• <tr id="yyy80"></tr>
  • <sup id="yyy80"></sup>
  • <tfoot id="yyy80"><noscript id="yyy80"></noscript></tfoot>
  • 99热精品在线国产_美女午夜性视频免费_国产精品国产高清国产av_av欧美777_自拍偷自拍亚洲精品老妇_亚洲熟女精品中文字幕_www日本黄色视频网_国产精品野战在线观看 ?

    Clinical evaluation of Fufangkushen combined with oxaliplatin in the treatment of advanced colorectal cancer

    2022-12-12 11:52:30ZHOUTongWANGShuoHUShuaihangLIZhengFANBingjieLIJingleiHOUWei
    Journal of Hainan Medical College 2022年20期

    ZHOU Tong, WANG Shuo, HU Shuai-hang, LI Zheng, FAN Bing-jie, LI Jing-lei, HOU Wei?

    1. Guang' anmen Hospital Affiliated to China Academy of Chinese Medical Sciences, Beijing 100053, China

    2. China Academy of Chinese Medical Sciences, Beijing 100700, China

    Keywords:Fufangkushen Chemotherapy Advanced colorectal cancer Curative effect Security Meta analysis

    ABSTRACT Objective: To systematically evaluate the efficacy and safety of compound Kushen injection combined with oxaliplatin chemotherapy in the treatment of advanced colorectal cancer. Methods: We searched PubMed, EMbase, the Cochrane Library, CNKI, VIP and Wan Fang database, SinoMed to collect compound Kushen injection combined with chemotherapy oxaliplatin into treatment of advanced colorectal cancer in randomised controlled trials; the databases weresearched from inception to December 2020. Meta-analysis of the included studies was performed using RevMan 5.4. Results: A total of 34 randomized controlled trials involving 2 664 patients with colorectal cancer were included. Results of Meta-analysis showed that compound Kushen injection combined with oxaliplatin chemotherapy regimen improved the objective response rate of tumor [RR=1.40, 95%CI(1.29,1.51), P<0.000 01] and disease control rate [RR=1.12, 95%CI(1.08,1,16), P 0.000 01] improved the quality of life[RR=1.24, 95%CI(1.14,1.36), P<0.000 01], and significantly reduced the incidence of leukopenia[RR=0.35,95%CI(0.23,0.52), P<0.000 01] and the incidence of diarrhea [RR=0.36, 95%CI(0.19,0.70),P=0.003], and improved the immune function of patients (CD3+, CD4+, CD4+/CD8+, NK cell levels).However, compared to the control group, the levels of CD8+ cells were decreased in the experimental group. Conclusion: Compound Kushen injection combined with oxaliplatin chemotherapy regimen can significantly improve the clinical efficacy of advanced colorectal cancer patients, improve the quality of life of patients, reduce the occurrence of adverse reactions, and has good efficacy and safety comparison with oxaliplatin chemotherapy regimen alone.?Corresponding author: HOU Wei, Professer, Doctoral Supervisor.E-mail: houwei1964@163.com

    1. Introduction

    Colorectal cancer (CRC) is one of the most common malignant tumors in the world[1]. According to statistics, the incidence and mortality of CRC ranked the third among all malignant tumors in the world in 2020, and the incidence and mortality of CRC ranked the fifth among all malignant tumors in China[2-3]. Patients with early colorectal cancer can choose the treatment method of colonoscopy combined with surgery with a high cure rate, but about 30-50% of them will have recurrence and metastasis after radical resection [4], and most of them are diagnosed as advanced stage, in which case chemotherapy becomes the first treatment. Oxaliplatin chemotherapy regimen is currently the standard chemotherapy regimen for patients with advanced colorectal cancer [5], which

    often causes multiple adverse reactions, including bone marrow suppression, digestive tract reaction and peripheral neurotoxicity,which seriously affects the quality of life of patients. Many patients are forced to give up chemotherapy, and the clinical efficacy is greatly reduced [6].

    In recent years, compound Kushen Injection (CKI) with sophora and cocos as the main active components has been widely used in clinical practice, and has played a good role in inducing tumor cell apoptosis and promoting host anti-tumor immune response[7].Most of the previous studies comprehensively reviewed colorectal cancer patients at all pathological stages, and did not strictly limit the chemotherapy regimen, which could not provide guidance for the clinical treatment of advanced colorectal cancer patients with infeasible surgery or postoperative recurrence and metastasis. This article aims to fill this gap and conduct a rigorous meta-analysis of the Randomized controlled trial (RCT) of compound matrine injection combined with oxaliplatin in the treatment of advanced colorectal cancer, in order to evaluate its efficacy and safety and guide clinical application.

    2. Materials and methods

    2.1 Inclusion and exclusion criteria

    2.1.1 Study typesRandomized controlled trial (RCT) of compound Matrine injection combined with oxaliplatin in the treatment of advanced colorectal cancer.

    2.1.2 Types of ParticipantsAll enrolled patients met the 8th American Joint Committee on Cancer (AJCC) diagnostic criteria for advanced colorectal cancer [8]or Dukes stage. Stage Ⅲ-Ⅳ patients with pathology, cytology and imaging diagnosis of infeasible surgical treatment or postoperative recurrence and metastasis.

    2.1.3 Types of InterventionControl group: oxaliplatin chemotherapy regimen group (including FOLFOX regimen and XELOX regimen); Experimental group:On the basis of control group, compound Matrine injection was combined.

    2.1.4 Outcomes

    ① Clinical efficacy: Objective response rate (ORR) and disease control rate (DCR) were used to judge the clinical efficacy:According to the World Health Organization (WHO) efficacy evaluation criteria for solid tumors [9] and RECIST efficacy evaluation criteria for solid tumors [10], the patients were divided into complete response (CR), partial response (PR), stable response (SD)and progressive response (PD). Objective response rate = (CR +PR)/total number × 100%. Disease control rate = (CR cases +PR cases+SD cases)/total cases ×100%. ② Quality of life: Karnofsky(KPS score) improvement rate was used to evaluate the quality of life.After treatment, KPS score increased by 10 was considered as improved, decreased by 10 was considered as decreased,and changed by <10 was considered as stable. Improvement rate=(improved cases + stable cases)/total cases × 100%. ③ Safety:The incidence of adverse reactions was used as the outcome index of safety evaluation. According to the Criteria for Acute and subacute Toxicity of Chemotherapy Drugs formulated by WHO in 1981 [11],adverse reactions include bone marrow suppression (hemoglobin toxicity, leukocyte toxicity, platelet toxicity), digestive tract reactions(nausea and vomiting, diarrhea), peripheral neurotoxicity, and abnormal liver function. ④ Immune function: The proportion of immune cell subsets after treatment was used as the evaluation index of immune function. Including CD3+, CD4+, CD8+, CD4+/CD8+, NK.

    2.1.5 Exclusion criteria

    ① Non-chemotherapy means such as radiotherapy and targeted drugs were used. ② Use other traditional Chinese medicine preparations except compound Matrine injection. ③ Repeatedly published literature (the first paper was retained), or the research data of different literatures were duplicated (the paper with the most complete data retained). ④Complete research data could not be obtained.

    2.2 Research Strategy

    Chinese literature databases include China National Knowledge Infrastructure (CNKI), Chongqing VIP Chinese Science and Technology Journal Database (VIP), WanFang Database and China Biomedical Literature Service (SinoMed). The English databases are PubMed, EMBASE and Cochrane Library. Databases such as CLINICALTRIALS.GOV and WHO REGISTRY were manually searched for ongoing clinical trials or unpublished grey literature data. Retrieval date Self-built database to December 31, 2020.According to the RCT search strategy listed in Cochrane Systematic Review manual, the search terms were divided into two parts: target disease and intervention, and the combination of subject terms and free terms was used. The Chinese search terms were "colon cancer","rectal cancer", "colorectal cancer", "colorectal cancer", "compound matrine injection", "compound Matrine injection", "compound Matrine injection", "Yanshu injection", "Yanshu". The English search words are "Colorectal Neoplasms", "Colonic Neoplasms", "Rectal Neoplasms", "Compound Kushen Injection", "Fufangkushen","yanshu".

    2.3 Literature screening and data extraction

    By reading the title and abstract, the papers that obviously do not meet the inclusion criteria are excluded, and the full text is analyzed to determine whether to be included. The screening was performed by two investigators independently and cross-checked. In case of disagreement, the third investigator evaluated and handled the screening. In case of missing documents, contact the author by email or telephone to supplement them. The main contents of the extracted data include: ① basic information; ② Study population data; ③Intervention measures; ④ Control measures; ⑤ Outcome indicators.

    2.4 Literature quality evaluation

    The methodological quality of the included studies was assessed using the Cochrane Manual of Systematic Reviews 5.1.0 Risk of Bias Assessment tool. The evaluation included 7 aspects: random sequence generation, random concealment, patient/investigator blinding, outcome rater blinding, outcome data integrity, selective outcome reporting, and other sources of bias. Each evaluation Angle determines the risk type according to the risk of bias evaluation standard [12].

    2.5 Data synthesis

    Revman 5.4 software was used for statistical analysis. Clinical efficacy, quality of life and safety outcome indicators were dichotomous data, and relative risk (RR) was used as the effect indicator. The outcome index of immune function was continuous variable data, and the mean deviation (MD) was used as the effect index, and 95% confidence interval (CI) and P value were calculated. If P>0.1 and I250%, there was no significant statistical heterogeneity, and fixed effects model was used for analysis. If P 0.1 and I2>50%, the heterogeneity between studies was significant.Random effects model was used for analysis, and the source of heterogeneity was determined by sensitivity analysis or subgroup analysis. Funnel plots were used to analyze the publication bias of the included studies.

    3. Results

    3.1 Literature search results

    A total of 810 articles were retrieved from the database according to the retrieval strategy. The obtained articles were imported into NoteExpress software, and 503 duplicated articles were eliminated.By reading the title and abstract, 247 articles that did not meet the inclusion and exclusion criteria were excluded, and 26 articles with inconsistent baseline data or low literature quality were excluded from the full text of the remaining 60 articles. Finally, 34 RCTS were included. See Figure 1 for the literature screening process.

    3.2 Study Characteristics

    34 RCTs[13-46] were included, with a total sample size of 2 664 cases, including 1 343 cases in the experimental group and 1 321 cases in the control group. The minimum sample size was 21 cases and the maximum was 125 cases. The intervention measures in the control group included FOLFOX and XELOX chemotherapy regimens, while those in the experimental group were compound Matrine injection +FOLFOX/XELOX chemotherapy regimens.4 studies [30,31,38,40] course of treatment > 4 cycles, 23 studies courses 4 cycles. 16 [13,16,18,24,27,28,35,37,38-43,45,46] on the basis of KPS score grading evaluation of quality of life improved, 15 research [15,17,18,21,2428,34-38 9] are described, what is happening to adverse reactions In one study [13], the number of hemoglobin, white blood cells and platelets was detected by flow cytometry without grading. Specific literature characteristics are shown in Table 1.

    3.3 Quality evaluation of included studies

    Fig 1 Flowchart of literature screening

    Tab1 Document characteristic information table

    The 34 RCTS [13-46] included in the evaluation showed no statistically significant differences in baseline levels. Nine studies described stochastic methods, among which 7 studies [15,18-20,22,23,41] used random number table method,1 study [37] used stratified random equalization method, and 1 study [31] used computerized random blinding method. If the outcome indicators only included objective outcome indicators such as ORR and DCR, the implementation of blinding method would not affect the outcome bias, so it was evaluated as "low risk". If objective outcome indicators were not included, the risk of bias was evaluated as"high risk". If the outcome indicators included subjective outcome indicators such as quality of life and adverse reactions, the risk of bias was evaluated as "unclear". 34 RCTS [13-46] were not terminated early, and all of them had complete outcome reports. As shown in Figure 2.

    Fig 2 Assessment of risk of bias of the included studies

    3.4 Results of Meta-analysis

    3.4.1 Objective response rate

    3.4.1.1 WHO efficacy criteria for solid tumors 24 study [14,1622,24-28,30-32,34,36,38,40,41,43,44,46]using the WHO solid tumor curative effect evaluation standard for objective response rate statistics, statistical heterogeneity between studies smaller (P=0.42,I2= 3%), it USES the fixed effect model combined effect quantity.The results of meta-analysis showed that the experimental group could increase the ORR to 1.43 times of the control group, and the difference was statistically significant. (RR=1.43, 95%CI(1.31,1.55),P<0.000 01)

    3.4.1.2 RECIST Efficacy evaluation criteria for solid tumors

    The objective response rate of 7 studies [13,23,29,33,35,42,45] was calculated using the RECIST efficacy evaluation criteria for solid tumors. The statistical heterogeneity among the studies was small(P=0.96, I2=0%), so the effect size was pooled using the fixedeffect model. The results of meta-analysis showed that the ORR of the experimental group was better than that of the control group, and the difference was statistically significant. (RR=1.27,95%CI(1.051,1.54), P=0.01)

    Comprehensive data analysis showed that the objective remission rate of the experimental group was better than that of the control group, and the difference was statistically significant. (RR=1.40,95%CI(1.29,1.51), P<0.000 01). As shown in Figure 3.

    2.4.2 Disease control rate

    2.4.2.1 WHO efficacy criteria for solid tumors

    24 study[14,1622,24-28,30-32,34,36,38,40,41,43,44,46] using solid tumor WHO curative effect evaluation standard of disease control statistics,statistical heterogeneity between studies smaller (P = 0.39, I2=5%), it USES the fixed effect model combined effect quantity. The results of meta-analysis showed that DCR of the experimental group was better than that of the control group, and the difference was statistically significant. (RR=1.11, 95%CI(1.07,1.16), P < 0.000 01)

    3.4.2.2 Efficacy evaluation criteria of RECIST solid tumors

    The objective response rate of 7 studies[13,23,29,33,35,42,45] was calculated using the RECIST efficacy evaluation criteria for solid tumors. The statistical heterogeneity among the studies was small(P=0.79, I2=0%), so the effect size was pooled using the fixedeffect model. The results of meta-analysis showed that DCR of the experimental group was better than that of the control group, and the difference was statistically significant. (RR=1.13, 95%CI(1.03,1.24),P=0.01)

    Comprehensive data analysis showed that the disease control rate of the experimental group was better than that of the control group, and the difference was statistically significant.(RR=1.12,95%CI(1.08,1,16),P < 0.000 01).

    3.4.3 Quality of life evaluation

    16 [13,16,18,24,27,28,35,37,38-43,45,46] original data are stable and the number of cases in Karnofsky score growth or ratio of the total sum of the cases take statistics as the evaluation standard of quality of life improved, the statistical heterogeneity (P=0.006, I2=54%),so the random effect model was used to combine the effect sizes.The results of meta-analysis showed that the quality of life in the experimental group was better than that in the control group, and the difference was statistically significant. (RR=1.24, 95%CI(1.14,1.36),P < 0.000 01). As shown in Figure 5.

    Due to the moderate heterogeneity, the literature was excluded one by one for analysis. When the study of Gao Wei et al. [18] was excluded, the heterogeneity decreased to 23%, indicating that this study was the main source of heterogeneity. The oxaliplatin in the chemotherapy regimen of this study was 130 mg/m2, while the other studies were mostly 85 mg/m2or 100 mg/m2. Therefore, the source of heterogeneity was considered to be related to the high dose of chemotherapy drugs in this study.

    Fig 3 Forest plot of objective response rate

    3.4.4 Adverse reactions

    A total of 15 studies [15,17,18,21,2428,34-38,41] reported adverse reactions after treatment, and the detailed analysis results are shown in Table 2. Compared with the control group, experimental group to reduce the incidence of hemoglobin incidence, the incidence of leukopenia, thrombocytopenia, incidence of nausea and vomiting,diarrhea incidence, the incidence of peripheral nerve toxicity,reduced incidence of liver function damage, the results showed that compound sophora injection to reduce leukopenia and the incidence of adverse reactions of diarrhea curative effect is distinct,The difference was statistically significant(P<0.05). There was no significant difference in hemoglobin reduction rate between the experimental group and the control group(P>0.05).

    Due to heterogeneity in the rate of hemoglobin reduction, the incidence of nausea and vomiting, and the incidence of peripheral neurotoxicity, all indicators were removed from the study one by one for analysis. It was found that all the above indicators included this study, and the heterogeneity index of each indicator I2decreased to 0% after removal. And one by one to eliminate the remaining literature, statistical result of combined effect quantity and total amount effect were no significant difference, and statistical heterogeneity, there was no apparent change, illustrate Xi Rui’s research is the main source of heterogeneity, after the comprehensive analysis of research shows that the study intervention time about 6 cycles, as included in the study period is the elder, Therefore, the main reason for considering large heterogeneity is related to the long duration of treatment.

    Fig 4 Forest map of disease control rate

    3.4.5 Immune functionA total of 3 studies [15,20,24] have evaluated the immune function of patients, and the specific analysis results are shown in Table 3. Compared with the control group, the levels of CD3+, CD4+,CD4+/CD8+and NK cells in the experimental group were higher than those in the control group after treatment, and the differences were statistically significant(P<0.05). The level of CD8+cells in experimental group was lower than that in control group, and the difference was statistically significant(P<0.05). The heterogeneity of CD4+and CD8+ index was significant, which was considered to be related to the small number of studies and samples. Table 3.

    3.5 Publication bias

    Funnel plots were drawn for objective response rate and disease control rate, and it was found that the research distribution was relatively symmetrical and there was no obvious publication bias.See Figure 6 and 7.

    Tab 2 Meta-analysis of adverse reactions of CKI combined with oxaliplatin chemotherapy in the treatment of colorectal cancer

    Fig 5 Forest plot of quality of life

    Tab 3 Meta-analysis of immunologic function of CKI combined with oxaliplatin chemotherapy in the treatment of colorectal cancer

    Fig 6 Funnel plot of objective response rate

    Fig 7 Funnel plot of disease control rate

    4. Disscussion

    Past for CKI system evaluation is for the treatment of colorectal cancer are relationship, but more is the early, middle and late curative effect evaluation on the colorectal cancer study mixed together, did not give specific clinical staging of into the object of study, lead to clinical efficacy evaluation conclusion heterogeneity is bigger, can't give late infeasible the post-operation relapse and metastasis of CRC surgery or clinical practice provides guidance significance. In addition, previous studies have not restricted the chemotherapy intervention program, and the efficacy evaluation of FOLFOX, XELOX, FOLFIRL, chemotherapy combined with targeted therapy and immunotherapy is mixed, which is difficult to reflect the specific clinical efficacy of the first-line chemotherapy regimen of compound matrine injection combined with oxaliplatin alone. This study systematically evaluated the efficacy and safety of CKI combined with oxaliplatin in the treatment of advanced CRC from four aspects: clinical efficacy, quality of life, adverse reactions and immune function.

    In our country, the number of death cases caused by CRC is 187 100, accounting for 8.01% of all malignant tumor deaths [47]. The 5-year relative survival rate of stage Ⅰ colorectal cancer can reach 90%, while the 5-year relative survival rate of stage Ⅳ colorectal cancer with distant metastasis is only 14%[48]. At present, FOLFOX and XELOX chemotherapy regimens are the most commonly used first-line chemotherapy regimens in clinical practice [49]. Oxaliplatin is a third-generation platinum-based broad-spectrum cytotoxic drug,which belongs to DNA-damaging chemotherapy drugs containing 1,2-diaminocyclohexane group. Platinum atoms antagonize replication and transcription of DNA by cross-binding with DNA, and have obvious anti-cancer activity [5,50]. How to combine drugs to reduce the toxic and side effects of oxaliplatin chemotherapy regimen,improve the clinical efficiency of drug-resistant patients, and improve the quality of life of patients is an urgent clinical problem to be solved.

    CKI is the relationship of sophora and clay three flavour drug extracting effective ingredients of traditional Chinese medicine injection, has clear heat cool blood, fights the efficacy of detoxification, through the joint action of targets, mechanism, the comprehensive control proto-oncogenes and tumor suppressor gene,inducing tumor cell apoptosis, promote the host antitumor immune response, inhibit the formation of tumor angiogenesis [51] has good effect. Molecular biological studies have confirmed that CKI can affect the expression of BCL-2 proto-oncogene and telomerase,reduce the level of survivin, and induce apoptosis of tumor cells, so as to achieve anti-tumor effect [52]. Through in vitro experiments,Wang Hongqian et al. found that the CKI group, oxaliplatin group and the combination group had certain killing effects on colon cancer cell lines SW620, HT29 and LOVO, while the inhibition effect of the combination group on cell line proliferation was significantly stronger than that of the oxaliplatin group and CKI group, showing a dose-dependent effect [53].

    A total of 34 studies [13-46] were included in this study, including 2 664 patients, 1 343 in the experimental group and 1 321 in the control group. Results compared with oxaliplatin, CKI combined with oxaliplatin could improve the objective response rate of advanced CRC patients by about 17% and the disease control rate by about 9%, and the differences were statistically significant (P<0.05).At the same time, it can reduce the occurrence of adverse reactions such as bone marrow suppression, digestive tract reaction, liver function injury, peripheral neurotoxicity, especially in reducing the adverse reactions of leukopenia and diarrhea. In terms of immune function, CD3+reflects the level of cellular immunity of the body,while CD4+expands the immune response mainly by secreting lymphokines and plays a synergistic role with other immunizations.CD8+can inhibit CD4+cells and B cells [54]. The decrease of CD4+/CD8+ratio represents the decrease of cellular immune function in patients. As one of the evaluation criteria of anti-tumor, NK cells play an important role in immune surveillance and killing mutant cancer cells [55]. In the included study, the levels of CD3+, CD4+,CD4+/CD8+and NK in the experimental group were higher than those in the control group, while the levels of CD8+were lower than those in the control group, suggesting that CKI may improve the immune function of the body by enhancing CD3+, CD4+, CD4+/CD8+and NK.

    Limitations of this study: (1) The included study was a singlecenter study: all the included literatures were single-center studies,so the test efficacy was insufficient; (2) The methodological quality of the included studies was poor: most of the studies did not mention the evaluation report on the concealment of the randomized protocol and the degree of blinding implementation. In the study of tumor diseases, considering the side effects of chemotherapy and the long treatment cycle, it is difficult for patients to completely complete the treatment according to the predetermined protocol. However,34 studies [13-46] did not mention the situation of loss to follow-up or dropping off, so there is potential bias in the selective outcome report. (3) Lack of long-term outcome indicators in the included studies: Most of the outcome indicators of each study were based on clinical efficacy and quality of life. For example, there was only one study that analyzed the end points of clinical trials, such as progression-free survival, disease-free survival, and time to disease progression. There were too few data available for analysis,suggesting that other RCTS should pay attention to long-term survival indicators in the future. To provide research data for longterm clinical benefit of compound Matrine injection. (4) Different drug courses of included chemotherapy regimens: Although the drugs of specific chemotherapy regimens were strictly limited,there were differences in chemotherapy cycles among different studies, which would lead to potential bias in research conclusions.Therefore, large-sample, multicenter RCT is still needed for further verification.

    Author’s contribution:

    The first author, Zhou Tong, was responsible for the design and writing of the paper, and completed the literature screening and data extraction; Wang Shuo and Hu Shuai-hang were responsible for independently screening the literature and extracting data; Li Zheng and Fan Bing-jie checked and consulted and assisted in revising the format of the paper and related charts; Li Jing-lei was responsible for revising the paper; and corresponding author Hou Wei was responsible for topic selection, design and revision.

    All authors declare no conflict of interest.

    天天躁狠狠躁夜夜躁狠狠躁| 精品熟女少妇八av免费久了| 18禁国产床啪视频网站| 精品电影一区二区在线| 国产一区二区三区视频了| 亚洲一区中文字幕在线| 少妇熟女aⅴ在线视频| 香蕉久久夜色| 香蕉久久夜色| 熟妇人妻久久中文字幕3abv| 十八禁人妻一区二区| 日韩欧美三级三区| 国产私拍福利视频在线观看| 久久亚洲精品不卡| 两个人免费观看高清视频| 亚洲国产精品sss在线观看| 在线视频色国产色| 国产在线观看jvid| 欧美+亚洲+日韩+国产| 亚洲欧美日韩无卡精品| 国产精品久久久av美女十八| 成人国产一区最新在线观看| 乱人伦中国视频| 亚洲精品一区av在线观看| 999久久久国产精品视频| 一级毛片精品| 91精品国产国语对白视频| 免费在线观看日本一区| 精品欧美国产一区二区三| 两个人视频免费观看高清| 久久国产精品男人的天堂亚洲| 国产男靠女视频免费网站| 精品久久久久久,| 18禁观看日本| 日韩欧美国产一区二区入口| 成人国产一区最新在线观看| 亚洲 国产 在线| 亚洲五月色婷婷综合| 成年版毛片免费区| 亚洲av成人一区二区三| 国产熟女xx| 国产成+人综合+亚洲专区| 可以在线观看毛片的网站| 亚洲欧美日韩高清在线视频| 中出人妻视频一区二区| 两人在一起打扑克的视频| 可以免费在线观看a视频的电影网站| 亚洲人成伊人成综合网2020| 99香蕉大伊视频| 国产国语露脸激情在线看| 极品人妻少妇av视频| 在线av久久热| 精品久久蜜臀av无| 亚洲欧洲精品一区二区精品久久久| 亚洲一区高清亚洲精品| 亚洲欧美激情综合另类| 久久久久久亚洲精品国产蜜桃av| 久久精品国产99精品国产亚洲性色 | 午夜久久久久精精品| 午夜久久久久精精品| 久久青草综合色| 欧美最黄视频在线播放免费| 看片在线看免费视频| 性欧美人与动物交配| 亚洲自偷自拍图片 自拍| 国产成人av教育| 99国产精品一区二区蜜桃av| 免费无遮挡裸体视频| 黄色a级毛片大全视频| 免费一级毛片在线播放高清视频 | 欧美午夜高清在线| 亚洲男人天堂网一区| 国产成年人精品一区二区| 美女高潮到喷水免费观看| 嫩草影院精品99| 久久精品国产亚洲av高清一级| 69av精品久久久久久| 十八禁人妻一区二区| av福利片在线| 亚洲一区高清亚洲精品| 成人三级做爰电影| 亚洲第一电影网av| 黑人欧美特级aaaaaa片| 麻豆一二三区av精品| av电影中文网址| 国产精品亚洲美女久久久| 欧美激情久久久久久爽电影 | 一级,二级,三级黄色视频| 给我免费播放毛片高清在线观看| 久久久精品国产亚洲av高清涩受| 日韩一卡2卡3卡4卡2021年| 熟女少妇亚洲综合色aaa.| 最近最新中文字幕大全电影3 | 久久久国产成人免费| 女警被强在线播放| 国产单亲对白刺激| 成熟少妇高潮喷水视频| 日本在线视频免费播放| 久久久久久久久免费视频了| 国产激情欧美一区二区| 熟妇人妻久久中文字幕3abv| 亚洲色图av天堂| 精品一区二区三区视频在线观看免费| 一级a爱视频在线免费观看| 久久久久久免费高清国产稀缺| 亚洲精品中文字幕在线视频| 久久久久亚洲av毛片大全| 啦啦啦免费观看视频1| 宅男免费午夜| 亚洲精品美女久久av网站| АⅤ资源中文在线天堂| 久久久久久国产a免费观看| 日本 av在线| 日本精品一区二区三区蜜桃| 亚洲人成77777在线视频| 国产精品 国内视频| 人人妻人人澡人人看| 可以免费在线观看a视频的电影网站| 国内久久婷婷六月综合欲色啪| 怎么达到女性高潮| netflix在线观看网站| 久久久久国产精品人妻aⅴ院| 久久香蕉精品热| 日本五十路高清| 亚洲精品久久成人aⅴ小说| 亚洲熟妇熟女久久| 人成视频在线观看免费观看| 嫁个100分男人电影在线观看| 国产区一区二久久| 高清在线国产一区| 色播在线永久视频| 麻豆成人av在线观看| 老熟妇仑乱视频hdxx| 久久狼人影院| 免费高清视频大片| 男女下面插进去视频免费观看| 中文字幕人妻熟女乱码| 国产精品久久电影中文字幕| 久久久久久久久中文| 国产精品1区2区在线观看.| 老司机靠b影院| 搡老岳熟女国产| 老汉色av国产亚洲站长工具| 亚洲国产精品成人综合色| 国产欧美日韩一区二区精品| 性欧美人与动物交配| 怎么达到女性高潮| 国产精品一区二区精品视频观看| 国产成人欧美| 美女免费视频网站| 久久久水蜜桃国产精品网| 亚洲五月天丁香| 无人区码免费观看不卡| 午夜老司机福利片| 国产精品久久电影中文字幕| 国产精品电影一区二区三区| 免费在线观看视频国产中文字幕亚洲| 午夜两性在线视频| av中文乱码字幕在线| 国产精品久久久人人做人人爽| 90打野战视频偷拍视频| 十八禁人妻一区二区| 精品午夜福利视频在线观看一区| 两个人看的免费小视频| 午夜福利影视在线免费观看| 一区二区三区激情视频| 国产在线观看jvid| 黄色视频不卡| 在线观看午夜福利视频| 国产麻豆成人av免费视频| 久久影院123| 无限看片的www在线观看| 久久香蕉精品热| 亚洲美女黄片视频| 国产一区二区激情短视频| 久久精品91无色码中文字幕| 免费不卡黄色视频| 欧美久久黑人一区二区| 日韩国内少妇激情av| 女人被躁到高潮嗷嗷叫费观| av视频免费观看在线观看| 亚洲av日韩精品久久久久久密| 在线观看免费日韩欧美大片| 精品久久蜜臀av无| 中文字幕高清在线视频| 一边摸一边做爽爽视频免费| 国产不卡一卡二| 一个人免费在线观看的高清视频| 这个男人来自地球电影免费观看| 亚洲成国产人片在线观看| 波多野结衣巨乳人妻| 国产精品亚洲一级av第二区| 亚洲国产精品999在线| 美女高潮到喷水免费观看| 国产精品久久视频播放| 国产亚洲欧美98| 日日摸夜夜添夜夜添小说| 久久婷婷成人综合色麻豆| 国产精品久久久人人做人人爽| 少妇裸体淫交视频免费看高清 | 久久影院123| 女人爽到高潮嗷嗷叫在线视频| 亚洲精品国产区一区二| 一区二区日韩欧美中文字幕| 日本a在线网址| 操美女的视频在线观看| 91老司机精品| 一级黄色大片毛片| 国产又色又爽无遮挡免费看| 成在线人永久免费视频| 99在线视频只有这里精品首页| 国产日韩一区二区三区精品不卡| 色婷婷久久久亚洲欧美| 波多野结衣高清无吗| 亚洲中文av在线| 国产av又大| 午夜久久久久精精品| 在线观看日韩欧美| 成人18禁高潮啪啪吃奶动态图| 久久精品亚洲精品国产色婷小说| 少妇粗大呻吟视频| 国产精品免费一区二区三区在线| 国产伦人伦偷精品视频| 老司机午夜十八禁免费视频| 日日爽夜夜爽网站| 动漫黄色视频在线观看| 久久精品国产亚洲av香蕉五月| 国产成人精品久久二区二区91| 精品久久蜜臀av无| 精品久久久精品久久久| 妹子高潮喷水视频| 搡老岳熟女国产| 视频区欧美日本亚洲| 大香蕉久久成人网| www.熟女人妻精品国产| 美国免费a级毛片| 麻豆久久精品国产亚洲av| 亚洲视频免费观看视频| 日韩欧美免费精品| 18禁黄网站禁片午夜丰满| 高潮久久久久久久久久久不卡| 中文亚洲av片在线观看爽| 日韩欧美一区二区三区在线观看| 免费搜索国产男女视频| 老司机福利观看| 色播在线永久视频| www.自偷自拍.com| 亚洲熟妇中文字幕五十中出| a在线观看视频网站| 亚洲第一电影网av| 欧美精品亚洲一区二区| 亚洲精品久久成人aⅴ小说| 亚洲一码二码三码区别大吗| 久久这里只有精品19| 精品高清国产在线一区| 老司机靠b影院| 男女床上黄色一级片免费看| 制服诱惑二区| 91老司机精品| 亚洲精品中文字幕在线视频| 一进一出好大好爽视频| 欧美成人一区二区免费高清观看 | 色综合婷婷激情| 午夜福利高清视频| 99精品欧美一区二区三区四区| 日韩高清综合在线| www.精华液| 岛国在线观看网站| avwww免费| 亚洲国产精品成人综合色| 成人18禁高潮啪啪吃奶动态图| 国产伦一二天堂av在线观看| 国产三级在线视频| а√天堂www在线а√下载| 老司机午夜福利在线观看视频| 亚洲自偷自拍图片 自拍| 久久人人精品亚洲av| 久久香蕉国产精品| 在线观看日韩欧美| 丁香六月欧美| 国产精品影院久久| 久久中文字幕人妻熟女| 极品人妻少妇av视频| 亚洲国产精品合色在线| 精品一品国产午夜福利视频| 满18在线观看网站| 亚洲成国产人片在线观看| 欧美激情久久久久久爽电影 | 十分钟在线观看高清视频www| 波多野结衣巨乳人妻| 日韩欧美国产一区二区入口| 国产成人精品在线电影| 国产极品粉嫩免费观看在线| 免费观看精品视频网站| 成人av一区二区三区在线看| 99国产精品免费福利视频| 国产欧美日韩综合在线一区二区| 国产成人精品久久二区二区免费| 欧美亚洲日本最大视频资源| 久久久水蜜桃国产精品网| 日本一区二区免费在线视频| 一级毛片女人18水好多| 涩涩av久久男人的天堂| 99国产综合亚洲精品| 国产激情久久老熟女| 亚洲精品中文字幕在线视频| 深夜精品福利| 久久午夜亚洲精品久久| 50天的宝宝边吃奶边哭怎么回事| 999久久久精品免费观看国产| 十八禁网站免费在线| 亚洲色图 男人天堂 中文字幕| 黄色a级毛片大全视频| 母亲3免费完整高清在线观看| 人人妻人人爽人人添夜夜欢视频| 欧美色视频一区免费| 午夜成年电影在线免费观看| 九色亚洲精品在线播放| 欧美黑人精品巨大| 久久精品成人免费网站| 亚洲欧洲精品一区二区精品久久久| 麻豆成人av在线观看| 国产欧美日韩一区二区三| 电影成人av| 中文字幕最新亚洲高清| 精品一区二区三区视频在线观看免费| 国产黄a三级三级三级人| 欧美日韩福利视频一区二区| 精品久久久久久久人妻蜜臀av | 亚洲精品美女久久av网站| 日本vs欧美在线观看视频| 亚洲国产日韩欧美精品在线观看 | 久久这里只有精品19| 亚洲精品av麻豆狂野| 午夜免费成人在线视频| 国产av精品麻豆| 午夜福利成人在线免费观看| 一夜夜www| 国内精品久久久久久久电影| 色播在线永久视频| 亚洲欧美日韩无卡精品| 久久精品国产亚洲av高清一级| 国产精品久久电影中文字幕| 精品国产亚洲在线| 亚洲熟妇熟女久久| 久久久国产成人免费| 国产成人免费无遮挡视频| 婷婷精品国产亚洲av在线| 亚洲无线在线观看| 国产精品秋霞免费鲁丝片| 国产熟女xx| 精品人妻在线不人妻| 给我免费播放毛片高清在线观看| 亚洲精品av麻豆狂野| 啦啦啦免费观看视频1| 大香蕉久久成人网| 一级毛片高清免费大全| 97人妻精品一区二区三区麻豆 | 美女午夜性视频免费| 99riav亚洲国产免费| 一级毛片女人18水好多| 国产亚洲精品第一综合不卡| 中亚洲国语对白在线视频| 脱女人内裤的视频| 女人高潮潮喷娇喘18禁视频| 国产成人精品无人区| 亚洲情色 制服丝袜| 成人国产一区最新在线观看| 大陆偷拍与自拍| 国产精品永久免费网站| 一边摸一边做爽爽视频免费| 琪琪午夜伦伦电影理论片6080| 久久精品国产99精品国产亚洲性色 | 伦理电影免费视频| 女人被躁到高潮嗷嗷叫费观| 国产亚洲精品久久久久5区| 国产精品永久免费网站| 嫩草影视91久久| 亚洲精品中文字幕一二三四区| 正在播放国产对白刺激| 人人妻,人人澡人人爽秒播| 久久久久久久久久久久大奶| 久久人妻av系列| 好男人电影高清在线观看| 国产精品久久久久久人妻精品电影| 日韩大尺度精品在线看网址 | 麻豆国产av国片精品| 免费在线观看视频国产中文字幕亚洲| 久久婷婷人人爽人人干人人爱 | 侵犯人妻中文字幕一二三四区| 国产三级黄色录像| 午夜福利成人在线免费观看| 亚洲电影在线观看av| or卡值多少钱| 午夜久久久在线观看| 久久人人97超碰香蕉20202| 视频在线观看一区二区三区| 最新美女视频免费是黄的| 国产av在哪里看| 国产精品久久视频播放| 波多野结衣巨乳人妻| 精品人妻在线不人妻| 99久久国产精品久久久| 欧美绝顶高潮抽搐喷水| 长腿黑丝高跟| 性欧美人与动物交配| 免费在线观看影片大全网站| 丝袜美腿诱惑在线| 日韩欧美国产在线观看| 最好的美女福利视频网| www.www免费av| 国产亚洲精品av在线| 精品国产美女av久久久久小说| 三级毛片av免费| 变态另类成人亚洲欧美熟女 | 看免费av毛片| 美女午夜性视频免费| 制服诱惑二区| 又黄又爽又免费观看的视频| 国产精品九九99| 午夜久久久在线观看| 一进一出抽搐gif免费好疼| 高清黄色对白视频在线免费看| 日韩高清综合在线| 亚洲国产看品久久| 久99久视频精品免费| 精品久久久久久久久久免费视频| 亚洲 国产 在线| 国产精品 国内视频| 日韩大尺度精品在线看网址 | 视频区欧美日本亚洲| 首页视频小说图片口味搜索| 国语自产精品视频在线第100页| 日韩成人在线观看一区二区三区| 午夜福利视频1000在线观看 | 香蕉丝袜av| xxx96com| avwww免费| 精品无人区乱码1区二区| 精品国产超薄肉色丝袜足j| 黄频高清免费视频| 真人做人爱边吃奶动态| 国产高清激情床上av| 日韩一卡2卡3卡4卡2021年| 妹子高潮喷水视频| 国产精品自产拍在线观看55亚洲| 国产片内射在线| 啦啦啦免费观看视频1| 国产国语露脸激情在线看| 久久精品91蜜桃| 亚洲国产精品成人综合色| 亚洲av片天天在线观看| 亚洲激情在线av| 91麻豆av在线| 纯流量卡能插随身wifi吗| 久久天躁狠狠躁夜夜2o2o| 日韩国内少妇激情av| av有码第一页| 久久午夜综合久久蜜桃| 日本 av在线| 亚洲成国产人片在线观看| 好男人电影高清在线观看| 久久性视频一级片| 日韩精品中文字幕看吧| 嫩草影院精品99| 中文字幕久久专区| 国产不卡一卡二| 亚洲成a人片在线一区二区| 日韩免费av在线播放| 丝袜人妻中文字幕| 757午夜福利合集在线观看| 免费在线观看完整版高清| 午夜久久久在线观看| 欧美av亚洲av综合av国产av| 国产成人影院久久av| 脱女人内裤的视频| 欧美av亚洲av综合av国产av| 一级作爱视频免费观看| 久久香蕉精品热| 一区二区三区精品91| 午夜日韩欧美国产| 国产av在哪里看| 午夜福利免费观看在线| 成人手机av| 国产精品 欧美亚洲| 国产伦一二天堂av在线观看| 久久国产精品影院| 一级a爱片免费观看的视频| 中国美女看黄片| 91在线观看av| 久久中文看片网| 校园春色视频在线观看| 91成人精品电影| 国产麻豆69| 一进一出抽搐gif免费好疼| 国产成人影院久久av| 女性被躁到高潮视频| 亚洲九九香蕉| 国产成人精品久久二区二区免费| 十八禁网站免费在线| 久久人人爽av亚洲精品天堂| 一a级毛片在线观看| av片东京热男人的天堂| ponron亚洲| 男人操女人黄网站| 麻豆成人av在线观看| 中亚洲国语对白在线视频| 在线十欧美十亚洲十日本专区| or卡值多少钱| 亚洲色图综合在线观看| 宅男免费午夜| 午夜久久久久精精品| av在线播放免费不卡| e午夜精品久久久久久久| 日韩精品青青久久久久久| 禁无遮挡网站| 中文亚洲av片在线观看爽| av超薄肉色丝袜交足视频| 成年版毛片免费区| 嫩草影院精品99| 在线国产一区二区在线| 黄色视频不卡| 啦啦啦观看免费观看视频高清 | 可以免费在线观看a视频的电影网站| 女人高潮潮喷娇喘18禁视频| 久久这里只有精品19| 成人国产一区最新在线观看| 欧美人与性动交α欧美精品济南到| 国产精品亚洲一级av第二区| 这个男人来自地球电影免费观看| 久久久久国产精品人妻aⅴ院| 免费女性裸体啪啪无遮挡网站| 搞女人的毛片| 日本免费a在线| 国产亚洲精品一区二区www| 丝袜美腿诱惑在线| 热re99久久国产66热| 国产成年人精品一区二区| 精品一区二区三区av网在线观看| 亚洲成人国产一区在线观看| 高清在线国产一区| 一区福利在线观看| 欧美日韩亚洲国产一区二区在线观看| 成人三级黄色视频| 免费不卡黄色视频| 村上凉子中文字幕在线| 99久久精品国产亚洲精品| 精品人妻1区二区| 亚洲成a人片在线一区二区| 人人妻人人澡欧美一区二区 | 91字幕亚洲| 精品国产一区二区久久| 神马国产精品三级电影在线观看 | 成人三级黄色视频| 久久久久国产一级毛片高清牌| 国产精品久久久av美女十八| 大码成人一级视频| av在线播放免费不卡| 中国美女看黄片| 9热在线视频观看99| 国产成人精品无人区| 亚洲av五月六月丁香网| a级毛片在线看网站| 一边摸一边做爽爽视频免费| 色精品久久人妻99蜜桃| 亚洲欧美精品综合一区二区三区| 久久精品成人免费网站| 亚洲熟女毛片儿| 久久久久九九精品影院| 亚洲成人免费电影在线观看| 香蕉国产在线看| 亚洲中文字幕一区二区三区有码在线看 | 亚洲中文字幕日韩| 大香蕉久久成人网| 亚洲欧美日韩另类电影网站| 亚洲精华国产精华精| 一级a爱视频在线免费观看| 亚洲五月天丁香| 黄色成人免费大全| 丝袜人妻中文字幕| 国产视频一区二区在线看| 丝袜人妻中文字幕| 夜夜看夜夜爽夜夜摸| 91国产中文字幕| 国产99白浆流出| 好男人在线观看高清免费视频 | www日本在线高清视频| 少妇裸体淫交视频免费看高清 | 精品国产亚洲在线| 禁无遮挡网站| 999精品在线视频| 精品国产一区二区久久| 国产成人系列免费观看| 亚洲第一欧美日韩一区二区三区| 国产高清激情床上av| 精品第一国产精品| 变态另类丝袜制服| 国产亚洲精品一区二区www| 大型av网站在线播放| 国产亚洲av高清不卡| 午夜精品久久久久久毛片777| 自线自在国产av| 中文字幕色久视频| 国产精品久久久久久精品电影 | 精品一区二区三区av网在线观看| 黄色视频不卡| 韩国av一区二区三区四区| 高清黄色对白视频在线免费看| 黑人巨大精品欧美一区二区mp4| 精品欧美国产一区二区三| 日韩精品青青久久久久久| 狂野欧美激情性xxxx| 在线永久观看黄色视频| 国产精品一区二区免费欧美| 久久久久久久午夜电影|