a new 1,4-dihydropyridine calcium ion antagonist, were developed. The elaborated methods of m-nisoldipine enantiomers separation were successfully performed using an anionic CD-sulfobutyl ether-beta-CD (SBE-beta-CD) or carboxymethyl-beta-CD as chiral selector. However, the results indicated that SBE-beta-CD was a better chiral selector for enantioseparation of the neutral m-nisoldipine. Furthermore, comparing the two SBE-beta-CDs, the derivative with a higher degree of substitution (DS) of 7.0 induced better enantioresolution than the one with low DS (4.0). In addition, possible chiral recognition mechanisms of dihydropyridines were discussed.

Tissues distribution of R-(-)- and S-(+)-m-nisoldipine after single enantiomer administration in rats.

Rapid, sensitive, and selective high-performance liquid chromatography methods were developed and validated for determination of m-nisoldipine enantiomers in rat tissues. All of the samples were prepared based on a simple and efficient liquid-liquid extraction method. After validating that no racemation occurred by ULTRON ES-OVM (Japan), m-nisoldipine enantiomers were determined, respectively, on a reverse-phase C(18) column (5 microm, 250 x 4.6 mm). This method was applied to study tissue distribution of m-nisoldipine enantiomers in rats after a single administration of m-nisoldipine enantiomers. By the two-sample t test, there were basically no significant differences between the two enantiomers in each tissue ( p > .05), which indicates that they may have the same potency in rats. In small intestine, lung, liver, and spleen, the concentrations of R-(-)- and S-(+)-m-nisoldipine were high at 30 and 150 min than that at 90 min, which showed that m-nisoldipine enantiomers may have the phenomenon of hepatoenteral circulation. A small quantity of the prototype of R-(-)- and S-(+)-m-nisoldipine in brain showed that they can cross the blood-brain barrier to arrive at the brain tissue. The high quantity of distribution in lung and brain implied that the lipophilicity of the drug was powerful.

Pharmacokinetics and tissue distribution study of orientin in rat by liquid chromatography.

A simple HPLC-UV method was established for the determination of orientin in plasma and different tissues of rat (heart, liver, spleen, lung, kidney, brain, stomach and small intestine). The separation was achieved by HPLC on a C(18) column with a mobile phase composed of acetonitrile-0.1% acetic acid (20:80, v/v), UV detection was used at 348 nm. Good linearity was found between 0.250-50.0 microg/ml (r(2) = 0.9966) for plasma samples and 0.050-50.0 microg/ml (r(2)> or =0.9937) for the tissue samples, respectively. Within- and between-day precisions expressed as the relative standard deviation (R.S.D.) for the method were 2.3-9.6% and 3.0-7.4%, respectively. The relative recoveries of orientin ranged from 95.4 to 100.6% for plasma and 93.1 to 107.9% for tissue homogenates. The developed method was successfully applied to the pharmacokinetics and tissue distribution research after intravenous administration of a 20 mg/kg dose of orientin to healthy Sprague-Dawley rats. The main pharmacokinetics parameters obtained presented that orientin was quickly distributed and eliminated within 90 min after intravenous administration. The tissue distribution results showed that liver, lung and kidney were the major distribution tissues of orientin in rats, and that orientin had difficulty in crossing the blood-brain barrier. It was also found that there was no long-term accumulation of orientin in rat tissues.