Bridging the structure gap between pellets in artificial dissolution media and in gastro-intestinal tract in rats

Changes in structure of oral solid dosage forms (OSDF) elementally determine the drug release and its therapeutic effects. In this research, synchrotron radiation X-ray micro-computed tomography was utilized to visualize the 3D structure of enteric coated pellets recovered from the gastrointestinal tract of rats. The structures of pellets in solid state and in vitro compendium media were measured. Pellets in vivo underwent morphological and structural changes which differed significantly from those in vitro compendium media. Thus, optimizations of the dissolution media were performed to mimic the appropriate in vivo conditions by introducing pepsin and glass microspheres in media. The sphericity, pellet volume, pore volume and porosity of the in vivo esomeprazole magnesium pellets in stomach for 2 h were recorded 0.47, 1.55 × 108 μm3, 0.44 × 108 μm3 and 27.6%, respectively. After adding pepsin and glass microspheres, the above parameters in vitro reached to 0.44, 1.64 × 108 μm3, 0.38 × 108 μm3 and 23.0%, respectively. Omeprazole magnesium pellets behaved similarly. The structural features of pellets between in vitro media and in vivo condition were bridged successfully in terms of 3D structures to ensure better design, characterization and quality control of advanced OSDF.

MFN1 ubiquitination mediates lipopolysaccharide-induced mitochondrial dysfunction and pyroptosis in Raw264.7 mouse macrophages / 中华微生物学和免疫学杂志

Objective:To investigate the regulatory effects of mitofusin 1 (MFN1) on lipopolysaccharide (LPS)-induced Raw264.7 mouse macrophages pyroptosis and to provide reference for further study on the prevention of inflammation and fibrosis caused by macrophage dysfunction.Methods:Raw264.7 mouse macrophages were cultured in vitro and used to construct a model of LPS-induced pyroptosis. CCK-8 staining, PI staining, LDH release assay and Western blot were used to verify the Raw264.7 pyroptosis induced by LPS. MFN1 expression was detected by Western blot. DCFH-DA probe was used to detect the synthesis of total reactive oxygen species (ROS); Mito-SOX was used to detect mitochondrial ROS; JC-1 mitochondrial membrane potential was detected by fluorescence probe to reflect mitochondrial damage. Based on Ubibrowser database, it was predicted that MFN1 could bind to a variety of E3 ubiquitin ligases. Then, immunofluorescence and co-immunoprecipitation (CO-IP) were used to analyze MFN1 ubiquitination. An overexpression plasmid for MFN1 was constructed and transfected into Raw264.7 cells to detect the changes in pyroptosis and mitochondrial function. Results:LPS could induce the pyroptosis of Raw264.7 cells and mitochondrial dysfunction. MFN1 expression was decreased after LPS stimulation. Ubiquitinated MFN1 was detected by CO-IP. Ubiquitination inhibitor MG-132 inhibited LPS-induced expression of pyroptosis-related proteins including NLRP3, Pro-caspase-1, Caspase-1, IL-1β and IL-18 and improved mitochondrial function. MFN1 overexpression relieved the mitochondrial dysfunction and pyroptosis of Raw264.7 cells induced by LPS.Conclusions:The ubiquitination of MFN1 induced by LPS was involved in mitochondrial dysfunction and macrophage pyroptosis, suggesting that MFN1 was a potential target for the treatment of macrophage-induced inflammation and related diseases.

Metal-organic frameworks for advanced drug delivery

Metal-organic frameworks (MOFs), comprised of organic ligands and metal ions/metal clusters

Prescription Technology Optimization of RPV Modified Paclitaxel and Schisandrin B Liposomes and Preliminary Evaluation of Antitumor Activity in vitro / 中国药房

OBJECTIVE：To prepare paclit axel and schisandrin B liposomes modified by cell penetrating peptide RPV ，and to preliminarily evaluate its anti-tumor activity in vitro . METHODS ：RPV modified paclitaxel and schisandrin B liposomes were prepared by film dispersion method. Box-Benhken design-response surface methodology was used to optimize the prescription technology of RPV modified paclitaxel and schisandrin B liposomes using the amount of cholesterol and paclitaxel ，the time interval of ultrasound probe as factors ，average entrapment efficiency of paclitaxel and schisandrin B was used as the index. The liposomes prepared by the optimal technology were characterized. Sulfonylrhodamine B staining method was used to investigate in vitro toxicity of RPV modified blank liposomes ，paclitaxel and schisandrin B liposomes ，RPV modified paclitaxel and schisandrin B liposomes to human ovarian cancer cell SK-OV- 3. The effects of 3 kinds of liposomes on the migration and invasion ability of SK-OV-3 cells were investigated by cell scratch test and Transwell chamber invasion test. RESULTS ：The optimal prescription technology was phospholipid 44 mg，cholesterol 8 mg，paclitaxel 0.64 mg，schisandrin B 1.5 mg，ultrasonic probe time interval 5 s，prescription dosage 5 mL. According to the optimal prescription technology ，the liposomes were spherical in shape ，and the particle size was （126.49±1.19）nm，Zeta-potential was （－4.83±0.61）mV，average entrapment efficiency of liposomes was （93.88±1.67）％. Compared with RPV modified blank liposomes ，after treated with paclitaxel and schisandrin B liposomes and RPV modified paclitaxel and schisandrin B liposomes ，the survival rate ，migration inhibition rate and invasion rate of SK-OV- 3 cells were significantly decreased （P＜0.05）. The effects of RPV modified paclitaxel and schisandrin B liposomes was better than those of paclitaxel and schisandrin B liposomes （P＜0.05）. CONCLUSIONS ：RPV modified paclitaxel and schisandra B liposome are successfu lly prepared ，and they have certain antitumor activity in vitro .

Scoliosis and associated factors among middle school students in Guangzhou City / 中国学校卫生

Objective@#To investigate the general situation of scoliosis and influencing factors among middle school students in Guangzhou, so as to provide evidence for behavioral intervention measures.@*Methods@#By stratified cluster random sampling method, 2 121 students from 8 middle schools of Guangzhou were selected to conduct questionnaire survey and physical examination.@*Results@#The detection rate of scoliosis among middle school students in Guangzhou was 8.20%, girls (9.50%)＞boys (7.00%), urban area (10.45%)＞suburb area (4.77%), senior high school (10.08%)＞junior school (6.39%) ( P ＜0.05). Among the most of the 174 positive students were found to have large thoracic curve, right lateral bending, being girls with medium scoliosis. Multivariate Logistic regression analysis showed that students in urban area ( OR=2.56, 95%CI =1.71-3.82), with mobile electronic devices usage time≥3 h/d( OR=1.59, 95%CI =1.12-2.27), prolonged near vision work ≥1 h ( OR=1.40, 95%CI =1.00-1.95), outdoor activity time＜2 h/d( OR=1.82, 95%CI =1.24-2.67) had a higher detection rate of scoliosis ( P <0.05).@*Conclusion@#The detection rate of scoliosis among middle school students in Guangzhou is much higher, which might be related to district, mobile electronic devices usage, prolonged near vision work and insufficient outdoor activity. Health education regarding spinal knowledge should be strengthened.

Effect of skull drilling combined with artificial dermis and vacuum sealing drainage in repairing scalp defect with skull exposure / 中华医学美学美容杂志

Objective:To investigate the therapeutic effect of skull drilling and/or grinding combined with artificial dermis and vacuum sealing drainage in repairing scalp defects with skull exposure.Methods:From October 2014 to May 2018, 18 patients with scalp defect and skull exposure were treated in the Department of Burn and Plastic Surgery, the Second Clinical College of North Sichuan Medical College, including 10 males and 8 females, with an average age of 64 years (range, 34-86 years). The patients were divided into two groups: group A (by drilling skull or/and grinding combined with artificial dermis cover and vacuum sealing drainage plus two split thickness skin graft repair) and group B (by drilling skull or/andgrinding combined with artificial dermis cover plus two covering leather grinding stage split thickness skin graft repair), 9 cases in each group. The head wound granulation tissue, postoperative complications, skin graft survival rate and wound healing time were compared between the two groups. Vancouver scar assessment scale (VSS) was used to evaluate the wound healing in the two groups.Results:The time of granulation cultivation in group A and group B was (16.44±1.42) days and (29.11±13.32) days, the difference was statistically significant ( P<0.05); The wound healing time of group A and group B was (26.00±3.32) days and (40.67±14.37) days, the difference was statistically significant ( P<0.05); The postoperative complications of group A and group B were 1 case and 5 cases respectively, the difference was statistically significant ( P<0.05). The skin graft survival rates of group A and group B were (97.11±3.44)% and (95.00±4.74)%, the difference was not statistically significant ( P>0.05); The wound scar VSS scores of group A and group B were (7.67±1.32) points and (8.78±1.99) points, the difference was not statistically significant ( P>0.05). Conclusions:By drilling skull and/or grinding combined with artificial dermis cover and vacuum sealing drainage and two stage split thickness skin graft for repairing scalp defect with skull exposure wound can not only better scalp defect with skull exposure wounds, and reduce the postoperative complications, and significantly accelerate wound healing, but also can effectively improve the quality of wound healing, which is worthy of clinical application.

Three-dimensional CT classification of fracture site and injury mechanism of axis ring / 中华骨科杂志

Objectives:To observe the anatomical location and mechanism of axis ring fractures (ARF) using 3-D CT scans, and propose a new classification for such fractures.Methods:By reviewing prospectively maintained database collecting ARF from 7 medical centers in China, 202 patients were included in this study. According to anatomical location, ARFs were classified into axis arthrosis fracture (AAF) and axis bony damage (ABD). The axis ring was divided into anterior, middle, and posterior rings, based on the border of the pars interarticularis (or pedicle) of axis. According to the features of ARF and previous study, a new classification was proposed based on the anatomical features of different fracture patterns, which was divided into three types and six subtypes (A1, A2, B1, B2, C1 and C2). The incidence of AAF and ABD and their distribution in different location of axis ring and the new classification, were observed.Results:In 202 patients with ARF, 501 anatomical structures were involved. 288 AAFs were found in 178 patients (288/501, 57%), while 213 ABDs were found in 149 patients (213/501, 43%). In anterior ring, 304 structures (304/501, 61%) were involved in injury, with 225 AAF and 79 ABD. In middle ring, 99 structures (99/501, 20%) were involved in injury, and all of them were ABD. In posterior ring, 98 structures (98/501, 19%) were involved in injury, with 63 AAF and 35 ABD. The anterior ring injuries (61%) were more common than middle (20%) or posterior ring (19%). In anterior ring, AAF (84%) were morecommon than ABD (16%); In middle ring, all the injuries were ABD; In posterior ring, AAFs (64%) were more common than ABD (36%). Type A fractures were featured with pedicle fractures and were identified in 30 patients (30/202, 15%). Type A1 fractures were bilateral pedicle fracture lines symmetrically or asymmetrically and identified in 12 (6%) patients; Type A2 fractures were pedicle fracture lineson one side and inferior articular facet injuries or lamina fractures on the otherside and identified in 18 (9%) patients. Type B fractures were featured with superior articular facet injuries or posterior wall of C2 body fractures on one side and identified in 136 patients (67%). Type B1 fractures were superior articular facet injuries or posterior wall of C2 body fractures on one side and pedicle fracture on the other side and identified in 57 (28%) patients; Type B2 fractures were superior articular facet injuries or posterior wall of C2 body fractures on one side and inferior articular facet injuries or lamina fractures on the otherside and identified in 79 (39%) patients. Type C fractures were featured with bilateral superior articular facet injuries or posterior wall of C2 body fractures and identified in 36 patients (18%). Type C1 fractures were bilateral superior articular facet injuries or posterior wall of C2 body fractures symmetrically and identified in 22 (11%) patients; Type C2 fractures were bilateral superior articular facet injuries or posterior wall of C2 body fractures asymmetrically and identified in 14 (7%) patients.Conclusion:ARF could occur in different anatomical locations, and most of these fractures were caused by hyperextension and axial load on superior articular facet on one or two sides. The new CT classification of ARF with three types and six subtypes might provide all fracture patterns, which could be useful for the choice of proper diagnosis and treatment for such fractures.

Analysis and Consideration of Pediatric Medication in National Essential Medicine List （2018 Edition） / 中国药房

OBJECTIVE： To provide reference for improving pediatric medication of National Essential Medicine List （NEML） and establishing Chinese essential medicine list for children. METHODS： NEML （2018 edition） were compared with WHO Essential Medicines List for Children （WHO EMLc） in respects of target population， special symbols， categories and varieties， dosage form and specification. The related suggestions were put forward. RESULTS & CONCLUSIONS： WHO EMLc is specifically used for children under 12 years old， and defines specific age and body mass. NEML is applicable to all age groups （including children）. WHO EMLc includes 4 types of special symbols， i.e. “□” （the drug with the best efficacy and safety in the same kind of drugs， which matches the selection principle of NEML）， “a” （limited age or body weight， not found in NEML）， “*” （special dosage， specially emphasized indications and age not recommended for use， listing substitute drugs， not found in NEML）， “[c]” （placed next to a drug or a specification indicating that they are only used by children； and placed next to a supplementary list indicating that they need expert diagnosis， monitoring facilities， medical care for children， similar to the “Δ” in NEML）. NEML in China includes chemical drugs and biological products， Chinese patent medicines and TCM decoction pieces. Among them， there are 26 categories and 417 types of chemical drugs and biological products. Compared with WHO EMLc， NEML has no blood products and special drugs for newborns. As far as antimicrobial agents are concerned， WHO EMLc has strict limits and classifications. However， due to the lack of guidelines for special antimicrobial agents for children in China， the application of NEML antimicrobial agents in pediatrics is still difficult to define and classify. The number of coincident varieties in the 2 lists was 149， and the coincidence rate was 35.2％. In terms of drug dosage， WHO EMLc’s dosage form are more abundant and flexible， such as scored tablet， compressible fragments， intramuscular injections， and oral solutions suitable for children which are not included in NEML. In terms of drug specifications， 2 lists basically consider about the special needs of children taking small dosage and to some extent take into account the complementarity of dosage forms and specifications. The author suggests that the relevant departments in China should draw lessons from the mature experience of WHO EMLc， add new labeling symbols in NEML， expand drug dosage forms， implement classified management of antimicrobial drugs， and timely launch Chinese Essential Medicines List for Children so as to lay a solid foundation for further improving the accessibility and safety of essential medicines for children in China.

Effect of MMP-8 on cornea collagen / 重庆医学

Objective To investigate the effect of MMP-8 on cornea. Methods Fifteen C57BL/6J healthy mice were selected. The right eyes corneal stroma was injected by 10μL MMP-8 as the experimental group and the left eyes were injected by same amount of normal saline as the control group. At 0,4,8 h, the two-photon microscope second harmonic generation imaging technology was used to scan mice corneal stroma layer by layer in vivo. The obtained images were performed the 3D reconstruction by Imaris software and the signal intensity of the images were calculated. At 4,8 h, the corneal opacity degree was evaluated under slit lamp. At 8 h,mice were killed and corneas were collected to determine the hydroxyproline concentration. Results The cornea stromal fiber signal strengthes at 0 h in the experimental group and control group were (89.7±11.2) and (85.3±7.0),which at 4 h were (14.5±3.4) and (46.6±14. 0) respectively,which at 8 h were (11.0±4.6) and (34.6±12.5) respectively. The cornea stromal signal strength at 4,8 h in the experiemental group was significantly decreased compared with that in the control group (P<0.05) ;the cornea at 4 ,8 h in the experimental group was significantly turbid than that in the control group (P<0.05);the cornea hydroxyproline concentrations detected at 8h in the experiemental group and control group were (0.433±0. 090) μg/mg and (0. 590±0. 133) μg/mg respectively,the experimental group was significantly lower than the control group (F=7. 193,P=0. 014). Conclusion MMP-8 has obvious degradation and destroy effect on mice corneal stroma collagen,which leads to the decrease of corneal opacity.

Advances of covalently modified drugs / 中国药科大学学报

Covalently modified drugs,which exert their pharmacological effects by covalently binding to the targets,have been avoided as far as possible for a long time in drug design due to the potential off-target effects and other side-effects.With the in-depth study of binding modes of market blockbuster covalent drugs,more and more attention has been concentrated on covalently modified drugs.Current challenges remain in development of potent selective covalently modified drugs with fewer adverse effects.This paper reviews the classification of some covalently modified drugs,the drug-target binding modes and the new strategies of designing covalently modified drugs,in order to provide reference for rational design of covalent drugs.

Absorption and distribution characteristics of terbinafine hydrochloride nanoemulsions in cornea after instillation / 中华实验眼科杂志

Background Nanoemulsions (NEs) is one of the most popular ophthalmic colloidal drug delivery system due to its long-term stability, low toxicity and irritancy, considerable capacity for solubilization of lipophilic drug molecules and great potential in bioavailability improvement.The cornea pathway is the main route of intraocular absorption after topical use of NEs.Though NEs possess numerous physiological and physicochemical advantages,the use of NEs cannot always obtain satisfactory results.Objective This study was to investigate the impacts of epithelium and stroma on the corneal permeation of topical ophthalmic terbinafine hydrochloride nanoemulsions (TH-NEs).Methods TH-NEs was prepared by the self-emulsification method.The size and Zeta potential of the oil droplets in the formulation were analyzed using a dynamic light-scattering particle size analyzer.The high performance liquid chromatography (HPLC) was used for the in vitro release study.Sixty New Zealand albino rabbits were randomly divided into intact cornea group and cornea epithelium debrided group.The cornea epithelium of the left eyes was debrided in the cornea epithelium debrided group.The TH-NEs were instilled into the lower conjunctival sac of left eyes.Six rabbits were executed from each group 15,30,60,120 and 240 minutes after dosing,respectively.The corneas were collected and analyzed by HPLC.The fluorescein diacetate (FDA) was used to label the TH-NEs.Two C57BL/6 mice with left cornea epithelium debrided and 2 normal mice were used for the fluorescence tracing study.The fluorescence distribution of FDA labeled TH-NEs was observed by a two-photon laser confocal scanning microscope 30 minutes and 60 minutes after single instillation.Results The average size and Zeta potential of the oil droplets were 51.37 nm and-0.232 7 mV respectively,and 0.482％ of encapsulated drugs was released from the TH-NEs after 12 hours.The peak concentrations of TH in the intact cornea and epithelium debrided cornea were (17.85 ± 2.79) μg/g and (4.40± 1.75) μg/g respectively, which occurred 15 minutes postdose.The drug concentrations in the intact cornea were significantly higher than that in the debrided cornea 15,30,60 and 120 minutes after dosing, with significant differences between them (t =9.998,8.658,6.903,7.576;all at P=0.000).The fluorescence was observed in the cornea epithelium when the cornea was intact.The fluorescence intensity in the superior layer of corneal epithelium was obviously higher than that in the deep layers of corneal epithelium 30 minutes and 60 minutes after dosing.No fluorescence was observed in the cornea stroma of both eyes.Conclusions The cornea epithelium is the main of absorption and distribution position of TH-NEs.The cornea stroma is the dominating permeation barrier for the intraocular transportation of the TH-NEs.The cornea stroma may stop the permeation of TH-NEs by molecular exclusion mechanism.

Effects of porcine bone protein on serum phosphorus level and bone mineral density in a rat model of osteoporosis / 中国组织工程研究

BACKGROUND: Several studies have demonstrated that many American women who are at high risk of developing osteoporosis have higher levels of serum phosphorus. This indicates that some substances which can lower the serum level of phosphorus will supply a new and effective method to prevent and treat osteoporosis.OBJECTIVE: To observe the influences of porcine bone protein on bone mineral density (BMD) and serum levels of calcium and phosphorus in a rat model of osteoporosis.METHODS: Wistar rat models of osteoporosis were established by intramuscular injection of dexamethasone. Rat models were randomly divided into physiological saline, Jiegu Qili tablet, 50, 100, 200 mg/kg porcine bone protein groups. Rats that did not receive any treatments served as normal controls. After 12 weeks of treatment, serum was collected and serum levels of phosphorus and calcium were determined by biochemistry method. At the same time, tibia sections were made to determine tibial DMD by QDR-400 dual energy X-ray absorptiometry and to observe tibia marrow cavity by hematoxylin-eosin staining.RESULTS AND CONCLUSION: There was no significant difference in serum level of calcium among groups (P＞0.05).Compared with the physiological saline group, serum level of phosphorus in the 50, 100, 200 mg/kg porcine bone protein groups was significantly decreased (P ＜ 0.05). BMD was significantly higher in the 50, 100, 200 mg/kg porcine bone protein, Jiegu Qili tablet groups than in the physiological saline group (P ＜ 0.05). The tibia marrow cavity was smallest in the normal control group and largest in the physiological saline group. The tibia marrow cavity was larger in the 50, 100, 200 mg/kg porcine bone protein,Jiegu Qili tablet groups than in the physiological saline group. These results indicate that porcine bone protein cannot change the serum level of calcium, but it lowers serum level of phosphorus, and increases BMD, in a rat model of osteoporosis. However, the dose-dependent effect of porcine bone protein was not observed within the present experimental dosage. In addition, porcine bone protein can also reduce the marrow cavity of the tibia of rats with osteoporosis.