[Current status of registered drug and vaccine pediatric clinical trials in China].

Objective: To evaluate the current status of the registered pediatric drug or vaccine clinical trials in China for the purpose of providing a reference for the development of pediatric clinical trials in China. Methods: We collected the data about registered pediatric clinical trials that were conducted from September 6, 2013(Mandatory registration start date) to September 6, 2019 (Cut-off date) at Chinadrugtrials.org.cn platform. The survey items included trial name and number, drug classification, sponsor's information, current trial status, completion status, etc. The clinical trials were categorized by drug group (includes chemical medicine, traditional Chinese medicine and natural medicine, biological products) and by vaccine group. Results: During the six years 349 pediatric clinical trials were registered on the platform, including 162 pediatric drug trials and 187 vaccine trials. The numbers of chemical drugs and biological products registered in 2018 were 23 and 11, respectively, the highest in the history. The number of pediatric clinical trials of traditional Chinese medicine and natural medicine was 11 in 2014, but from 2015 to 2018 only 2 to 4 trials were registered each year. The overall completion rates of the registered drug and vaccine clinical trials were 22.8% (37/162) and 41.7%(78/187), respectively. Only 42 international multicenter pediatric clinical trial projects were registered on the platform. The numbers of drug and vaccine phase Ⅰ clinical trials were 4 and 46, respectively. Thirty-six pediatric endocrine system agent clinical trials were carried out, with the largest number of all the drug categories registered on the platform. Conclusions: In recent years the number of registered pediatric drug and vaccine clinical trials increased in China. However, the number is still very limited. It is urgent to further promote the development of pediatric clinical trials.

Danshen (Salvia miltiorrhiza) protects ovariectomized rats fed with high-saturated fat-sucrose diet from bone loss.

Dietary patterns may interfere with the efficacy of herbal intervention. Our results demonstrated the protective effects of Salvia miltiorrhiza aqueous extract (SMA) on bone metabolism were influenced by levels of dietary fat and sucrose in ovariectomized (OVX) rats through its actions on attenuating lipid deposition and oxidative stress in rats. INTRODUCTION: Salvia miltiorrhiza (SM), also known as Danshen, has been tested as an osteoporosis treatment in a series of small, short human trials that generally report improvements in bone property. However, dietary patterns may interfere with the effects of herbal intervention. We hypothesized that dietary fat and sucrose levels could influence the effects of SM supplementation on bone in estrogen-deficient animals. METHODS: Six-month-old Sprague-Dawley sham or OVX rats were fed either a low-saturated fat-sucrose (LFS, a diet that was similar in composition to normal rat chow) or a high-fat-sucrose (HFS) diet and OVX rats were treated (8 rats/group) with SM aqueous extract (SMA, 600 mg/kg/day), 17ß-estradiol (1 mg/kg/day), or vehicle for 12 weeks. RESULTS: SMA significantly improved bone properties as revealed by the increase in trabecular bone mineral density and decrease in trabecular separation at proximal metaphysis of the tibia (PT) in HFS-fed OVX rats, but not in LFS-fed OVX rats. SMA greatly reduced lipid deposition and malondialdehyde levels, improved the activities of superoxide dismutase, catalase, and glutathione peroxidase in the livers of HFS-fed OVX rats. SMA could directly improve the proliferation and differentiation in vitro in an H2O2-induced preosteoblast cell model by attenuating cellular reactive oxygen species levels. CONCLUSIONS: The protective effects of SMA on bone metabolism were influenced by dietary fat and sucrose levels in OVX rats. The ability of SMA to reduce bone loss in HFS-fed OVX rats was associated with the attenuation of lipid deposition and oxidative stress levels.

Dietary l-arginine supplementation improves semen quality and libido of boars under high ambient temperature.

l-Arginine is a nutritionally essential amino acid for spermatogenesis and plays versatile roles in animal health and can be utilized as a potential agent to improve reproductive performance of boars under high ambient temperature. The present study aimed to determine whether dietary l-arginine could alleviate heat stress-induced infertility in boars. In all, 20 boars (PIC 1040; 248.59±3.84 kg BW and 407.65±6.40 days of age) were selected and randomly assigned to four groups (group 0.0%, basal diet; group 0.6%, 0.8% or 1.0%, basal diet added with 0.6%, 0.8% or 1.0% l-arginine (wt:wt), respectively.) The four diets were made isonitrogenous by addition of appropriate amounts of l-alanine. Boars were pre-fed the corresponding experimental diet for 42 days. Then, the semen characteristics and libido were accessed for 6 weeks during the hot summer period (25.5° to 33.0°C). Results show that dietary l-arginine remarkably improved sperm motility, normality, total sperm number and effective total sperm number. Also, dietary l-arginine improved semen antioxidant capacity, such as decrease of malondialdehyde and 8-Hydroxy-2'-deoxyguanosine content in sperm (P<0.05), increase of the ratio of glutathione and oxidized glutathione, total antioxidant capacity, glutathione peroxidase and catalase activities in seminal plasma (P<0.05). Most of mitochondria contained intact ultrastructure in l-arginine-supplemented group which also accompany with higher ATP content than the 0.0% group. The boars fed 0.8% l-arginine show increased levels of estradiol-17ß and testosterone and exhibit improved libido performance than boars in the 0.0% group. Adding dietary l-arginine linearly increased (P=0.002) nitric oxide content (as l-arginine increased). The scrotal surface temperature in the 0.6%, 0.8% and 1.0% group were decreased by 0.9°C, 0.9°C and 0.4°C, respectively, compared with the 0.0% group. l-Arginine levels caused linear effect on semen quality and antioxidant capacity, also caused quadratic effect on libido performance. During the hot summer months, the predicted optimal l-arginine levels for best semen quality and antioxidant capacity was 0.8% to 1.0% and for best libido performance was 0.8%. It can be concluded that l-arginine can be used as an effective agent to alleviate heat stress-induced infertility of boar, and that 0.8% to 1.0% can be considered as the optimum dosage.

Dietary zinc may attenuate heat-induced testicular oxidative stress in mice via up-regulation of Cu-Zn SOD.

Zinc (Zn) is important for male mammalian reproduction. In this study, we sought to clarify the role of Zn in heat-induced testicular damage in mice. Eighteen mice were divided into either control (con), heat (heat) and heat plus Zn (H+Zn) treatment groups, and fed diets containing 60 (con and heat groups) or 300 (H+Zn group) mg/kg Zn sulfate for one month. Mice in the con group were then maintained at 25°C, while mice in heat and H+Zn groups were exposed to 40°C for 2 h daily, for eight days. Mouse testes and serum from each animal were analyzed. Zinc levels in serum and testes were positively correlated to Zn feed concentrations. Mice in the heat group had higher testes index than those in the other two groups (7.22 ± 0.75, heat; 4.92 ± 0.20, con; 4.80 ± 0.30 mg/g, H+Zn; P < 0.05). Testicular antioxidant status showed malondialdehyde levels in heat group mice were increased compared to control mice (2.34 ± 0.15 versus 1.55 ± 0.23 nmol/mg protein; P < 0.05), and Cu-Zn superoxide dismutase (SOD) level differed between heat and H+Zn groups (14.04 ± 0.74 versus 18.27 ± 1.53 U/mg protein; P < 0.05). Testicular Cu-Zn SOD protein expression levels were significantly lower in the heat than in the control group (0.30 ± 0.11 versus 1.22 ± 0.13; P < 0.05). These results suggest that dietary Zn may elevate the activity and protein concentration of Cu-Zn SOD, to attenuate testicular oxidative stress induced by heat exposure.

Temsirolimus combined with sorafenib in hepatocellular carcinoma: a phase I dose-finding trial with pharmacokinetic and biomarker correlates.

BACKGROUND: Based upon preclinical evidence for improved antitumor activity in combination, this phase I study investigated the maximum-tolerated dose (MTD), safety, activity, pharmacokinetics (PK), and biomarkers of the mammalian target of rapamycin inhibitor, temsirolimus, combined with sorafenib in hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Patients with incurable HCC and Child Pugh score ≤B7 were treated with sorafenib plus temsirolimus by 3 + 3 design. The dose-limiting toxicity (DLT) interval was 28 days. The response was assessed every two cycles. PK of temsirolimus was measured in a cohort at MTD. RESULTS: Twenty-five patients were enrolled. The MTD was temsirolimus 10 mg weekly plus sorafenib 200 mg twice daily. Among 18 patients at MTD, DLT included grade 3 hand-foot skin reaction (HFSR) and grade 3 thrombocytopenia. Grade 3 or 4 related adverse events at MTD included hypophosphatemia (33%), infection (22%), thrombocytopenia (17%), HFSR (11%), and fatigue (11%). With sorafenib, temsirolimus clearance was more rapid (P < 0.05). Two patients (8%) had a confirmed partial response (PR); 15 (60%) had stable disease (SD). Alpha-fetoprotein (AFP) declined ≥50% in 60% assessable patients. CONCLUSION: The MTD of sorafenib plus temsirolimus in HCC was lower than in other tumor types. HCC-specific phase I studies are necessary. The observed efficacy warrants further study.

Subchronic toxicity studies with ginsenoside compound K delivered to dogs via intravenous administration.

Compound K, i.e., 20-O-ß-d-glucopyranosyl-20(S)-protopanaxadiol, is the main metabolite of the protopanaxadiol type of ginseng saponin produced by intestinal bacteria after oral administration of ginseng extract. In the present study, the toxicity of compound K was evaluated in male and female dogs after 90 days continuous intravenous infusion. Beagle dogs were treated with compound K at doses of 6.7, 20 and 60 mg/kg/day, and observed for 90 days followed by recovery periods. Measurements included clinical observations, body weight, food consumption, temperature, electrocardiogram (ECG), hematology, blood chemistry, urinalysis, gross necropsy, organ weight and histopathology. Under the conditions, the clinical condition of the animals, body weights, body weight gains and food consumption were unaffected by compound K administration relative to the control group. Hematology, ECG data and urinalysis parameters were also unaffected. However, the hepatotoxicity was evident from the observation of multiple parameters, including histopathological evaluation of liver tissue upon necropsy as well as large increases in plasma levels of liver enzymes (alanine aminotransferase, ALT, Gamma-glutamyltranspeptidase, γ-GT, alkaline phosphatase,ALP) in groups receiving compound K (20 or 60 mg/kg/day), and this hepatoxicity might be reversible. In addition, the NOAEL of compound K is 6.7 mg/kg/day in this 90 days toxicity study.

Leiocyclocin C and D, two cyclopeptides from Goniothalamus leiocarpus.

Two new cyclopeptides, leiocyclocin C (1) and D (2), were isolated from the seeds of Goniothalamus leiocarpus (Annonaceae). Their structures were determined as cyclo-(Gly1-Ser-Pro2-Tyr2-Gly2-Tyr1-Pro1-Pro3) and cyclo-(Gly1-Leu-Pro1-Gly2-Phe-Tyr-Pro2), respectively, by means of spectral and chemical methods.

[Clinical observation on verrucous gastritis with combined therapy of traditional Chinese and Western medicine].

Controlled study of verrucous gastritis treated with combined therapy of TCM-WM was compared with that of WM only. The result showed that the total effective rate and the cured rate of former were 97.83% and 84.78%, while that of latter were 77.14% and 22.86% respectively. The TCM-WM revealed better results than WM alone. Follow-up was done after six months, the recurrence rates of the two groups were 9.10% (2/22) and 43.75% (7/16) respectively, the difference was significant (P < 0.05). There was no side effect in combined therapy and the therapy was convenient for use.

[Studies on the indole alkaloids of Winchia calophylla A. DC].

Winchia calophylla A. DC. (Apocynaceac) is one traditional medicine of the Dai Nationality in Xishuangbanna, Yunnan Province, for the treatment of trachitis. Four indole alkaloids have been isolated from the stem bark and the leaves of this plant by aluminum oxide and silica gel chromatography. Three of them were identified as echitamine chloide (I), echitamidine (II) and Nb-demethyl-echitamine (III) by comparison with literature. One of them are new, with structures elucidated as 22-O-acetyl-Nb-demethyl-echitamine (IV) by chemical and spectroscopic methods.

[Prevention and treatment of isoproterenol induced ventricular fibrillation in rats by aqueous extract of Salvia miltiorrhiza].

Acute fatal ventricular fibrillation (VF) in male Sprague-Dawley rats was induced by subcutaneous injection of isoproterenol (1 mg or 5 mg/kg body weight) to two groups of rats of different body weights (525 +/- 21 g or 387 +/- 11 g) respectively. VF occurred in all control rats resulting in 96% death with only 4% spontaneously reverted and survived. Pretreatment of animals, with or without pentobarbital anaesthesia, with an aqueous extract of Salvia miltiorrhiza (SM-H, i.p., 5 g herb/kg body weight) significantly reduced J-point displacement and VF induced by isoproterenol. Survival rate was significantly raised compared with the control (P less than 0.05). Immediate intravenous injection of SM-H (5 g herb/kg body weight) to poisoned rats which developed VF caused 71% of them to recover temporarily their sinus rhythm and significantly prolonged their survival time (P less than 0.05).