• <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 ?

    Efficacy and safety of newly developed preservativefree latanoprost 0.005% eye drops versus preserved latanoprost 0.005% in open angle glaucoma and ocular hypertension: 12-week results of a randomized,multicenter, controlled phase III trial

    2021-11-08 01:45:48JoonMoKimKyungRimSungJiWoongLeeHaksuKyungSeungsooRhoChanYunKim
    International Journal of Ophthalmology 2021年10期

    Joon Mo Kim, Kyung Rim Sung, Ji Woong Lee, Haksu Kyung, Seungsoo Rho, Chan Yun Kim

    1Department of Ophthalmology, Kangbuk Samsung Hospital,Sungkyunkwan University School of Medicine, Seoul 03181,Republic of Korea

    2Department of Ophthalmology, Seoul Asan Medical Center,Ulsan University College of Medicine, Seoul 05505, Republic of Korea

    3Department of Ophthalmology, Pusan National University Hospital, Pusan National University Medical School, Busan 49241, Republic of Korea

    4Department of Ophthalmology, National Medical Center,Seoul 04564, Republic of Korea

    5Department of Ophthalmology, CHA Bundang Medical Center, CHA University, Seongnam 13496, Republic of Korea

    6Department of Ophthalmology, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea

    Abstract

    ● KEYWORDS: latanoprost; benzalkonium chloride;intraocular pressure; preservative-free;

    INTRODUCTION

    Glaucoma is a major cause of irreversible blindness worldwide, and 111.8 million patients are expected globally by 2040[1]. Although many factors have been suggested as causes of glaucoma development, intraocular pressure (IOP)is still thought to be a major factor in the development and progression of glaucoma[2-3]. Many studies have reported that treatments that lower IOP decrease glaucoma progression[4-8].To date, control of IOP is the only proven way to suppress the progression of glaucoma. Therefore, IOP reduction remains the cornerstone of glaucoma management[9].

    Prostaglandin analogue (PGA) has been used more and more frequently as it is preferred as a first-time glaucoma drug,which is effective and has less severe systemic side effects and requires only one dose per day[10]. Among the various PGAs,latanoprost, which was first developed, is the most widely used in ocular hypertension (OHT) and primary open angle glaucoma (POAG) due to its good effect and less side effects such as conjunctival hyperemia compared to other PGAs[10-12].However, latanoprost eye drops currently commonly used have a high concentration of benzalkonium chloride (BAK)and contain sodium phosphate, which could cause side effects such as conjunctivitis and corneal surface epithelial toxicity when administered for a long time[13-14]. Ocular surface changes that occur using prostaglandin eye drops with BAK can be significantly related to the concentration-dependent cytotoxicity of these preservatives[15]. In addition, the side effects of BAK may have a greater impact on glaucoma patients who need to use their medicine for life. On the other hand, in the case of preservative-free (PF) latanoprost, few apoptosis cells were found in the superficial layer of the corneal epithelium in human and toxic animal models[15-16]. Therefore, in the 2009 EMA guideline, the European Glaucoma Society recommends PF products for patients with glaucoma who have dry eye or ocular surface diseases[17].

    Recently, a PF latanoprost generic eye drop was developed,TJO-002 (Xalost?S in Korea). TJO-002 has been formulated to have several presumed advantages over the conventional latanoprost preparation, which contains BAK. Polyoxyl 40 hydrogenated castor oil, carbomer (mucoadhesive polymer),and high-concentration sorbitol were used to promote substance stabilization and penetration into the eyeball instead of BAK and sodium phosphate. In order to improve the tolerability,instead of having a pH of 5.5 like the conventional latanoprost formulation [Xalatan?], TJO-002 has a physiologically active pH range of 7.0-7.3. This new formulation focuses on high stability, tolerability and non-inferior efficacy compared with the conventional formulation. This study aimed to compare TJO-002 with BAK-preserved latanoprost for IOP-lowering efficacy, safety and tolerability in patients with POAG/OHT.

    SUBJECTS AND METHODS

    Ethical Approval This study was approved by the Institutional Review Board of each center. This study was performed according to the tenets of the Helsinki Declaration and compliance with the International Conference on Harmonization Good Clinical Practice guidelines and Korean regulations. All patients were fully informed and provided written consent for participation before enrollment.

    Study Design and Patients The study was a multicenter,randomized, investigator-masked, active control, and parallelgroup phase III clinical trial (NCT03419975). It was conducted in 17 clinical sites from 3 December 2015 to 5 March 2018.This study compared the newly developed PF latanoprost formulation TJO-002 (Taejoon Pharmaceutical Co., Ltd.,Yongin, Republic of Korea) with BAK-preserved latanoprost(Xalatan?, Pfizer Inc., Belgium NV Puurs, Belgium) during a 3-month treatment period. Given that TJO-002 is supplied in single dose units and BAK latanoprost in bottles, the investigational drug was managed by dividing the blind part and the unblind part and the investigator was blind part so that they could not know which eyedrop to be administered, only the investigator measuring IOP during the ophthalmological examination was masked to the study medication.

    This study enrolled adult patients (≥19 years of age) with POAG/OHT. Patients with an IOP of 21 to 35 mm Hg at 9a.m.(±1h) in eligible eyes after a run-in period were randomized 1:1 and assigned the treatment schedule with TJO-002 or BAK latanoprost administered as one drop daily in each eye.We excluded the patients who had 20/80 or below of bestcorrected visual acuity on the Snellen chart and medical history of chronic intraocular inflammation in progress or within 3mo prior to screening. Patients who needed to use contact lenses during the clinical study and women who were pregnant, planning to become pregnant, currently nursing,of childbearing potential, or not using a reliable form of contraception were also excluded. Patients were randomized if IOP was >21 mm Hg in the eligible eye(s). If both eyes met the criteria, the eye with the higher IOP was selected. If the IOP was equal, the right eye was selected. Patients were instructed to instill one drop in each eye once daily in the evening(9p.m.±1h) and were scheduled for follow-up visits at 4, 8,and 12wk. The subjects were asked to keep a daily indication of whether or not to take an investigational drug in their diary table every time they administered, and were asked to answer the symptoms that they felt bad for the last week before the visit.

    Assessment Parameters The primary efficacy variable was the change in IOP between baseline and 12wk in the study eye.Diurnal IOP (average of 2 consecutive IOP measurements)was measured at the same hour (9a.m.±1h and 5p.m.±1h)at each visit using a calibrated Goldmann applanation tonometer(Figure 1). All patients underwent ocular examinations, including visual acuity assessment, slit lamp biomicroscopy, gonioscopy,standard automated perimetry, and ophthalmoscopy. IOP was measured (at 9a.m.and 5p.m.) during the baseline visit and at the 8-week and 12-week visits after eye-drop instillation. At the 4-week visit after instillation, IOP was measured only at 9a.m. Safety outcome measures included adverse events (AEs) reporting, visual acuity, and tolerability.

    Table 1 Patient demographics

    Figure 1 Study schedule Eligible patients were randomized to either the TJO-002 group or the BAK-preserved latanoprost group.

    Tolerability was evaluated with the frequency and percentage of distributions of severity level by symptoms in each group after administration at 4, 8, and 12wk with questionnaire in the blind part (investigator). The symptoms checked during follow-up visits were pruritus, burning/stinging, blurred vision,sticky eye sensation, eye dryness sensation, and foreign body sensation. Each of symptoms was written by investigator about the symptoms subjects feel after instilling investigational drugs. The tolerability was evaluated by checking how the symptoms were changed based on the symptoms of the worst degree among the records written about the symptoms of the investigational drug administration for a week before visit.

    Statistical Analysis The primary objective was to demonstrate the non-inferiority of the trial drug to the control drug in terms of diurnal IOP variation after the administration of the drugs for 12wk. If the maximum value of the confidence intervals was less than 1.5 mm Hg, the trial group was judged to be non-inferior to the control group[18]. The upper limit of noninferiority was set at 1.5 mm Hg as this is the standard acceptance level for noninferiority in glaucoma studies[19-21].The adjusted average and standard error of the IOP variations in the trial and control groups, the difference between the average and adjusted average, 95% two-tailed confidence intervals of adjusted average difference andP-values were calculated by conducting an analysis of covariation(ANCOVA) with baseline IOP as covariate and treatment as a parameter for IOP variations. Additionally, if there were any statistically significant variables among sex, ages, and BMI distribution, an ANCOVA was performed that corrected for these variables as a sensitivity analysis. Statistical analyses were performed using SAS v9.2 (SAS Institute, Cary, NC,USA). Tolerability was evaluated with the frequency and percentage of severity level distribution for each symptom in each group at 4, 8, and 12wk, and those differences between the groups were evaluated through Chi-square tests or Fisher’s exact tests. When there was a missing value, the last observation carried forward method was used.

    RESULTS

    Among 196 consenting subjects, 52 people were excluded(38 patients with “Deviation of inclusion/exclusion criteria”,13 with “Consent withdrawal” and 1 with “Other”), and 144 people were randomized. The full description of the inclusion and exclusion steps is outlined in Figure 2.

    Demographic Characteristics There were 78.38% menvs21.62% women in the TJO-002 group and 60.00% men vs 40.00% women in the BAK latanoprost group. The sex ratios between the two groups were statistically significantly different(P=0.0167). There were no differences in other characteristics between the two groups (P>0.05; Table 1).

    Efficacy Twelve weeks after initiation of drug administration,the mean diurnal IOP change was -7.21±3.10 mm Hg in the TJO-002 group and -7.02±3.17 mm Hg in the BAK latanoprost group. Both groups showed a statistically significant decrease of average diurnal IOP (P<0.0001) compared with baseline,but there was no significant difference in the follow-up IOPs and IOP changes between the two groups (Table 2).

    Table 3 shows the change in the mean IOP at 9a.m.of each follow-up visit after drug administration compared to baseline.Both groups showed a statistically significant decrease in IOP at each follow-up visit (P<0.0001 each) from the baseline IOPs, but there was no statistically significant difference in the follow-up IOPs between the two groups.

    Although the IOP in the TJO-002 group was less than that of the BAK latanoprost group at 9a.m.at 8wk after the beginning of the instillation, the difference was not statistically significant(P=0.06). Table 4 shows diurnal IOP fluctuation from 9a.m.to 5p.m.at 8 and 12wk of drug administration compared to that of baseline. The IOP fluctuations of the TJO-002 group were less than those of the BAK latanoprost group during the entire study period. However, the difference did not reach statistical significance except by 8wk after instillation (P<0.0342).

    Figure 2 Study progress diagram FAS: Full analysis set; PPS: Per protocol set.

    Table 2 Diurnal IOP by measurement time at baseline and 12wk of the treatment groups by ITT and PP mean±SD, mm Hg

    Table 3 IOP by measurement time at baseline, 4, 8 and 12wk of the treatment groups by ITT and PP mean±SD, mm Hg

    Table 4 Diurnal IOP fluctuation from 9 a.m. to 5 p.m. at baseline, 8 and 12wk of the treatment groups by ITT and PP mean±SD, mm Hg

    Table 5 Number of patients with ocular adverse events and drug-associated systemic adverse events

    Safety Table 5 shows ocular and systemic AEs in both groups. The incidence of AEs regardless of relationship with the study medications was 24.66% (18/73 people, 26 cases)in the TJO-002 group and 25.00% (17/68, 27 cases) in the BAK latanoprost group; there was no statistically significant difference between the groups (P=0.9625). The incidence of“Eye disorders” in the BAK latanoprost group was 10.29%(7/68 people, 10 cases), and in the TJO-002 group, it was 12.33% (9/73, 13 cases). The difference in incidence between the groups was not statistically significant (P=0.7035). Drugassociated systemic adverse events other than ocular adverse events included nasopharyngitis (1) and cerebral infarction (1)in the TJO-002 group and atypical mycobacterial pneumonia(1), bronchiolitis (1), sinusitis (1), acute myeloid leukemia (1)and rash (1) in the BAK latanoprost group. However, those AE did not appear to be associated with the study medications.

    Tolerability Severity of pruritus, burning/stinging, blurred vision, sticky eye sensation, eye dryness sensation, and foreign body sensation were compared between the two groups at 4-, 8-, and 12-week visits in the PP population among them,the severity of pruritus (12wk:P=0.0117), burning/stinging(4wk:P=0.0256, 8wk:P=0.0003, 12wk:P<0.0001), and sticky eye sensation (8wk:P=0.0010) were significantly different between the groups. TJO-002 showed a statistically significantly better tolerability than BAK latanoprost in three categories (Table 6).

    DISCUSSION

    In this randomized, investigator-masked multicenter trial in patients with POAG/OHT, the newly formulated PF latanoprost, TJO-002, showed similar efficacy and better tolerability compared with BAK latanoprost. In terms of efficacy, TJO-002 was non-inferior to BAK latanoprost in lowering IOP at all study follow-up assessment points (week 4, 8, and 12). In terms of tolerability, TJO-002 showed lower incidence of pruritus, burning/stinging, and sticky eye sensation than BAK latanoprost for the study duration.There was no difference in systemic side effects between the two groups. TJO-002 appeared to have better efficacy and tolerability compared with BAK latanoprost eyedrops.

    Measured IOPs were significantly reduced at all follow-up periods from baseline in the groups, and neither the magnitudenor the distribution of the IOP reduction at any visits were statistically different between the two groups. When the IOP measured at 9a.m.was analyzed separately, as it approximates the time of maximal IOP reduction by both medications, it was decreased and maintained for the entire duration of the study.This means that TJO-002 was at least non-inferior to BAK latanoprost in terms of the ability to lower IOP. The reduction of mean IOP at 9a.m.of the last visit compared with baseline was -8.13 mm Hg (33.16%) for TJO-002 and -7.43 mm Hg(31.05%) for BAK latanoprost, which was consistent with the range of the optimal IOP reduction associated with latanoprost 0.005% (approximately 28%-31%) reported previously[22-24].Aspberget al[22]reported that latanoprost was associated with a 28% decrease from the baseline IOP. These results are in agreement with the result of a study in which the IOPlowering efficacy of latanoprost was not dependent on the presence of BAK. Pellinen and Lokkila[25]demonstrated comparable corneal penetration of preserved and PF tafluprost in the aqueous humor of rabbits. Aiharaet al[26]reported that fewer ocular surface complications without significant IOP changes were observed with BAK-free travoprost than with BAK latanoprost, with a reduced prevalence of superficial punctate keratitis and less hyperemia, in a long-term 12-month prospective study. Harasymowyczet al[23]reported that PF latanoprost showed the same efficacy, along with improved local tolerance, compared with BAK latanoprost.

    Table 6 Number of patients with symptoms categorized by severity level comparing the TJO-002 group and the BAK latanoprost group n (%)

    Considering the importance of adherence and the fact that glaucoma requires long-term treatment, local ocular tolerability as well as efficacy is an important factor in preserving the quality of life in patients with glaucoma. In this study, TJO-002 showed better tolerability compared with BAK latanoprost, in terms of pruritus, burning/stinging, and sticky eye sensation.

    There are several presumed reasons for the favorable tolerability of TJO-002. One may be the absence of BAK. While BAK is a commonly used preservative in ophthalmic eye drops,its ocular toxicity is well known. Some studies have shown ocular surface damage, including inflammatory and toxic effects, associated with BAK[14,27-28]. Martinez-de-la-Casaet al[29]reported that the preservative appeared to have an impact on tear cytokine levels. Latanoprost with BAK increased the levels of interleukin, basic fibroblast growth factor, plateletderived growth factor, and tumor necrosis factor-α in tear film. Baudouinet al[28]also suggested that BAK in topical eye drops induces tear film instability, conjunctival inflammation,subconjunctival fibrosis, epithelial apoptosis, and corneal surface impairment. Long-term use of BAK could lead to apoptosis of conjunctival cells and chronic conjunctival inflammation[30]. Furthermore, Desbenoitet al[31]reported that BAK was found in the iris, lens capsule, and trabecular meshwork tissue of rabbits after topical exposure, thus suggesting the penetration of BAK into deep ocular structures.Pisellaet al[32]demonstrated that removal of preservative from timolol ophthalmic solution was associated with improvement of corneal epithelial barrier function, prevention of ocular surface inflammation, and reduction of complaints. Yanget al[33]suggested that topical latanoprost treatment itself could induce dry eyeviainflammation. They reported the effects of latanoprost in mice: it decreased tear production,induced conjunctival goblet cell loss, disrupted the corneal epithelial barrier, and promoted cell apoptosis in the ocular surface. Therefore, latanoprost itself may cause ocular surface problems, and BAK can further aggravate that problem. The new BAK-free formulation of latanoprost in this study, TJO-002,appeared to minimize the discomfort by eliminating BAK toxicity.Another reason may be the ocular tissue-friendly composition of TJO-002, which includes carbomer and sorbitol as the excipient. Carbomer has been widely used for artificial tears[30].Carbomers are anionic polymers and strongly interact with anionic mucin[34]. This mucoadhesive interaction causes carbomer-based formulations to bind with the mucin layer to prolong adhesion[35]. Reports have demonstrated that the ocular retention time of carbomer gel was significantly longer than that of other low-viscosity eye drops[36-37]. In a previous study,when compared to sodium hyaluronate, carbomer showed equivalent therapeutic effects on symptom severity in moderate dry eye[37]. The properties of carbomer seem to play a role in reducing ocular AEs. Furthermore, due to the characteristics of the carbomer, latanoprost may stay on the surface of the eye longer, possibly resulting in a better IOP reduction. The IOP at 9a.m.after 8wk in the TJO-002 group was lower than that in the BAK latanoprost group. Sorbitol is used to enhance the stability of the topical composition in TJO-002.In a 4-week test of stability under severe conditions (55°C,relative humidity 75%), the main ingredient, latanoprost,was maintained without loss. This result showed that the latanoprost preparation containing sorbitol was kept more stable than the preparation without sorbitol (data not shown here). Sorbitol appeared to maintain the stability of TJO-002 at room temperature for 3y. In addition, the appropriate pH for activation and maintenance of TJO-002 is pH 7.0-7.3, at which TJO-002 is neutral, while that of BAK-preserved latanoprost used in this study (Xalatan?, Pfizer Inc., Belgium NV Puurs,Belgium) is pH 5.5. This may be one of the reasons why there is less tingling sensation with TJO-002 than with BAK latanoprost.Gonneringet al[38]showed that the optimal pH range to prevent corneal damage is 6.5 to 8.5, which includes the pH of lacrimal fluid (approximately pH 7.4). Although corneas perfused at pH 5.5 showed changes in endothelial morphology, those perfused at pH values of 7.0, 8.0, and 8.5 maintained normal endothelial morphology[38]. While conjunctival hyperemia was more common in TJO-002 (3vs1). Considering the absence of stimulation by BAK, it was expected to appear less, but the opposite result was obtained. The exact reason for this is not known. In our opinion, the carbomer contained in TJO-002 may be the result of prolonging the hyperemia effect of latanoprost by causing latanoprost to stay in the conjunctival sac for a long time. Severe foreign body sensation was shown in 2 cases of TJO-002 at 4wk after instillation and were lost over time, but in BAK latanoprost, severe case was shown at 12wk. Further study is needed.

    Despite various efforts, this study has several limitations.First, there was no objective examination for ocular surface evaluation, such as tear film break-up testing and corneal/conjunctival staining evaluations. Second, the study was performed using data from one ethnic group; thus, results may not be applicable to other ethnic groups. Third, we did not evaluate all adverse effects of prostaglandin analogue(e.g.,lid pigmentation, deepening of upper eyelid sulcus, and growth of eyelashes) due to the relatively short follow-up duration. Fourth, other ingredients in addition to BAK may have been involved, but comparisons were not made. Since not all of the component of two drugs are the same except for BAK, all other ingredients in the drug may be involved. Fifth,our study conducted a relatively short follow-up duration,12wk. Considering that responses may vary from person to person, the duration of the study may not be appropriate.Further longterm study is needed. Sixth, we did not measure the 24-hour IOP variation, but only examined IOP twice in a day to estimate a certain daily change. However, despite the above limitations, we consider that we sufficiently evaluated and compared TJO-002, PF latanoprost, with conventional latanoprost containing preservative in terms of IOP reduction and ocular surface adverse effects. Finally, compared to previous studies, the subjects in our study are more male and have a relatively young average age. Other similar studies show that the average age is mostly over 60, with similar sex ratios or more female than male[39-42]. However, since our study is a multicenter study, and we have not tried to control the sex ratio of patients, it is not known why this structure was established. Considering the possible reasons, our study was performed in tertiary hospital and general hospitals. These hospitals in Korea are located in large cities, and residents of large cities and office workers around them participated in the study, so it seems that there were relatively more males and younger people than other studies. In addition, male have a higher prevalence of glaucoma than female in Korea[43]. It will be difficult to put our study on the same line with other existing studies and compare it, but it will be a good reference considering age and gender.

    In conclusion, PF latanoprost generic, TJO-002, offers a useful alternative to the available prostaglandin analogues containing BAK for the treatment of POAG/OHT and is likely to be associated with fewer ocular surface problems, without any reduction in efficacy. On the basis of our result, PF-latanoprost could be considered as an alternative to conventional latanoprost, especially in patients suffering from pre-existing or concomitant ocular surface diseases. In the future, it is also of interest to study the comparison of the difference between efficacy and safety with and without preservatives in three different prostaglandin analogues in relation to the surface eye effect of PF.

    ACKNOWLEDGEMENTS

    Foundation:Supported by Taejoon Pharmaceutical.

    Conflicts of Interest:Kim JM, None; Sung KR, None;Lee JW, None; Kyung H, None; Rho S, None; Kim CY,None.

    xxx96com| 成年人黄色毛片网站| 欧美黄色淫秽网站| 久久精品国产综合久久久| 亚洲五月色婷婷综合| 丁香欧美五月| 亚洲狠狠婷婷综合久久图片| 中文字幕人妻熟女乱码| 日日摸夜夜添夜夜添小说| 成人特级黄色片久久久久久久| 搡老岳熟女国产| 极品教师在线免费播放| 性少妇av在线| 久久 成人 亚洲| 热re99久久精品国产66热6| 日韩欧美一区视频在线观看| 69av精品久久久久久| 免费不卡黄色视频| 香蕉久久夜色| 最好的美女福利视频网| 啦啦啦 在线观看视频| 1024视频免费在线观看| 很黄的视频免费| 国产精品久久电影中文字幕| 婷婷丁香在线五月| 国产成人av激情在线播放| 黑人巨大精品欧美一区二区mp4| 50天的宝宝边吃奶边哭怎么回事| 岛国在线观看网站| 999久久久国产精品视频| 天天躁狠狠躁夜夜躁狠狠躁| 天堂√8在线中文| 精品久久久久久久毛片微露脸| 久久精品国产亚洲av高清一级| 1024视频免费在线观看| 精品久久久久久电影网| 搡老乐熟女国产| 一级毛片精品| 9热在线视频观看99| 精品国产亚洲在线| 国产又色又爽无遮挡免费看| 成人免费观看视频高清| 国产精品自产拍在线观看55亚洲| 免费搜索国产男女视频| 三级毛片av免费| 免费不卡黄色视频| 50天的宝宝边吃奶边哭怎么回事| 老司机亚洲免费影院| 又紧又爽又黄一区二区| 女人高潮潮喷娇喘18禁视频| 日韩欧美国产一区二区入口| 国产又色又爽无遮挡免费看| 久热爱精品视频在线9| 每晚都被弄得嗷嗷叫到高潮| 亚洲精品一卡2卡三卡4卡5卡| 亚洲精品国产区一区二| 国产精品久久久人人做人人爽| 亚洲熟妇熟女久久| 在线观看午夜福利视频| 成人国语在线视频| 亚洲欧美日韩高清在线视频| 久久精品亚洲精品国产色婷小说| 不卡一级毛片| 欧美黑人精品巨大| 久久人妻熟女aⅴ| a在线观看视频网站| 无人区码免费观看不卡| 人妻久久中文字幕网| 欧美久久黑人一区二区| 亚洲va日本ⅴa欧美va伊人久久| 亚洲国产欧美日韩在线播放| 久久国产精品男人的天堂亚洲| 99精品欧美一区二区三区四区| 精品久久久精品久久久| 99久久人妻综合| 久久久久久大精品| 桃色一区二区三区在线观看| 国产精品乱码一区二三区的特点 | 国产在线精品亚洲第一网站| 热99国产精品久久久久久7| 激情视频va一区二区三区| 国产野战对白在线观看| 国产精品日韩av在线免费观看 | 女生性感内裤真人,穿戴方法视频| 黄频高清免费视频| 国产国语露脸激情在线看| 女警被强在线播放| 国产aⅴ精品一区二区三区波| 国产亚洲精品综合一区在线观看 | 人人妻,人人澡人人爽秒播| 精品人妻在线不人妻| 国产亚洲欧美在线一区二区| 91国产中文字幕| 女人被狂操c到高潮| 久久国产精品人妻蜜桃| 欧美激情久久久久久爽电影 | 久久久国产欧美日韩av| 大型黄色视频在线免费观看| 日本五十路高清| 午夜福利,免费看| 日本免费a在线| 亚洲五月婷婷丁香| www.精华液| 亚洲中文日韩欧美视频| 亚洲五月色婷婷综合| 国产男靠女视频免费网站| 国产精品久久久人人做人人爽| 大陆偷拍与自拍| 久久亚洲真实| 久久精品国产99精品国产亚洲性色 | 国产成+人综合+亚洲专区| 变态另类成人亚洲欧美熟女 | 日韩精品免费视频一区二区三区| 午夜福利免费观看在线| 99在线视频只有这里精品首页| 人妻久久中文字幕网| 99国产精品99久久久久| 999精品在线视频| 精品一区二区三卡| 亚洲性夜色夜夜综合| 黄片大片在线免费观看| 色尼玛亚洲综合影院| 黑人操中国人逼视频| 国产视频一区二区在线看| 午夜影院日韩av| 国产午夜精品久久久久久| av超薄肉色丝袜交足视频| 国产麻豆69| 最近最新中文字幕大全电影3 | 精品国产美女av久久久久小说| 久久久久久久午夜电影 | 久久热在线av| 又紧又爽又黄一区二区| 1024香蕉在线观看| 夜夜爽天天搞| 91麻豆av在线| 亚洲 欧美一区二区三区| 亚洲一区中文字幕在线| 欧美日本亚洲视频在线播放| 中文字幕另类日韩欧美亚洲嫩草| 免费在线观看黄色视频的| 国产高清videossex| 无限看片的www在线观看| 国产精品影院久久| 琪琪午夜伦伦电影理论片6080| 日韩高清综合在线| 制服人妻中文乱码| 国产免费男女视频| 国产三级在线视频| 久久久久久久午夜电影 | 成在线人永久免费视频| 三级毛片av免费| 精品国内亚洲2022精品成人| 亚洲欧美一区二区三区久久| 99久久久亚洲精品蜜臀av| 久久国产精品男人的天堂亚洲| 视频区欧美日本亚洲| 国产一区二区激情短视频| 一级,二级,三级黄色视频| 99riav亚洲国产免费| 99久久综合精品五月天人人| 国产精品电影一区二区三区| 身体一侧抽搐| 亚洲精品美女久久av网站| 国产精品成人在线| 久久人妻av系列| 亚洲色图av天堂| 亚洲成人精品中文字幕电影 | 一级,二级,三级黄色视频| 在线av久久热| 国产亚洲精品一区二区www| 国产欧美日韩一区二区三区在线| 久久中文看片网| 色精品久久人妻99蜜桃| 久久久国产一区二区| 高清欧美精品videossex| 97碰自拍视频| 国产精品九九99| 久久性视频一级片| 人妻丰满熟妇av一区二区三区| 精品久久久久久久久久免费视频 | 国产亚洲精品久久久久久毛片| 波多野结衣av一区二区av| 国产有黄有色有爽视频| 一区二区三区精品91| 首页视频小说图片口味搜索| 欧美国产精品va在线观看不卡| av中文乱码字幕在线| 久久精品影院6| 桃红色精品国产亚洲av| 久久久久精品国产欧美久久久| 国产aⅴ精品一区二区三区波| 亚洲五月色婷婷综合| 日韩精品免费视频一区二区三区| 久久久久久久久久久久大奶| 久久国产亚洲av麻豆专区| 不卡一级毛片| 国产免费现黄频在线看| 99热国产这里只有精品6| 亚洲在线自拍视频| 九色亚洲精品在线播放| 国产蜜桃级精品一区二区三区| 久久精品91无色码中文字幕| 欧美另类亚洲清纯唯美| 亚洲一区中文字幕在线| 日韩精品免费视频一区二区三区| 久久久久久久久久久久大奶| 伦理电影免费视频| 动漫黄色视频在线观看| 久久精品影院6| 亚洲人成电影免费在线| 丝袜美足系列| 午夜视频精品福利| 一级,二级,三级黄色视频| www.www免费av| 精品国产乱子伦一区二区三区| 亚洲精品av麻豆狂野| 午夜免费鲁丝| 97人妻天天添夜夜摸| 成人永久免费在线观看视频| 黄网站色视频无遮挡免费观看| 午夜免费成人在线视频| 最好的美女福利视频网| 亚洲精品一二三| 露出奶头的视频| 亚洲国产欧美一区二区综合| 国产国语露脸激情在线看| 久久影院123| 中文字幕精品免费在线观看视频| 亚洲 欧美 日韩 在线 免费| 欧美国产精品va在线观看不卡| 悠悠久久av| 国产又爽黄色视频| 一进一出好大好爽视频| 欧美激情极品国产一区二区三区| 交换朋友夫妻互换小说| 国产成人av教育| 极品人妻少妇av视频| 男人的好看免费观看在线视频 | 精品一区二区三区四区五区乱码| 午夜久久久在线观看| 91老司机精品| 中文字幕高清在线视频| 亚洲欧美一区二区三区久久| 怎么达到女性高潮| 老司机亚洲免费影院| 久久婷婷成人综合色麻豆| 国产精品亚洲一级av第二区| 新久久久久国产一级毛片| 欧美黄色片欧美黄色片| 日韩欧美三级三区| 香蕉丝袜av| 免费在线观看完整版高清| 天堂动漫精品| 精品免费久久久久久久清纯| 97超级碰碰碰精品色视频在线观看| 亚洲av成人一区二区三| 乱人伦中国视频| 久久久久久大精品| 久久草成人影院| 中文字幕精品免费在线观看视频| 国产免费av片在线观看野外av| 色综合站精品国产| 满18在线观看网站| a级毛片在线看网站| 男人操女人黄网站| 婷婷丁香在线五月| xxx96com| 两性午夜刺激爽爽歪歪视频在线观看 | 脱女人内裤的视频| 欧美 亚洲 国产 日韩一| 国产精品99久久99久久久不卡| 亚洲全国av大片| 精品国产美女av久久久久小说| 在线看a的网站| 午夜精品久久久久久毛片777| 久久久国产成人精品二区 | 国产在线观看jvid| 欧美在线一区亚洲| 国产精品一区二区在线不卡| 动漫黄色视频在线观看| 女生性感内裤真人,穿戴方法视频| 久久久精品国产亚洲av高清涩受| 热99国产精品久久久久久7| 两个人免费观看高清视频| 在线观看免费日韩欧美大片| 精品一区二区三区四区五区乱码| 无限看片的www在线观看| 亚洲成人免费av在线播放| 俄罗斯特黄特色一大片| 色哟哟哟哟哟哟| 久久精品aⅴ一区二区三区四区| 男女之事视频高清在线观看| 国产激情久久老熟女| 一级毛片精品| 97碰自拍视频| 一夜夜www| 欧美中文综合在线视频| 一区二区三区激情视频| 视频区欧美日本亚洲| 美女 人体艺术 gogo| 女人爽到高潮嗷嗷叫在线视频| 亚洲精品一区av在线观看| 亚洲av熟女| 欧美大码av| 999久久久国产精品视频| 免费观看人在逋| 亚洲精品国产一区二区精华液| 黑人巨大精品欧美一区二区mp4| 国产一区二区在线av高清观看| 国产区一区二久久| 亚洲午夜精品一区,二区,三区| 日本精品一区二区三区蜜桃| 亚洲人成伊人成综合网2020| 欧美人与性动交α欧美软件| 18禁国产床啪视频网站| 18禁黄网站禁片午夜丰满| 两性午夜刺激爽爽歪歪视频在线观看 | av电影中文网址| 亚洲自拍偷在线| 免费人成视频x8x8入口观看| 久久久久久久久免费视频了| av天堂在线播放| 国产精品久久久久久人妻精品电影| 中文字幕最新亚洲高清| 好男人电影高清在线观看| 日韩欧美免费精品| 丰满人妻熟妇乱又伦精品不卡| 亚洲精品国产区一区二| 国产免费av片在线观看野外av| 欧美乱妇无乱码| 人人妻人人添人人爽欧美一区卜| 婷婷精品国产亚洲av在线| 亚洲国产精品一区二区三区在线| 国产在线精品亚洲第一网站| 巨乳人妻的诱惑在线观看| 一区二区三区精品91| 国产成人精品久久二区二区免费| 亚洲精品久久成人aⅴ小说| 真人一进一出gif抽搐免费| 中文字幕高清在线视频| 亚洲激情在线av| 国内久久婷婷六月综合欲色啪| 在线国产一区二区在线| 欧美日韩黄片免| 免费高清在线观看日韩| 搡老乐熟女国产| 色哟哟哟哟哟哟| 免费女性裸体啪啪无遮挡网站| 在线播放国产精品三级| 妹子高潮喷水视频| 长腿黑丝高跟| √禁漫天堂资源中文www| 亚洲精品成人av观看孕妇| 亚洲成av片中文字幕在线观看| 操出白浆在线播放| 国产视频一区二区在线看| 黑丝袜美女国产一区| 丰满人妻熟妇乱又伦精品不卡| 亚洲av成人不卡在线观看播放网| 久久久久国内视频| 成人永久免费在线观看视频| 欧美黑人欧美精品刺激| 精品午夜福利视频在线观看一区| 超碰97精品在线观看| 俄罗斯特黄特色一大片| 老鸭窝网址在线观看| 91老司机精品| 久热这里只有精品99| 美女 人体艺术 gogo| 国产精品国产高清国产av| 亚洲成人国产一区在线观看| 久久精品国产99精品国产亚洲性色 | 一个人观看的视频www高清免费观看 | 最新美女视频免费是黄的| 久久热在线av| 一二三四在线观看免费中文在| 日韩欧美一区视频在线观看| 欧美在线一区亚洲| 老司机福利观看| 亚洲色图av天堂| 久热这里只有精品99| 久久久久九九精品影院| 国产aⅴ精品一区二区三区波| 亚洲欧美激情在线| 日本 av在线| 69av精品久久久久久| 女警被强在线播放| 精品国产国语对白av| 99久久人妻综合| 黄频高清免费视频| 国产单亲对白刺激| 女人爽到高潮嗷嗷叫在线视频| 每晚都被弄得嗷嗷叫到高潮| 亚洲av美国av| a在线观看视频网站| 两人在一起打扑克的视频| 怎么达到女性高潮| 国产一区二区三区视频了| 80岁老熟妇乱子伦牲交| 长腿黑丝高跟| 别揉我奶头~嗯~啊~动态视频| 最新美女视频免费是黄的| 黄色成人免费大全| 黄色女人牲交| 99riav亚洲国产免费| 在线播放国产精品三级| 麻豆成人av在线观看| 在线永久观看黄色视频| 国产一区二区三区视频了| 女人高潮潮喷娇喘18禁视频| 国产三级黄色录像| 精品久久久久久成人av| 亚洲av五月六月丁香网| 免费观看人在逋| xxxhd国产人妻xxx| 少妇被粗大的猛进出69影院| 中文字幕色久视频| 丝袜在线中文字幕| 亚洲一码二码三码区别大吗| 亚洲性夜色夜夜综合| 级片在线观看| 91成人精品电影| 免费看十八禁软件| 搡老熟女国产l中国老女人| 亚洲成人国产一区在线观看| 法律面前人人平等表现在哪些方面| 97碰自拍视频| 一区在线观看完整版| 一级黄色大片毛片| 免费人成视频x8x8入口观看| 午夜福利影视在线免费观看| 女性生殖器流出的白浆| 黄片播放在线免费| avwww免费| 美女 人体艺术 gogo| 麻豆成人av在线观看| 制服诱惑二区| 亚洲av成人不卡在线观看播放网| 欧美成人免费av一区二区三区| 精品久久久久久,| 精品日产1卡2卡| 精品人妻在线不人妻| 国产精品一区二区免费欧美| 亚洲中文av在线| 在线国产一区二区在线| 狠狠狠狠99中文字幕| 777久久人妻少妇嫩草av网站| 在线观看免费日韩欧美大片| 黑人巨大精品欧美一区二区蜜桃| 久久精品国产亚洲av香蕉五月| 丝袜人妻中文字幕| 中文字幕精品免费在线观看视频| 欧美激情极品国产一区二区三区| 9色porny在线观看| av视频免费观看在线观看| 精品午夜福利视频在线观看一区| 嫩草影视91久久| 国产熟女午夜一区二区三区| 在线观看舔阴道视频| 亚洲片人在线观看| 国产区一区二久久| 亚洲 国产 在线| 国产精品久久视频播放| 亚洲国产精品合色在线| 国产一区二区三区在线臀色熟女 | 国产精品亚洲一级av第二区| 国产精品爽爽va在线观看网站 | 亚洲专区国产一区二区| 一夜夜www| 一级毛片精品| 欧美黄色片欧美黄色片| 狠狠狠狠99中文字幕| 亚洲在线自拍视频| 亚洲国产毛片av蜜桃av| av福利片在线| 国产精品国产高清国产av| 88av欧美| 国产精品 欧美亚洲| 国产一区在线观看成人免费| 欧美黄色淫秽网站| 久热爱精品视频在线9| 精品免费久久久久久久清纯| 亚洲国产欧美网| 两个人免费观看高清视频| 免费不卡黄色视频| 人人妻,人人澡人人爽秒播| 久久久国产成人免费| 手机成人av网站| 久久中文字幕人妻熟女| 久久香蕉激情| 亚洲精品中文字幕在线视频| 午夜精品在线福利| 亚洲 欧美 日韩 在线 免费| 18禁裸乳无遮挡免费网站照片 | 亚洲精品一区av在线观看| 麻豆国产av国片精品| 超碰97精品在线观看| 青草久久国产| 亚洲熟女毛片儿| 亚洲中文av在线| 黑人欧美特级aaaaaa片| 两个人免费观看高清视频| 国产精品二区激情视频| 一边摸一边抽搐一进一小说| 日韩中文字幕欧美一区二区| 午夜福利在线观看吧| 亚洲欧美精品综合一区二区三区| cao死你这个sao货| 亚洲一区中文字幕在线| 亚洲av第一区精品v没综合| 夫妻午夜视频| 丁香欧美五月| e午夜精品久久久久久久| 精品人妻1区二区| 嫩草影院精品99| 日日爽夜夜爽网站| 日本黄色日本黄色录像| 国产99久久九九免费精品| 亚洲成av片中文字幕在线观看| 国产精品一区二区在线不卡| 久久久久久人人人人人| 麻豆av在线久日| 国产精品1区2区在线观看.| 亚洲aⅴ乱码一区二区在线播放 | 最近最新中文字幕大全免费视频| 三级毛片av免费| 亚洲成人久久性| 91国产中文字幕| 欧美人与性动交α欧美软件| 搡老岳熟女国产| 欧美成人免费av一区二区三区| 天天躁狠狠躁夜夜躁狠狠躁| 99久久综合精品五月天人人| 日韩 欧美 亚洲 中文字幕| 久久久久国产一级毛片高清牌| 日韩成人在线观看一区二区三区| 亚洲一区二区三区欧美精品| 变态另类成人亚洲欧美熟女 | 高清毛片免费观看视频网站 | 18禁裸乳无遮挡免费网站照片 | 法律面前人人平等表现在哪些方面| 欧美日韩精品网址| 在线观看免费午夜福利视频| 精品国产一区二区三区四区第35| 亚洲欧美激情综合另类| 在线观看66精品国产| 久久亚洲真实| 757午夜福利合集在线观看| 人成视频在线观看免费观看| 国产精品1区2区在线观看.| 久久久久久久久久久久大奶| 可以在线观看毛片的网站| 精品久久久久久,| av片东京热男人的天堂| 午夜影院日韩av| 欧美日韩乱码在线| 久久香蕉精品热| 成年人黄色毛片网站| 一区二区三区激情视频| 国产成人精品无人区| 日韩国内少妇激情av| 久久精品国产亚洲av高清一级| 老司机亚洲免费影院| 国产成人精品无人区| 欧美精品啪啪一区二区三区| 午夜福利一区二区在线看| √禁漫天堂资源中文www| 亚洲激情在线av| 久久热在线av| 国产精品一区二区三区四区久久 | x7x7x7水蜜桃| 成人av一区二区三区在线看| 一区在线观看完整版| 午夜视频精品福利| 国产成人av教育| 自线自在国产av| 很黄的视频免费| 日本五十路高清| 精品国产一区二区久久| ponron亚洲| 久久久精品国产亚洲av高清涩受| 亚洲精品在线观看二区| 最新在线观看一区二区三区| 国产亚洲精品第一综合不卡| 成人亚洲精品av一区二区 | 日韩欧美免费精品| 欧美性长视频在线观看| 大陆偷拍与自拍| 欧美日韩瑟瑟在线播放| 久久久久久久精品吃奶| 一二三四在线观看免费中文在| www.www免费av| 在线观看免费视频日本深夜| 十八禁人妻一区二区| 成人特级黄色片久久久久久久| 一边摸一边抽搐一进一小说| 一级a爱视频在线免费观看| 国产精品久久久久久人妻精品电影| 欧美日韩瑟瑟在线播放| 免费高清视频大片| 日日爽夜夜爽网站| 国产一区二区三区在线臀色熟女 | 亚洲自偷自拍图片 自拍| 一夜夜www| 中文字幕av电影在线播放| 亚洲人成77777在线视频| 在线十欧美十亚洲十日本专区| 黄频高清免费视频| 日韩国内少妇激情av| 少妇裸体淫交视频免费看高清 | 欧美中文综合在线视频| 搡老岳熟女国产| 亚洲国产中文字幕在线视频| 亚洲第一青青草原|