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Objective To prepare flumazenil sublingual tablets and study its bioavailability. Methods Flumazenil sublingual tablets were prepared by compressing flumazenil inclusion compound with hydroxypropyl-β-cyclodextrin as the inclusion material. In a double-cycle crossover trial, twelve beagle dogs were randomly divided into two groups, one group receiving flumazenil sublingual tablets and the other receiving flumazenil injections. LC-MS method was developed and validated to determine flumazenil plasma concentration. The pharmacokinetic parameters and bioavailability were calculated using WinNonlin pharmacokinetic software. Results In the pharmacokinetic study, AUClast of flumazenil injection and sublingual tablet was （8.41±2.15） and （8.86±2.83） h·ng·ml−1, respectively; Cmax was （10.96±2.62） and （6.36±2.14） ng/ml, respectively; tmax was （0.18±0.05） and （0.58±0.24） h, respectively. The bioavailability of flumazenil sublingual tablet was 52.68%. Conclusion Clathrates were used to prepare flumazenil sublingual tablets to achieve safe and efficient delivery. LC-MS method was established for the determination of flumazenil plasma concentration, and the advantages were simple, accurate and sensitive.
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Objective:To develop a novel, flexible, dual-arm, master-slave digestive endoscopic minimally invasive surgical robot system named dual-arm robotic endoscopic assistant for minimally invasive surgery (DREAMS) and to evaluate its feasibility for endoscopic submucosal dissection (ESD) by using ex vivo porcine stomachs.Methods:A novel endoscopic robot (DREAMS) system was developed which was composed of a flexible two-channel endoscope, two flexible robotic manipulators, a master controller, a robotic arm, and a control system. A total of 10 artificial round-like lesions with diameters ranging from 15 to 25 mm were created (5 in gastric antrum and 5 in gastric body) by using fresh peeled stomach of healthy pigs as the model. Submucosal dissection was performed with the assistance of the DREAMS system by two operators. The main outcome was submucosal dissection speed, and the secondary outcomes included muscular injury rate, perforation rate, and grasping efficiency of the robot.Results:All 10 lesions were successfully dissected en bloc by using the DREAMS system. The diameter of the artificial lesions was 22.34±2.39 mm, dissection time was 15.00±8.90 min, submucosal dissection speed was 141.79±79.12 mm 2/min, and the number of tractions required by each ESD was 4.2 times. Muscular injury occurred in 4/10 cases of ESD. No perforation occurred. Conclusion:The initial animal experiment shows the DREAMS system is safe and effective.
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Objective To investigate the lethal effect of melittin on human hepatocellular carcinoma cell line SMMC-7721 and its possible mechanism. Methods MTT assay was used to investigate the killing effect of different concentrations melittin on human hepatocellular carcinoma cells SMMC-7721. Meanwhile, the inhibitory effect of specific programmed necrosis inhibitors necrostain-1(Nec-1) on melittin killing SMMC-7721 cells was detected. Programmed cell necrosis observed by Hoechst 33342 and PI double staining. The necrotosis rate was detected by flow cytometry. Ultrastructural changes of cell was detected by transmission electron microscopy. The expression of receptor interacting protein 1(RIP1) was detected by Western blotting. Results Compared with the control group, the proliferation activity of SMMC-7721 cells was significantly decreased after treatment with different concentrations of melittin for 24 hours (P < 0. 05) . Cells stained in dark blue and red. Cell membrane integrity was destroyed, organelle swelling, organelle membrane was destroy, that demonstrates cell was necrosis. Westen blotting result showed an increased proportion of RIP1 expression in SMMC-7721 cells. Compared with the melittin group, cell proliferation activity was significantly increased, cell necrotosis rate was decreased, and intracellular RIP1 expression was down-regulated in the Nec-1 pretreatment group. Conclusion Melittin induces cell death in SMMC-7721 cells through the RIP1-mediated programmed necrosis pathway.
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A 51-year-old woman presented with metachronous tumor development in bilateral breasts, thyroid, and endometrium. Additional signs and symptoms fulfilled the National Comprehensive Cancer Network criteria for Cowden syndrome. Immunohistochemistry showed loss of PTEN expression in all tumors. Single nucleotide variants, 647 germline variants (including one each in PTEN and MSH3), and 21 somatic mutations within exons were detected in all tumors after whole-exome sequencing. There were 0, 11, and 46 specific somatic mutations in bilateral breasts, thyroid, and endometrial cancers, respectively.Although PTEN mutation is key to the development of Cowden syndrome, DNA repair dysfunction might be the initial driver of mutations. Fewer mutations were required to induce initial bilateral breast carcinomas, with subsequent thyroid and endometrial carcinomas requiring more mutations for induction. When genetic screening is unavailable, breast cancer patients with clinical manifestations of Cowden syndrome must be carefully assessed for secondary malignancies, such as thyroid and endometrial carcinomas.
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Modern military actions and non-military operations characterized by high-intensity, sudden emergencies and long continuous working inevitably lead to sleep deprivation of military personnel. High-intensity actions require military personnel to maintain excellent action abilities all the times; sudden emergencies need them to maintain alert; and the continuous work need them to maintain a healthy mental state. Therefore, how to effectively combat sleep deprivation, keep alert and have high stress ability have become the focus of modern military medical research. This article reviews the research progress of central nervous system stimulants, preventive sleep medications, sleep induction and rapid recovery drugs, and non-drug measures to combat sleep deprivation.
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A 51-year-old woman presented with metachronous tumor development in bilateral breasts, thyroid, and endometrium. Additional signs and symptoms fulfilled the National Comprehensive Cancer Network criteria for Cowden syndrome. Immunohistochemistry showed loss of PTEN expression in all tumors. Single nucleotide variants, 647 germline variants (including one each in PTEN and MSH3), and 21 somatic mutations within exons were detected in all tumors after whole-exome sequencing. There were 0, 11, and 46 specific somatic mutations in bilateral breasts, thyroid, and endometrial cancers, respectively.Although PTEN mutation is key to the development of Cowden syndrome, DNA repair dysfunction might be the initial driver of mutations. Fewer mutations were required to induce initial bilateral breast carcinomas, with subsequent thyroid and endometrial carcinomas requiring more mutations for induction. When genetic screening is unavailable, breast cancer patients with clinical manifestations of Cowden syndrome must be carefully assessed for secondary malignancies, such as thyroid and endometrial carcinomas.
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Objective:To explore the levels of vitamin A(VA) and vitamin D(VD) in blood of children with tic disorder (Tic disorder, TD) and their associations with tic symptoms severity and clinical types, so as to provide evidence for better prevention and treatment of TD.Methods:A total of 245 children with TD from September 2018 to April 2019 in the department of child Health care, affiliated hospital of qingdao university were enrolled as the case group and 63 healthy children who underwent routine physical examination at the same time as the control group. The levels of VA and VD were measured and their relationship with the severity of tic symptoms and clinical types were analyzed.Results:(1)The VD level of the case group was significantly lower than that of the control group ((23.72±8.87) μg/L , (26.61±7.59) μg/L, t=-2.24, P=0.03), and the proportion of insufficiency or even lack (37.31%, 75/201) was higher than the control group (15.79%, 9/57) (χ 2=9.37, P=0.002). (2)According to the Yale global tic severity scale(YGTSS), the children in the case group were divided into mild TD group, and moderate-to-severe TD group. ①There were significant differences in serum VA and VD levels in mild TD group, moderate-to-severe TD group and the control group ( F=29.79, P<0.01; F=10.90, P<0.01). Among them, the content of VA and VD in moderate-to-severe TD group were lower than those in mild TD group and control group (VA: (0.29±0.06)mg/L, (0.35±0.06)mg/L, (0.34±0.06)mg/L; VD: (21.01±8.30)μg/L, (25.84±8.76)μg/L, (26.61±7.59)μg/L). ②VA and VD levels of children with TD were negatively correlated with the severity of symptoms ( r=-0.325; P<0.01; r=-0.228; P=0.001). (3)According to DSM-V classification criteria, TD children were divided into PTD group, CTD group and TS group. ①There was no significant difference in serum VA level among different clinical types of TD children ( F=0.87, P=0.46). ②The levels of serum VD were different among the four groups ( F=4.13, P=0.007). Among them, the VD level in TS group was the lowest, and its content was significantly lower than that in control group ((21.83±7.60)μg/L, (26.61±7.59)μg/L, P<0.05)). The prevalence of insufficient or even lack of serum VD in children with different subtypes of TD was higher than that in the control group (χ 2=10.88, P=0.01). Conclusion:Vitamin D deficiency exists in children with TD. The level of vitamin A and vitamin D in serum of children with TD is related with the severity of tic symptoms.The VD level is related with clinical type of TD.
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OBJECTIVE: To research the teratogenic and mutagenic toxicity of agarwood extracts produced by agar-wit technique for functional food development (slices dose 0.60 g•d-1). METHODS: Pregnant rats of 6 to 15 d were given with agarwood extracts at 45, 105, 150 mg•kg-1 by gastric perfusion directly every day, then killed and anatomized after being pregnant for 20 d. During the whole course of treatment, the activity and body weight of pregnant rats, fetal survival rate, absorption number, malformation type and number of fetus were observed and recorded. RESULTS: The agarwood extracts had no effect on the body weight of pregnant rats at 45, 105, 150 mg•kg-1 dosages, and the numbers of implantation, live fetuses, fetuses and stillbirths of fetus, malformation type and number had no significant difference compared with the control group (P>0.05). CONCLUSION: Agarwood extracts have no teratogenic and mutagenic toxicity for rat fetuses.
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OBJECTIVE: To assess the chronic toxicity of agarwood extracts produced by agar-wit. METHODS: Agarwood usage in Chinese Pharmacopoeia was referred. SD rats were used as the experimental animal and fed with agarwood extracts at pharmaceutical dosages (1 262.4, 631.2 and 157.8 mg•kg-1) and functional food dosages (150, 105 and 45 mg•kg-1) for 90 d. The weight and food utilization were recorded. The rats were killed on the 90th day, blood and urine were collected for routine blood, serum biochemical indicators and urine index tests, and the bodies were dissected for histological examination. RESULTS: The two groups of rats showed same results. The body weight, food utilization, routine blood, serum biochemical indicators and urine index were not significantly changed compared with the control group (P>0.05). Histological examination showed that the male and female rats both had some lesions, but the group of high dose extracts had no significant difference compared with the control group, also indicating that the lesions had no relationship with agarwood extracts. CONCLUSION: The agarwood extracts produced by agar-wit have no chronic toxicity for mammal in regards of body weight, biochemical indicators and pathology at both pharmaceutical dosages and functional food dosages.
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OBJECTIVE: To evaluate the acute toxicity and genotoxicity of agarwood extracts produced by agar-wit technology for functional food development (slices dose 0.60 g•d-1). METHODS: SD rats were used as animal model, the total dose of 10 g•kg-1 was administered to the rats twice within 24 h, activity and poisoning of rats were observed and recorded in the next 14 d, and Ames test, mammalian erythrocyte micronucleus test and in vitro mammalian cells chromosome aberration test were used to research the genotoxicity comprehensively. RESULTS: The rats showed normal activity and no poisoning symptoms appeared during acute toxicity test at 10 g•kg-1 dose. In the three genotoxicity test, extracts had no significant difference compared with the negative control (P>0.05), but significant difference compared with positive control (P<0.01). CONCLUSION: Under the condition of this study, the agarwood extracts have neither acute toxicity nor genotoxicity on rats.
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Background@#The potential benefit of arthroscopic surgery for osteoarthritic knee associated with medial meniscus tear is controversial. This study was conducted to determine the effect of pre-operative medial meniscus extrusion (MME) on arthroscopic surgery outcomes in the osteoarthritic knee associated with medial meniscus tear during a minimum 4-year follow-up.@*Methods@#This was a retrospective review of a total of 131 patients diagnosed with osteoarthritic knee associated with medial symptomatic degenerative meniscus tear who underwent arthroscopic surgery from January 2012 to December 2014 and were observed for more than 4 years. Patients were classified into two groups: MME ≥3 mm (major MME group, n = 54) and MME <3 mm (non-major MME group, n = 77). Clinical assessments, including the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and radiographic assessments, including the Kellgren-Lawrence (K-L) grade and medial joint space width (JSW), were evaluated pre-operatively and at final follow-up. The longitudinal changes of clinical and radiographic parameters (WOMAC and the medial JSW change, K-L grade progression) were compared between groups unadjusted and adjusted for age, sex, and body mass index. Four-year survival rates (without progression to knee replacement [KR]) were also evaluated using a log-rank test and Cox proportional hazard regression model.@*Results@#Major MME was present in 41% of patients. After a minimum 4-year follow-up, the mean WOMAC total and pain scores improved significantly in both groups. However, the medial JSW and K-L grade worsened significantly. Patients with pre-operative major MME worsened more in WOMAC total (adjusted mean difference [MD] 3.800, 95% confidence interval [CI]: 0.900, 11.400; P = 0.037) and function (adjusted MD 3.100, 95% CI: 0.700, 6.300; P = 0.038) scores than patients with pre-operative non-major MME, and no significant difference was observed in WOMAC pain and stiffness score between groups. The group with major MME had significantly higher joint space narrowing (adjusted MD -0.630, 95% CI: -1.250, -0.100; P = 0.021) and K-L rate progression (adjusted mean relative risk [RR] 1.310, 95% CI: 1.100, 1.600; P = 0.038) than the group with non-major MME. There was a significantly more KR progression in patients with major MME compared with those with non-major MME (adjusted RR 3.100, 95% CI: 1.100, 9.200; P = 0.042 and adjusted hazard ratio 3.500, 95% CI 1.100, 9.500; P = 0.022).@*Conclusions@#Osteoarthritic knee patients associated with medial meniscus tear with non-major MME are more responsive to arthroscopic surgery in terms of the clinical and radiologic outcomes and survival for at least 4-year follow-up; however, in terms of pain relief, arthroscopic surgery in patients with major MME is also beneficial as well as in patients with non-major MME.
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BACKGROUND@#The potential benefit of arthroscopic surgery for osteoarthritic knee associated with medial meniscus tear is controversial. This study was conducted to determine the effect of pre-operative medial meniscus extrusion (MME) on arthroscopic surgery outcomes in the osteoarthritic knee associated with medial meniscus tear during a minimum 4-year follow-up.@*METHODS@#This was a retrospective review of a total of 131 patients diagnosed with osteoarthritic knee associated with medial symptomatic degenerative meniscus tear who underwent arthroscopic surgery from January 2012 to December 2014 and were observed for more than 4 years. Patients were classified into two groups: MME ≥3 mm (major MME group, n = 54) and MME <3 mm (non-major MME group, n = 77). Clinical assessments, including the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and radiographic assessments, including the Kellgren-Lawrence (K-L) grade and medial joint space width (JSW), were evaluated pre-operatively and at final follow-up. The longitudinal changes of clinical and radiographic parameters (WOMAC and the medial JSW change, K-L grade progression) were compared between groups unadjusted and adjusted for age, sex, and body mass index. Four-year survival rates (without progression to knee replacement [KR]) were also evaluated using a log-rank test and Cox proportional hazard regression model.@*RESULTS@#Major MME was present in 41% of patients. After a minimum 4-year follow-up, the mean WOMAC total and pain scores improved significantly in both groups. However, the medial JSW and K-L grade worsened significantly. Patients with pre-operative major MME worsened more in WOMAC total (adjusted mean difference [MD] 3.800, 95% confidence interval [CI]: 0.900, 11.400; P = 0.037) and function (adjusted MD 3.100, 95% CI: 0.700, 6.300; P = 0.038) scores than patients with pre-operative non-major MME, and no significant difference was observed in WOMAC pain and stiffness score between groups. The group with major MME had significantly higher joint space narrowing (adjusted MD -0.630, 95% CI: -1.250, -0.100; P = 0.021) and K-L rate progression (adjusted mean relative risk [RR] 1.310, 95% CI: 1.100, 1.600; P = 0.038) than the group with non-major MME. There was a significantly more KR progression in patients with major MME compared with those with non-major MME (adjusted RR 3.100, 95% CI: 1.100, 9.200; P = 0.042 and adjusted hazard ratio 3.500, 95% CI 1.100, 9.500; P = 0.022).@*CONCLUSIONS@#Osteoarthritic knee patients associated with medial meniscus tear with non-major MME are more responsive to arthroscopic surgery in terms of the clinical and radiologic outcomes and survival for at least 4-year follow-up; however, in terms of pain relief, arthroscopic surgery in patients with major MME is also beneficial as well as in patients with non-major MME.
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Objective To study the effect of flumazenil on hypnotic mice induced by diazepam and zolpidem ,and to eval-uate the possibility of flumazenil oral administration .Methods First ,Kunming mice were injected intraperitoneally with nor-mal saline and sodium pentobarbital (S + W) ,diazepam and pentobarbital sodium (D + W) ,zolpidem and pentobarbital sodi-um (Z + W) .The hypnotic effect of diazepam and zolpidem on prolonging the sleep time of pentobarbital sodium would be ver-ified by (D + W) group and (Z + W) group .Then the mice were injected intraperitoneally with flumazenil .The sleep time was used as the evaluation index to evaluate the effect of flumazenil against hypnosis . Finally , the oral administration of flumazenil was observed against hypnosis ,which was evaluated by using sleep time as an index .Results Compared with the control group (S+W) ,the diazepam group (D+W) and the zolpidem group (Z+W) significantly prolonged the sleep time in-duced by pentobarbital sodium (P<0 .001 ,P<0 .05);After Intraperitoneal injection of flumazenil ,compared with the diazepam group (D+W) and the zolpidem group (Z+W) ,the sleep time of the diazepam group [F(ip)+D+W] and the zolpidem group [F(ip)+Z+W] were significantly shorter (P<0 .001 ,P<0 .05);After oral administration of flumazenil ,the sleep time of the diazepam group [F(ig)+ D+ W] and the zolpidem group [F(ig)+ Z+ W] were also significantly shorter (P< 0 .001 ,P<0.05) .Conclusion Flumazenil ,whether intraperitoneal injection or intragastric administration ,could antagonize the hypnotic effect of diazepam and zolpidem .It was proved that oral administration of flumazenil had the same effect compared with intrap-eritoneal injection of flumazenil ,which provided the possibility of preparation of oral administration of flumazenil .
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Vitamin A plays a significant role in maintaining normal metabolism, cell differentiation, reproduction, vision and anti-infection. As a major food source of vitamin A for infants, the level of vitamin A in breast milk is highly important. Recent studies have shown that vitamin A levels in breast milk varied significantly in different stages of lactation, populations, regions and gestational ages at delivery. Moreover, studies demonstrated that it was also affected by many factors, such as maternal serum vitamin A levels and amounts of supplements during pregnancy, maternal vitamin A intake during lactation, maternal diet, high or low risk pregnancy, and vitamin A reservation in maternal liver. It is vital to understand the level of vitamin A in breast milk and its influencing factors to improve breast-feeding.
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Objective To investigate the effect of inhalation of budesonide combined with ambroxol hydrochloride in the treatment of chronic obstructive pulmonary disease ( COPD ) in acute exacerbation stage . Methods 60 patients with acute exacerbation of COPD treated in the Department of respiratory medicine of Zhenhai People's Hospital from January 2013 to December 2015 were selected as the research subjects in Ningbo , and they were randomly divided into control group and observation group according to the digital table ,with 30 cases in each group.The control group received routine treatment, the observation group was given budesonide and ambroxol hydrochloride inhalation on the basis of conventional therapy .After 1 week of treatment ,the clinical efficacy indicators of pulmonary function,arterial blood gas analysis index,time of symptoms were compared between the two groups . Results The total effective rate of the observation group was 100.0％,which was higher than 83.3％of the control group (χ2 =5.455,P<0.05).After treatment,the forced expiratory volume in one second (FEV1),the ratio of FEV1 and forced vital capacity (FVC) (FEV1/FVC),arterial partial pressure of carbon dioxide (PaCO2),arterial oxygen pressure (PaO2) in the observation group were (2.09 ±0.69)L,(58.94 ±15.67)％,(35.08 ±3.79)mmHg, (85.92 ±4.97)mmHg,respectively,which in the control group were (1.43 ±0.57)L,(43.12 ±11.03)％,(48.47 ± 4.24)mmHg,(79.54 ±4.56)mmHg,respectively,the differences between the two groups were statistically significant (t=4.039,4.522,12.896,5.181,all P<0.05).The remission time of shortness of breath ,cough,expectoration in the observation group were (2.04 ±0.86)d,(4.49 ±1.25)d,(4.56 ±1.34)d,respectively,which were shorter than those in the control group [(3.36 ±1.08)d,(6.53 ±1.82)d,(6.78 ±1.91)d],the differences between the twogroups were statistically significant (t=5.237,5.061,5.212,all P<0.05).Conclusion Inhalation of budesonide combined with ambroxol hydrochloride in the treatment of acute exacerbation of COPD can effectively improve the treatment effect , and the pulmonary ventilation function and arterial blood gas status , and shorten the time of remission,and is benefit to disease control .
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Flumazenil ,a benzodiazepine antagonist ,specifically binds the benzodiazepine receptors in central nervous system and reduces the release of gamma-aminobutyric acid .It is used for the reversal of sedative effects of benzodiazepine and benzodiazepine-induced anesthesia .In this article ,the clinical applications of flumazenil and the developments of different dos-age forms were reviewed .
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Photo-sensitive reactive oxygen species (ROS) responsive liposomes loaded with 1,4,8,11,15, 18,22,25-octabutoxypalladium phthalocyanine[PdPC(OBu)8] and doxorubicin hydrochloride (DOX) (LPD) were prepared by (NH4)2SO4-gradient method. LPD was characterized with transmission electron microscopy (TEM), dynamic light scattering particle size, zeta potentials, photo-sensitive ROS-responsive DOX release behaviors and the serum stability in vitro. LPD cytotoxicity, DOX uptake and singlet oxygen production in MCF-7 cells were evaluated. The results showed that the particle size of LPD was (169.3 ±1.2) nm, PDI of LPD was 0.198 ±0.003 and zeta potentials of LPD was (-39.8 ±0.8) mV. The accumulated release of DOX reached 95.5% in 5 min under 730 nm laser irradiation (300 mW·cm-2). The DOX uptake of liposome was increased and 1O2 was generated. The half inhibition concentration (IC50) of DOX in LPD with irradiation group was decreased by 85.7% and no irradiation group was decreased by 67.9% compared with free DOX group in MCF-7 cells. Therefore, photo-sensitive ROS-responsive liposomes would be a promising drug delivery system for tumor therapy.
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Excessive reactive oxygen species (ROS) is associated with an array of pathological conditions, including cancer, diabetes, cardiovascular diseases, and neurodegenerative diseases. However, ROS-responsive materials have drawn attention in the development of drug delivery systems. There are many types of ROS-responsive materials explored in drug delivery applications, including sulfur-based responsive polymers, selenium-based responsive polymers, tellurium-based responsive polymers, oxalate ester-containing polymers, phenylboronic ester-containing polymers and unsaturated lipids. When integrated with ROS-responsive drug delivery systems, a photosensitizer is used as a light-sensitive element to generate ROS, mainly singlet oxygen (1O2), which in turn activates the ROS-triggered drug delivery.
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Objective To analyze the viral infection in patients with acute exacerbation of chronic obstructive pulmonary disease(COPD)and its clinical significance.Methods 350 patients with acute exacerbation of COPD were collected.The viral infection and clinical manifestations,pulmonary function and imaging features were detected and analyzed.Results A total of 104 patients with viral infection,the proportion was 29.7%.Single virus infection in 74 cases(71.2%),the highest proportion was FluB(19.2%)in pathogen type,followed by FluA(15.4%).Multiple virus infection in 30 cases(28.8%),the highest proportion was RSV+FluB(11.5%).The virus infection in patients with sore throat(20.2% vs.6.9%),lung function grade(32.7% vs.20.3%),presence of pulmonary inflammatory lesions(57.7% vs.40.7)and the death rate(12.5% vs.0.8%)were significantly higher than those of the combined group of virus infection,the proportion of lung function was significantly lower than patients without viral infection,the differences were statistically significant(x2=6.546,5.477,4.987,4.124,3.997,all P<0.05).The proportion of respiratory failure in patients with acute COPD infection was 86.5%,which was higher than 62.6% of patients without viral infection,the difference was statistically significant(x2=19.837,P<0.05).Conclusion Acute exacerbation of COPD has a high proportion of virus infection,and the prognosis of patients is poor.
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The selective melatonin receptor agonism effect of ramelteon is useful for insomnia. Here we wanted to present a refractory chronic migraine case, who had significant improvements in migraine after using ramelteon. The possible mechanism for the ramelteon in the migraine relief might be related to melatonin effects.