IL-1β inhibitor sensitizes to olaparib in homologous recombination deficiency proficient ovarian cancer cells / 中华妇产科杂志

Objective:To investigate the inhibitory effect of combined strategy of poly adenosine diphosphate ribose polymerase (PARP) inhibitor and interleukin-1β (IL-1β) inhibitor on homologous recombination deficiency (HRD)-proficient ovarian cancer cells.Methods:(1) HRD-proficient ovarian cancer cell lines OVCAR3 and CAOV3 were treated with PARP inhibitor olaparib. Screening by RNA sequencing analysis, the expression level of IL-1β was validated by enzyme-linked immunosorbent assay (ELISA) and western blot. (2) The dose-response curves of IL-1β inhibitor diacerein were evaluated by cell counting kit-8 (CCK-8) assays in OVCAR3 and CAOV3 cells. CCK-8 assays were further applied to determine the viabilities of OVCAR3 and CAOV3 cells. (3) To evaluate the synergistic effects of olaparib and IL-1β inhibitor in vivo, the transplanted ovarian cancer model was constructed. BALB/c-nude mice ( n=16) were injected intraperitoneally with 1×10 7 OVACR3 cells labelled with luciferase (OVCAR3-Luc). Immunohistochemistry (IHC) assay was performed to determine nuclear antigen associated with cell proliferation (Ki-67) expression. (4) Blood routine tests, kidney and liver function tests were performed to analyze the toxic reaction of different drug treatments. The potential drug-induced injuries of vital organs including heart, liver, spleen, lungs and kidneys of nude mice were determined by hematoxylin-eosin (HE) staining. Results:(1) The RNA sequencing results showed that the mRNA level of IL-1β was the most significantly increased among the 25 differentially expressed genes in OVCAR3 cells treated with olaparib, compared to the negative control group. Olaparib treatment significantly promoted the secretion and expression of IL-1β protein in both OVACR3 and CAOV3 cells by ELISA [(36.2±3.5) and (49.5±3.5) pg/ml, respectively; all P<0.001] and western bolt (2.87±0.37 and 2.05±0.08, respectively; all P<0.01). (2) The half maximal inhibitory concentration (IC 50) value of IL-1β inhibitor was determined as follows: 75 μmol/L for OVACR3 cells and 100 μmol/L for CAOV3 cells. The treatments were divided into four groups including control group, olaparib monotherapy group, IL-1β inhibitor monotherapy group and the combination therapy group. The cell viabilities of each group in OVCAR3 and CAOV3 were determined by CCK-8 assay. The data in each group were showed as follows for OVCAR3 and CAOV3 cells: (100.0±0.4)% and (100.0±3.5)% in control group; (63.1±6.2)% and (63.3±3.8)% in olaparib monotherapy group; (61.6±4.7)% and (63.8±3.5)% in IL-1β inhibitor monotherapy group; and (32.9±5.2)% and (30.0±1.3)% in the combination therapy group. The viability assay showed that the combined strategy exhibited a significant inhibition effect on OVACR3 and CAOV3 cells, compared to the monotherapy group and the control group (all P<0.01). (3) All mice with transplanted tumors of HRD-proficient ovarian cancer cells were randomly divided into four groups, and treated with four different treatments as mentioned above, respectively. After 4 weeks (on day 29), the vivo fluorescence imaging were determined. The results showed that the amount of fluorescence of transplanted tumors was mostly decreased in the combination therapy group [(0.5±0.4)×10 10 p/s], compared to the control group [(4.2±1.0)×10 10 p/s] or the groups treated with any single drug [(3.1±0.9)×10 10, (2.2±0.9)×10 10 p/s; all P<0.05]. Mice were then sacrificed under anesthesia, and all transplanted tumors detached and weighed for further investigation. The weight of transplanted tumors was significantly decreased in the combination therapy group [(0.09±0.03) g], compared to that in control group [(0.25±0.05) g] or groups treated with any single drug [(0.17±0.03), (0.19±0.04) g; all P<0.05]. The measurement of the expression of Ki-67 showed that it was significantly decreased in the combination therapy group (0.33±0.10), compared to that in the control group (1.00±0.20) or monotherapy groups (0.76±0.07, 0.77±0.12; all P<0.05). (4) There were no significant differences of body weights, blood routine test, renal and liver function tests among mice with different treatments (all P>0.05). Moreover, no significant injuries were observed in the vital organs among the four groups. Conclusions:The combination of olaparib and IL-1β inhibitor synergistically exhibits significant cytotoxicity in HRD-proficient ovarian cancer cells. Moreover, the blood routine and blood biochemistry results confirmed the biosafety of the combination of olaparib and IL-1β inhibitor.

Applications of nuclear magnetic resonance spectroscopy in the screening of new psychoactive substances / 中国药科大学学报

@#GC-MS and LC-MS are the main techniques used for the structural identification of new psychoactive substances at present. However, they are hard to give accurate structure information because of the hardly available corresponding reference standards and the quickly changing status of these compounds. This leads tremendous obstacle on the rapid identification of new psychoactive substances. Nuclear magnetic resonance spectroscopy is one of the most effective methods for structures identification. Therefore, NMR is especially suitable for the analysis and identification of new psychoactive substances even with rapid structural changes. This article summarizes the NMR applications for the structural analysis of new psychoactive substances including synthetic cannabinoids, synthetic cathinones, piperazines, phenethylamines, ketamine & phencyclidine-type substances, and fentanyls. It is found that the NMR signals of the main frame structure of each kind of the new psychoactive substances are basically the same. Hence, these frame structure NMR signals can provide scientific evidence for the rapid identification of new psychoactive substances. This article also look ahead the prospect for the application of LC-NMR and DOSY in new psychoactive substances, which provides new ideas for the screening of new psychoactive substances.

Study on the roles of SDF-1/CXCR4 axis in imatinib resistance of K562 cells co-cultured with the bone marrow stromal cells / 中国医师杂志

Objective To investigate influences of co-culture with the bone marrow stromal cells (BMSCs) on imatinib sensitivity,and the role of stromal cell-derived factor-1 (SDF-1)/chemokine receptor 4 (CXCR4) axis in imatinib resistance of K562 cells in the co-culture model.Methods The model was constructed by co-culturing K562 cells with BMSCs isolated and cultured from the patients with chronic myeloid leukemia.The apoptosis rate and the CXCR4 expressing rate of the K562 cells exposed to 0.5 μmol/L imatinib for 72 hours were detected by fluorescent-activated cell scanning (FACS) machine.The K562 cells were exposed to 0.5 μmol/L imatinib for 4 hours,and labelled by calckin-AM fluorescent labeling sytem.The adhesion rate of the K562 cells co-cultured with BMSCs for 24 hours was calculated with fluorescence intensity.The IC50 value of K562 cells exposed to imatinib was detected by methyl thiazolyl tetrazolium (MTT) assay while the SDF-1/CXCR4 axis was blocked by 10 μg/ml monoclonal antibody of CXCR4.Results The apoptosis rate of K562 cells exposed to 0.5 μmol/L imatinib for 72 hours in co-culture group and suspension culture group was (15.48 ±4.17) ％ and (32.01 ±6.83) ％,respectively.The apoptosis rates of K562 cells in the two groups were significantly different (t =5.587,P =0.001).For the co-culture group,the CXCR4 expressing rates of K562 cells unexposed and exposed to 0.5 μmol/L imatinib for 72 hours were (20.31 ± 3.76) ％ (suspension cultured:11.28％ ± 3.44％) and (53.64 ± 5.35) ％ (suspension cultured:25.34％ ± 3.21％),respectively.Those results showed that co-culture with BMSCs and exposure to imatinib induced the K562 cells to express CXCR4.The adhesion rates of the K562 cells to the BMSCs were elevated from (42.18 ± 6.17) ％ to (68.97 ± 11.08) ％ when the K562 cells were exposed to 0.5 μmol/L imatinib for 4 hours.The IC50 values of block group (the SDF-1/CXCR4 axis was blocked by 10 μg/ml monoclonal antibody of CXCR4) and unblock group were (0.68 ± 0.04) μmol/L and (1.27 ± 0.05) μmol/L,respectively.The IC50 values of two groups were significantly different(t =4.869,P =0.001).Conclusions The K562 cells co-cultured with the BMSCs from the patients with chronic myeloid leukemia can obtain resistance to imatinib,which was related with that co-culture with the BMSCs and exposure to imatinib can induce the K562 cells to express CXCR4.To a certain extent,the imatinib resistance mediated by co-culture with BMSCs can be reversed by monoclonal antibody of CXCR4.

Clinical study on sildenafil in treatment of pregnant women with pulmonary arterial hypertension / 中华妇产科杂志

Objective To explored the effect of sildenafil in treatment of pregnant women with pulmonary arterial hypertension.Methods From January 2012 to November 2013,64 pregnant women with pulmonary arterial hypertension (PAH) were randomly divided into group and control group.Control group:16 cases with mild and 16 cases with moderate PAH.To treatment with low-flow oxygen,low-salt diet therapy,cardiac,etc.sildenafil group:15 cases were mild pulmonary hypertension,and 17 cases moderate PAH.Treatment sildenafil 25 mg,rid in this study.Then the variation of the blood oxygen saturation,pulmonary artery systolic pressure,hemodynamic parameters and pregnancy outcome,including delivery modes,neonatal weight,morbidity of mother and fetus were compared.Results (1) Cardiac function and pulmonary hypertension:control group:the proportion of cardiac functional class Ⅰ-Ⅱ reduced from 81％ (26/32) to 56％ (18/32) significantly after treatment (P ＜ 0.05).Sildenafil group:the proportion of cardiac functional class Ⅰ-Ⅱ increased from 75％ (24/32) to 84％ (27/32) significantly after treatment (P ＜ 0.05).Between two groups,the proportion of mild and moderate turning to server PAH patients were significant differentce (P ＜ 0.05).(2) The pregnancy outcome of two group:the premature birth rate,low birth weight rate and cesarean section rate of 9％ (3/32),9％ (3/32)and 69％ (22/32)in sildenafil group were significantly lower than 16％ (5/32),19％ (6/32) and 81％ (26/32) in control group (P ＜0.05).The rate of vaginal delivery,term pregnancy and neonatal weight of 31％ (10/32),91％ (29/32) and (3 214 ±306) g in sildenafil group were different with 19％ (6/32),84％ (27/32) and (3 004 ±458) g in control group (P ＜ 0.05).(3) Hemodynamic parameters:in control group,arterial partial pressure of oxygen,oxygen saturation and left ventricular ejection fraction,pulmonary systolic pression were (80 ± 5) ％ to (72 ±8)％,(87 ±8) to(83±9) mmHg(1 mmHg=0.133 kPa),0.77 ±0.24 to 0.70 ±0.38 and (63 ±9) to (69 ± 12) mmHg before and after treatment,which showed remarkable decreased trends(P ＜ 0.05).The other parameter were not significantly different (P ＞ 0.05).In sildenafil group,arterial partial pressure of oxygen,oxygen saturation and left ventricular ejection fraction,pulmonary systolic pression showed increased trend before and after treatment,which were (80 ± 9) ％ to (88 ± 9) ％,(84 ± 3) to (89 ± 7) mmHg,0.70 ± 0.32 to 0.79 ± 0.27 (P ＜ 0.05),in the mean time,pulmonary systolic pression showed decreased trend from (65 ± 18) to (60 ± 13) mmHg (P ＜0.05).The other parameter did not show significant different (P ＞ 0.05).Conclusions Sildenafil treatment can significantly improve the clinical symptoms,cardiac function and hemodynamic parameters.It also could significantly improve pregnancy outcomes,reduce premature delivery,the incidence of low birth weight children,and cesarean section rate.

Adherence to treatment with imatinib in chronic myeloid leukemia: a study of the first decade of responses obtained at a Brazilian hospital

Objetive: The aim of this study was to identify the reasons for failure in adherence to imatinib mesylate treatment in chronic myeloid leukemia. Methods: A retrospective review was performed of 100 non-electronic records of patients with Ph+ chronic myeloid leukemia treated with imatinib mesylate. The study period was from January 2001 to January2011. Data were analyzed by Chi-Square and Correspondence analysis using the Statistical Analysis System software package. Results: At the beginning of treatment 41% of patients were in advanced stages of the disease. The unavailability of the drug (44.8%) and myelotoxicity (25.7%) were the most frequent reasons for interruption. The adherence rate was < 90% in 47% of the cases. The low adherence influenced the cytogenetic response (p-value = 0.020) and molecular response (p-value = 0.001). Very high adherence (> 95%) induced complete cytogenetic response, major cytogenetic response and major molecular response. Conclusion: The population of this study obtained lower-than-expected therapeutic responses compared to other studies. .

Chronic myeloid leukemia: an overview of the determinants of effectiveness and therapeutic response in the first decade of treatment with imatinib mesylate in a Brazilian hospital

Background: In the last decade, there has been a revolution in chronic myeloid leukemia treatment with the introduction of tyrosine kinase inhibitors with imatinib mesylate becoming the frontline therapy. Objective: To evaluate the therapeutic efficacy of imatinib mesylate in treating chronic myeloid leukemia patients and to identify factors related to therapeutic efficacy. Methods: This retrospective study was based on information obtained from patients'records in the Hematology Service of Hospital Universitário Walter Cantídio of the Universidade Federal do Ceará (HUWC / UFC). All patients diagnosed with chronic myeloid leukemia that took imatinib mesylate for a minimum of 12 months in the period from January 2001 to January 2011 were included. From a population of 160 patients, 100 were eligible for analysis. Results: The study population consisted of 100 patients who were mostly male (51%) with ages rangingbetween 21 and 40 years (42%), from the countryside (59%), in the chronic phase (95%), with high-riskprognostic factors (40%); the prognosis of high risk was not associated with complete hematologic responseor complete cytogenetic response, but correlated to complete molecular response or major molecularresponse. Reticulin condensation was associated with complete hematologic response and completecytogenetic response. It was found that 53% of patients had greater than 90% adherence to treatment. Thehigh adherence was correlated to attaining complete cytogenetic response in less than 12 months. Moreover,20% of patients had good response. Conclusion: Significant changes are indispensable in the monitoring of patients with chronic myeloid leukemia. Thus, the multidisciplinary team is important as it provides access to the full treatment and not just to medications. .

Chronic myeloid leukemia BCR/ABL1 mutation clonal evolution and treatment strategies / 中华检验医学杂志

Application of imatinib has made a lot of chronic myeloid leukemia (CML) patients longterm survival,but the CML BCR/ABL1 kinase domain mutations (KDM) will result in drug resistance of imatinib.There are many KDM types.The different types appear randomly.The leukemic clone with different KDM characteristics has a certain evolution.In the period of imatinib treatment,a higher degree of drug resistance mutations in cells likely to develop as the dominant clone.It is suggested that the treatment of imatinib-resistant CML in addition to efforts to develop next-generation tyrosine kinase inhibitors outside,but also consider the use of traditional medicine to help cure.

Imatinib resistance: a review of alternative inhibitors in chronic myeloid leukemia

The development of point mutations in the BCR-ABL kinase domain is the main reason for imatinib resistance in chronic myeloid leukemia. Different detection methods are used in chronic myeloid leukemia monitoring, such as direct sequencing, denaturing high performance liquid chromatography and allele specific polymerase chain reaction. Mutation analysis has become mandatory during patient workup of chronic myeloid leukemia in order for the physician to choose the most suitable tyrosine kinase inhibitor. This article, a review of possible therapies used to overcome imatinib resistance, investigates the current position by searching the PubMed electronic database using the following keywords: imatinib, dasatinib, nilotinib, aurora kinase, SRC kinase, mutation, treatment, drugs and resistance. New tyrosine kinase inhibitors include BCR-ABL kinase selective inhibitors, dual ABL/SRC kinase inhibitors and aurora kinase inhibitors. Awareness of the spectrum of new drugs against mutations, in particular the T315I mutation, makes it possible to properly select the best therapy for each patient.

Influence of sildenafil and buflomedil on survival of randomized flaps in rats: an experimental study / Influência do buflomedil e do sildenafil na sobrevivência de retalhos randomizados em ratos: estudo experimental

BACKGROUND: Microcirculation dysfunction, as a consequence of localized vascular insufficiency, is considered to be one of the dominant causes of surgical flap necrosis. Several vasoactive drugs have been tested for the pharmacological treatment of tissue ischemia, with varying degrees of success. This study aimed to assess the impact of buflomedil and sildenafil on the viability of random skin flaps in rats. METHODS: Caudally pedicled skin flaps (10 x 3 cm) were created on the backs of rats. The animals were randomly assigned, in groups of 10, to three treatment groups: one group served as the vehicle control group, one group received buflomedil (10 mg/kg/d, orally), and a third group received the same dosage of sildenafil. Following seven days of dosing, the animals were sacrificed, and the viable flap area was determined. RESULTS: The average viable flap area for each group was: 16.2 ± 3.56 cm² (control group), 17.69 ± 2.54 cm² (buflomedil group), and 18.28 ± 3.74 cm² (sildenafil group). Data analysis by the Kruskal-Wallis test failed to show a statistically significant difference between the three groups. CONCLUSIONS: Neither buflomedil nor sildenafil showed a reduction in the necrotic area of random skin flaps in rats.

INTRODUÇÃO: A insuficiência no aporte sanguíneo e a consequente disfunção gerada no fluxo da microcirculação são consideradas causas dominantes de sofrimento de um retalho cirúrgico. Várias drogas vasoativas têm sido testadas para o tratamento farmacológico da isquemia tecidual, porém com graus variáveis de sucesso. Este estudo teve como objetivo avaliar a influência do buflomedil e do sildenafil na viabilidade de retalhos cutâneos ao acaso, em ratos. MÉTODO: Foram confeccionados retalhos cutâneos no dorso de ratos, com dimensões de 10 x 3 cm e base caudal. Foram utilizados 30 ratos, divididos em três grupos de 10 ratos cada: um grupo que recebeu apenas o veículo da solução (grupo controle); um grupo que recebeu buflomedil (grupo buflomedil); e um terceiro grupo que recebeu sildenafil (grupo sildenafil). A via de administração foi a oral e a dose foi de 10 mg/kg/dia para cada droga, durante sete dias. Ao final desse período, os animais foram sacrificados, sendo realizada a determinação das áreas viáveis dos retalhos. RESULTADOS: A média das áreas viáveis dos retalhos foi de 16,2 ± 3,56 cm² para o grupo controle, de 17,69 ± 2,54 cm² para o grupo buflomedil, e de 18,28 ± 3,74 cm² para o grupo sildenafil. A análise dos dados pelo teste de Kruskal-Wallis não demonstrou significância estatística entre os três grupos. CONCLUSÕES: A utilização do buflomedil e do sildenafil demonstrou não diminuir a área de necrose de retalhos randomizados em ratos.

Efficacy and impact of premedication with eszopiclone on sleep structure of patients with acute insomnia / 中华神经科杂志

Objective To evaluate the efficacy of eszopiclone for patients with acute insomnia and the impact of premedication with eszopiclone on sleep structure of patients with acute insomnia.Methods In an open-label,self-control trial was conducted at Changzheng Hospital Sleep Centers,and patients (n =32) with acute insomnia (12 men,20 women; mean age,36.2 years) were administered eszopiclone 3 mg for three consecutive nights.Sleep was monitored via polysomnography.The insomnia severity index (ISI),and mini-mental state examination (MMSE) were used to assess the degree of insomnia and impact of drugs on cognitive function during the day.Results Eszopiclone can shorten sleep latency ( before treatment:(52.92 ± 11.71 ) min,after treatment:(28.2 ± 10.11 ) min; t =-4.376,P ＜0.01 ),prolong total sleep time(before treatment:(365.22 ±30.13) min,after treatment:(429.18 ±26.93 ) min; t =4.102,P ＜ 0.01 ),decrease wake up times( before treatment:( 5.00 ± 1.92 ) times,after treatment:( 2.73 ± 0.91 )times; t =- 4.592,P ＜ 0.01 ),improve sleep efficiency ( before treatment:72.69％ ± 6.32％,after treatment:82.67％ ± 4.16％ ; t =3.371,P ＜ 0.01 ),reduce awake time ( before treatment:( 88.51 ±17.48) min,after treatment:(65.93 ±21.l0)min; t =-4.592,P ＜0.01 ),decrease light sleep ( NREM1 period) the percentage of time ( before treatment:12.54％ ± 2.10％,after treatment:7.30％ ± 2.90％ ;t=-3.155,P ＜ 0.01 ),and increase the percentage of slow wave sleep (before treatment:8.03％ ±5.37％,after treatment:9.31％ ±5.29％; t =4.228,P ＜0.01).No effect was observed on the percentage of NERM2 period (t =0.731,P ＞0.05) and REM period (t =-0.813,P ＞0.05).Eszopiclone can improve the quality of subjective assessment of sleep ( ISI score decreased,t =- 2.551,P ＜ 0.05) and has no significant effect on cognitive function on first the morning after patients taking the medication.Conclusion Eszopiclone can positively regulate the sleep structure in patients with acute insomnia and improve subjective assessment of sleep quality.It is safe and has no significant effect on cognitive function.

Efficacy of different doses of urapidil in preventing pituitrin-induced cardiovascular responses in patients undergoing laparoscopic myomectomy / 中华麻醉学杂志

ObjectiveTo evaluate the efficacy of different dones of urapidil in preventing pituitrin-induced cardiovascular responses in patients undergoing laparoscopic myomectomy.MethodsSixty ASA Ⅰ or Ⅱ patients,aged 27-41 yr,weighing 55-65 kg,scheduled for elective laparoscopic myomectomy under general anesthesia,were randonly divided into 4 groups (n =15 each):control group (group C) and urapidil 0.3,0.5 and 0.8 mg/kg groups (groups U1-3).Urapidil 0.3,0.5 and 0.8 mg/kg were injected intravenously in U1-3 groups respectively,while normal saline 5 ml was given in group C.The mixture of pituitrin 6 U and normal saline 20 ml was injected into the site of hysteromyoma 5 min later.The operation was then started.BIS value was maintained at 45-55.The occurrence of cardiovascular responses was recorded.ResultsThe incidences of cardiovascular responses were 100％,67％,40％ and 20％ in groups C and U1-3 respectively.The incidence of cardiovascular responses was significantly lower in groups U1-3 than in group C,and in groups U2.3 than in group U1 ( P ＜ 0.01 ).There was no significant difference in the incidence of cordiovascular responses between U2 and U3 groups (P ＞ 0.05).ConclusionUrapidil can prevent pituitrin-induced cardiovascular responses in patients undergoing laparoscopic myomectomy and the optimal dose is 0.5 mg/kg.

α1A-adrenocepter chromatography in studying biological affinity of piperazine compounds / 第二军医大学学报

Objective: To use α1A-AR (α1A- adrenoceptor) chromatography for studying the biological affinity of piperazine compounds. Methods: Affinity chromatography was used to purify α1A-AR obtained from rabbit heart. α1A-AR was immobilized on macroporous silica through the covalent bond by mild chemical coupling methods. The retention characteristics of α1A-AR column were investigated with terazosin, norepinephrine, tamsulosin, metaraminol, and urapidil. Six piperazine compounds were synthesized, and the interactions between the compounds and α1A-AR were investigated by the chromatographic model. Results: Biological affinity was found between the synthesized piperazine compounds and α1A-AR, with the order of affinity intensities being compound 3> compound 4> compound 1> compound 2> compound 5> compound 6. Conclusion: α1A-AR chromatography is a specific and reliable biological affinity chromatography and can be used for preliminary study of drug activity.

Monitoring imatinib plasma concentrations in chronic myeloid leukemia

Imatinib has proved to be effective in the treatment of chronic myeloid leukemia, but plasma levels above 1,000 ng/mL must be achieved to optimize activity. Therapeutic drug monitoring of imatinib is useful for patients that do not present clinical response. There are several analytical methods to measure imatinib in biosamples, which are mainly based on liquid chromatography with mass spectrometric or diode array spectrophotometric detection. The former is preferred due to its lower cost and wider availability. The present manuscript presents a review of the clinical and analytical aspects of the therapeutic drug monitoring of imatinib in the treatment of chronic myeloid leukemia. The review includes references published over the last 10 years. There is evidence that the monitoring of plasmatic levels of imatinib is an useful alternative, especially considering the wide pharmacokinetic variability of this drug.

Dasatinib: clinical trials and management of adverse events in imatinib resistant/intolerant chronic myeloid leukemia

Dasatinib is a highly effective second generation tyrosine kinase inhibitor approved for the treatment of imatinib-resistant or intolerant chronic myeloid leukemia and Philadelphia-positive acute lymphoblastic leukemia. This article reviews the results of phase I, II and III studies and looks at the efficacy and safety of dasatinib. This review also provides practical recommendations for the management of side effects.

Effects of N,N'-dinitrosopiperazine on cell proliferation in nasal and nasopharyngeal epithelia and expression levels of TRAF2 and p16 genes in transgenic mice / 中国耳鼻咽喉头颈外科

OBJECTIVE To investigate the effects of N,N'-Dinitrosopiperazine (DNP) on the cell proliferation of nasal and nasopharyngeal epithelia and the expression levels of TRAF2 and p16 genes in TgN (p53mt-LMP1)/HT transgenic mice and the relationships between them.METHODS The epithelial proliferating characteristics of nasal cavity and nasopharynx in TgN (p53mt-LMP1)/HT cancerous lesion inducing group treated by DNP (TI),TgN (p53mt-LMP1)/HT controlling group (TC), C57BL/6J cancerous lesion inducing group (CI) treated by DNP and C57BL/6J controlling group (CC) were observed for pathological evaluation by HE staining,and the expression levels of TRAF2 and p16 genes in these tissue samples were determined by immunohistochemical methods.RESULTS The occurring rates of precancerous lesions in nasal and/or nasopharyngeal epithelia in TI,TC,CI and CC groups were 90%,10%,0 and 0,respectively (P

Pharmacokinetics of dipfluzine hydrochloride in Beagle dogs after single intravenous dose / 中国药理学通报

Aim To investigate the pharmacokinetics of dipfluzine hydrochloride,a novel piperazines calcium antagonist.Methods Eighteen Beagle dogs were randomly divided into three groups,which were administered with dipfluzine hydrochloride at iv single dose of 1.5,3.0 and 6.0 mg?kg-1,respectively.The blood was collected at different time.A RP-HPLC method was developed to determine the concentration of dipfluzine hydrochloride in plasma.The pharmacokinetic parameters were calculated by 3P97 software.Results The specificity,lowest limit of detection and quantification,extraction recoveries,the precision of intra-and inter-day and stability were qualified to the pharmacokinetic study.The concentration-time courses of dipfluzine hydrochloride were best fitted to a two-compartment open model at three doses.The main pharmacokinetic parameters at three doses were 24.7,24.2 and 29.6 h for T12?,0.44,1.12 and 2.86 g?min?L-1 for AUC,1.30,1.22 and 1.28 L?kg-1 for Vc,and 3.4?10-3,2.7?10-3 and 2.1?10-3 L?kg-1?min-1 for CL,respectively.Conclusions The developed RP-HPLC method for determination of dipfluzine hydrochloride in plasma can satisfy the requirement of pharmacokinetic study after iv dipfluzine hydrochloride.Analysis of plasma concentration-time curves indicates a biphasic decrease.There was a linear relationship between AUC and dosage.

Neuroprotective effects of AM-36 on traumatic brain injury induced by fluid percussion in rats / 中华创伤杂志

Objective To investigate neuroprotective effect of AM-36 on secondary brain injury following traumatic brain injury(TBI)in rats.Methods A total of 38 male Sprague-Dawley rats were divided into an experimental group,a control group and a sham operation group,then sustained to moder- ate TBI.AM-36(0.1 ml/100 g)was administered intraperitoneally in the experimental group and isoton- ic saline solution was administered intraperitoneally in the control and the sham operation groups at 30 mi- nutes,24 and 48 hours after TBI,respectively.The brain water content was determined at 24 hours after TBI.Rats were sacrificed by decapitation at 24 hours or one week after TBI for observing histological changes in peripheral cortex,thalamus and hippocampus by means of Hematoxylin and Eosin staining and Fluoro-Jade(F-J)staining.Results The brain water content of bilateral hemispheres 24 hours after TBI in the experimental group was significantly decreased,compared to that of the control group.Histo- logical examination revealed less degenerating neurons(F-J positive neurons)in the cortex,thalamus, CAI and CA3 of the hippocampus in AM-36 treated rats 24 hours and one week after injury(P＜0.05). Conclusion Systemic administration of AM-36 at the early stage after TBI can decrease brain water content and exert neuroprotective effect on TBI.F-J staining can be used for histopathologic quantitation of neuronal damage,for it can accurately exhibit pathologic changes following TBI induced by fluid per- cussion.

Experimental study on protective effects of Urapidil on heart muscle ischemia and reperfusion injury in rats / 中国医师杂志

Objective To observe the effects of ?1-receptor antagonist Urapidil on the size of myocardial infarction and arrhythmias in the rats model of ischemia-reperfusion(I/R) and to investigate the dose-effect relationship.Methods One hundred Sprague-Dawley rats were randomly divided into 5 groups with 20 rats each: sham operation group,I/R group and therapy group(Urapidil 3 mg/kg,6 mg/kg,12 mg/kg).Ten rats in each group were subjected to 10 min of left anterior descending branch of coronary artery ligation and 15 min of reperfusion and Urapidil was injected 5 min before the ligation.The ventricular arrhythmias of ischemia-reperfusion was observed.The other 10 rats in each group were subjected to 30 min of left anterior descending branch of coronary artery ligation and 40 min of reperfusion.Urapidil was injected 15 min before blood circulation was regained.The content of serumal enzyme and the myocardial infarct size were observed.Results Compared with the I/R group,the incidence of ventricular arrhythmias was lower and the duration of arrhythmias was significantly shorten,as well as the incidence of ventricular fibrillation(VF) and mortality was lower with the treatment of Urapidil in the therapy group.The result showed that the effect of Urapidil was of dose dependent.The release of serumal enzyme resulted from ischemia-reperfusion injury was reduced in therapy group than that of I/R group and there was no significant difference among the different dosages in the therapy group.The myocardial infarct size was significantly lower in the therapy group than that of I/R group and there was no obvious difference among the different dosages in the therapy group.Conclusion There is protective effect on the ischemia-reperfusion injury in rats with the treatment of urapidil with the dosage of 3,6 and 12 mg/kg respectively.

Preparation and bioavailability study of calcitonin oral microparticle in rats / 第二军医大学学报

Objective: To prepare the calcitonin oral microparticle. Methods: The oral delivery system of salmon calcitonin was made using diketopiperazine microparticles as carrier by the method of sole solifification. The parameters including the shape of microparticle,dissolving in vitro , the effect of reducing bleed calcium and bioavailability etc . were observed. Results: The diameter of the microparticles was 1 3 ?m, and the drug concentration was 0.42%. The rate of encapsulating was 91.1%. The drug did not release within 2 h in artificial gastric fluid and completely released in artificial intestinal fluid within 6 h. The microparticles had obvious effect of reducing bleed calcium 3 h after it was taken, the effect lasted for 12 h. Conclusion: The microparticles of salmon calcitonin release slowly and have better effects of reducing bleed calcium by oral delivery system.

Effects of urapidil on discharges of pain-sensitive neurons in thalamic parafascicular nucleus evoked by coronary artery occlusion in rats / 中华麻醉学杂志

Objective To investigate the changes in discharge rates of pain-sensitive neurons (PSN) in thalamic parafaseicular nucleus ( Pf) following coronary artery occlusion (CAO) and the effects of urapidil, a partial 5-HT agonist. Methods One-hundred male SD rats weighing 260-300 g were operated upon under urethane anesthesia and local infiltration of the skin incision. The animals were tracheotomized and mechanically ventilated. A hole was drilled in the skull until the brain was exposed. A single-barrel glass electrode was inserted, aiming at the PSN, the discharges of which were filtered, amplified and recorded. Chest was opened and heart was exposed. A tie was placed around the anterior descending branch of left coronary artery which can be occluded whenever needed. The study was divided into 3 groups : group I CAO alone; group II CAO + urapidil and group III CAO + urapidil + methysergide ( a potent serotonin antagonist). Urapidil 0.21 mg.kg-1 was given intravenously 15 min after CAO. Methysergide 0.1 mg.kg-1 was given iv 20 min after urapidil. Results Discharges of PSN were recorded in 45 animals out of the 100, and the recordings were complete for investigation in 31 animals. CAO evoked significant increase in the discharge frequency of PSN in 18/31 animals. After intravenous urapidil the increased frequency of nociceptive discharges was inhibited; however intravenous methysergide could partially antagonize the antinociceptive effect of urapidil. Conclusion The results indicate that (1 )the nociceptive response could be induced by CAO in rats; (2) Pf nucleus of thafamus is involved in the myocardial ischemia-induced nociceptive response of central nervous system; (3) serotonin plays a critical role in the modulation of the nociceptive signal of acute myocardial ischemia.