Calcium dobesilate-induced hyperpyrexia: A case report.

RATIONALE: Calcium dobesilate, a vasoprotective and antioxidant agent, is gradually being used for the treatment of chronic kidney disease. Calcium dobesilate-induced hyperpyrexia is a rare clinical event, and few studies have reported it. PATIENT CONCERNS: The patient took calcium dobesilate, which caused high fever. After stopping calcium dobesilate, his body temperature returned to normal. DIAGNOSES: Based on the medical history, symptoms and signs, the patient was diagnosed with drug fever caused by calcium dobesilate. INTERVENTIONS: Calcium dobesilate was stopped, and supportive treatment was given at the same time. OUTCOMES: The present case was initially misdiagnosed as a fever caused by a bacterial infection, but treatment with the antibiotic moxifloxacin was ineffective. Based on the patient's medical history, laboratory and examination results, body temperature changes, and Naranjo Advanced Drug Response Scale, calcium dobesilate-induced hyperpyrexia was diagnosed. After discontinuation of calcium dobesilate, the patient's body temperature normalized, and no additional episode of fever was observed at follow-up. LESSON: Moreover, misdiagnosis and mistreatment of this condition can deteriorate the patient's condition. Herein, we report a case of calcium dobesilate-induced hyperpyrexia that occurred during the treatment of chronic renal insufficiency. Subsequently, a systematic analysis of the patient's diagnosis and treatment was reviewed. If unexplained high fever develops during the use of calcium dobesilate, calcium dobesilate-induced hyperpyrexia should be considered. Accordingly, calcium dobesilate should be discontinued.

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.

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.

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.

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.

Effect of calcium dobesilate on progression of early diabetic retinopathy: a randomised double-blind study.

BACKGROUND: The study was carried out to confirm the effect of calcium dobesilate (CaD) compared to placebo (PLA) on the blood-retinal barrier (BRB) permeability in early diabetic retinopathy (DR). METHODS: Adults with type II diabetes and early diabetic retinopathy (below level 47 of ETDRS grading and PVPR between 20 and 50x10(-6)/ min, plasma-free fluorescein) were included in this double-blind placebo-controlled study. Treatment was 2 g daily for 24 months. The primary parameter, posterior vitreous penetration ratio (PVPR), was measured every 6 months by fluorophotometry. Secondary parameters were fundus photography, fluorescein angiography and safety assessments. Metabolic control was performed every 3 months. RESULTS: A total of 194 patients started the treatment (98 CaD, 96 PLA) and 137 completed the 24-month study (69 CaD, 68 PLA). Both treatment groups were comparable at baseline, with ETDRS level 10 in about 59% of patients. Mean PVPR change from baseline after 24 months was significantly (P=0.002) lower in the CaD group [-3.87 (SD 12.03)] than in the PLA group [+2.03 (SD 12.86)], corresponding to a 13.2% decrease in the CaD group and a 7.3% increase in the PLA group. PVPR evolution was also analysed by HbA1c classes (<7%, between 7 and 9%, > or =9%) and results confirmed the superiority of CaD independently of the diabetes control level. A highly significant difference [CaD: -3.38 (SD 13.44) versus PLA: +3.50 (SD 13.70)] was also obtained in a subgroup of patients without anti-hypertensive and/or lipid-lowering agents (P=0.002 at 24 months). A further analysis of the secondary parameters showed significant changes in favour of CaD in the evolution from baseline to the last visit of haemorrhages (P=0.029), DR level (P=0.0006) and microaneurysms (P=0.013). Regarding safety, only 2.5% (n=5 patients/ events) of all adverse events reported were assessed as possibly or probably related to the test drug, while all serious adverse events were reported as unlikely. There was no statistical difference between groups. CONCLUSION: Calcium dobesilate 2 g daily for 2 years shows a significantly better activity than placebo on prevention of BRB disruption, independently of diabetes control. Tolerance was very good.

Calcium dobesilate in the treatment of diabetic retinopathy.

The incidence of diabetic retinopathy is still increasing in developed countries. Tight glycemic control and laser therapy reduce vision loss and blindness, but do not reverse existing ocular damage and only slow the progression of the disease. New pharmacologic agents that are currently under development and are specifically directed against clearly defined biochemical targets (i.e. aldose reductase inhibitors and protein kinase C-beta inhibitors) have failed to demonstrate significant efficacy in the treatment of diabetic retinopathy in clinical trials. In contrast, calcium dobesilate (2,5-dihydroxybenzenesulfonate), which was discovered more than 40 years ago and is registered for the treatment of diabetic retinopathy in more than 20 countries remains, to our knowledge, the only angioprotective agent that reduces the progression of this disease. An overall review of published studies involving calcium dobesilate (CLS 2210) depicts a rather 'non-specific' compound acting moderately, but significantly, on the various and complex disorders that contribute to diabetic retinopathy. Recent studies have shown that calcium dobesilate is a potent antioxidant, particularly against the highly damaging hydroxyl radical. In addition, it improves diabetic endothelial dysfunction, reduces apoptosis, and slows vascular cell proliferation.

Safety of calcium dobesilate in chronic venous disease, diabetic retinopathy and haemorrhoids.

The aim of the present review is to consider the adverse effects and the safety profile of calcium dobesilate. Calcium dobesilate (Doxium) is a veno-tonic drug, which is widely prescribed in more than 60 countries from Europe, Latin America, Asia and the Middle East for three main indications: chronic venous disease, diabetic retinopathy and the symptoms of haemorrhoidal attack. Data sources used for this review comprise the international literature (1970-2003), a postmarketing surveillance (PMS) report for calcium dobesilate from OM Pharma (Geneva, Switzerland) covering the period 1974-1998, and periodic safety update reports (PSUR) covering the period 1995-2003 from the French Regulatory authorities pharmacovigilance database and OM Pharma. Data from the PMS report for 1974-1998 indicated that adverse events with calcium dobesilate did not occur very frequently and had the following distribution in terms of frequency: fever (26%), gastrointestinal disorders (12.5%), skin reactions (8.2%), arthralgia (4.3%), and agranulocytosis (4.3%). No deaths were attributed to calcium dobesilate in the PMS report. Using data on product use in the Swiss Compendium we estimated the prevalence of agranulocytosis to be 0.32 cases/million treated patients, i.e. ten times less than the calculated prevalence of agranulocytosis in the general population. Most adverse events are type B, i.e. rare and unrelated to the pharmacological properties of calcium dobesilate. This review concludes that the risk of an adverse effect with calcium dobesilate 500-1500 mg/day is low and constant over time. The recently raised problem of agranulocytosis (a total of 13 known cases drawn from all data sources) appears to be related to methodological bias. Such a review reinforces the need for a strong international pharmacovigilance organisation using similar methods to detect and analyse the adverse effects of drugs.

Chronic venous insufficiency of the lower limbs: suitability of transcutaneous blood gas monitoring as an endpoint to evaluate the outcome of pharmacological treatment with calcium dobesilate.

This pilot clinical trial was designed to further investigate the effects of calcium dobesilate in the treatment of chronic venous insufficiency (CVI) by means of a novel endpoint, transcutaneous oxygen pressure (TcPO2), and to evaluate the suitability of this endpoint for future research. Patients with mild to moderate CVI without active ulcers were randomized to receive calcium dobesilate 1000 mg/day, 2000 mg/day or placebo for 12 weeks. The primary efficacy endpoint was TcPO2 in the distal third of the internal side of the leg. Secondary endpoints included assessment of venous reflux and clinical symptoms. Patients in the dobesilate 1000 mg/day and placebo groups showed a mild increase in TcPO2 (adjusted mean change 2.67 mmHg and 1.56 mmHg, respectively), while those treated with 2000 mg/day of the active drug showed a decrease (adjusted mean change -0.53 mmHg). Conversely, clinical symptoms and venous reflux improved in all groups, especially with dobesilate, but differences with placebo were not significant. Treatment was very well tolerated. Although the absence of significant differences prevented confirmation of sensitivity, a trend favoring calcium dobesilate in clinical and hemodynamic parameters was observed. This improvement was not reflected by TcPO2.

The effect of calcium dobesilate on vascular endothelial function, blood pressure, and markers of oxidation in obese male smokers: a placebo-controlled randomised clinical trial.

This randomised double-blind, placebo-controlled, clinical trial investigated the effect of 3 months of treatment with calcium dobesilate on endothelium-dependent vasodilation, markers of endothelial function, blood pressure, and markers of oxidation in obese, male smokers. Vascular effects may depend on the type of vessel and we, therefore, investigated both smaller arteries, i.e. resistance arteries and small arterioles, and large conduit arteries. Vascular function was measured by acetylcholine- and sodium-nitroprusside-mediated vasodilation, and capillary recruitment, in the skin microcirculation; by forearm blood flow (FBF) responses to several agonists and to N-G-monomethyl L-arginine (L-NMMA) in the forearm vascular bed; by flow-mediated vasodilation in the brachial artery; and by determination of soluble levels of vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1) and E-selectin. Twenty-eight individuals received dobesilate and 24 placebo. No effect of calcium dobesilate on endothelial function, blood pressure or markers of oxidation was observed compared with placebo. The difference in acetylcholine-mediated vasodilation in the microcirculation was -52.1%-point (95% confidence interval -132.8 to 28.1); in sodium-nitroprusside-mediated vasodilation in the microcirculation, 2.6%-point (-95.1 to 100.2); in capillary recruitment, 2.5%-point (-6.8 to 11.7); in acetylcholine-induced increases in FBF (n=28), 23%-point (-173 to 126); in L-NMMA-induced reduction of basal FBF, -2.8%-point (-29.3 to 23.8); in flow-mediated vasodilation of the brachial artery, 0.3%-points (-2.7 to 3.3); in 24-h systolic blood pressure, 2.1 mmHg (-1.3 to 5.5); in soluble VCAM-1, 54 ng/ml (-8 to 115); in soluble ICAM-1, 9 ng/ml (-49 to 67); in sE-selectin, -17 ng/ml (-44 to 11); in ketocholesterol 5 nM (-17 to 26); and in oxidised LDL -1.6 U/l (-6.7 to 3.5). We have shown that endothelial function, blood pressure, and markers of oxidation were not affected by 3 months of treatment with calcium dobesilate in mildly obese, smoking men. Thus, our data provide no evidence of an effect on vascular function of calcium dobesilate in humans.

Risk of drug-induced agranulocytosis: the case of calcium dobesilate.

BACKGROUND: In the last 20 years, some cases of agranulocytosis associated with calcium dobesilate consumption in Spain have been reported. A high risk of dobesilate-associated agranulocytosis (121 cases per million per year) calculated using both a case-control and a case-population strategy has been published. However few spontaneous reports have been noted in the same period of time. No explanation exists for this disagreement. METHODS: Estimated incidence rates of agranulocytosis in the IAAAS study and the calculated risk of dobesilate-associated agranulocytosis were used as background risks in a Poisson-based methodology, to calculate the number of coincidental reports of agranulocytosis among patients treated with dobesilate. The influence of treatment duration, notification rate and population characteristics were calculated. RESULTS: During the period 1978-2000, a total of 23 cases would have taken place if the background risk of agranulocytosis were 4.7 per million per year (IAAAS's risk); however, only 9 spontaneous cases of agranulocytosis associated to dobesilate were noted. A simulation showed that with notification rates equal to or higher than 17%, it was not possible to exclude that the 9 cases were false-positives. With notification rates equal or inferior to 16%, it would be unlikely that cases of agranulocytosis were noted in this population with a risk of 4.7 per million per year; therefore, it is necessary to assume a higher agranulocytosis risk. More than 1 case per year could be a false-positive if the background risk of agranulocytosis is 9.5 per million per year, this being the appropriate risk for a population of patients older than 60 years. The duration of treatment beyond 30 days increases the probability of a random coincidence of the intake of drug and an agranulocytosis event. CONCLUSIONS: The disagreement between calculated dobesilate-associated agranulocytosis risk and the number of noted spontaneous reports may be explained by at least three different factors: under-reporting, duration of treatment and age of patients. It is possible, with the methodology presented, to estimate the influence of these factors to avoid confusion with possible false-positive cases and then to design the correct prospective trial that can provide the true agranulocytosis risk.

Agranulocitosis secundaria al uso de vasoprotectores / Agranulocytosis due to phlebotonics

La presencia de agranulocitosis se demuestra por una concentración de neutrófilos en sangre menor de 500 por mm3. Presentamos el caso de un varón de 88 años que desarrolló una agranulocitosis después de tomar dobesilato cálcico y troxerutina como tratamiento para su retinopatía diabética.Aunque solamente hay descritos casos esporádicos de agranulocitosis por uso de dobesilato y ninguno con la troxerutina, la eficacia de estos vasoprotectores no ha sido demostrada. Dado que la agranulocitosis tiene una mortalidad de aproximadamente un 15 por ciento, consideramos que antes de la prescripción de estos fármacos deberían sopesarse sus riesgos y beneficios (AU)

Clinical evaluation of the efficacy and safety of calcium dobesilate in patients with chronic venous insufficiency of the lower limbs.

Several venotonic drugs have been used in the treatment of chronic venous insufficiency (CVI) of the lower limbs, most of them from natural sources. Calcium dobesilate, from synthetic origin, has been shown to improve clinical symptoms of these venous conditions. Three hundred fifty-two patients with CVI in grades I and II of Widmer's classification were included from an open population between January 1999 and June 2000; patients received calcium dobesilate 500 mg every 8 hours for 9 weeks. A basal recording and recordings every 3 weeks were made of heaviness, pain, cramps, and paresthesias of the lower limbs with a severity scale, and edema was assessed by measurement of the circumference of ankles and calves. Two hundred eighty-six patients (81.3%) were women and 66 (18.7%) were men with a mean age of 45.7 +/-14.1 years; 200 patients (56.8%) were grade I and 150 (42.6%) were grade II of Widmer's classification, and two patients had no classification, with a mean duration of symptoms of 6.5 +/-7.4 years. All of the symptoms had a significant reduction from the first to the final visit of treatment; 70% of the patients complained of moderate to severe heaviness of the lower limbs at the beginning of the study, whereas 10% of the patients presented this symptom at the end of treatment. Likewise, 75%, 37%, and 41% of the patients, respectively, complained of moderate to severe pain, cramps, and paresthesias of the lower limbs at the beginning of the study, with a reduction in this prevalence to 6%, 2%, and 4%, respectively, at the end of treatment (p<0.001, Wilcoxon test). In regard to edema of ankles and calves, a significant reduction in circumferences was registered in both sites at the end of treatment; for instance, the mean circumference of the right ankle was reduced from 23.78 +/-0.27 to 22.71 +/-0.31 cm while the right calf had a reduction from 35.08 +/-0.41 to 33.83 +/-0.5 cm (p<0.001, paired t test). Side effects were registered in 17.9% of the patients. This trial shows that calcium dobesilate had significant efficacy in the improvement of all the symptoms in patients with CVI, achieving this effect with an acceptable safety profile.

[Risk of drug-induced agranulocytosis: an approximation to risk analysis arising from spontaneous notification of agranulocytosis cases among patients treated with calcium dobesilate]. / Riesgo de agranulocitosis por fármacos: una aproximación al análisis de riesgos a partir de notificaciones espontáneas de casos de agranulocitosis en pacientes tratados con dobesilato de calcio.

BACKGROUND: Frequently, decisions about the safety of drugs are based on isolated cases of patients that develop a disease, while they have been taken a drug. A new method to detect, using spontaneous reporting, increases in agranulocytosis risk among patients treated with calcium dobesilate is shown. METHOD: Using data of dobesilate sales, the maximum number of patients treated in a year was calculated. Spontaneous reports of agranulocytosis associated to dobesilate notified along the period 1985-2000 were identified. The number and the maximum number of cases explained by the agranulocytosis risk in a general population were calculated using the distribution of Poisson, assuming several reporting rates. Similarly, the influence of number of patients older than 60 and the duration of exposure to the drug were analysed. RESULTS: The number of spontaneously reporting cases of agranulocytosis associated to dobesilate, in the period 1985-2000 was not greater than the maximum number of cases predicted by the agranulocytosis risk in a general population. Probably, a high number of dobesilate-treated patients had an advanced age and/or took the drug during several months. In these conditions, it is more difficult to identify an increase of risk associated to drug. CONCLUSIONS: To calculate the risk of agranulocytosis associated to a drug is required to consider the basal risk of agranulocytosis in a general population as well as its possible modifications in the population of patients treated with the drug.

Agranulocytosis associated with calcium dobesilate clinical course and risk estimation with the case-control and the case-population approaches.

OBJECTIVE: Calcium dobesilate is used in the treatment of diabetic retinopathy, chronic venous insufficiency, haemorrhoids and other ill-defined vascular conditions. It has been associated with agranulocytosis in anecdotal reports. We describe the clinical course of a series of patients who developed agranulocytosis while taking this drug, and we estimate the risk by means of both a case-control and a case-population strategy. METHODS: All cases of agranulocytosis meeting strict predefined diagnostic criteria in an area of 3.3 to 3.9 x 106 inhabitants in the period 1980-1998 were identified. Cases and age-, gender- and hospital-matched controls were interviewed with a structured questionnaire including a detailed drug history. Each case was reviewed and confirmed by a haematologist, who was blind with respect to drug exposures. Consumption data were used to estimate the risk of agranulocytosis associated with calcium dobesilate using a case-population approach in which the incidence of agranulocytosis among users of calcium dobesilate was compared with that among the non-exposed population. RESULTS: After a follow up of 68.55 x 10(6) person-years, 345 cases of agranulocytosis (242 community cases) were assembled. Reliable information was obtained from 216 cases. Two patients exhibited positive rechallenge. Twelve cases (5.6%) and 5 of 1380 controls (0.4%) had taken calcium dobesilate in the week before. With the case-control approach, the odds ratio was 23.66 [95% confidence interval (CI), 7.54-74.24], the attributable risk was 5.3% (95% CI, 3.0-9.4), and the number of cases attributable to dobesilate in the study area during the study period was 12.8. The case-population estimates were an incidence of 121.03 cases per 10(6) patient-years, a relative risk of 39.55 (95% CI, 17.96-77.49), an attributable risk of 6.73% (CI 3.4-12.9), and 16.30 cases attributable to dobesilate in the study area during the study period. DISCUSSION: This study adds to evidence indicating that the case-population method is adequate for the study of rare type B adverse drug reactions. An additional advantage of this approach is that the incidence of the disease of interest among those exposed to the drug can be estimated. The risk of agranulocytosis associated with calcium dobesilate should be considered in relation to poor evidence of its clinical efficacy.

Calcium dobesilate lowers the blood pressure in mild to moderate midtrimester hypertension: a pilot study.

To test the effects of calcium dobesilate (Doxium) in pregnancies complicated with pregnancy-induced hypertension or mild/moderate pre-eclampsia a double-blind, placebo-controlled pilot study was carried out. Primigravida patients (gestational age

Calcium dobesilate: pharmacology and future approaches.

1. Calcium dobesilate (2,5-dihydroxybenzene sulfonate) is a drug commonly used in the treatment of diabetic retinopathy and chronic venous insufficiency. 2. The pharmacology of calcium dobesilate reveals its ability to decrease capillary permeability, as well as platelet aggregation and blood viscosity. 3. Furthermore, recent data show that calcium dobesilate increases endothelium-dependent relaxation owing to an increase in nitric oxide synthesis.