Deletion of discoidin domain receptor 2 attenuates renal interstitial fibrosis in a murine unilateral ureteral obstruction model.

Background: Renal interstitial fibrosis is a common pathway of chronic kidney disease to end-stage renal disease, which is characterized by an imbalance between the synthesis and degradation of the collagen-rich extracellular matrix (ECM). While, discoidin domain receptor 2 (DDR2) can be activated when it binds to some types of collagen. Therefore, we hypothesized that DDR2 may be a major player in renal interstitial fibrosis. Methods: Renal histologic analysis, real-time PCR analyses and hydroxyproline assay were performed in DDR2-deficient mice and wild-type mice after unilateral ureteral obstruction; C57 mice were randomly divided into sham operation group (Sham group, n = 4), renal interstitial fibrosis model group (UUO group, n = 4), and calcium dobesilate treatment group (CDT group, n = 4), preparation of renal interstitial fibrosis model by unilateral ureteral obstruction (UUO), CDT Group was treated with calcium dobesilate orally, Sham group and UUO group were given double distilled water, HE staining, Masson staining, real-time quantitative PCR were detected after 14 days of UUO in mice to observe the renal interstitial fibrosis degree. Results: DDR2 expression was dramatically increased in the obstructed kidney; In contrast to wild-type mice that developed severe interstitial fibrosis, the DDR2-deficient mice displayed only moderate fibrotic changes; Compared with the UUO group, the degree of renal interstitial fibrosis in CDT group was relieved after operation 14 day. Conclusion: DDR2 might play an important role in the development of RIF; Calcium dobesilate can affect the expression of DDR2 and improve the renal interstitial fibrosis in mice.

Effect of grape seed proanthocyanidin extract on hard exudates in patients with non-proliferative diabetic retinopathy.

PURPOSE: To evaluate the efficacy and safety of orally administered grape seed proanthocyanidin extract (GSPE) in patients with non-proliferative diabetic retinopathy (NPDR). METHODS: In this randomized (1:2:2), multicentre, double-blind trial, patients (n = 124; age: 40-78 years) were administered placebo, calcium dobesilate (CD; 750 mg/d), or GSPE (150 mg/d) orally for up to 12 months. All patients had retinal thickening with hard exudates (HEs) that met predefined criteria; the median best-corrected visual acuity was 0.8, as assessed using the Snellen visual acuity card. The main outcome measure was an improvement in HEs by at least 1 grade on a 10-grade severity scale. This was evaluated using fundus photography over 1 year. RESULTS: The rate of improvement in the HE severity was higher in the GSPE group than in the CD group. No statistically significant difference existed among the study groups in optical coherence tomography parameters, such as central subfield macular thickness and total macular volume (TMV). However, in the GSPE group, TMV after 9 months of treatment was significantly decreased compared with that at baseline. The GSPE group showed a significantly greater improvement in HE severity than did the placebo or CD group. Four cases in the GSPE group and 2 in the CD group were determined to have developed potential treatment-related adverse reactions, which were all gastrointestinal in nature. CONCLUSIONS: Oral GSPE therapy for 1 year improved HEs in patients with NPDR. The efficacy of GSPE for HEs was higher than that of oral CD in the study patients.

Calcium dobesilate: A drug treatment for diabetic retinopathy can negatively interfere with the measurement of glycated albumin using the enzymatic method.

BACKGROUND: We reported that calcium dobesilate, a vasoprotective agent mainly used for diabetic retinopathy (DR), negatively interferes with glycated albumin (GA) assays involving enzymatic methods. METHODS: A calcium dobesilate standard was added to 3serum pools in vitro to prepare concentration-response series according to Clinical and Laboratory Standards Institute EP7-A2 guidelines. Percentage deviation between each drug concentration and the drug-free sample was calculated for 6 commercially available GA assays. The acceptable limit of deviation for GA was ±5.61%. For in vivo analyses, changes in serum concentrations of GA and calcium dobesilate were monitored in eight healthy participants before and after oral calcium dobesilate administration. RESULTS: At 16 µg/ml calcium dobesilate, within the therapeutic range, the percentage deviations for Asahi Kasei, Maccura, Leadman, Homa, and Medicalsystem assays were -8.7% to -49.7%, -2.0% to -47.7%, and -10.1% to -35.7% for low-, medium- and high-GA level interference pools, respectively, exhibiting dose-dependent negative interference. In vivo, calcium dobesilate ingestion was associated with statistically significant, falsely decreased measurements in 5 GA assays, 2 h after daily 500 mg administration. CONCLUSIONS: Calcium dobesilate ingestion was associated with erroneously low measurements in 5 GA assays. The degree of interference varied greatly among the assays examined.

[Drug Treatment of Chronic Venous Diesease]. / Medikamentöse Behandlung chronischer Venenerkrankungen.

Chronic venous disease (CVD) affects at least 15-25 % of the general population incurring not only high morbidity but also considerable economical burden. The mainstay of modern treatment of CVD are endovenous therapeutic procedures and compression therapy. As far as the pathogenesis of CVD is being gradually unraveled the interest in drugs able to impact the process is growing. Here we have presented an overview of a majority of oral preparations used so far to treat CVD including venous leg ulcers. After several decades of clinical use a few flavonoid preparations, in the first place micronized purified flavonoid fraction, collected enough evidence to recommend them as a short-term adjunct treatment of CVD. However, other compounds are also promising in this regards. Yet, we need more larger and longer-term clinical trials to more precisely define effects, cost-effectiveness and, above all, capacity for prophylactic application of the drugs. Learning more about basis of CVD will help design new drugs directed at specific aspects of the disease process.

Does calcium dobesilate protect against intestinal ischemia-reperfusion injury induced in rats?

OBJECTIVE: In this study, we investigated whether the administration of calcium dobesilate (CD) affects oxidative stress markers and histopathological outcomes in a rat model of intestinal ischemia-reperfusion (IR) injury. MATERIALS AND METHODS: This study was conducted with 30 male Wistar rats. The rats were randomly assigned to three groups as follows: a sham group (n = 10), an IR group (n = 10), and an IR + CD group (n = 10). In the sham group, superior mesenteric artery (SMA) dissection alone was performed during laparotomy. In the IR group, the procedure included SMA occlusion for 60 min, followed by reperfusion for 60 min. In the IR + CD group, CD (100 mg/kg/day) was additionally given for two days before laparotomy by intragastric lavage. In all the rats, 2 ml of blood were drawn, and an ileal segment (approximately 2 cm in size) was removed to evaluate oxidative stress markers. The ileal segment removed was divided into two pieces, and one piece was reserved for histopathological evaluation. RESULTS: Compared to the other groups, both serum and tissue oxidative stress indices were lower in the IR + CD group. The decrease was due to CD increasing the total antioxidant capacity. Moreover, the histological analysis showed that CD reduced tissue injury. CONCLUSIONS: CD may exert a protective effect against intestinal IR injury by increasing antioxidant capacity.

A randomized, double-blind, placebo-controlled, clinical study on the efficacy and safety of calcium dobesilate in the treatment of chronic venous insufficiency.

OBJECTIVE: To show the superiority of 500 mg calcium dobesilate vs. placebo in reduction of edema of the lower limbs in patients with chronic venous insufficiency, Clinical, Etiological, Anatomical and Pathophysiological classes C3/C4. METHODS: A total of 351 patients were randomized (n = 174 calcium dobesilate, n = 177 placebo). Active treatment was 500 mg calcium dobesilate, three times daily for 12 weeks, with a 12-week follow-up. RESULTS: At the end of treatment, the relative volume change in the most pathological leg was -0.6 ± 4.8% with calcium dobesilate compared to -0.3 ± 3.3% with placebo (p = 0.09). At the end of follow-up, this was -1.01 ± 5.4% for calcium dobesilate vs. -0.08 ± 3.5% for placebo (p = 0.002). CONCLUSIONS: Calcium dobesilate treatment resulted in no significant volume change in the most pathological leg between baseline and end of treatment. However, the calcium dobesilate group showed a significantly greater volume decrease in the most pathological leg at the end of follow-up. Calcium dobesilate was well-tolerated, with a safety profile consistent with previously published data.

Durable recovery of the macular architecture and functionality of a diagnosed age-related macular degeneration 1 year after a single intravitreal injection of dobesilate.

Among the age-related diseases that affect vision, age-related macular degeneration is the most frequent cause of blindness in patients older than 60 years. In this communication, we report the full anatomical and functional recovery of a patient diagnosed with wet age-related macular degeneration 1 year after a single intravitreal injection of dobesilate.

Treatment of Stargardt disease with dobesilate.

Stargardt disease is a common inherited macular degeneration characterised by a significant loss in the central vision during the first or second decade of the life. Bilateral atrophic changes in the central retina are associated with degeneration of photoreceptors and underlying retinal pigment epithelium, and yellow flecks are extending from the macula. We present a patient with Stargardt disease treated with an intravitreal injection of dobesilate, showing an improvement of visual acuity 4 weeks after treatment.

Intravitreal dobesilate in the treatment of choroidal neovascularisation associated with age-related macular degeneration: report of two cases.

This case report presents the effectiveness of intravitreal administration of dobesilate, a synthetic fibroblast growth factor inhibitor, in two patients showing neovascular age-related macular degeneration of the classic, and of the occult choroidal neovascularisation types, respectively. Our study demonstrates that the treatment induces the regression of both forms of this pathology, as assessed by spectral optical coherence tomography. Improvement of the lesions was accompanied of visual acuity improvement.

Dramatic response to inhaled dobesilate in a patient with lung squamous cell cancer.

The effectiveness of local application, by inhalation, of dobesilate, an inhibitor of fibroblast growth factor signalling, in a patient with squamous cell lung carcinoma is reported. To our knowledge, these are the first published data on the efficacy of dobesilate in the treatment of this disease. The antimitotic, antiangiogenic, proapoptotic and anti-inflammatory activities of dobesilate can be important factors to consider, in explaining the efficacy of the treatment. Dobesilate administration can be a therapeutic option in patients with lung cancer having poor performance status or severe complications.

Chronic cystoid macular oedema treated with intravitreal dobesilate.

Dobesilate is an anti-inflammatory and antipermeability agent. Intravitreal administration of this compound is a therapeutically beneficial agent in the treatment of chronic cystoid macular oedema.

Short-term efficacy of intravitreal dobesilate in central serous chorioretinopathy.

PURPOSE: To report the anatomic and functional outcome of intravitreal dobesilate to treat recurrent central serous chorioretinopathy (CSC). METHODS: This is an interventional case report in which dobesilate was intravitreally injected in a case of recurrent CSC. Main measures included fundoscopy, Snellen visual acuity (VA) testing, fluorescein angiography and optical coherence tomography (OCT). RESULTS: We present anatomical and functional evidences, obtained as early as eleven days after the treatment, of the efficacy of intravitreal dobesilate, in the treatment of chronic CSC condition. The effect after intravitreal dobesilate injection for CSC might be related to the normalization of retinal architecture. CONCLUSIONS: Intravitreal dobesilate may be an effective treatment option for recurrent CSC.

Treatment of dry age-related macular degeneration with dobesilate.

The authors present anatomical and functional evidences of dry age-macular degeneration improvement, after intravitreal treatment with dobesilate. Main outcomes measures were normalisation of retinal structure and function, assessed by optical coherence tomography, fundus-monitored microperimetry, electrophysiology and visual acuity. The effect might be related to the normalisation of the outer retinal architecture.

Calcium dobesilate in patients suffering from chronic venous insufficiency: a double-blind, placebo-controlled, clinical trial.

OBJECTIVE: To test the efficacy of calcium dobesilate (CaD) in chronic venous insufficiency (CVI). METHOD: Double-blind, parallel groups, placebo-controlled, multicentre trial in adult patients with symptomatic CVI and pitting oedema. Wearing of compression stockings Class II was admitted. During treatment period of eight weeks, the patients received CaD 3 × 500 mg/day or placebo. The leg volume calculation was based on a truncated cone model. RESULTS: A total of 256 patients was randomized to treatment (dobesilate: n = 132, placebo: n = 124); the demographic and anamnestic data at admission were comparable in the two therapeutic groups. The volume of the lower calf diminished in the dobesilate group at the end of the active treatment period by -64.72 ± 111.93 cm³ (mean ± SD), independent of the concomitant usage of compression stockings versus placebo +0.8 ± 152.98 cm³ (P = 0.0002). The symptoms of pain, discomfort, heavy legs, tired legs, tingling, itching and cramps, as well as the global assessments by investigators and patients, also improved significantly (P < 0.05) better in the dobesilate group at the end of the treatment. The observed adverse events correspond to the known profile. CONCLUSION: Dobesilate reduces leg oedema and improves the symptoms of objectively diagnosed CVI, independent of the concomitant usage of compression stockings.

Evaluation of calcium dobesilate for its anti-cataract potential in experimental animal models.

The present study evaluated the protective action of calcium dobesilate (CDO) in various experimental models of cataract. CDO was studied in hydrocortisone-induced cataract in developing chick embryos and selenite-induced cataract in pups. CDO anti-cataract activity was also evaluated after oral and topical application as eye drops in galactose (30%) fed rats. This study was further extended to evaluate the intraocular penetration of a single dose of 1% CDO (50 microL) in rabbits. CDO exhibited significant protection against cataract in experimental models and considerable penetration after single topical application. Anti-cataract activity may be due to its antioxidant as well as aldose reductase inhibitor properties. Further studies are in progress to evaluate its clinical efficacy in diabetic cataract.

Calcium dobesilate and oxerutin: effectiveness of combination therapy.

OBJECTIVES: Chronic venous insufficiency (CVI) is an important cause of discomfort and inability to work. Hydroxyethylrutosides (Venoruton); 0-[beta-hydroxyethyl]-rutosides) has been used for decades for the treatment of CVI. Studies have reported symptomatic relief and a decreased capillary filtration after the administration of the oral preparations. Calcium dobesilate is a synthetic venoactive drug acting on several levels. It inhibits capillary permeability; it has antioxidant properties; and it inhibits the synthesis of prostaglandins and thromboxanes, reducing platelet and erythrocyte aggregation, as well as blood viscosity. The aim of this study is to determine whether the combination of both drugs is more effective in decreasing patients' complaints. METHODS: One hundred and fifty patients with primary venous insufficiency were randomized into three groups: Group A receiving calcium dobesilate only, Group B receiving oxerutin only and Group C receiving both calcium dobesilate and oxerutin. Patients were evaluated with a questionnaire before and four weeks after treatment regarding following parameters: itching, fatigue, heaviness, numbness, cramp, swelling and sensitiveness. Patients rated their symptoms from 0 to 4 (0: absent; 1: mild; 2: moderate; 3: severe; 4: very severe). RESULTS: Complaints, which were scored by patients before and after treatment, decreased. Among the single-drug groups, itching score decreased more in Group B, whereas scores of fatigue, heaviness, numbness, cramp and swelling decreased more in Group A. But the difference was not significant, statistically. But all complaints decreased significantly in Group C. Difference of scores after treatment revealed no statistical significance in Group A and B, but scores of Group C produced a significant difference when compared with Group A and B. CONCLUSION: Results demonstrate that a combination of calcium dobesilate and oxerutin shows a better improvement of complaints. These observations have to be confirmed in larger series with objective tests. Changes of quality of life after a combination therapy might also be of interest.

Randomized, double blind, placebo-controlled clinical trial to evaluate the lymphagogue effect and clinical efficacy of calcium dobesilate in chronic venous disease.

The aims of the present study were to investigate the effect of calcium dobesilate on lymph flow and lymphovenous edema in patients with chronic venous disease. It was a randomized, placebo-controlled, double-blind clinical trial. Patients received 1 capsule of 500 mg calcium dobesilate every 8 hours (1.5 g/day) or placebo by 49 days. By the end of the treatment period, only the patients treated with calcium dobesilate had normalization of lymphogammagraphy (capture index and speed of lymph flow; 80 and 78%, respectively). Only patients treated with calcium dobesilate had statistically significant reduction in the perimeter of leg, calf, and ankle. Twenty-two out of 25 (88%) calcium dobesilate-treated patients presented clinical improvement versus 5 out of 24 (20.8%) in the placebo group. One patient on calcium dobesilate developed rash and one patient on placebo complained of vomiting. In the present study, calcium dobesilate normalized lymph physiology and improved symptoms in patients with chronic venous disease.

Cardioprotective effect of calcium dobesilate during open-heart surgery.

OBJECTIVE: The purpose of this double-blind, controlled, prospective randomized study was to investigate the possible effects of the preoperative use of calcium dobesilate (CLS2210) on the biochemical markers of myocardial injury during open-heart surgery, and to determine if it has any myocardial protective effects. METHODS: Twenty-four patients undergoing elective cardiac surgery were included in this study and randomized into two groups. CLS2210 was given orally to 12 patients for 14 days before the operation (CD group), but not to the other 12 patients (control group). Serum CK, CK-MB, myoglobin and troponin-T levels were measured from venous blood samples before and after the operation for evaluation of the effect of this drug against myocardial damage. Blood samples were also taken from the radial artery and the coronary sinus before the institution of cardiopulmonary bypass (CPB), and 2 and 15 minutes after the removal of the cross-clamp in order to measure the lactate levels and calculate the lactate extraction of the myocardium. RESULTS: First, CK-MB levels in patients of the CD group were significantly lower than those of the control group (p < 0.05) at the 2nd and 18th postoperative hour. Second, myoglobin and troponin-T levels in the CD group were significantly lower than those of the control group (p < 0.05) at the 2nd, 18th and 48th postoperative hour. Third, there was a significant difference in lactate extraction calculation values between the groups at the 2nd minute after removal of the cross-clamp (p < 0.05). CONCLUSIONS: We concluded that preoperative use of CLS2210 has some beneficial effects in protecting the myocardium and decreasing the myocardial injury during the cardioplegic arrest period in open-heart surgery.

Dihydroxy-2,5 benzenesulphonate (dobesilate) elicits growth arrest and apoptosis in glioma cells.

OBJECTIVES: Dihydroxy-2,5 benzenesulphonate (dobesilate) is used as an oral agent for treatment of vascular complications of diabetic retinopathy. We previously showed that blockade of fibroblast growth factor (FGF) driving angiogenesis with dobesilate inhibited new blood vessel formation in a mouse gelatine plug assay. In the present study we assessed the effects of dobesilate in rat glioma cells. METHODS: Rat C6 cells line were grown as adherent cells in Dulbecco modified Eagle medium supplemented with 1% (v/v) fetal bovine serum and antibiotics. Calcium dobesilate was added in independent experiments at the following concentrations: 10, 25, 50, 75 and 100 microM, and cells were incubated for 24 hours. Effects of dobesilate in glioma cell proliferation and survival were assessed using crystal violet staining and TUNEL assay, respectively. RESULTS: Incubation of glioma cells with dobesilate for 24 hours concentration-dependently decreased cell proliferation with an apparent IC50 of 25 microM, and this antiproliferative effect was related to a significant increase in glioma cell apoptosis. CONCLUSIONS: The results suggest that dobesilate is a promising candidate leading to the development of a new adjuvant therapeutic strategy for gliomas.