Search

Objectives: Janus kinase (JAK) inhibitors are a new class of medication for treatment of rheumatoid arthritis (RA), and such inhibitors alter levels of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) in RA patients. However, the extent of such changes has not been systematically reviewed., Method: A systematic review and network meta-analysis was performed on randomized trials in RA patients in response to JAKi identified from Pubmed, Medline, Embase, and Cochrane Controlled Trials Register. The primary outcome was mean change of HDL-C and LDL-C from baseline. Mean treatment differences and the rank of the effect of various JAKi on HDL-C and LDL-C were estimated., Results: Based on data from 18 unique studies involving five approved JAK inhibitors and 6697 RA patients (JAKi = 3341, placebo = 3356), such inhibitors led to a mean increase of 8.11 mg/dl (95% CI 6.65-9.58, I 2  = 82%) in HDL levels from baseline, and a mean increase of 11.37 mg/dl (95% CI 7.84-14.91, I 2  = 88%) in LDL levels from baseline. Cardiovascular disease risk did not differ significantly between patients who received JAK inhibitors or those who received placebo or active agents., Conclusions: Our analysis suggests that, at their recommended doses, all five JAK inhibitors lead to an increase in HDL and LDL levels in RA patients. Further long-term research is required to extend these results and understand whether changes in lipid levels in RA patients can affect cardiovascular risk. Key Points • This is the first systematic review and NMA examining the effect of all five clinically approved JAK inhibitors on lipid levels in RA patients. • Recommended doses of JAK inhibitors used for the treatment of RA patients can induce a significant increase in HDL and LDL levels. • Indirect pairwise comparisons suggest that only upadacitinib and peficitinib have significantly different ability to induce LDL change in RA patients., (© 2021. International League of Associations for Rheumatology (ILAR).)

Context: Capsule of alkaloids from the leaf of Alstonia scholaris (L.) R.Br. (Apocynaceae) (CALAS) is a new investigational botanical drug (No. 2011L01436) for bronchitis, post-infectious cough and asthma., Objective: To observe the clinical safety and tolerability of CALAS., Materials and Methods: Subjects were assigned to eight cohorts, and each received randomly CALAS or placebo in one of single ascending dose (SAD) of 8, 40, 120, 240, 360, 480, or in one of multiple ascending dose (MAD) of 40 or 120 mg, three times daily for 7 days. Each cohort contained two placebo subjects., Results: Sixty-two enrolled volunteers completed the study and no serious adverse events and clinically significant changes in vital signs, electrocardiography, and upper abdominal Doppler ultrasonography were observed. The ratios of treatment-emergent adverse events (TEAEs) were reported in 11/46 (23.91%) of CALAS groups and 3/16 (18.75%) of the placebo group ( p  > 0.05), respectively, based on the results of SAD and MAD. All TEAEs were mild, transient, and disappeared without any intervention. The TEAEs possibly related to CALAS treatment were as followings: hiccups (4/46: 8%), dry mouth and nausea (3/46: 6%), increased sleep (2/46: 4%), abdominal distension (1/46: 2%), bilirubin elevated (1/46: 2%)., Discussion and Conclusions: CALAS is safe and well-tolerated with no unexpected or clinically relevant safety concerns up to a single dose of 360 mg and three times daily for 7 days up to 120 mg in healthy Chinese volunteers, supporting further Phase II studies.

Alstonia scholaris could be used as a traditional medicinal plant in China for the treatment of acute respiratory, which might be caused by respiratory tract infections. The investigation tested the anti-infective effects of total alkaloids extract (TA) from leaves of A. scholaris, and as a result, TA inhibited herpes simplex virus type 1 (HSV-1), respiratory syncytial virus (RSV) and influenza A virus (H1N1) in vitro respectively. In addition, the survival days of mice were prolonged, and the lung weights and mortality of mice were decreased significantly, after oral administrated TA in H1N1 and beta-hemolytic streptococcus infectious models in vivo respectively. The finding supported partly the traditional usage of A. scholaris in the treatment of respiratory infections.

Background: This study aims to assess the tolerability and safety of DQTM tablet, which contains a complex mixture of Salvia miltiorrhiza salvianolic acids and Panax notoginseng saponins., Methods: A double-blind, randomized, placebo-controlled phase I dose escalation study was conducted in 84 healthy volunteers. In a single ascending dose study, active ingredients were administered in various doses (90, 270, 540, 1080, 1800, 2880, 4320 or 5760 mg) to 60 subjects in cohorts 1-8. In a multiple ascending dose study, active ingredients were administered at doses of 360, 720 or 2160 mg twice daily to 24 subjects in cohorts 9-11 for 14 consecutive days. Safety was evaluated based on clinical symptoms, vital signs, physical examinations, electrocardiography, laboratory tests and adverse events., Results: No serious adverse events or clinically significant changes in vital signs or electrocardiography were observed. One subject experienced mildly elevated levels of alanine aminotransferase and aspartate transaminase but recovered spontaneously. Five subjects experienced a small increase in the number of daily stools., Conclusions: DQTM tablet was well tolerated at single doses of up to 5760 mg and twice-daily doses of up to 2160 mg for 14 consecutive days. The most frequent adverse event was an increase in the number of daily stools.

Background: Yogliptin is a novel xanthine dipeptidyl peptidase-4 (DPP-4) inhibitor targeting type 2 diabetes. After promising preclinical pharmacological studies, the first human trial of yogliptin was designed., Methods: A randomized, double-blind, parallel, placebo-controlled phase I single-dose escalation study was designed to evaluate the pharmacokinetics, pharmacodynamics, and tolerability after single oral doses of yogliptin in healthy Chinese subjects. Healthy subjects were assigned to nine cohorts, which received a single dose of yogliptin at 2.5, 5, 10, 25, 50, 100, 200, 400, or 600 mg. Two subjects in each cohort received placebo. Blood samples were collected before dosing and up to 192 h afterwards. Urine samples were collected until 120 h after dosing. Plasma and urine drug concentrations were determined using liquid chromatography coupled with tandem mass spectrometry, and DPP-4 activity was measured using a semi-quantitative, fluorescence-based kinetic assay., Results: A total of 104 subjects were enrolled, 103 of whom completed the study (mean age, 25.3 years; mean weight, 58.8 kg; mean BMI, 21.8 kg/m 2 ). A total of 27 adverse events (AEs) occurred in 25 of 86 yogliptin subjects (29.1%), and 3 AEs occurred in 3 of 18 placebo subjects (16.7%). Yogliptin was absorbed with a median time of maximum observed concentration (T max ) of 3.0 h and was eliminated slowly with a t 1/2 of 25.45-43.84 h. The maximum observed concentration (C max ) and area under the curve (AUC) varied slightly more than dose-proportionally over the dose range from 2.5 to 400 mg. The fraction of drug excreted in urine ranged from 8.39% to 24.77%. Mean DPP-4 inhibition at 24 h after dosing ranged from 97.7% to 99.5%, and DPP-4 inhibition was >80% for 72 h at doses from 25 to 400 mg. DPP-4 inhibition was >80% for 1 week in the group receiving 400 mg., Conclusion: Yogliptin was well tolerated in healthy subjects, with no dose-limiting toxicity observed in the range from 2.5 to 600 mg. Yogliptin inhibited plasma DPP-4 activity for 72 h at single doses of 25-200 mg and for 1 week at 400 mg, suggesting that once-weekly dosing of yogliptin is possible in type 2 diabetes patients., Trial Registration: ChiCTR-IIR-17010311 (Chictr.org)., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Alstonia scholaris (Apocynaceae) was reported to be a rich source of indole alkaloids, which exhibited remarkably bioactivities. The leaf of A. scholaris has been used in 'dai' ethno-medicine for treatment of respiratory diseases, and the defined indole alkaloids from leaf of A. scholaris has been registered as investigational new botanical drug (No. 2011L01436) and was approved for phase I/II clinical trials by China Food and Drug Administration (CFDA)., Purpose: The aim of the trial is to evaluate the safety and explore the relationship of dosing frequency and pharmacokinetics after oral administration of capsule of alkaloids from leaf of A. scholaris (CALAS) at different doses., Methods: In this randomized, open-labelled, single-center clinical trial, the safety and pharmacokinetics of CALAS were assessed in eligible healthy Chinese volunteers after oral administration of different doses. Each volunteer (n = 10 per group) received single dose of CALAS from 20 mg, 40 mg, 80 mg to 120 mg orally. The pharmacokinetics of CALAS was investigated in healthy Chinese subjects' plasma by a fully-validated LC-MS/MS method. Safety was assessed biochemically and clinically throughout the study, and drug re-excitation research was conducted to verify the correlation between investigational product and minor adverse events. The trial was registered on August 26, 2015 (http://www.chictr.org.cn/showproj.aspx?proj=11736), number ChiCTR-IPR-15006976., Results: 40 subjects completed the study, and as a result, vallesamine had the highest concentration in plasma of healthy volunteers, and the AUC exposure level in each compounds in turn is vallesamine > scholaricine > 19-epischolaricine > picrinine. For the safety evaluation of CALAS, two cases of minor adverse events were observed during the trial, but the drug re-excitation research indicated that these two adverse events were related to the individual's physiological variation., Conclusion: Pharmacokinetic characteristics of each ingredient showed different patterns. 19-epischolaricine, vallesamine and picrinine were match to the linear pharmacokinetic characteristics, but scholaricine conformed to the characteristics of nonlinear pharmacokinetics. The CALAS was safe in healthy subjects under the current dose regimen., (Copyright © 2019. Published by Elsevier GmbH.)

Background: Targeted neutrophil inhibitory-hirulog (TNHH) is a novel hybrid glycoprotein that may be a potential drug candidate for acute ischaemic stroke., Objective: The aim of this study was to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of TNHH in healthy volunteers and thereby determine the dose range for future clinical studies., Methods: This randomized, placebo-controlled study was a single ascending dose design with dose levels of 0.05-1.8 mg/kg (n = 4-6 active, 2 placebos per cohort) in 68 participants. In the TNHH 0.2-1.8 mg/kg and control cohorts, pharmacokinetic and pharmacodynamic blood samples were collected over 168 h after intravenous (IV) administration. TNHH occupancy in peripheral blood neutrophils and blood coagulation were evaluated as the markers of target engagement., Results: Two subjects withdrew from the trial before administration of the study treatment, 66 subjects are included in the data analysis. TNHH was well tolerated in all dose regimens. In total, five mild, self-limiting adverse events (AEs) were observed in 4 of the 66 study subjects. Dose-proportional increases in maximum plasma concentration (C max ) and area under the curve (AUC 0-t ) of TNHH were observed. Traces of TNHH were excreted in urine. The elimination half-life (t ½ ) ranged from 0.6 to 1.3 h in the eight groups with ascending dose levels. TNHH combined with CD11b/CD18 quickly achieved > 90% receptor occupancy in groups with doses above 0.2 mg/kg. The C max and AUC of binding TNHH with CD11b/CD18 increased with the dose. A significant prolongation with dose was observed on thrombin time (TT), and weak influences were observed on prothrombin time (PT) and activated partial thromboplastin time (APTT)., Conclusion: TNHH was well-tolerated following IV infusion. The pharmacokinetic and pharmacodynamic characteristics of TNHH indicate that it merits clinical trials. It is recommended that the single dose of TNHH should be 1.0 mg/kg in future studies, and the expected effect may be achieved after 5-7 days of continuous administration., Trial Registration: The study is registered at http://www.chictr.org.cn as ChiCTR-TQR-14004752.

Background: Moguisteine is a non-narcotic peripheral antitussive drug that has been effective and well-tolerated in clinical studies. The aim of the present work was to investigate the pharmacokinetics of moguisteine given as single or multiple doses to healthy Chinese subjects., Methods: In Stages 1-3 of this study, 12 healthy Chinese subjects (6 males and 6 females) participated in a randomized, open-label, single-dose, 3-period, 3-way crossover study, with a 24-h washout period between each treatment. Eligible subjects were randomized to receive a single dose of 100, 200 or 400 mg moguisteine. Blood was sampled before and up to 10 h after administration. In those receiving 200 mg moguisteine, urine was sampled at intervals of 0-2, 2-4, 4-6, 6-10, and 10-24 h. In Stage 4, subjects received a moguisteine tablet containing 200 mg three times daily for five consecutive days. Blood was sampled for up to 10 h after the last dose. HPLC-tandem mass spectrometry was used to determine concentrations of the moguisteine metabolite M1 in serum, while HPLC-UV was used to determine concentrations of M1 in urine. Safety of the dosing schedules was assessed based on physical examination, recording of adverse events, 12-lead electrocardiography, and laboratory tests., Results: All subjects completed all four stages of the study. M1 was detectable at the shortest time points after moguisteine administration; the time to achieve peak concentration was 0.5-1.0 h in single dosing and 1.5 h in multiple dosing. Elimination half-life (t 1/2 ) was 0.91-1.54 h in single dosing and 1.57 h in multiple dosing. AUC increased roughly proportionally with dose, while C max increased much more gradually with dose. During 5-day dosing of three tablets per day, a steady state concentration was reached on day 3, and the mean accumulation ratio was 0.87. At 24 h after a single dose of 200 mg moguisteine, approximately 34.0% of the resulting M1 was recovered in urine. Pharmacokinetics of moguisteine did not differ significantly between men and women, except among those receiving a single dose of 100 mg (P < 0.05). Mild adverse events (nausea, loose stool, abdominal distention, or dizziness) occurred in six subjects and resolved without treatment, while no serious adverse events were observed., Conclusion: Moguisteine was safe and well-tolerated by our healthy subjects, and it exhibited dose linearity but not proportionality when a single dose of 100-400 mg was given. M1 did not accumulate in subjects after multiple doses of moguisteine., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The aim of this study is to evaluate the ability of the random forest algorithm that combines data on transrectal ultrasound findings, age, and serum levels of prostate-specific antigen to predict prostate carcinoma. Clinico-demographic data were analyzed for 941 patients with prostate diseases treated at our hospital, including age, serum prostate-specific antigen levels, transrectal ultrasound findings, and pathology diagnosis based on ultrasound-guided needle biopsy of the prostate. These data were compared between patients with and without prostate cancer using the Chi-square test, and then entered into the random forest model to predict diagnosis. Patients with and without prostate cancer differed significantly in age and serum prostate-specific antigen levels (P < 0.001), as well as in all transrectal ultrasound characteristics (P < 0.05) except uneven echo (P = 0.609). The random forest model based on age, prostate-specific antigen and ultrasound predicted prostate cancer with an accuracy of 83.10%, sensitivity of 65.64%, and specificity of 93.83%. Positive predictive value was 86.72%, and negative predictive value was 81.64%. By integrating age, prostate-specific antigen levels and transrectal ultrasound findings, the random forest algorithm shows better diagnostic performance for prostate cancer than either diagnostic indicator on its own. This algorithm may help improve diagnosis of the disease by identifying patients at high risk for biopsy.

Objective: To evaluate the integrated performance of age, serum PSA, and transrectal ultrasound images in the prediction of prostate cancer using a Tree-Augmented NaÏve (TAN) Bayesian network model., Methods: We collected such data as age, serum PSA, transrectal ultrasound findings, and pathological diagnoses from 941 male patients who underwent prostate biopsy from January 2008 to September 2011. Using a TAN Bayesian network model, we analyzed the data for predicting prostate cancer, and compared them with the gold standards of pathological diagnosis., Results: The accuracy, sensitivity, specificity, positive prediction rate, and negative prediction rate of the TAN Bayesian network model were 85.11%, 88.37%, 83.67%, 70.37%, and 94.25%, respectively., Conclusions: Based on age, serum PSA, and transrectal ultrasound images, the TAN Bayesian network model has a high value for the prediction of prostate cancer, and can help improve the clinical screening and diagnosis of the disease.

Aims: Sulfonylurea drugs exert an insulinotropic effect through ATP-sensitive potassium (KATP) channel inhibition in pancreatic islet cells. These channels are also expressed in cardiomyocytes and vascular smooth muscle cells (VSMCs), suggesting potential for adverse cardiovascular effects. We evaluated the effects of Gliquidone (Glq) on sulfonylurea receptors in HIT-T15 cells (SUR1), cardiomyocytes (SUR2A), and VSMCs (SUR2B)., Methods: The concentration-dependent effects of Glq (0.001-500 μM) on KATP channels were assessed using whole-cell patch clamp in HIT-T15 cells, rat cardiomyocytes, and VSMCs. Parallel studies using Glibenclamide (Glb) (0.001-10 μM) and Gliclazide (Glc) (0.01-500 μM)were conducted as controls., Results: In HIT-T15 cells, Glb exhibited the lowest IC50 (0.03 μM), as compared to Glq (0.45μM) and Glc (1.21μM). However, Glq had higher IC50 in cardiomyoctes and VSMCs, as compared to Glb (119.1 vs. 0.01 and 149.7 vs. 0.09 μM, respectively), suggesting that Glq is more selective to β-cells than Glb. Thus, Glq may have fewer side effects in cardiomyoctes and VSMCs., Conclusions: Glq is a highly selective SUR secretagogue with moderate affinity to β-cells, but low affinity to cardiomyocytes and VSMCs. Our data also reveal the non-selective nature of Glb, as evidenced by high binding affinity to KATP channels in all the three cell types examined., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Aims: The aims of the study were to assess the pharmacokinetics, pharmacodynamics, safety and tolerability of a novel, pegylated recombinant human consensus interferon-α variant (PEG-IFN-SA) in healthy volunteers. A pharmacokinetic and pharmacodynamic comparison of PEG-IFN-SA and peginterferon-α-2a in healthy subjects was evaluated., Methods: A randomized, dose-escalating, single administration dose phase I clinical study was conducted. Thirty healthy subjects received PEG-IFN-SA as a single dose of 0.5-2.0 μg kg(-1) by subcutaneous (s.c.) injection in four parallel groups. Eight subjects received peginterferon-α-2a as a single dose of 180 μg s.c., Results: The incidence rates of adverse events for PEG-IFN-SA and peginterferon-α-2a were 29 of 30 and 7 of 8, respectively. The adverse events for PEG-IFN-SA were mild to moderate and similar to those of peginterferon-α-2a. Within 168 h after injection, the mean values of maximal concentration and area under the plasma concentration-time curve from time of dosing to 168 h [AUC(0-168h) ] for 2',5'-oligoadenylate, neopterin and β2 -microglobulin for PEG-IFN-SA at 1.5 μg kg(-1 ) s.c. were similar to or higher than those for peginterferon-α-2a at a dose of 180 μg s.c. After s.c. injection of PEG-IFN-SA at 1.5 μg kg(-1) , the mean geometric mean values of plasma half-life, time to maximal concentration, maximal concentration and AUC(0-168h) were 55.3 h, 26.9 h, 0.53 μg l(-1) and 44.0 μg l(-1)  h, respectively., Conclusions: The tolerance, pharmacokinetic and pharmacodynamic characteristics of PEG-IFN-SA support its administration by s.c. injection as a single dose of 1.5 μg kg(-1) or at 2.0 μg kg(-1) per week., (© 2014 The British Pharmacological Society.)

Background: Alcohol has been used for treating simple renal cysts since 1981. Since then, various observational studies have examined the technique, but they differ significantly in the details of the procedures and efficacy measures used. This has made it difficult to assess the safety and efficacy of this technique. We carried out a randomized controlled trial to evaluate the efficacy and safety of ultrasound-guided alcohol sclerotherapy involving single-session multiple injections to treat simple renal cysts., Methods: A total of 144 patients with simple renal cysts were randomly allocated to either the treatment group (ultrasound-guided percutaneous drainage and alcohol sclerotherapy with single-session multiple injections) or control group (ultrasound-guided simple percutaneous drainage). Follow-up CT scans of ablated cysts were collected 3 and 6 months after the procedure. The outcome was considered successful if cyst volume between baseline and 6 months decreased by at least 87.5%., Results: Intention-to-treat analysis revealed an average volume reduction of 94.2% in the treatment group and 50.8% in the control group (P < 0.0001). The percentage of patients achieving successful outcomes was 88.9% (95%CI 77.0% - 100.0%) in the treatment group and 22.2% (95%CI 6.54% - 37.9%) in the control group (P < 0.0001). The corresponding results in the per-protocol analysis were an average volume reduction of 96.4% in the treatment group and 50.8% in the control group (P < 0.0001). The percentage of patients achieving a successful outcome was 94.3% (95%CI 85.6% - 100.0%) in the treatment group and 22.2% (95%CI 6.54% - 37.9%) in the control group (P < 0.0001)., Conclusion: Alcohol sclerotherapy involving single-session multiple injections is safe and efficacious in the treatment of renal cysts.

Objective: To examine the apoptotic effect of ent-11α-hydroxy-15-oxo-kaur-16-en-19-oic-acid (5F), a compound isolated from Pteris semipinnata L (PsL), in human lung cancer A549 cells., Methods: A549 cells were treated with 5F (0-80 μg/ml) for different time periods. Cytotoxicity was examined using a MTT method. Cell cycle was examined using propidium iodide staining. Apoptosis was examined using Hoechst 33258 staining, enzyme-linked immunosorbent assay (ELISA) and caspase-3 activity analysis. Expression of representative apoptosis-related proteins was evaluated by Western blot analysis. Reactive oxygen species (ROS) level was measured using standard protocols. Potential interaction of 5F with cisplatin was also examined., Results: 5F inhibited the proliferation of A549 cells in a concentration- and time-dependent manner. 5F increased the accumulation of cells in sub-G1 phase and arrested the cells in the G2 phase. Exposure to 5F induced morphological changes and DNA fragmentation that are characteristic of apoptosis. The expression of p21 was increased. 5F exposure also increased Bax expression, release of cytochrome c and apoptosis inducing factor (AIF), and activation of caspase-3. 5F significantly sensitized the cells to cisplatin toxicity. Interestingly, treatment with 5F did not increase ROS, but reduced ROS production induced by cisplatin., Conclusion: 5F could inhibit the proliferation of A549 cells by arresting the cells in G2 phase and by inducing mitochondrial-mediated apoptosis.

Five hydroxylated derivatives of glycyrrhetinic acid by Mucor polymorphosporus were isolated. Among them, 6beta, 7beta-dihydroxyglycyrrhentic acid (2) and 27-hydroxyglycyrrhentic acid (3) are new compounds. Their chemical structures were identified by spectral methods including 2D-NMR., (Copyright 2009 John Wiley & Sons, Ltd.)

Objective: To determine the contents of chlorogenic acid and total caffeoylquinic acid in 6 Folium Lonicerae in Sichuan province and Chongqing city for evaluating the quality of them., Methods: The HPLC analysis and spectrophotometry analysis were used., Results: The contents of chlorogenic acid and total caffeoylquinic acid in 6 Folium Lonicerae had been determined., Conclusion: The method is accurate, simple and has a good reproducibility. The results can be used as a reference for the reasonable medication, quality control and further study of Folium Lonicerae.