CALCIUM DOBESILATE – THE VASOACTIVE DRUG

1 DOBEST1 CALCIUM DOBESILATE THE VASOACTIVE DRUGINTRODUCTIONC alcium DOBESILATE is a VASOACTIVE drug with presumed effects on endothelial integrity,capillary permeability and blood viscosity. It is often recommended for venous disorders,and also prescribed for diabetic retinopathy and other microvascular OF ACTIONC alcium DOBESILATE has a comprehensive mode of action. It increases endothelial nitricoxide levels by enhancing the activity of nitric oxide synthase and decreasing capillaryhyperpermeability. CALCIUM DOBESILATE shows anti-platelet and fibrinolytic activities byinhibiting platelet activation factor (PAF) and enhancing the release of tissue plasminogenactivator (tPA), thereby improving the local blood flow to tissues, otherwise inhibited due tothrombosis. CALCIUM DOBESILATE also inhibits the two pathophysiological reactions in diabetes,viz. polyol pathway and glycation of proteins, due to its inhibitory effects on aldose DOBESILATE acts on the endothelial layer and basement membrane of the reduces histamine and bradykinin-induced hyperpermeability.

2 It increases red blood cellmembrane flexibility and reduces capillary fragility. CALCIUM DOBESILATE can reduce theplatelet aggregation stimulated by collagen and thrombin, but not by arachidonic DOBESILATE may also inhibit the formation of sorbitol, thus providing anotherpossible mechanism for its usefulness in diabetic inhibits the formation of both type I and type II collagen formation. Calciumdobesilate does not affect type I inhibition by glucose but accelerates type II collagenfibrillogenesis, a major structural component of the arterial DOBESILATE has angioprotective action by reducing the permeability and fragility ofmicrovessels, which should restrict fluid extravasation into the cardiac interstitium. Itsantiplatelet effect counteracts thrombosis and its reduction of plasma viscosity ON HEMORHEOLOGY AND MICROCIRCULATIONS tudies suggest that CALCIUM DOBESILATE has a favorable effect on Since blood is not a liquid in the conventional sense but should rather beviewed as a suspension, a number of factors play a role in hemorheology which may giverise to various changes.

3 Its formed elements give blood elastic properties, which are includedin all viscosimetrical techniques available to study by Koltringer et al2 tried to separate the apparent viscosity of whole blood, whichincludes both its elastic and viscous properties, into these two components and then to studythem separately for alterations so as to assess the effects of the test compound more this purpose, 50 patients with impaired cerebral or peripheral blood flow were studied. Ofthe randomly recruited patient sample, 33 subjects suffered from cerebrovascular insufficiency,DOBEST2the remaining 17 sufferedfrom impaired peripheralarterial blood flow stage IIaaccording to Fontaine. Allpatients were given 500 mgcalcium DOBESILATE threetimes daily for a period oftwo weeks. They had notreceived any rheologicallyactive medication. Beforethe start of the study and at14 days, viscoelasticity ofwhole blood and plasma aswell hematocrit and micro-circulation were viscosity and elasticityvalues fell in a highly significant manner, with plasma viscosity showing the greatest addition to the decrease in viscoelasticity, hematocrit also showed a highly significantdecrease.

4 Microcirculation was found to increase highly significantly. shows thepercentage distribution of values before and after results fully justify the use of CALCIUM DOBESILATE in hyperviscosity syndromes in thecontext of the treatment of impaired blood ON DIABETIC RETINOPATHY AND GLAUCOMAThe pathogenic mechanisms of diabetic retinopathy (DR) are, as yet Severalexplanations have been offered (Fig. 2). One suggestion is that hyperglycemia leads tochanges in biochemical processes that may result in anatomical and functional changes inthe retinal Platelet hyperaggregation normally follows the vascular lesionsand is responsible for microthrombi and hypoxia. Hypoxia, in turn, causes vascularproliferation (increased vascular endothelial growth factor). Blood hyperviscosity is observedlater in 30-40% of background retinopathy cases and is responsible for increased bloodstasis and vascular occlusions. Proliferation and neovascularization, the final stages in DR,affect the microvessels (capillaries, venules and arterioles) and even the retinal veins andarteries, and it finally results in vitreous hemorrhage, retinal detachment and to Brunet et al,5 CALCIUM DOBESILATE induced in vitro dose-dependent reductionof superoxide radicals generated by the xanthine/xanthine-oxidase couple and of thechemiluminescence induced by platelet activating factor (PAF) in humanpolymorphonuclear cells.

5 An anti-PAF activity of CALCIUM DOBESILATE was previouslydemonstrated in a dose-dependent manner, by inhibiting the production of PAF of anendothelial cell-line (EA926) stimulated in vitro by CALCIUM DOBESILATE decreasedlipid oxidation by oxygen-free radicals on human erythrocyte membranes and lowered theincrease in cytosolic free CALCIUM induced by hydrogen peroxide on cultured bovine arterialendothelial +8+6+4+2 2 4 6 : Percentage deviation of parameters from baseline(median)123412341234123412341234 12341234123123123 HematocritWhole blood viscosityWhole blood elasticity (2/s)12341234123412341234123412341234 Whole blood elasticity (50/s)Plasma viscosityMicrocirculationDOBESTIn 1977, Hudomel etal7 reported a statisti-cally significantreduction of whole-blood viscosity in pa-tients with diabeticretinopathy aftertreatment with theangioprotectiveagent calciumdobesilate, a findingwhich was repro-duced by Barras andGraf8 in 1980, whenthey observed that a3-month course ofcalcium dobesilatesignificantly loweredboth whole-bloodand plasma viscosityin this complicationof et al9 found significant increases in intravascular retention of [131] I-albumin, in totalserum protein and in serum albumin in diabetics after a 6-month course of CALCIUM DOBESILATE ,effects which they described to reduction by CALCIUM DOBESILATE , as a result of its vessel-sealing property of excessive transcapillary protein study10 was conducted to observe effect of CALCIUM DOBESILATE on the rheological status,the intraocular pressure (IOP)

6 , and the clinical condition in diabetic subjects with retinopathyand open-angle glaucoma. Fifty patients with diabetic retinopathy and open glaucomawere randomly allocated to treatment with 3 x 500 mg capsules of CALCIUM DOBESILATE dailyfor 3 months or to 3 placebo capsules daily for the same period. A basic criterion foradmission was the presence of blood outstanding finding in this study isthe significant reduction in hyperviscosity of whole blood, plasma and aqueous humor inpatients with diabetic retinopathy and open-angle glaucoma treated with CALCIUM dobesilatefor 3 months, the reduction being accompanied by improvements in the state of the retina,in the visual acuity, and in the visual fields and by a fall in IN CHRONIC VENOUS INSUFFICIENCYC hronic venous insufficiency (CVI) causes much discomfort and sick leave. It can result fromalterations in the venous wall and valvular incompetence, leading to hemodynamic changes inthe lower limbs.

7 High pressures distend the veins and separate the valves, rendering themincapable of preventing the retrograde flow of blood. The resulting venous stasis and dilatationcause an increase in microcirculatory disorders. Patients with venous insufficiency often complainof a dull ache in the leg, and examination reveals increased leg circumference, edema, and thepresence of other concomitant clinical symptoms (pain, cramps, swelling, heavy legs, paresthesia,3 Fig. 2: Postulated pathogenic mechanisms for incidence and progression ofdiabetic retinopathy3 HyperglycemiaBiochemical changes Protein kinase C activity Non-enzymatic glycosylation Aldose reductase activity Imbalance of VASOACTIVE substances(endothelin, prostanoids, nitrous oxide) Increased free-radical damage Growth-factor releaseFunctional changes Blood hyperviscosity Altered blood flow and oxygenation Electrophysiological defects Endothelial dysfunction Increase capillary permeabilityLoss of visual acuityAnatomical changes Thickening of capillarybasement membrane Pericyte loss Capillary closure Microaneurysm formation NeovascularizationDOBEST restless legs).

8 11 CALCIUM DOBESILATE exerts its therapeuticeffect in microcirculatory disorders byreducing capillary permeability, inhibitingplatelet aggregation and thrombusformation, lowering blood hyperviscosity,and increasing red cell flexibility. It alsoimproves lymphatic drainage, whichcontributes to its anti-edematous properties have been confirmed inseveral double-blind and open-label,multicenter studies, particularly in diabeticretinopathy and in study11 was designed to evaluate theefficacy and safety of CALCIUM dobesilatein a large population of ambulatory patients with overt chronic venous insufficiency, someof whom were unresponsive to other therapies. A large number of outpatients (n = 373;age range, 20 to 76 years) were treated for 28 days with g CALCIUM DOBESILATE per was assessed by measuring the ankle and calf circumferences and by evaluatingthe evolution of each symptom frequency (pain, cramps, swelling, heavy legs, paresthesia,restless legs) before and after 14 and 28 days of results show that CALCIUM DOBESILATE treatment produced significant clinical improve-ment in the CVI patients enrolled in this study.

9 A significant reduction of ankle and calfedemas, corresponding to and of the respective initial circumferences and rep-resenting a reduced volume of L, was noted in more than 82% of patients at theoutcome compared with baseline conditions. These objective measures resulted in indis-putable physical improvement. Symptoms such as pain, cramps, swelling, heavy legs, andparesthesia weremarkedly improved aswell (see Figs. 3,4).Ciapponi et al12 reporta meta-analysis of theeffectiveness andsafety of calciumdobesilate in CVI. Inten RCTs (778 pa-tients), calciumdobesilate was com-pared with placebo inthe treatment of dobesilatesignificantly improvednight cramps and dis-4385 -380 -375 -370 -365 -255 - 250 - 245 - 240 -014 28 DaysPerimeter (mm)CalfAnkleFig. 3: Evolution of ankle and calf perimeters after 14 (visit1) and 28 (visit 2) days of CALCIUM DOBESILATE therapycompared with entry - - - - - 0 -PainDay crampsNight crampsSwellingHeavy legsParesthesiaRestless legsMean Symptom FrequencyFig.

10 4: Mean symptom frequency as a function of time of treatment evaluated asfollows: 0 = none, 1 = once a week, 2 = twice or more a 1 (day 14)Visit 2 (day 28)DOBEST5comfort nearly twice as well as by the aforesaid evidence, CALCIUM DOBESILATE has been proved to be an ideal drugfor the treatment of diabetic retinopathy and various venous and microvascular Ernst E, Marshall M. Verbesserung der reduzierten Erythrozytenflexibilitat durch CALCIUM 1984;5 Koltringer P, Esber O, Rothlauer W, Klima G, Lind P, Langsteger W, Waonig P. CALCIUM dobesilateand its effects on hemorheology and microcirculation. Int J Clin Pharmacol Ther Toxicol 1988;26(10) Berthet P, Farine J-C, Barras J-P. CALCIUM DOBESILATE : pharmacological profile related to its use indiabetic retinopathy. IJCP 1999;53(8) Klein R, Klein BEK. Diabetic eye diseases. Lancet 1997;350 Brunet J, Farine J-C, Garay RP et al. In vitro antioxidant properties of CALCIUM DOBESILATE . Fund ClinPharmacol 1998;12 Bussolino F, Biffignandi P, Arese P.