(Results of prospective randomized open study)

Clinical efficacy of water-soluble dosage form of lipoxygenase inhibitor and antioxidant quercetin, i.e. of Corvitin for intravenous injection, was studied in 93 patients with acute myocardial infarction. It was found that an early use of Corvitin in a combined therapy of acute myocardial infarction improves clinical disease progress, reduces the mass of necrotized myocardium, dilatation of left ventricle cavity and improves electrophysiological properties of the myocardium. The preparation is most effective for reduction of necrosis areas and remodeling processes of left ventricle cavity in patients with infarct-inducing open coronary artery on the background of thrombolytic therapy and with dysfunction of myocardium left ventricle in patients with a high leukocytosis. The administration of Corvitin prior to starting therapy with fibrinolytic preparations facilitates elimination of thromboresistance and increase of infarction-inducing coronary artery recanalization frequency. The preparation stabilizes cardiomyocyte membranes by inhibiting lipids peroxidation and reduces the level of leukotriene C4. Key words: acute myocardial infarction, inhibitor of 5-lipoxygenase, quercetin, cytoprotection, injured area, clinic, hemodynamics. With exacerbation of cardiac ischemia, in particular with acute coronary syndrome with ST segment elevation (ACS + ST), mortality remains relatively high [18]. The application of a universally accepted medicamentous therapy including -adrenoblockers, anticoagulants, antithrombocitary agents, and nitrates in number of cases gives no anticipated results [5]. The development and use in clinical practice of infarction-inducing recanalization methods, i.e. of thrombolytic therapy, and of percutaneous transluminal coronary angioplasty (PTCA) made it possible to significantly improve results of treatment of patients with ACS + ST [5, 6, 13]. Along with this, even with an early myocardium revascularization treatment results often do not satisfy clinicians and the fact that blood flow recovery may be accompanied with myocardium lesion exacerbation makes the task of its protection from reperfusive and ischemic injury highly topical [6, 9]. To prevent ACS complications progressing damage of cardiomyocytes, metabolism failure, which occurs from first moment of myocardium ischemia, must be reduced [14, 20]. That is why cardiologists are now intensively elaborate methods of metabolic correction of statuses conditioned with ischemia/reperfusion in treatment of acute and chronic cardiac ischemia, in particular methods of myocardial cytoprotection [16]. While earlier investigators focused their efforts on the study of metabolic properties of hemodynamically active drugs, now they pay more attention to preparations having antioxidant and membrane-protecting properties and to catabolic ferment inhibitors [7, 8]. They include also quercetin, an inhibitor of some oxydase ferments, in particular of lipoxygenase [19], a powerful antioxidant [2, 15] and, as it was recently found [6, 17], a preparation promoting the increase of nitric oxide content in ischemized myocardium. As it is well known, with the development of acute blood circulation failure due to phospholipase activation the degradation of phospholipid bilayer of membranes occurs with accumulation of polyunsaturated fatty acids, in particular of arachidonic and linolic acids, as well as activation of oxidase ferments, in particular of lipoxygenase, resulting in three important aftereffects for the development of a pathological process: 1) Formation of biologically active compounds (leukotriens, lipoxines, lysophospholipids) with pronounced coronaroconstrictive, proaggregating, dysrhythmogenic and chemoattractive effects; 2) Formation of free radicals, especially with lipoxygenases activation; 3) Accumulation of polymorphonucleous neutrophiles – cells with significant prooxidant, lipoxygenaseous and proteolytic potentials. All these results in the activation of feedbacks in their essence and in progressing of ischemized cell damage. There is a reason to believe that weakening of such ties by the inhibition of such ferments as phospholipase A2, lipoxygenase and retardation of prooxidant processes may appear as most important links of pathogenic therapy of acute myocardial infarction and of reperfusive syndrome. The speed of development of metabolism failure and of pathologic process conditions the necessity of urgent therapy with intravenous injection of drugs. Theoretical grounding and experimental studies of Corvitin preconditioned this work to demonstrate that the preparation significantly reduces both hemodynamic troubles and necrotic damage volume with acute cardiac ischemia and reperfusion. This effect is conditioned by membrane stabilizing effect of Corvitin, which fact is evidenced with a sharp inhibition of membrane phospholipids degradation and with reduction of the accumulation of free fatty acids in ischemized myocardium as well as with inhibition of lipoxygenase activity and with an antioxidant effect [2 – 4, 17]. We think that the ability to increase the content of nitric oxide in heart tissues is a significant factor conditioning cardioprotecting properties of Corvitin. This phenomenon was proved in experiments with the culture of endotheliocytes of human umbilical vein and in experiments in vivo with a direct definition of NO content in myocardium and vascular walls in rabbits as well as in experiments in vivo with modeling of myocardium ischemia/reperfusion in dogs with definition of stable metabolite NO-NO2 [15, 17). The purpose of this work was the study of possible optimization of treatment of patients with ACS + ST in at early disease phase using water-soluble dosage from quercetin (Corvitin for intravenous injection), which was developed in Ukraine by joint efforts of employees of A.A. Bogomolets Institute of Physiology of the AMS of Ukraine (A.A. Moybenko, academician of the NAS of Ukraine), of the Institute of Pharmacology and Toxicology of the AMS of Ukraine (N.A. Mokhort, professor), and of the National A.A. Bogomolets Medical University (N.P. Maksiutina, professor). A pilot batch of the preparation was manufactured by SIC “Borshchahivskiy Chemical-Pharmaceutical Plant” CJSC, Kiev, Ukraine (L.V. Bezpalko, director general). Patients under study and methods used 198 patients with ACS +ST aged from 21 to 72 years, hospitalized for first 12 hrs after the moment of disease development (including 85.6% of patients hospitalized for first 6 hours), were studied. Diagnosis was established on the basis of clinical patterns, ECG and biochemical criteria. All patients were treated with basic therapy including the use of disaggregants, -adrenoblockers, anticoagulants, nitrates, and glucose-insulin-potassium-magnesium mixture. Thrombolytic therapy was provided for 46.0%, PTCA – for 23.7% of patients. In 30.3% of patients myocardium revascularization was not made on different reasons. 74.8% of patients with myocardium left ventricle dysfunction used APF inhibitors. With existence of indications diuretics, narcotic analgesics and anti-dysrhythmic agents were used. Two groups of patients with no statistically important differences in starting clinical anamnesis data and in applied basic therapy were formed using the method of a random selection (in the order of sequence of entrance). The first group included 93 patients, in whom, in addition to a basic therapy, Corvitin was intravenously injected dropwise for 30 to 45 min in accordance with our scheme (1st day – 0.5 g with 50 ml of sodium chloride solution three times at 2-h and 12-h intervals; 2nd – 3rd days – the same dose twice a day at 12-h interval; 4th – 5th days – a single dose 0.25 g; patent No. 37575a). The second (control) group included 105 patients. Peculiarities of clinical progress, necrosis formation dynamics were studied; the mass of necrotized myocardium (on the basis of serial definition of activity of creatininephosphokinase (CPK) and MB-CPK in peripheral venous blood serum), parameters of intracardial hemodynamics, heart rhythm variability were defined; ECG BP using M. Simpson’s method was made. For 46 patients stress-echocardiography with dobutamine (SED) was made [10]. The status of NO system was assessed by stable NO2 pool in peripheral blood, by the level of diene conjugates (DC) and by the quantity of leukotriene C4 (LTS4). The above tests were made jointly with the Institute of Biochemistry of the NAS of Ukraine. The obtained results were statistically analyzed using Student’s t criterion and Wilkinson’s double criterion. Differences with P<0.05 were="" considered="" as="" reliable="" results="" and="" discussion="" in="" patients="" with="" ocs="" st="" corvitin="" significantly="" inhibits="" lipids="" peroxidation="" accompanied="" dc="" reduction="" starting="" from="" the="" 2nd="" hour="" after="" preparation="" injection="" fig="" 1="" its="" maximal="" normalizing="" effect="" is="" achieved="" on="" 5th="" day="" of="" acute="" myocardial="" infarction="" reduced="" activity="" lipoxygenases="" which="" fact="" facilitated="" a="" stable="" lts4="" quantities="" during="" entire="" therapy="" period="" s="" probably="" due="" to="" this="" pathological="" action="" ischemia="" reperfusion="" myocardium="" gets="" reduced:="" it="" was="" stated="" derivatives="" formed="" arachidonic="" acid="" metabolism="" lt="" lipoxines="" lipoxygenase="" channel="" serve="" powerful="" coronaroconstrictors="" stimulating="" aggregation="" thrombocytes="" giving="" proarrhythmogenic="" 2="" 16="" well="" tolerated="" intravenous="" neither="" affected="" arterial="" tension="" nor="" changed="" heart="" rate="" early="" first="" administration="" recurrences="" anginal="" pain="" occurred="" more="" rare="" 1st="" group="" 30="" 5="" second="" one="" p="" 0="" 05="" doing="" so="" less="" need="" use="" narcotic="" analgesics="" cup="" off="" recurring="" syndrome="" 22="" 6="" 36="" correspondingly="" recorded="" addition="" decrease="" occurrences="" atrioventricular="" blockade="" 4="" 3="" 12="" course="" concentrations="" leukotriene="" c4="" diene="" conjugates="" blood="" serum="" -="" g="" l="" control="" hours="" analysis="" disease="" progress="" hospital="" has="" demonstrated="" that="" all="" cases="" who="" used="" almost="" three="" times="" than="" frequency="" ventricular="" extrasystolia="" 3rd="" by="" 45="" 01="" 7th="" 42="" left="" failure="" class="" iii="" 10="" classes="" ii="" 20="" 27="" 11="" mass="" necrotized="" necrosis="" area="" formation="" are="" main="" factors="" conditioning="" mortality="" adverse="" long-term="" prognosis="" acs="" there="" exists="" an="" intimate="" relation="" between="" volume="" infarction-damaged="" development="" origination="" hear="" rhythm="" disorder="" final="" may="" be="" protecting="" viable="" cells="" against="" progressing="" damage="" cpk="" peak="" then="" cat="" mb-cpk="" 23="" 26="" evidences="" minor="" differences="" initially="" time="" 13="" hrs="" 17="" 8="" 9="" 001="" necrotic="" calculated="" changes="" mb-cfk="" versus="" those="" equiv="" 61="" these="" conditioned="" for="" normalization="" activities="" average="" comparative="" achievement="" cardiospecific="" ferments="" evidence="" quicker="" their="" was-out="" prevention="" further="" cardiomyocytes="" different="" groups="" presented="" 1-="" positively="" affects="" cardiohemodynamics="" reduces="" dilation="" ventricle="" cavity="" diastolic="" systolic="" indexes="" remained="" unchanged="" days="" observation="" at="" same="" tendency="" increase="" index="" 10th="" ejection="" fraction="" ef="" grew="" both="" but="" growth="" greater="" group:="" best="" open="" coronary="" artery="" induced="" tlt="" no="" revascularization="" caim="" inducing="" percutaneous="" angioplasty="" without="" high="" leukocytosis="" thrombolytic="" purpose="" sed="" finding="" process="" asynergic="" sections="" not="" always="" lose="" contractility="" if="" certain="" onsets="" potentially="" recovered="" we="" have="" found="" 68="" 50="" obtained="" data="" under="" study="" able="" reduce="" expressiveness="" initial="" phase="" when="" immediately="" patient="" entrance="" improves="" electrophysiological="" properties="" prevents="" occasional="" damages="" ecg="" bp="" late="" potentials="" lfp="" markers="" called="" dysrhythmogenic="" substrate="" disappeared="" manifested="" background="" treatment="" make="" possible="" suppose="" existence="" pronounced="" anti-ischemic="" proved="" clinical="" vegetative="" nerve="" system="" tonus="" spectral="" variability="" parasympathetic="" section="" while="" 2dn="" dropped="" mechanisms="" such="" clarification="" however="" property="" makes="" preventing="" life0hazardous="" hart="" troubles="">

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Source:“Journal of the AMS of Ukraine”. 2003, Vol. 9, N 2. –P. 361 – 370. UDC 616.127-005.8-036.11-002.4:612.172:615.22 CLINICAL MEDICINE A.A. Moybenko – Academician of the AMS of Ukraine, doctor of medical sciences, A.N. Parkhomenko, medical science degree, S.N. Kozhukhov*, medical science degree A.A. Bogomolets Institute of Physiology of the AMS of Ukraine, Kiev, 01024, Ukraine N.D. Strazhesko Institute of Cardiology of the AMS of Ukraine, Kiev, 03151, Ukraine