Objectives To assess the effects of alpha-glucosidase inhibitors in patients with type 2 diabetes mellitus. Method We searched The Cochrane Library, MEDLINE, EMBASE, Current Contents, LILACS, databases of ongoing trials, reference lists of reviews on the topic of alpha-glucosidase inhibitors and we contacted experts and manufacturers for additional trials. Date of most recent search: December 2003 (Current Contents) and April 2003 (other databases). Randomised controlled trials of at least 12 weeks duration comparing alpha-glucosidase inhibitor monotherapy in patients with type 2 diabetes with any other intervention and that included at least one of the following outcomes: mortality, morbidity, quality of life, glycemic control, lipids, insulin levels, body weight, adverse events. Two reviewers read all abstracts, assessed quality and extracted data independently. Discrepancies were resolved by consensus or by the judgement of a third reviewer. A statistician checked all extracted data entrance in the database. We attempted to contact all authors for data clarification. Results We included 41 trials (8130 participants), 30 investigated acarbose, seven miglitol, one trial voglibose and three trials compared different alpha-glucosidase inhibitors. Study duration was 24 weeks in most cases and only two studies lasted amply longer than one year. We found only few data on mortality, morbidity and quality of life. Acarbose had a clear effect on glycemic control compared to placebo: glycated haemoglobin –0.77% (95% confidence interval –0.90 to –0.64), fasting blood glucose –1.1 mmol/L (95% confidence interval –1.4 to –0.9), post-load blood glucose –2.32 mmol/L (95% confidence interval –2.73 to –1.92). The effect on glycated haemoglobin by acarbose was not dose-dependent. We found a decreasing effect on post-load insulin and no clinically relevant effects on lipids or body weight. Adverse effects were mostly of gastro-intestinal origin and dose dependent. Compared to sulphonylurea, acarbose decreased fasting and post-load insulin levels by –24.8 pmol/L (95% confidence interval –43.3 to –6.3) and –133.2 pmol/L (95% confidence interval –184.5 to –81.8) respectively and acarbose caused more adverse effects. Conclusions It remains unclear whether alpha-glucosidase inhibitors influence mortality or morbidity in patients with type 2 diabetes. Conversely, they have a significant effect on glycemic control and insulin levels, but no statistically significant effect on lipids and body weight. These effects are less sure when alpha-glucosidase inhibitors are used for a longer duration. Acarbose dosages higher than 50 mg TID offer no additional effect on glycated haemoglobin but more adverse effects instead. Compared to sulphonylurea, alpha-glucosidase inhibitors lower fasting and post-load insulin levels and have an inferior profile regarding glycemic control and adverse effects.
ObjectiveTo analyze the concentrations of vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) in aqueous humor of patients with proliferative diabetic retinopathy (PDR) before and after intravitreal injection of ranibizumab. MethodsTwenty-five eyes of 20 PDR patients were collected as the PDR group. Twenty-five eyes of 21 senile cataract patients were collected as the control group. There were no statistical significance in gender (χ2=0.223), age (Z=-1.555) and intraocular pressure (Z=-0.225) between the two groups (P > 0.05). Samples of aqueous humor (0.1 ml) were collected just before and 7 days after the injection of ranibizumab in PDR group. Samples of aqueous (0.1 ml) humor were collected just before cataract surgery in control group. The concentrations of VEGF and PEDF in the aqueous humor were measured by enzyme-linked immunosorbent assay. ResultsThe VEGF and PEDF concentration in the aqueous humor were reduced significantly after intravitreal injection of ranibizumab in PDR group (Z=-4.072, -4.319; P < 0.05). The concentrations of VEGF and PEDF in the aqueous humor before intravitreal injection of ranibizumab in PDR group were significantly higher than the control group (Z=-5.228, 4.706; P < 0.05). The VEGF concentration in the aqueous humor after intravitreal injection of ranibizumab in PDR group were similar to control group (Z=-1.557, P > 0.05). However, the concentration of PEDF in the aqueous humor after intravitreal injection of ranibizumab in PDR group still higher than control group (Z=-2.475, P < 0.05). The ratio of VEGF/PEDF before and after intravitreal injection of ranibizumab was statistically different (Z=-2.058, P < 0.05), but was the same between PDR group and control group (Z=-0.456, -0.844; P > 0.05). The aqueous humor concentrations of VEGF and PEDF were not significantly correlated with each other, neither in PDR group (r=-0.195, -0.174; P > 0.05) nor in control group (r=-0.286, P > 0.05). ConclusionsAqueous humor concentrations of VEGF and PEDF are significantly elevated in eyes with PDR. Intravitreal injection of ranibizumab significantly decreased the VEGF and PEDF in the aqueous humor after 7 days.
Ras homolog family (Rho)/ Rho-associated coiled-coil kinase (ROCK) signaling pathway widely exists in human and mammal cells, which is closely related to inhibition of repair after optic nerve damage. The expression level of Rho/ROCK signaling pathway-related proteins is up-regulated in glaucoma, and related with the death of retinal ganglionic cell (RGC) and the axon activity. ROCK inhibitors can protect the surviving RGC and promote axon extension with a dose-dependent manner. ROCK inhibitors also can inhibit glial scar formation, lower intraocular pressure and inhibit inflammatory response to some degrees. Rho/ROCK signaling pathway correlates with the optic nerve disease progression, and ROCK inhibitors hope to become a new therapeutic drug.
Objective To explore the inhibitory effects of r-k4k5 on retinal neovascularization. Methods Eighty-eight one-week-old C57BL/6J mice were put into the environment with 75% oxygen for 5 days to establish models of vascular proliferation retinopathy. One eye of each mouse received an intravitreal injection of 500 ng of r-k4k5 (large-dosage group) and of 250 ng of r-k4k5(small-dosage group), and the same volume of BSS was injected into the other eye of the mice both in these two groups as a control. The ADPase histochemical staining was used for retinal flatmount to observe changes of retinal vessels. The inhibitory effects of r-k4k5 on retinal neovascularization were evaluated by counting the endotheliocyte nuclei of new vessels extending from retina to vitreous in the tissue-slice. Results Regular distributions and reduced density of retinal blood vessels in eyes in the treatment group were found in retinal flatmount. The number of the endotheliocyte nuclei of new vessels extending from retina to vitreous was less in the eyes in the treatment group than which in control group (Plt;0.001). The nuclei of new blood vessels in the large-dosage group were less than which in small-dosage group (Plt;0.001). No histologic evidence of retinal toxicity or inflammatory response was found in the tissue-slice after the injection of r-k4k5. Conclusions Retinal neovascularization can be inhibited by intravitreal injection of r-k4k5,which suggests that intravitreal injection of r-k4k5 may have potential therapeutic benifits in retinal vascular disease. (Chin J Ocul Fundus Dis，2003，19：121-124)
Objective To observe the degradation regulation of ubiquitinproteasome inhibitor nuclear factor kappa;B（NF-kappa;B）and its inhibitory signal protein Ikappa;B kinase in earlier period diabetic retinopathy（DR）,and the effects on retinal ganglion cells (RGC) apoptosis.Methods Forty healthy adult Wistar rats were randomly divided into control (group A）,DR（group B）,DR+lowconcentration MG132 treated （group C）and DR+high concentration MG132 treated（group D）groups,10 rats in each group.After 6 and 8 weeks,the results of body masses and fasting blood glucose (FBG) were detected,the expression of NF-kappa;B and Ikappa;B were observed by immunohistochemistry respectively.RGC apoptosis was assessed by the terminal deoxynucleotidyl transferase mediated dUTP-biotin nick-end labelling (TUNEL) method.Results The expression of NF-kappa;B was upregulated in group B compared with group A,its expression decreased in group D compared with group B; but the expression of Ikappa;B was contrary to NF-kappa;B; RGC apoptosis was followed a similar pattern with the expression of NF-kappa;B; the differences among them were statistically significant (P＜0.01).Compared the expression of NF-kappa;B，Ikappa;B and RGC apoptosis in group C and D, there were no statistically significant differences(P＞0.05).Conclusion Ubiquitin-proteasome inhibitor MG132 can block the activation of NF-kappa;B,inhibit ubiquitination of Ikappa;B degradation and RGC apoptosis.
Anti-vascular endothelial growth factor (VEGF) drugs, including monoclonal antibodies (such as bevacizumab and ranibizumab) and fusion protein agents (such as aflibercept and conbercept) have been clinically proven to be effective to treat exudative age-related macular degeneration AMD). However, there are still some patients do not or poorly respond to the initial anti-VEGF agents, usually after several injections, ophthalmologists may switch to another anti-VEGF agent. In general, switching of anti-VEGF agent is considered for recurrent AMD, AMD resistance to anti-VEGF treatments. Current switching protocols include the replacement of monoclonal antibodies with fusion protein agents, the replacement of fusion protein agents with monoclonal antibodies, the substitution of one monoclonal antibody with another one, and the replacement of monoclonal antibodies with fusion protein agents and switching back with monoclonal antibodies. However, current researches on the switching of anti-VEGF drugs for exudative AMD are mostly retrospective and single-arm studies, and there are some differences in the results of different studies. Therefore, for patients with exudative AMD who do not respond to or respond poorly to anti-VEGF drugs, the efficacy of switching of anti-VEGF drugs is uncertain right now. Switching of anti-VEGF agents may improve the retinal anatomical outcome of the affected eye but may not necessarily improve visual acuity. Thus it is an option in the clinical practice to treat AMD. To determine the benefits of above mentioned switching regimens, randomized controlled clinical trials with large sample number and long study period will be needed.
Objective To investigate the effects of celecoxib-poly lactide-co-glycolide microparticles (CEL-PLGA-MS) on rat retina after intravitreal injection. Methods A total of 32 male Brown Norway rats were randomly divided into CEL-PLGA-MS group and celecoxib group, 16 rats in each group. The rats in CEL-PLGA-MS group were divided into four dosage group, four rats in each group, which received intravitreal injection of PLGA with celecoxib at the concentration of 40, 80, 160, 320 mu;mol/L, respectively. The rats in celecoxib group were divided into four dosage group, four rats in each group, which received intravitreal injection of celecoxib at the concentration of 40, 80, 160, 320 mu;mol/L, respectively. Phosphate buffer solution (PBS) was injected in two rats as PBS control group. Two rats as normal control group received no treatment. The difference of retinal thickness among groups was measured by optical coherence tomography (OCT). The morphological and histological change of retina was evaluated under light microscope and transmission electron microscope. Results There was no difference of retinal thickness between normal control group and PBS control group (F=0.12,P＞0.05). At the first week after injection, the retinal thickness of CEL-PLGA-MS group and celecoxib group were thicker than that in normal control group and PBS control group (F=9.62, 46.13;P＜0.01). The retinal thickness of celecoxib group was thicker than that in CEL-PLGA-MS group (F=165.15,P＜0.01). The retinal thickness was estimated equal among 40, 80, 320 mu;mol/L dosage groups in CEL-PLGA-MS group (F=4.79,P＜0.01). The retinal thickness of 160, 320 mu;mol/L dosage group were thicker than that in 40, 80 mu;mol/L dosage group in celecoxib group (F=28.10,P＜0.01). At the second week after injection, there was no difference of retinal thickness between CEL-PLGA-MS and celecoxib group (F=3.79,P＞0.05); the retinal thickness of CEL-PLGA-MS and celecoxib group became thinner gradually compare to the first week after injection (F=7.28, 103.99; P＜0.01). At the fourth week after injection, the retinal thickness of celecoxib group was thicker than that in CEL-PLGA-MS group (F=19.11,P＜0.01). The retinal thickness of CEL-PLGA-MS group was approximately the same to normal control group and PBS control group (F=2.02,P＞0.05). The retinal thickness of celecoxib group was thicker than that in normal control group and PBS control group. No considerable abnormality of the retina was seen by light microscope and the retinal thickness corresponded with the values measured by OCT at the first week after injection. The abnormal structures of the retina were seen in 160, 320 mu;mol/L dosage group of celecoxib group and inner changed evidently by the transmission electron microscope. Disordered arrangement of microfilaments, dilated microtubule and some mitochondria vacuolation were observed in 320mu;mol/L dosage group of celecoxib group. Others changed slightly. Conclusions CEL-PLGA-MS has less toxicity on the retina than free-celecoxib after intravitreal injection. The safety of intravitreal injection with CEL-PLGA-MS is better than celecoxib.
ObjectiveTo observe the effects of angiostatin on the activity of extra-cellular signal-regulated protein kinase (ERK) of retinal microvascular endothelial cells of mice.MethodsAngiostatin was separated and purified by l-lysine sepharose 4B from human plasma. The primary retinal microvascular endothelial cells were divided into 4 groups: the control group, vascular endothelial growth factor (VEGF) 10 ng/ml group, angiostatin 130 μg/ml group, and VEGF (10 ng/ml) + angiostatin (130 μg/ml) group. The expression of ERK1 was assayed by Westernblotting method 1, 2, 5, 10, 15, and 30 minutes after the treatment of angiostatin.ResultsCompared with the control group, the expression of ERK-1 reduced 1 minute after treatment, reduced markedly after 10 minutes. After 30 minutes, no differences of the expression of ERK were seen between the control group and angiostatin group. The activation of ERK-1 of retinal microvascular endothelial cells occurred after stimulated by VEGF, and at the pitch at the peak after 5 minutes. The level of ERK in VEGF group increased 210% than that in the control (P＜0.05). After 30 minutes, no significant difference of the level of ERK between VEGF and the control group. And because of angiostatin, the expression of ERK-1 decreased 11.9%(1 minute)、17.9%(2 minutes)、38.7%(5 minutes)、49.3%(10 minutes) （P＜0.05）、27.9%(15 minutes)、1.12%(30 minutes) respectively.ConclusionsAngiostatin can effectively block the signal path through which VEGF transmits from outside of the cell to cellular nuclei. (Chin J Ocul Fundus Dis, 2005,21:170-173)
ObjectiveTo observe and analyze the risk factors related to vitreous re-hemorrhage (PVH) after anti-VEGF drugs combined with vitrectomy (PPV) in patients with proliferative diabetic retinopathy (PDR).MethodsRetrospective analysis study. From April 2017 to July 2018, 100 eyes of 87 PDR patients who were diagnosed in Jiaxing Eye Hospital and received anti-VEGF drugs combined with 25G PPV were included in the study. Among them, there were 44 eyes in 38 males and 56 eyes in 49 females. The age ranged from 26 to 83 years, with an average age of 57.72±8.82 years. All patients were type 2 diabetes, with an average duration of diabetes 10.84±6.03 years. All affected eyes were assisted by the same doctor with a non-contact wide-angle lens under the standard three-channel 25G PPV of the flat part of the ciliary body. Five to 7 days before the operation, intravitreal injection of ranibizumab or conbercept 0.05 ml (10 mg/ml) was performed. The incidence of PVH was observed. The age of PVH patients, duration of diabetes, vision before operation, average fasting blood glucose and average postprandial blood glucose before operation, systolic blood pressure and diastolic blood pressure before surgery, laser treatment before surgery, lens removal during operation, intraocular filling during operation, retinal laser points during operation, and fundus lesions during operation (hyperplasia film, Retinal hemorrhage, vascular occlusion, proliferative retinal traction, retinal hiatus, retinal detachment, exudation, neovascularization) were analyzed to find out the cause of PVH. Spearman bivariate correlation analysis and binary logistic regression analysis were performed on the data.ResultsOf the 100 eyes of 87 patients, PVH occurred in 17 eyes (17%). There were statistically significant differences in the number of eyes with vascular occlusion and proliferative traction during surgery in patients with and without PVH (χ2=5.741, 8.103; P＜0.05). There was no significant difference in age (t=－1.364), duration of diabetes (t=0.538), preoperative vision (t=1.897), preoperative fasting blood glucose level (t=1.938), preoperative postprandial blood glucose level (t=1.508), preoperative systolic blood pressure (t=－0.571), preoperative diastolic blood pressure (t=0.275), whether received laser treatment (χ2=2.678), the number of laser points during operation (t=0.565), whether received lens removal during operation (χ2=0.331), whether found new blood vessels during operation (χ2=2.741) and whether received intraocular filling during operation (χ2=0.060) between the patients with and without PVH (P＞0.05). Spearman's bivariate correlation analysis showed that patients with low vision, poor control of fasting blood glucose levels, vascular occlusion and proliferative retinal traction during the operation were related risk factors for PVH (rs=0.208, 0.229, 0.240, 0.285; P＜0.05). Binary logistic regression analysis showed that fundus vascular occlusion and hyperplastic retinal traction may be independent risk factors for PVH during surgery (OR=5.175, 13.915; P＜0.05).ConclusionFundus vascular occlusion and retinal traction caused by fibrovascular membrane hyperplasia in PPV may be independent risk factors for PVH in patients with PDR after anti-VEGF drugs combined with PPV.
Objective To estimate the efficacy and tolerability of combination of Amlodipine and different angiotensin-converting enzyme inhibitors (ACEIs) in comparison with Amlodipine monotherapy in the treatment of hypertension. Methods We searched the Cochrane Central Register of Controlled Trials (Issue 2, 2009), PubMed, MEDLINE, EMbase, CBM, and CNKI (from their inception to August 2009) for relevant studies. Two reviewers independently retrieved randomized controlled trials (RCTs) according to the inclusion and exclusion criteria, assessed the methodological quality of included trials, and extracted data. Meta-analysis was performed by Stata 10.0 soft. Results Seventeen RCTs involving 3 291 patients were ultimately identified. The results of meta-analyses showed combination had a greater systolic blood pressure reduction (WMD=5.72, 95%CI 4.10 to 7.33, P=0.016) and diastolic blood pressure reduction (WMD=3.62, 95%CI 4.85 to 2.39, P=0.000) than monotherapy. Combination had fewer overall adverse events (RR=0.86, 95% CI 0.75 to 0.99) than that of monotherapy. Conclusion The results of meta-analyses indicate that combination provides a superior blood pressure control to that of monotherapy and has fewer adverse events and better tolerability in hypertensive patients.