Intravitreal Ranibizumab Alone or in Combination with Calcium Dobesilate for the Treatment of Diabetic Macular Edema in Nonproliferative Diabetic Retinopathy Patients: 12-Month Outcomes of a Retrospective Study.

Objective: This study investigates the efficacy of CaD combined with intravitreal ranibizumab for the treatment of diabetic macular edema (DME) in patients with nonproliferative DR. Methods: This retrospective, observational, case-control study enrolled consecutive patients newly diagnosed with DME. The patients were treated with 3-monthly loading dose injections of intravitreal ranibizumab (IVR) followed by pro re nata injections (3 + PRN), with or without daily oral CaD. The patients were treated and followed up for 12 months. We reviewed their medical records to determine the optical coherence tomography (OCT) findings, number of injections, best-corrected visual acuity (BCVA), and central macular thickness (CMT) at 3, 6, and 12 months after the first injection. Results: We reviewed 102 eyes of 102 patients; 54 patients received IVR combined with oral CaD (IVR + CaD group) and 48 received only IVR (IVR group). In both groups, BCVA was higher, and CMT was lower, at 3, 6, and 12 months after the injection compared to those at the baseline (p < 0.05 for all), while there were no significant differences in BCVA improvement or CMT reduction between the two groups (p > 0.05). The mean number of IVR injections was significantly lower in the IVR + CaD group than the IVR group (5.4 ± 1.1 vs. 6.7 ± 1.6 injections, p < 0.05) during 1 year of treatment. No adverse events were noted in either group. Conclusions: Compared to IVR alone, the addition of oral CaD to IVR in DME patients was safe and effective for improving visual function and restoring the retinal anatomy and was associated with the need for fewer injections.

Phlebotonics for venous insufficiency.

BACKGROUND: Chronic venous insufficiency (CVI) is a condition in which veins are unable to transport blood unidirectionally towards the heart. CVI usually occurs in the lower limbs. It might result in considerable discomfort, with symptoms such as pain, itchiness and tiredness in the legs. Patients with CVI may also experience swelling and ulcers. Phlebotonics are a class of drugs often used to treat CVI. This is the second update of a review first published in 2005. OBJECTIVES: To assess the efficacy and safety of phlebotonics administered orally or topically for treatment of signs and symptoms of lower extremity CVI. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and Clinicaltrials.gov trials register up to 12 November 2019. We searched the reference lists of the articles retrieved by electronic searches for additional citations. We also contacted authors of unpublished studies. SELECTION CRITERIA: We included randomised, double-blind, placebo-controlled trials (RCTs) assessing the efficacy of phlebotonics (rutosides, hidrosmine, diosmine, calcium dobesilate, chromocarbe, Centella asiatica, disodium flavodate, French maritime pine bark extract, grape seed extract and aminaftone) in patients with CVI at any stage of the disease. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the quality of included RCTs. We estimated the effects of treatment by using risk ratios (RRs), mean differences (MDs) and standardized mean differences (SMDs), according to the outcome assessed. We calculated 95% confidence intervals (CIs) and percentage of heterogeneity (I2). Outcomes of interest were oedema, quality of life (QoL), assessment of CVI and adverse events. We used GRADE criteria to assess the certainty of the evidence. MAIN RESULTS: We identified three new studies for this update. In total, 69 RCTs of oral phlebotonics were included, but only 56 studies (7690 participants, mean age 50 years) provided quantifiable data for the efficacy analysis. These studies used different phlebotonics (28 on rutosides, 11 on hidrosmine and diosmine, 10 on calcium dobesilate, two on Centella asiatica, two on aminaftone, two on French maritime pine bark extract and one on grape seed extract). No studies evaluating topical phlebotonics, chromocarbe, naftazone or disodium flavodate fulfilled the inclusion criteria. Moderate-certainty evidence suggests that phlebotonics probably reduce oedema slightly in the lower legs, compared with placebo (RR 0.70, 95% CI 0.63 to 0.78; 13 studies; 1245 participants); and probably reduce ankle circumference (MD -4.27 mm, 95% CI -5.61 to -2.93 mm; 15 studies; 2010 participants). Moderate-certainty evidence shows that phlebotonics probably make little or no difference in QoL compared with placebo (SMD -0.06, 95% CI -0.22 to 0.10; five studies; 1639 participants); and similarly, may have little or no effect on ulcer healing (RR 0.94, 95% CI 0.79 to 1.13; six studies; 461 participants; low-certainty evidence). Thirty-seven studies reported on adverse events. Pooled data suggest that phlebotonics probably increase adverse events slightly, compared to placebo (RR 1.14, 95% CI 1.02 to 1.27; 37 studies; 5789 participants; moderate-certainty evidence). Gastrointestinal disorders were the most frequently reported adverse events. We downgraded our certainty in the evidence from 'high' to 'moderate' because of risk of bias concerns, and further to 'low' because of imprecision. AUTHORS' CONCLUSIONS: There is moderate-certainty evidence that phlebotonics probably reduce oedema slightly, compared to placebo; moderate-certainty evidence of little or no difference in QoL; and low-certainty evidence that these drugs do not influence ulcer healing. Moderate-certainty evidence suggests that phlebotonics are probably associated with a higher risk of adverse events than placebo. Studies included in this systematic review provided only short-term safety data; therefore, the medium- and long-term safety of phlebotonics could not be estimated. Findings for specific groups of phlebotonics are limited due to small study numbers and heterogeneous results. Additional high-quality RCTs focusing on clinically important outcomes are needed to improve the evidence base.

Investigation of the Mechanism Underlying Calcium Dobesilate-Mediated Improvement of Endothelial Dysfunction and Inflammation Caused by High Glucose.

BACKGROUND/AIMS: Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease. Calcium dobesilate (CaD) is widely used to treat diabetic retinopathy. Recent studies have demonstrated that CaD exerts protective effects against diabetic nephropathy. The aim of this study was to elucidate the molecular and cellular mechanisms underlying the protective effects of CaD. METHODS: Human umbilical vein endothelial cells (HUVECs) were cultured with different D-glucose concentrations to determine the effects of high glucose on HUVEC gene expression. HUVECs were also incubated with CaD (25 µM, 50 µM, and 100 µM) for 3 days to determine the effects of CaD on HUVEC viability. db/db mice were treated with CaD. 2-[(Aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1) blocked the nuclear factor-κB (NF-κB) pathway in HUVECs. A pentraxin 3 (PTX3) small interfering RNA (siRNA) intervention experiment was performed in the cells. An adenovirus-encapsulated PTX3 siRNA intervention experiment was performed in db/db mice. Western blot and real-time PCR analyses were used to detect PTX3, p-IKBa/IKBa (I-kappa-B-alpha), and p-eNOS/eNOS (endothelial nitric oxide synthase) expression in mice and HUVECs. Hematoxylin-eosin (HE) staining and periodic acid-Schiff (PAS) staining were used to observe renal tissue damage in mice. PTX3 expression was observed by immunohistochemical staining. RESULTS: CaD downregulated the expression of PTX3 and p-IKBa/IKBa and upregulated the expression of p-eNOS/eNOS in vitro. When TPCA-1 was used, high glucose induced high PTX3 expression, and the expression of p-eNOS/eNOS increased. After PTX3 gene silencing, the expression of p-eNOS/eNOS also increased. In vivo, CaD reduced the expression of PTX3 and p-IKBa/IKBa in the kidneys of db/db mice and increased the expression of p-eNOS/eNOS. After PTX3 gene silencing, the urine protein and renal function of db/db mice were ameliorated, the glomerular extracellular matrix was decreased, and the expression of p-eNOS/eNOS was increased. CONCLUSIONS: Our results suggested that CaD may inhibit the expression of PTX3 by altering the IKK/IKB/NF-κB pathway, thereby improving endothelial dysfunction in HUVECs. PTX3 may be a potential therapeutic target for DKD.

Diabetic Nephropathy Can Be Treated with Calcium Dobesilate by Alleviating the Chronic Inflammatory State and Improving Endothelial Cell Function.

BACKGROUND/AIMS: Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease. However, no effective treatments for this disease are available. Calcium dobesilate (CaD) is widely used to treat diabetic retinopathy. DKD and retinopathy often co-exist and have similar mechanisms of pathogenesis. The aim of the present study was to elucidate the safety and efficacy of CaD in the treatment of DKD. METHODS: In the prospective randomised controlled study, 100 DKD from Type 2 diabetes mellitus (DM) patients with a urinary albumin/ creatinine ratio (ACR) ≥30 mg/g and urinary protein level between 150 mg/24 h and 2 g/24 h with GFR> 90ml/min were enrolled. The patients were randomly divided into the treatment group (500 mg of CaD, administered orally, 3 times per day) and the control group. DKD patients were treated for 3 months. In the case control study, DM patients without proteinuria and healthy individuals were also enrolled. Clinical data and related biochemical parameters were collected. Endothelial function markers (VEGF, ET-1, eNOS, NO) and inflammatory markers (MCP-1, ICAM, PTX3) were detected by ELISA. RESULTS: In the prospective randomised controlled study, the 24 h urinary albumin and 24 h urinary protein levels significantly decreased after three months of treatment with CaD in the patients with DKD, but the cystatin C-based glomerular filtration rate (GFR) remained unchanged. In addition, the levels of inflammatory markers (PTX3, MCP-1, hsCRP, ICAM) and endothelial dysfunction markers (VEGF, ET-1) were significantly reduced compared to pre-treatment levels, NO was signifcantly increased post treatment. In the case control study, we found that PTX3, MCP-1, ICAM, VEGF and ET-1 levels were positively correlated with urinary albumin in DKD patients, while the NO level was negatively correlated. Logistic regression analysis showed that PTX3, NO and HbAlc were influential factors in DKD. After patients with DKD were treated with CaD for three months, the 24 h urinary albumin and 24 h urinary protein levels significantly decreased, but the cystatin C-based glomerular filtration rate (GFR) remained unchanged. In addition, the levels of inflammatory markers (PTX3, MCP-1, hsCRP, ICAM) and endothelial dysfunction markers (VEGF, NO, ET-1) were significantly reduced compared to pre-treatment levels. CONCLUSION: CaD can be safely and effectively used to treatdiabetic nephropathy.

Effects of alprostadil combined with calcium dobesilate in patients with diabetic peripheral neuropathy.

OBJECTIVE: To observe the clinical curative effects of alprostadil combined with calcium dobesilate in type 2 diabetes patients with peripheral neuropathy. METHODS: We randomly divided 120 type 2 diabetes patients with diabetic peripheral neuropathy into two groups. The treatment group was prescribed alprostadil (10 µg, once daily) and oral calcium dobesilate (0.5 g, 3 times daily), and the control group was prescribed alprostadil (10 µg, once daily) for a total treatment duration of 2 weeks. The Michigan Diabetic Neuropathy Score (MDNS) and the Michigan Neuropathy Screening Instrument (MNSI) were used to evaluate differences between the two groups before and after treatment. RESULTS: Following 2 weeks of treatment, the total effective rate in the treatment group was significantly better than that of the control group (p<0.05) and the MDNS and MNSI scores in the treatment group were significantly lower than those in the control group (p<0.05 or p<0.01). CONCLUSION: Combined alprostadil and calcium dobesilate treatment for type 2 diabetic peripheral neuropathy showed good clinical efficacy and an improved curative effect than single alprostadil treatment.

Phlebotonics for venous insufficiency.

BACKGROUND: Chronic venous insufficiency (CVI) is a common condition caused by valvular dysfunction with or without associated obstruction, usually in the lower limbs. It might result in considerable discomfort with symptoms such as pain, itchiness and tiredness in the legs. Patients with CVI may also experience swelling and ulcers. Phlebotonics are a class of drugs often used to treat CVI. This is an update of a review first published in 2005. OBJECTIVES: To assess the efficacy and safety of phlebotonics administered both orally and topically for treatment of signs and symptoms of lower extremity CVI. SEARCH METHODS: For this update, the Cochrane Vascular Trials Search Co-ordinator (TSC) searched the Specialised Register (August 2015), as well as the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 7). The reference lists of the articles retrieved by electronic searches were searched for additional citations. We also contacted pharmaceutical companies and searched the World Health Organization (WHO) International Clinical Trials Registry Platform Search Portal for ongoing studies (last searched in August 2015). SELECTION CRITERIA: Randomised, double-blind, placebo-controlled trials (RCTs) assessing the efficacy of rutosides, hidrosmine, diosmine, calcium dobesilate, chromocarbe, Centella asiatica, disodium flavodate, french maritime pine bark extract, grape seed extract and aminaftone in patients with CVI at any stage of the disease. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the quality of included RCTs. We estimated the effects of treatment by using risk ratios (RRs), mean differences (MDs) and standardised mean differences (SMDs), according to the outcome assessed. We calculated 95% confidence interval (CIs) and percentage of heterogeneity (I(2)). Additionally, we performed sensitivity analyses. MAIN RESULTS: We included 66 RCTs of oral phlebotonics, but only 53 trials provided quantifiable data (involving 6013 participants; mean age 50 years) for the efficacy analysis: 28 for rutosides, 10 hidrosmine and diosmine, nine calcium dobesilate, two Centella asiatica, two aminaftone, two french maritime pine bark extract and one grape seed extract. No studies evaluating topical phlebotonics, chromocarbe, naftazone or disodium flavodate fulfilled the inclusion criteria.Moderate-quality evidence suggests that phlebotonics reduced oedema in the lower legs compared with placebo. Phlebotonics showed beneficial effects among participants including reduced oedema (RR 0.70, 95% CI 0.63 to 0.78; I(2) = 20%; 1245 participants) and ankle circumference (MD -4.27 mm, 95% CI -5.61 to -2.93 mm; I(2) = 47%; 2010 participants). Low-quality evidence reveals no difference in the proportion of ulcers cured with phlebotonics compared with placebo (RR 0.94, 95% CI 0.79 to 1.13; I(2) = 5%; 461 participants). In addition, phlebotonics showed greater efficacy for trophic disorders, cramps, restless legs, swelling and paraesthesia, when compared with placebo. We identified heterogeneity for the variables of pain, itching, heaviness, quality of life and global assessment by participants. For quality of life, it was not possible to pool the studies because heterogeneity was high. However, high-quality evidence suggests no differences in quality of life for calcium dobesilate compared with placebo (MD -0.60, 95% CI -2.15 to 0.95; I(2) = 40%; 617 participants), and low-quality evidence indicates that in the aminaftone group, quality of life was improved over that reported in the placebo group (MD -10.00, 95% CI -17.01 to - 2.99; 79 participants). Moderate-quality evidence shows that the phlebotonics group had greater risk of non-severe adverse events than the placebo group (RR 1.21, 95% CI 1.05 to 1.41; I(2) = 0; 3975 participants). Gastrointestinal disorders were the most frequently reported adverse events. AUTHORS' CONCLUSIONS: Moderate-quality evidence shows that phlebotonics may have beneficial effects on oedema and on some signs and symptoms related to CVI such as trophic disorders, cramps, restless legs, swelling and paraesthesia when compared with placebo but can produce more adverse effects. Phlebotonics showed no differences compared with placebo in ulcer healing. Additional high-quality RCTs focused on clinically important outcomes are needed to improve the evidence base.

[Modern approach to early diagnosis and pathogenetic treatment of diabetic retinopathy]. / Sovremennye podkhody k rannei diagnostike, patogeneticheskomu lecheniyu diabeticheskoi retinopatii.

AIM: To improve the approach to pathogenetic treatment of diabetic retinopathy (DR) through early diagnosis and a new method for predicting disease progression. MATERIAL AND METHODS: The study enrolled 330 type 2 diabetes patients with DR (660 eyes), of whom women constituted 64.6%, men - 35.4%. The mean patient age was 62.3±2.3 years. Three groups were formed: the controls - 30 healthy volunteers (60 eyes) and 30 type 2 diabetes patients without ocular involvement (DR 0, 60 eyes); group 1 - 30 type 2 diabetes patients with DR I but no diabetic macular edema (DR I without DME, 60 eyes) that were treated with calcium dobesilate; group 2 - 240 type 2 diabetes patients, who had diabetic retinopathy of different stages (DR I, II, or III with DME, 480 eyes) and received laser retinal photocoagulation (LRP). The groups were all alike in terms of sex and age distribution. All patients underwent ophthalmic examination, including best corrected visual acuity (BCVA) and critical flicker fusion frequency (CFFF) testing, tonometry, biomicroscopy, MAIA fundus microperimetry, optical coherence tomography (OCT), and fluorescein angiography (FAG) of the retina. Traditionally we also determined blood sugar and glycated hemoglobin levels as well as vascular endothelial growth factor (VEGF-A) and monocyte chemoattractant protein (MCP-1) in tear fluid by ELISA. RESULTS: In group 1, which was under conservative therapy with calcium dobesilate, there was an increase in BCVA by the average of 0.95±0.02 and CFFF by 42.5±0.2 Hz (p<0,05). The mean central retinal thickness decreased reliably down to 265.1±12.1 µm (p<0.05). Light sensitivity of the macula improved and scored 24.13±12.3 dB (p<0.05). In group 2, the mean central retinal thickness appeared to be 383.1±221 µm, which was reliably higher than that in healthy individuals (p<0.05) and in type 2 diabetes patients without diabetic retinopathy (DR 0) (p<0.05). Tear assessment 12 months after the treatment revealed a significant decrease in VEGF-A and MCP-1 concentrations - down to 655.1±86.1 pg/ml and 1133 pg/ml, respectively (p<0.05). CONCLUSION: Conservative treatment with calcium dobesilate has proved effective in patients with DR I without DME as it ensures improvement and stabilization of the state of the retina (clinical and morphological) in one month already (judging from FAG and OCT findings). Laser treatment is rational in DR I, DR II, and DR III patients, whose condition is complicated with DME. Improvement and stabilization take, however, longer to be achieved - up to 1 year (according to FAG and OCT). Tear fluid assessment for particular participants in disease pathogenesis, such as VEGF-A and MCP-1, is a unique method for disease control and patient follow-up with account to different treatments. A new method for predicting the progression of diabetic retinopathy and diabetic macular edema has been suggested (RF patent for invention №2520826).

Study protocol for assessment of the efficacy of calcium dobesilate versus placebo on SARS-CoV-2 viral load in outpatients with COVID-19 (CADOVID study): a randomised, placebo-controlled, double-blind, monocentric phase II trial.

INTRODUCTION: SARS-CoV-2 mainly infects respiratory endothelial cells, which is facilitated through its spike protein binding to heparan sulphate. Calcium dobesilate (CaD) is a well-established, widely available vasoactive and angioprotective drug interacting with heparan sulphate, with the potential to interfere with the uptake of SARS-CoV-2 by epithelial cells. The CADOVID trial aims to evaluate the efficacy and safety of CaD in reducing the SARS-CoV-2 viral load in non-hospitalised adult patients diagnosed with COVID-19, confirmed by a positive SARS-CoV-2 PCR, including its efficacy to reduce the impact of persistent COVID-19 symptoms. METHODS AND ANALYSIS: This is a randomised, placebo-controlled, double-blind, monocentric phase II trial. Enrolment began in July 2022. A total of 74 adult patients will be randomly allocated to the CaD arm or the placebo group with a 1:1 ratio, respectively. Participants in the intervention arm will receive two capsules of CaD 500 mg two times per day and the placebo arm will receive two matching capsules of mannitol 312.5 mg two times per day, with a treatment period of 7 days for both arms, followed by a 77-day observational period without treatment administration. Participants will be asked to complete secured online questionnaires using their personal smartphone or other electronic device. These include a COVID-19 questionnaire (assessing symptoms, temperature measurement, reporting of concomitant medication and adverse events), a COVID-19 persistent symptoms' questionnaire and the Short Form 12-Item (SF-12) survey. SARS-CoV-2 PCR testing will be performed on nasopharyngeal swabs collected on days 1, 4, 8 and 21. The primary endpoint is the reduction from baseline of SARS-CoV-2 viral load determined by RT-PCR at day 4. ETHICS AND DISSEMINATION: This trial has received approval by the Geneva Regional Research Ethics Committee (2022-00613) and Swissmedic (701339). Dissemination of results will be through presentations at scientific conferences and publication in scientific journals. TRIAL REGISTRATION NUMBER: NCT05305508; Clinicaltrials.gov; Swiss National Clinical Portal Registry (SNCTP 000004938).

Calcium dobesilate reduces endothelin-1 and high-sensitivity C-reactive protein serum levels in patients with diabetic retinopathy.

PURPOSE: To determine the benefits of calcium dobesilate (CaD) administration on endothelial function and inflammatory status in patients with diabetic retinopathy through measurement of serum levels of endothelin-1 and high-sensitivity C-reactive protein (hsCRP). METHODS: In a double-blind, randomized clinical trial, 90 patients with either severe nonproliferative or proliferative diabetic retinopathy and with blood glucose level of 120-200 mg/dl were randomly allocated to treatment with either CaD tablets (500 mg daily) or placebo for 3 months. Visual acuity, intraocular pressure, and macular status were performed before the study. The serum levels of endothelin-1 and hsCRP were evaluated in both groups before and at the third month of the trial. RESULTS: The median serum level of hsCRP significantly differed between the groups 3 months following the CaD or placebo administration (2.2 mg/l in the CaD group versus 3.7 mg/l in the placebo group, p=0.01). The mean endothelin-1 serum level was 0.69±0.32 pg/ml in the CaD group and 0.86±0.30 pg/ml in the placebo group (p=0.01). Furthermore, in the CaD group, the serum levels of both endothelin-1 and hsCRP were significantly decreased 3 months after administration of CaD (p<0.001). CONCLUSIONS: Administration of the CaD in the patients with diabetic retinopathy may reduce the serum levels of endothelin-1 and hsCRP. This might imply amelioration of the endothelial function and inflammatory status following CaD therapy in these patients.

[Evaluation of calcium dobesilate for its anti-cataract potential in experimental rat models].

OBJECTIVE: To investigate the preventive and therapeutic effects of agent calcium dobesilate(CDO) with different doses on the galactose cataract of rats. METHODS: We chose fifty Wistar rats at 20- day old. Then, they were divided into 3 groups at random. Choose 10 rats as the control group and gave normal diet; 10 rats as the model group and fed with Gal solution ( drink 12.5% Gal solution from 1 to 7 days and 10%Gal solution from 8 to 21 days except for normal diet ) ; 30 rats as the treatment group and fed with the same Gal solution as the model group, besides they were divided into high dosage group, medium dosage group and low dosage group equally and gave 300 mg×kg(-1)×d(-1), 150 mg×kg(-1)×d(-1), 75 mg×kg(-1)×d(-1) dose of calcium dobesilate respectively from the first day to the end of experiment. The experiment lasts 21 days. Lens opacity were observed and recorded by slit-lamp examination regularly. Activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) and content of malondialdehyde (MDA) were determined to estimate the effect of CDO . Lens fibers changes and Histological changes were observed by scanning electron microscope (SEM) and light microscope (LM) separately. The apoptosis rate of lens epithelium were determined by TUNEL assay. RESULTS: The appearance of Lens opacity in model group was more quickly than that in treatment group in model group, 3 eyes in degree IV, 7 eyes in degree V, while in treatment group, 5 eyes in degree III, 3 eyes in degree IV, 2 eyes in degree V (H = 7.12, P < 0.05). The activity of SOD and GSH-px in treatment group is higher than mode group, but lower than control group on 8th day, there was difference noticed in the activity of SOD (50.01 ± 1.19), (39.39 ± 1.70) , treatment group (46.57 ± 1.09, 46.42 ± 0.87, 45.70 ± 1.46) U/mgProt (F = 88.70, P < 0.05) and the activity of GSH-px (42.92 ± 0.97) , (12.70 ± 1.17) , treatment group (29.16 ± 1.05, 29.08 ± 0.98, 28.25 ± 0.98) nmol/mgprot (F = 1071.89, P < 0.05) ]in 3 groups. The content of MDA in model group (3.43 ± 0.15)nmol/mgprot is higher than treatment group (2.89 ± 0.11, 2.99 ± 0.12, 2.99 ± 0.09)nmol/mgprot (F = 64.62; P < 0.05). There were no statistic significant differences among high dosage group, medium dosage group and low dosage group . The texture of lens fibres detected by SEM in the rats of model was more disorder than treatment group. After HE staining, Lens epithelial cell detected by LM in control group have a clear structure, however, Lens epithelial cell both in model group and treatment group have changed from the initial single layer to multi-storey. Junction between lenses fibers became decreased even disappeared . The apoptosis rate of lens epithelium in treatment group[(2.37 ± 0.17)%, (2.46 ± 0.26)%, (2.79 ± 0.41)%] is higher than control group (0.23 ± 0.07) %, but is much fewer than model group (4.99 ± 0.51) % (χ(2) = 40.41;P < 0.05). CONCLUSION: CDO with different doses could protect lens of rats against galactose damage and there were no significant differences among the different doses of groups.

Investigation of therapeutic effects of calcium dobesilate in cerebral hypoxia/ reperfusion injury in rats.

OBJECTIVES: Cerebral stroke is a serious clinical condition in which oxidative stress, inflammation, necrosis, apoptosis, and autophagy play important roles in its pathogenesis. This study investigated the neuroprotective and healing effects of calcium dobesilate (CD) on cerebral hypoxia/reperfusion injury in rats. METHODS: Forty Wistar albino male rats, each weighing 300-350 g, were separated into the Control group (no surgery and no pharmacological agent was administered); Sham-A group (only surgery was performed); DBL-A group (surgery was performed and CD 100 mg/kg/day was administered intraperitoneally for 3 days); Sham-C group (only surgery was performed); and DBL-C group (surgery was performed and 100 mg/kg/day CD was administered intraperitoneally for 10 days). Under sedation anesthesia, the bilateral common carotid arteries of all rats except the Control group were clipped for 30 min. After 4 h, the CD was given to the relevant groups, and then, all subjects were euthanized at scheduled times. The brain of each animal was removed for histopathological (hematoxylin and eosin staining), immunohistochemical (beclin-1, anti-MHC class II and anti-CD-68 staining), and biochemical (TNF, IL-1ß, IL-6, caspase-3, GSH/GSSG, malondialdehyde, protein carbonyl, LC3II/LC3I, and beclin-1 levels) evaluations. RESULTS: It was observed that CD could reduce necrosis and mitigate polarization of microglia to the M1 phenotype, autophagy, free oxygen radicals, protein carbonylation, lipid peroxidation, IL-1ß, IL6, TNF, caspase-3, beclin-1, and LC3II/LC3I levels in acute and chronic periods of hypoxia/reperfusion injury. CONCLUSION: From these results, it was observed that CD treatment could reduce neuronal necrosis and create anti-inflammatory, anti-edema, anti-oxidant, anti-apoptotic, and anti-autophagic effects in hypoxia/reperfusion injury in rats.

Phlebotonics for haemorrhoids.

BACKGROUND: Haemorrhoids are variceal dilatations of the anal and perianal venous plexus and often develop secondary to the persistently elevated venous pressure within the haemorrhoidal plexus (Kumar 2005). Phlebotonics are a heterogenous class of drugs consisting of plant extracts (i.e. flavonoids) and synthetic compounds (i.e. calcium dobesilate). Although their precise mechanism of action has not been fully established, they are known to improve venous tone, stabilize capillary permeability and increase lymphatic drainage. They have been used to treat a variety of conditions including chronic venous insufficiency, lymphoedema and haemorrhoids.Numerous trials assessing the effect of phlebotonics in treating the symptoms and signs of haemorrhoidal disease suggest that there is a potential benefit. OBJECTIVES: The aim of this review was to investigate the efficacy of phlebotonics in alleviating the signs, symptoms and severity of haemorrhoidal disease and verify their effect post-haemorrhoidectomy. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library 2011 issue 9 , MEDLINE (1950 to September 2011) and EMBASE (1974 to September 2011). SELECTION CRITERIA: Only randomised controlled trials evaluating the use of phlebotonics in treating haemorrhoidal disease were used. No cross-over or cluster-randomized trials were included for analysis and any trial which had a quasi-random method of allocation was excluded. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the data and analysed the eligibility of the data for inclusion. Disagreements were resolved by meaningful discussion. MAIN RESULTS: We considered twenty-four studies for inclusion in the final analysis. Twenty of these studies (enrolling a total of 2344 participants) evaluated the use of phlebotonics versus a control intervention. One of these twenty studies evaluated the use of phlebotonics with a medical intervention and another study with rubber band ligation.The remaining four studies included two which compared different forms of phlebotonics with each other, one study which evaluated phlebotonics with a medical intervention and one study which compared the use of phlebotonics with infrared photocoagulation. Eight studies were excluded for various reasons including poor methodological quality.Phlebotonics demonstrated a statistically significant beneficial effect for the outcomes of  pruritus (OR 0.23; 95% CI 0.07 to 0.79) (P=0.02), bleeding (OR 0.12; 95% CI 0.04 to 0.37) (P=0.0002), bleeding post-haemorrhoidectomy (OR 0.18; 95% 0.06 to 0.58)(P=0.004), discharge and leakage (OR 0.12; 95% CI 0.04 to 0.42) (P=0.0008) and overall symptom improvement (OR 15.99 95% CI 5.97 to 42.84) (P< 0.00001), in comparison with a control intervention. Although beneficial they did not show a statistically significant effect compared with a control intervention for pain (OR 0.11; 95% CI 0.01 to 1.11) (P=0.06), pain scores post-haemorrhoidectomy (SMD -1.04; 95% CI -3.21 to 1.12 ) (P= 0.35) or post-operative analgesic consumption (OR 0.54; 95% CI 0.30 to 0.99)(P=0.05). AUTHORS' CONCLUSIONS: The evidence suggests that there is a potential benefit in using phlebotonics in treating haemorrhoidal disease as well as a benefit in alleviating post-haemorrhoidectomy symptoms. Outcomes such as bleeding and overall symptom improvement show a statistically significant beneficial effect and there were few concerns regarding their overall safety from the evidence presented in the clinical trials.However methodological limitations were encountered. In order to enhance our conclusion further, more robust clinical trials which take into account these limitations will need to be performed in the future.

Effect of Chinese Patent Medicines on Ocular Fundus Signs and Vision in Calcium Dobesilate-Treated Persons With Non-Proliferative Diabetic Retinopathy: A Systematic Review and Meta-Analysis.

Background: Diabetic retinopathy (DR), one of the commonest microvascular complications in diabetic patients, is featured by a series of fundus lesions. Conventional Western medicine therapies for DR are always with modest treatment outcome. This paper is to assess the ocular fundus signs, vision and safety of Chinese patent medicines (CPMs) as an add-on treatment for DR. Method: 7 electronic databases were searched to determine eligible trials. Randomized controlled trials (RCTs) of non-proliferative diabetic retinopathy (NPDR) in which the intervention group received CPMs combined with calcium dobesilate (CD), and the control group received only CD were included for analysis. Two reviewers extracted the data independently. Results expressing as mean differences (MD) and relative risks (RR) were analyzed with a fixed-effects or random-effects models. Results: 19 RCTs involved 1568 participants with 1622 eyes met our inclusion criteria. The results suggested that compared with CD alone, CPMs plus CD for NPDR was superior at reducing the microaneurysm volume (MD -3.37; 95% confidence interval [CI], -3.59 to -3.14), microaneurysm counts (MD -2.29; 95%CI -2.97 to -1.61), hemorrhage area (MD -0.79; 95%CI -0.83 to -0.75), and macular thickness (MD -59.72; 95%CI -63.24 to -56.20). Participants in CPMs plus CD group also achieved a better vision. No obvious adverse events occurred. Conclusion: CPMs as an add-on therapy for NPDR have additional benefits and be generally safe. This meta-analysis demonstrated that CPMs combined with CD could improve retinal microaneurysm, hemorrhage, macular thickness, visual acuity, fasting blood glucose (FBG), and glycosylated hemoglobin (HbAlc) compared with CD alone. Further studies are needed to provide more conclusive evidence. Systematic Review Registration: PROSPERO https://www.crd.york.ac.uk/prospero/, identifier CRD42021257999.

Evaluation of the therapeutic effects of calcium dobesilate in sciatic nerve crush injury in rats.

INTRODUCTION: Proinflammatory cytokines released from nerve endings and surrounding injured tissue after nerve damage can prolong the inflammation process, delay nerve healing or result in poor quality nerve healing. In this case, due to the loss of function in the muscles innervated by the damaged nerve, the patient may have neurological and functional difficulties which may reduce the patient's quality of life and create an economic burden. Although the attempts of many pharmacological agents to heal crush injury of peripheral nerves have been recorded in literature, a drug that can provide adequate recovery of the crushed nerve and can be applied in daily life has not been defined as yet. This study aimed to assess the effects of calcium dobesilate on sciatic nerve crush injury in a rat model. METHODS: A total of 26 male Wistar albino rats were separated into four groups as follows: CONTROL group (healthy subjects, n=6); SHAM group (crush injury was created, n=6); MP group (after created crush injury, methylprednisolone was administered, n=7); and CAD group (after created crush injury, calcium dobesilate was administered, n=7). A crush injury was created, then the electrophysiological findings and sciatic nerve functional index (SFI) were recorded before euthanasia. After the euthanasia of all the rats, samples of the crushed nerve and gastrocnemius muscle were evaluated histopathologically, immunohistochemically, and biochemically. RESULTS: Both pharmacological agents were histopathologically effective in axon regeneration and repair. Calcium dobesilate did not preserve total muscle mass but was seen to prevent atrophy microscopically. Immunohistochemistry and biochemistry results showed that calcium dobesilate and methylprednisolone had anti-inflammatory, anti-oxidant, anti-apoptotic, and anti-autophagic activity in the crushed sciatic nerve. Neither calcium dobesilate nor methylprednisolone improved the nerve conductance level. SFI values obtained on day 30 from the CAD group were numerically closer to the values of the healthy animals but not at a statistically significant level. CONCLUSION: The study results demonstrated that calcium dobesilate could suppress inflammatory processes and provide histopathological and functional improvements in the injured nerve in rats. Therefore, further clinical studies are recommended to investigate in detail the therapeutic effects of calcium dobesilate on peripheral nerve crush injury.

[Medical treatment of chronic venous disease: evolution or involution?]. / Trattamento medico della malattia venosa cronica: evoluzione o involuzione?

Chronic venous disease (CVD) is an important clinical condition with substantial epidemiological implications and socio-economic repercussions. In the Western world the consequences of its high prevalence, the costs of diagnosis and therapy, the significant loss of working hours and the repercussions on patients'quality of life are well known. Pharmacotherapy for CVD has greatly developed over the last 40 years and largely used in the symptomatic treatment of CVD together with compression therapy and to make patients more comfortable. The clinical efficacy on the symptoms (feeling of heaviness, pain, paresthesia, heat and burning sensations, night cramps, etc.) has long been confirmed by Level III, IV and V evidence, but there are now Level I and II trials on specific drugs. For the bioflavonoids double-blind, randomised trials have used micronized purified flavonoid fraction; rutosides; escin; anthocyanosides; and synthetic calcium dobesilate. It was therefore surprising some recent difficulties in the use of this important treatment in health national system in Italy. In this up-date we use the method on evidence-based medicine from the medical literature. We have started a governance and economic analysis of the problem in Italy. Particular consideration was given to the evidence set out in review, meta-analysis, guidelines and Consensus Statements in this field. The evidence for pharmacological agents in the treatment of CVD suggests today a wide use in all CEAP classes.

Efficacy of calcium dobesilate in treating Chinese patients with mild-to-moderate non-proliferative diabetic retinopathy (CALM-DR): protocol for a single-blind, multicentre, 24-armed cluster-randomised, controlled trial.

INTRODUCTION: Calcium dobesilate (CaD) has been used in the treatment of diabetic retinopathy (DR) due to its potential in protecting against retinal vascular damage. However, there is limited evidence exploring its efficacy in combating DR progression. This study is aimed at evaluating whether CaD could prevent DR progression into an advanced stage among Chinese patients with mild-to-moderate non-proliferative DR (NPDR). METHODS AND ANALYSIS: This study is a single-blind, multicentre, cluster-randomised, controlled superiority trial. A total of 1272 patients with mild-to-moderate NPDR will be enrolled and randomly assigned at a 1:1 ratio into the control group (conventional treatment group) and the intervention group (conventional treatment plus CaD (500 mg three times per day) for 12 months). Patients will be followed at 1, 3, 6 and 12 months after randomisation and receiving treatments, with the severity of DR assessed by the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. The primary endpoint is the progression of DR during follow-up, which is defined as an increase of two or more steps in the ETDRS scale. The secondary endpoints include the concomitant changes in visual acuity, presence, number, location and type of retinal lesions, and retinal blood vessel diameter as well as the arteriovenous ratio at different visits. ETHICS AND DISSEMINATION: Each local ethics committee (first Vote: Ethical Review Committees of Zhongda Hospital of Southeast University (2019ZDSYLL132-P01)) has approved the study. The results will be published in high impact peer-reviewed scientific journals aimed at the general reader. TRIAL REGISTRATION NUMBERS: NCT04283162.

Protective Effect of Calcium Dobesilate on Induced AKI in Severely Burned Mice.

BACKGROUND: Early acute kidney injury (AKI) predicts a high mortality rate in severely burned patients. However, the pathophysiology of early AKI induced by severe burn has not been well-defined. This study was designed to examine the protective effects of calcium dobesilate (CaD) against severe burn-induced early AKI in mice and explore the mechanism. METHODS: The shaved backs of mice were immersed in 100°C water for 10 s to make severe burn (40% of the total body surface area). CD-57 male mice were randomly divided into sham, burn, burn + vehicle, and burn + CaD groups. Renal function, reactive oxygen species generation, tubular necrosis, and phosphorylation of mitogen-activated protein kinase, protein kinase B (Akt), and nuclear factor (NF)-κB were measured at 24 and 48 h after the burn. Renal histology, ELISA, qRT-PCR, and Western blotting were performed on the renal tissue of mice to examine the effects and mechanisms at 24 and 48 h after the burn. RESULTS: Tubular damage, cast formation, and elevations of serum creatinine, BUN, and renal tissue kidney injury molecule 1 levels were all observed in the burned mice, and these were all alleviated in the mice with CaD treatment. In addition, the levels of oxidation-reduction potential and malondialdehyde were decreased, while the activities of the endogenous antioxidative enzymes were increased in the kidney tissues from the mice after CaD treatment. Furthermore, the activities of Akt, p38, extracellular sign-regulated kinase, Jun N-terminal kinase, and NF-κB signaling were increased in the kidney of burned mice and normalized after CaD treatment. CONCLUSION: This study has established, for the first time, the protective effect of CaD against early AKI in severely burned mice. CaD may exert its protective effect through alleviating oxidative stress, apoptosis, and inflammation, as well as modulating some signaling pathways in the kidney.

Calcium dobesilate prevents cisplatin-induced nephrotoxicity by modulating oxidative and histopathological changes in mice.

Cisplatin is one of the synthetic cancer medicines with nephrotoxicity being one of its major side effects. Past research shows that calcium dobesilate (CaD), as a vascular protective agent in diabetic retinopathy, has antioxidant properties. Thus, this study aims to evaluate the protective effects of CaD in cisplatin-induced nephrotoxicity in mice. A many as 28 mice, in the present experimental research, were randomly distributed into four groups, including control, cisplatin (the intraperitoneal administration of 20 mg/kg cisplatin only on the first day of the experiment), cisplatin + CaD 50 (cisplatin with the oral administration of 50 mg/kg CaD), and cisplatin + CaD 100 (cisplatin with the oral administration of 100 mg/kg CaD). The treated groups received CaD by oral gavage for 4 constitutive days. On the fifth day, the mice were sacrificed, and some biochemical (serum levels of Cr and BUN, renal tissue levels of MDA, and renal activities of SOD and GPx) and pathological parameters were evaluated. Based on the results, there was a significant decrease in the renal SOD and GPx activities; in contrast, there was a significant increase in the BUN, Cr, and renal MDA levels following administering cisplatin. However, the CaD treatment (100 mg/kg) significantly attenuated these alterations. In addition, the kidney's histological examination of kidneys confirmed the nephroprotective effects of CaD. The findings proved the protective impact of CaD on cisplatin-induced nephrotoxicity by an improvement in the oxidative stress factors.

Detecting treatment response in a model of human breast adenocarcinoma using hyperpolarised [1-13C]pyruvate and [1,4-13C2]fumarate.

BACKGROUND: The recent introduction of a dynamic nuclear polarisation technique has permitted noninvasive imaging of tumour cell metabolism in vivo following intravenous administration of (13)C-labelled cell substrates. METHODS: Changes in hyperpolarised [1-(13)C]pyruvate and [1,4-(13)C(2)]fumarate metabolism were evaluated in both MDA-MB-231 cells and in implanted MDA-MB-231 tumours following doxorubicin treatment. RESULTS: Treatment of MDA-MB-231 cells resulted in the induction of apoptosis, which was accompanied by a decrease in hyperpolarised (13)C label flux between [1-(13)C]pyruvate and lactate, which was correlated with a decrease in the cellular NAD(H) coenzyme pool. There was also an increase in the rate of fumarate conversion to malate, which accompanied the onset of cellular necrosis. In vivo, the decrease in (13)C label exchange between pyruvate and lactate and the increased flux between fumarate and malate, following drug treatment, were shown to occur in the absence of any detectable change in tumour size. CONCLUSION: We show here that the early responses of a human breast adenocarcinoma tumour model to drug treatment can be followed by administration of both hyperpolarised [1-(13)C]pyruvate and [1,4-(13)C(2)]fumarate. These techniques could be used, therefore, in the clinic to detect the early responses of breast tumours to treatment.

Effect of calcium dobesilate on occurrence of diabetic macular oedema (CALDIRET study): randomised, double-blind, placebo-controlled, multicentre trial.

BACKGROUND: Medical treatment for diabetic retinopathy could have an important role in prevention of complications such as visual loss. We aimed to assess the effect of calcium dobesilate on occurrence of diabetic macular oedema. METHODS: We undertook a randomised, double-blind, placebo-controlled, multicentre study in 40 centres in 11 countries. We enrolled outpatients with adult-onset type 2 diabetes and mild-to-moderate non-proliferative diabetic retinopathy, and randomly allocated them via sealed envelopes either calcium dobesilate (1500 mg per day) or placebo. The primary endpoint was development of clinically significant macular oedema (CSME) within a follow-up period of 5 years. Patients who dropped out of the study early were censored. Analysis was by intention to treat. FINDINGS: We enrolled 635 patients. 324 were randomly allocated calcium dobesilate and 311 were assigned placebo. In the calcium dobesilate group, 86 patients developed CSME compared with 69 in the placebo group. Accounting for censored cases, estimated cumulative 5-year CSME probability was 35% and 28%, respectively (hazard ratio 1.32, 95% CI 0.96-1.81; p=0.0844). Adverse events did not differ between treatment groups (78 [24%] on calcium dobesilate and 90 [29%] with placebo). No relevant drug-related complications were noted. Nine patients (3%) died in the calcium dobesilate group and eight (3%) deaths were recorded on placebo. INTERPRETATION: Calcium dobesilate did not reduce the risk of development of CSME.