MD4412C1 - Use of 4-({2-butyl-5-[2-carboxy-2-(thiophene-2-ylmethyl)et-1-en-1-yl]-1H-imidazole-1-yl}methyl)benzoic acid to improve vascular elasticity in the prevention of complications of hypertensive genesis - Google Patents
Use of 4-({2-butyl-5-[2-carboxy-2-(thiophene-2-ylmethyl)et-1-en-1-yl]-1H-imidazole-1-yl}methyl)benzoic acid to improve vascular elasticity in the prevention of complications of hypertensive genesis Download PDFInfo
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- MD4412C1 MD4412C1 MDA20140092A MD20140092A MD4412C1 MD 4412 C1 MD4412 C1 MD 4412C1 MD A20140092 A MDA20140092 A MD A20140092A MD 20140092 A MD20140092 A MD 20140092A MD 4412 C1 MD4412 C1 MD 4412C1
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Abstract
Invenţia se referă la medicină, în special la cardiologie şi poate fi utilizată în tratamentul complex al pacienţilor cu hipertensiune arterială, pentru ameliorarea elasticităţii vasculare în profilaxia complicaţiilor severe ca accident vascular cerebral, insuficienţă renală, retinopatie hipertensivă, infarct miocardic.Esenţa invenţiei constă în utilizarea acidului 4-({2-butil-5-[2-carboxi-2-(tiofen-2-ilmetil)et-1-en-1-il]-1H-imidazol-1-il}metil) benzoic pentru ameliorarea elasticităţii vasculare în profilaxia complicaţiilor de geneză hipertensivă, care se administrează per os, câte 600…1200 mg, o dată pe zi.The invention relates to medicine, in particular to cardiology and can be used in the complex treatment of patients with hypertension, for improving the vascular elasticity in the prophylaxis of severe complications such as stroke, renal failure, hypertensive retinopathy, myocardial infarction. The essence of the invention is to use 4 - ({2-Butyl-5- [2-carboxy-2- (thiophen-2-ylmethyl) et-1-en-1-yl] -1H-imidazol-1-yl} methyl) benzoic acid to improve elasticity vascular in the prophylaxis of complications of hypertensive genesis, administered by bone, 600 ... 1200 mg, once daily.
Description
Invenţia se referă la medicină, în special la cardiologie şi poate fi utilizată în tratamentul complex al pacienţilor cu hipertensiune arterială, pentru ameliorarea elasticităţii vasculare în profilaxia complicaţiilor severe ca accident vascular cerebral, insuficienţă renală, retinopatie hipertensivă, infarct miocardic. The invention relates to medicine, especially to cardiology and can be used in the complex treatment of patients with arterial hypertension, to improve vascular elasticity in the prophylaxis of severe complications such as stroke, renal failure, hypertensive retinopathy, myocardial infarction.
Este cunoscută utilizarea preparatului Ramipril - inhibitor al enzimei de conversie a angiotensinei II, pentru majorarea elasticităţii vaselor în profilaxia accidentelor vasculare, care se administrează câte 2,5 mg o dată pe zi, aceasta fiind doza iniţială, apoi doza de menţinere de 2,5…20 mg o dată pe zi sau divizată în 2 prize [1]. It is known to use the preparation Ramipril - inhibitor of the angiotensin II converting enzyme, to increase the elasticity of vessels in the prevention of vascular accidents, which is administered 2.5 mg once a day, this being the initial dose, then the maintenance dose of 2.5 …20 mg once a day or divided into 2 doses [1].
Dezavantajul preparatului utilizat pentru majorarea elasticităţii vaselor în profilaxia accidentelor vasculare este efectul lui redus asupra musculaturii netede a vaselor de calibru mare şi mic. The disadvantage of the preparation used to increase the elasticity of vessels in the prevention of vascular accidents is its reduced effect on the smooth muscles of large and small vessels.
Problema pe care o rezolvă invenţia propusă constă în elaborarea unor metode cu utilizarea unor preparate medicamentoase pentru o perioadă îndelungată, care dincolo de scăderea valorilor tensionale să posede efecte pleiotrope importante ce pot ameliora indicii elasticităţii arteriale, cu scop de profilaxie a accidentelor vasculare şi fără complicaţii severe la administrarea lui de lungă durată. The problem that the proposed invention solves consists in the development of methods with the use of medicinal preparations for a long period, which, beyond the decrease in blood pressure values, have important pleiotropic effects that can improve arterial elasticity indices, with the aim of preventing vascular accidents and without complications severe with its long-term administration.
Esenţa invenţiei constă în utilizarea acidului 4-({2-butil-5-[2-carboxi-2-(tiofen-2-ilmetil)et-1-en-1-il]-1H-imidazol-1-il}metil) benzoic pentru ameliorarea elasticităţii vasculare în profilaxia complicaţiilor de geneză hipertensivă, care se administrează per os, câte 600…1200 mg, o dată pe zi. The essence of the invention consists in the use of 4-({2-butyl-5-[2-carboxy-2-(thiophen-2-ylmethyl)eth-1-en-1-yl]-1H-imidazol-1-yl}methyl acid ) benzoic for improving vascular elasticity in the prophylaxis of complications of hypertensive origin, which is administered orally, 600...1200 mg, once a day.
Rezultatul invenţiei constă utilizarea acidului 4-({2-butil-5-[2-carboxi-2-(tiofen-2-ilmetil)et-1-en-1-il]-1H-imidazol-1-il}metil) benzoic care, fiind un blocant al receptorilor angiotensinergici II, posedă efect antihipertensiv şi de majorare a elasticităţii pereţilor vaselor de calibru mare şi mic, totodată este mai eficient decât preparatele cunoscute şi nu duce la apariţia complicaţiilor severe la administrarea lui de lungă durată. The result of the invention is the use of 4-({2-butyl-5-[2-carboxy-2-(thiophen-2-ylmethyl)eth-1-en-1-yl]-1H-imidazol-1-yl}methyl) acid benzoic which, being a blocker of angiotensin II receptors, has an antihypertensive effect and increases the elasticity of the walls of large and small vessels, at the same time it is more effective than known preparations and does not lead to the appearance of severe complications with its long-term administration.
Miza de suport a tratamentului indicat pacientului hipertensiv este reducerea maximă a riscului de morbiditate, mortalitate cardiovasculară şi renală pe termen lung. Şi pentru că riscul cardiovascular este direct proporţional cu creşterea valorilor tensiunii arteriale (TA), primul obiectiv al terapiei antihipertensive este scăderea valorilor tensionale până la cifre normale - 140/90 mmHg în populaţia generală, de 130/80 mmHg pentru anumite categorii de pacienţi (diabetici sau boala renală cronică) şi de 125/75 mmHg pentru pacienţii cu proteinurie mai mare de 1 g/24 ore. The main aim of the treatment indicated for the hypertensive patient is the maximum reduction of the risk of morbidity, cardiovascular and renal mortality in the long term. And because the cardiovascular risk is directly proportional to the increase in blood pressure (BP), the first objective of antihypertensive therapy is to reduce blood pressure to normal values - 140/90 mmHg in the general population, 130/80 mmHg for certain categories of patients ( diabetics or chronic kidney disease) and 125/75 mmHg for patients with proteinuria greater than 1 g/24 hours.
Per ansamblu, sub acţiunea medicaţiei antihipertensive se reduce riscul de accident vascular cerebral (AVC) cu 35…40%, cel de infarct miocardic acut (IMA) cu 20…25%, insuficienţă cardiacă cronică cu 50%, insuficienţă renală cronică cu 16…26% (Blood Pressure Lowering Treatment Trialists Collaboration. Effects of different regimens to lowering blood pressure on major cardiovascular events in older and younger adults: Meta-analysis of randomized trials. Br. Med. J. 2008, 336, p. 1121-1123). Overall, under the action of antihypertensive medication, the risk of stroke is reduced by 35...40%, that of acute myocardial infarction (AMI) by 20...25%, chronic heart failure by 50%, chronic renal failure by 16... 26% (Blood Pressure Lowering Treatment Trialists Collaboration. Effects of different regimens to lowering blood pressure on major cardiovascular events in older and younger adults: Meta-analysis of randomized trials. Br. Med. J. 2008, 336, p. 1121-1123 ).
Endoteliul normal este un organ autocrin, paracrin şi endocrin şi joacă un rol cheie în protecţia vasculară împotriva aterosclerozei, hipertensiunii arteriale, diabetului zaharat ş.a. prin reglarea tonusului vascular, scăderea nivelului de lipide, al inflamaţiei şi trombogenezei. Factorii de risc convenţionali pot favoriza şi stimula disfuncţia endotelială, ca urmare a diminuării biodisponibilităţii oxidului nitric, principalul mediator al funcţiilor endoteliale. The normal endothelium is an autocrine, paracrine and endocrine organ and plays a key role in vascular protection against atherosclerosis, hypertension, diabetes, etc. by regulating the vascular tone, decreasing the level of lipids, inflammation and thrombogenesis. Conventional risk factors can favor and stimulate endothelial dysfunction, as a result of decreasing the bioavailability of nitric oxide, the main mediator of endothelial functions.
Afectarea endoteliului în patogenia hipertensiunii arteriale (HTA) este oportună nu numai prin prisma creşterii tonusului vascular bazal reglat constitutiv de către oxidul nitric, dar şi a potenţării efectului vasoconstrictor al stimulărilor adrenergice, angiotensinice şi endotelinice. Endoteliul disfuncţional implică infiltrarea LDL-colesterolului, urmată de oxidarea lui la nivelul intimei arteriale. Această modificare a fracţiunii LDL induce eliberarea de fosfolipide care potenţează disfuncţia endotelială, cu activarea procesului inflamator şi eliberarea factorilor de creştere cu proliferarea celulelor musculare netede vasculare şi producerea în exces a colagenului în matricea celulară. Affecting the endothelium in the pathogenesis of arterial hypertension (HT) is opportune not only from the perspective of the increase in basal vascular tone constitutively regulated by nitric oxide, but also from the potentiation of the vasoconstrictor effect of adrenergic, angiotensinic and endothelin stimulations. The dysfunctional endothelium involves the infiltration of LDL-cholesterol, followed by its oxidation at the level of the arterial intima. This modification of the LDL fraction induces the release of phospholipids that potentiate endothelial dysfunction, with the activation of the inflammatory process and the release of growth factors with the proliferation of vascular smooth muscle cells and the excess production of collagen in the cellular matrix.
Datele cercetărilor clinice au evidenţiat că HTA este caracterizată de un proces de rigidizare a arterelor de calibru mare (Kannel W., Wolf P., McGee D. et col. Systolic blood pressure, arterial rigidity, and risk of stroke. The Framingham study. 1981, 245, p.1225-1229), care are drept substrat degradarea ţesutului elastic din tunica medie a acestor vase şi substituirea lui cu fibre de colagen (Franklin S., Izzo J. Aging, Hypertension and Arterial Stiffnes. In: Hypertension Primer, 3rd Edition, 2003, American heart Assocition; Lippincott Williams&Wilkins, p. 170-175). Rigidizarea arterlor mari a fost studiată şi în raport cu un alt organ ţintă al complicaţiilor din HTA - rinichiul. Indicii de rigidizare arterială s-au corelat cu prezenţa microalbuminuriei, cu reducerea clearance-ului de creatinină serică la pacienţii cu insuficienţă renală cronică de diversă severitate (Pedrinelli R., Dell'Ommo G., Penno G. et colab. Microalbuminuria and pulsepressure in hypertensive and atherosclerotic men, Hypertension. 2000, 35, p. 48-54). Un moment hotărâtor în demonstrarea utilităţii de a evalua indicii de rigidizare a vaselor îl constituie publicarea de către Williams H.M. şi colab. a rezultatelor studiului CAFE (terapie combinată a amlodipinei, perindopril, atenolol, HCTZ), care a urmărit eficienţa comparativă a tratamentului cu preparate β-adrenoblocante cu sau fără diuretice versus un antagonist de calciu cu sau fără IECA II. Rigidizarea arterială are o valoare predictivă independentă pentru mortalitatea generală în ansamblu şi morbiditatea cardiovasculară în particular, pentru diferite evenimente coronariene şi accidente vasculare cerebrale la pacienţii cu hipertensiune esenţială necomplicată. Deci, o utilizare clinică mai largă a indicilor elasticităţii arteriale şi aprecierea rezistenţei vasculare periferice poate aduce un plus la precizia evaluării leziunilor vasculare. Clinical research data have shown that HTN is characterized by a process of stiffening of large-caliber arteries (Kannel W., Wolf P., McGee D. et al. Systolic blood pressure, arterial rigidity, and risk of stroke. The Framingham study. 1981, 245, p.1225-1229), which has as its substrate the degradation of the elastic tissue in the middle tunic of these vessels and its replacement with collagen fibers (Franklin S., Izzo J. Aging, Hypertension and Arterial Stiffness. In: Hypertension Primer , 3rd Edition, 2003, American heart Association; Lippincott Williams&Wilkins, p. 170-175). The stiffening of the large arteries has also been studied in relation to another target organ of HTN complications - the kidney. Arterial stiffening indices were correlated with the presence of microalbuminuria, with the reduction of serum creatinine clearance in patients with chronic renal failure of various severity (Pedrinelli R., Dell'Ommo G., Penno G. et al. Microalbuminuria and pulsepressure in hypertensive and atherosclerotic men, Hypertension. 2000, 35, p. 48-54). A decisive moment in the demonstration of the utility of evaluating vessel stiffening indices is the publication by Williams H.M. et al. of the results of the CAFE study (combined therapy of amlodipine, perindopril, atenolol, HCTZ), which followed the comparative effectiveness of treatment with β-adrenoblocking preparations with or without diuretics versus a calcium antagonist with or without ACEI II. Arterial stiffness has an independent predictive value for general mortality in general and cardiovascular morbidity in particular, for various coronary events and strokes in patients with uncomplicated essential hypertension. So, a wider clinical use of arterial elasticity indices and the assessment of peripheral vascular resistance may add to the accuracy of the assessment of vascular lesions.
În prezent se focalizează atenţia asupra indicilor care evaluează non-invaziv rigiditatea arterială - indicii elasticităţii arterelor de calibru mare şi mic, viteza undei de puls, analiza morfologică a undei de puls, indicele de augmentare. Progresul tehnic a fost impulsionat de necesitatea de a studia fenomenul rigidizării arterelor mari şi de a verifica în raport cu acesta eficienţa unor soluţii terapeutice specifice. În consecinţă, au fost concepute şi produse o serie de aparate care permit evaluarea non-invazivă a indicilor rigidizării arteriale. Ele au constituit substratul metodologic a numeroase studii clinice care s-au derulat în ultimii ani şi care au contribuit la constatarea rigidităţii arteriale drept mecanism fundamental al hipertensiunii arteriale. Currently, attention is focused on indices that non-invasively assess arterial stiffness - indices of elasticity of large and small arteries, pulse wave speed, morphological analysis of the pulse wave, augmentation index. The technical progress was driven by the need to study the phenomenon of stiffening of the large arteries and to verify the effectiveness of specific therapeutic solutions in relation to it. Consequently, a series of devices have been designed and produced that allow the non-invasive evaluation of arterial stiffening indices. They constituted the methodological substrate of numerous clinical studies that took place in recent years and that contributed to the finding of arterial stiffness as the fundamental mechanism of arterial hypertension.
Datele cercetărilor clinice au evidenţiat că formele de HTA sunt caracterizate de un proces de rigidizare a arterelor de calibru mare care are drept substrat esenţial degradarea ţesutului elastic din tunica medie a acestor vase şi substituirea lui cu fibre de colagen. Clinical research data have shown that forms of hypertension are characterized by a process of stiffening of large-caliber arteries whose essential substrate is the degradation of the elastic tissue in the middle tunic of these vessels and its replacement with collagen fibers.
Din punct de vedere hemodinamic rigidizarea se repercută asupra undei de puls, generând două modificări majore - creşterea vitezei undei de puls (PWV) şi modificarea morfologică a undei de puls, caracterizată de o presiune a pulsului (PP) şi un indice de augmentare (IxA) crescute la nivel central. From a hemodynamic point of view, the stiffening affects the pulse wave, generating two major changes - the increase in pulse wave speed (PWV) and the morphological change of the pulse wave, characterized by a pulse pressure (PP) and an augmentation index (IxA ) raised at the central level.
Posibilitatea de a evalua non-invaziv parametrii de rigiditate arterială a permis derularea unor studii epidemiologice longitudinale care au demonstrat că rigiditatea arterială, presiunea pulsului sau indicele de augmentare sunt factorii predictivi independenţi ai evenimentelor cardiovasculare. Rigiditatea arterială are valoare predictivă independentă pentru mortalitatea de orice cauză, mortalitatea cardiovasculară, evenimentele coronariene fatale şi non-fatale, accident vascular cerebral fatal în HTA esenţială, în diabet zaharat, la pacienţi cu boală renală cronică terminală. The possibility of non-invasively evaluating the parameters of arterial stiffness allowed the development of longitudinal epidemiological studies that demonstrated that arterial stiffness, pulse pressure or augmentation index are the independent predictive factors of cardiovascular events. Arterial stiffness has independent predictive value for all-cause mortality, cardiovascular mortality, fatal and non-fatal coronary events, fatal stroke in essential hypertension, in diabetes mellitus, in patients with end-stage chronic kidney disease.
Aportul rigidizării arterelor de calibru mare în iniţierea hipertensiunii arteriale şi posibilitatea tehnică de a evalua acest fenomen constituie premisele unui demers deosebit de important de a găsi soluţii terapeutice individualizate pentru pacienţii cu HTA. În ultimii ani preparatele antihipertensive au fost evaluate în raport cu aptitudinea lor de a influenţa indicii rigidităţii arteriale, în special PWV sau indexul de augmentare, dar studiile efectuate în acest scop s-au realizat pe un număr restrâns de pacienţi şi pe o durată scurtă de monitorizare. De asemenea, foarte puţine studii au evaluat măsura în care diferite clase de preparate antihipertensive afectează presiunea sistolică din artera brahială, în comparaţie cu cea din aortă. Morgan T. şi colab. au publicat în 2004 rezultatele unui studiu în care au fost analizate efectele inhibitorului enzimei de conversie a angiotensinei II (IECA II), β-blocantelor, blocantelor canalelor de calciu şi diureticelor asupra tensiunii arteriale sistolice din artera brahială comparativ cu efectele lor asupra indicilor de rigidizare a aortei. S-a constatat că cea mai importantă reducere a presiunii aortice centrale s-a obţinut cu blocantele de calciu combinate cu diuretice, autorii avertizând că terapia ghidată de măsurătorile pe artera brahială poate supraestima efectele β -blocantelor sau poate subestima efectele IECA II/blocantelor canalelor de calciu asupra presiunii sistolice centrale. The contribution of the stiffening of large-caliber arteries in the initiation of arterial hypertension and the technical possibility to evaluate this phenomenon constitute the premises of a particularly important approach to find individualized therapeutic solutions for patients with HTN. In recent years, antihypertensive drugs have been evaluated in relation to their ability to influence indices of arterial stiffness, especially PWV or augmentation index, but the studies carried out for this purpose were carried out on a limited number of patients and on a short duration of monitoring. Also, very few studies have evaluated the extent to which different classes of antihypertensive drugs affect systolic pressure in the brachial artery, compared to that in the aorta. Morgan T. et al. published in 2004 the results of a study in which the effects of angiotensin II converting enzyme inhibitor (ACEI II), β-blockers, calcium channel blockers and diuretics on brachial artery systolic blood pressure were analyzed compared to their effects on stiffening indices of the aorta. The most significant reduction in central aortic pressure was found to be obtained with calcium blockers combined with diuretics, with the authors cautioning that therapy guided by brachial artery measurements may overestimate the effects of β-blockers or underestimate the effects of ACE II/calcium channel blockers on pressure central systolic.
Noi terapii încep să fie evaluate cu preparate care nu au drept efect principal scăderea tensiunii arteriale, dar vizează cauzele subiacente ale rigidităţii arteriale, cum ar fi inflamaţia vasculară sau modificările vasculare care duc la degradarea elastinei şi glicarea colagenului. New therapies are beginning to be evaluated with preparations that do not have the primary effect of lowering blood pressure, but target the underlying causes of arterial stiffness, such as vascular inflammation or vascular changes that lead to elastin degradation and collagen glycation.
Doar o treime din indivizii cu hipertensiune arterială, aparent controlată terapeutic, sunt realmente protejaţi de accidentul vascular cerebral sau atacurile de cord şi doar 20% dintre pacienţii cu HTA ating valorile ţintă ale TA. Aceste date atenţionează asupra faptului că există verigi patofiziologice specifice diverselor forme clinice de hipertensiune arterială şi că trebuie validate strategii terapeutice care dincolo de scăderea valorilor tensionale posedă efecte pleiotrope importante ce pot ameliora indicii elasticităţii arteriale. Only one-third of individuals with apparently therapeutically controlled hypertension are actually protected from stroke or heart attack, and only 20% of patients with hypertension achieve BP target values. These data draw attention to the fact that there are pathophysiological links specific to the various clinical forms of arterial hypertension and that therapeutic strategies must be validated that, beyond lowering blood pressure values, have important pleiotropic effects that can improve arterial elasticity indices.
Drept recapitulare, efectul antihipertensiv, cardio-, nefro- şi vasoprotector al IEC a ARA II Ramipril este bine elucidat în studii de divers calibru. Totodată, ARA II Eprosartan apărut recent pe piaţa farmaceutică nu a fost studiat pe segmentele clinice enumerate mai sus, dar şi graţie faptului că este deosebit prin mecanismul dublu de acţiune de ceilalţi reprezentanţi ai clasei, am considerat oportun de a iniţia un studiu de durată dedicat perfectării tacticii de tratament al HTA esenţiale în scopul minimalizării afectării organelor ţintă şi, respectiv, ameliorării pronosticului. As a summary, the antihypertensive, cardio-, nephro- and vasoprotective effect of the ACE II ARA Ramipril is well elucidated in studies of various caliber. At the same time, ARA II Eprosartan, which recently appeared on the pharmaceutical market, has not been studied in the clinical segments listed above, but also thanks to the fact that it is distinguished by its double mechanism of action from the other representatives of the class, we considered it appropriate to initiate a long-term study dedicated to perfecting essential hypertension treatment tactics in order to minimize the damage to the target organs and, respectively, improve the prognosis.
Importanţa studiului realizat de noi este bazată pe testarea unui antihipertensiv nou din grupul antagoniştilor receptorilor de angiotensină II - acidului 4-({2-butil-5-[2-carboxi-2-(tiofen-2-ilmetil)et-1-en-1-il]-1H-imidazol-1-il}metil) benzoic (Eprosartan), comparat cu Ramipril - inhibitor al enzimei de conversie a angiotensinei II. Deşi se aplică cu succes remedii din acest grup tratamentul optim preventiv al evoluţiei hipertensiunii arteriale, asociată cu disfuncţie diastolică, sistolică, nefropatie hipertensivă, insuficienţă renală, boală cerebrovasculară, necesită studii suplimentare în vederea perfectării în continuare. The importance of the study carried out by us is based on the testing of a new antihypertensive from the group of angiotensin II receptor antagonists - 4-({2-butyl-5-[2-carboxy-2-(thiophen-2-ylmethyl)eth-1-ene acid) -1-yl]-1H-imidazol-1-yl}methyl) benzoic (Eprosartan), compared with Ramipril - angiotensin II converting enzyme inhibitor. Although remedies from this group are successfully applied, the optimal preventive treatment of the evolution of arterial hypertension, associated with diastolic and systolic dysfunction, hypertensive nephropathy, renal failure, cerebrovascular disease, requires additional studies in order to further perfect it.
Alegerea acidului 4-({2-butil-5-[2-carboxi-2-(tiofen-2-ilmetil)et-1-en-1-il]-1H-imidazol-1-il}metil) benzoic (Eprosartan) ca obiect de cercetare este fundamentată pe câteva raţiuni: Choice of 4-({2-butyl-5-[2-carboxy-2-(thiophen-2-ylmethyl)eth-1-en-1-yl]-1H-imidazol-1-yl}methyl)benzoic acid (Eprosartan ) as a research object is based on several reasons:
- sunt absente relatările vizavi de efectele acestui remediu asupra rigidităţii vasculare sistemice la pacienţii hipertensivi; - there are no reports regarding the effects of this remedy on systemic vascular stiffness in hypertensive patients;
- un alt argument ar fi şi faptul că Eprosartanul este unicul antagonist al receptorilor de angiotensină II cu acţiune directă asupra sistemului nervos central şi de blocare a receptorilor presinaptici; - another argument would be the fact that Eprosartan is the only angiotensin II receptor antagonist with direct action on the central nervous system and by blocking presynaptic receptors;
- prin blocarea receptorilor AT1 preparatul examinat nu influenţează degradarea bradikininei şi eliberarea oxidului nitric, dezvoltă efect antiaritmogen şi anticitotoxic miocardic direct. - by blocking AT1 receptors, the examined preparation does not influence the degradation of bradykinin and the release of nitric oxide, it develops a direct myocardial antiarrhythmic and anticytotoxic effect.
Dovezile obţinute au reliefat importanţa rigidităţii arteriale sistemice (artere de calibru mare şi cele rezistive) în patogenia HTA şi în pronosticul evolutiv al pacientului hipertensiv. The obtained evidence highlighted the importance of systemic arterial stiffness (large-caliber and resistive arteries) in the pathogenesis of HTN and in the evolutionary prognosis of the hypertensive patient.
Metoda de studiu aplicată pentru aprecierea indicilor elasticităţii vasculare s-a bazat pe analiza de contur diastolic al pulsului (Modelul Windkessel) cu dispozitivul HDI PW CR-2000. The study method applied to assess vascular elasticity indices was based on the diastolic contour analysis of the pulse (Windkessel Model) with the HDI PW CR-2000 device.
Aprecierea indicilor elasticităţii arteriale ne-a permis să evaluăm gradul de rigiditate arterială ce creşte odată cu înaintarea în vârstă, precum şi în prezenţa hipertensiunii arteriale, diabetului zaharat, hipercolesterolemiei şi disfuncţiei renale. Appreciation of arterial elasticity indices allowed us to evaluate the degree of arterial stiffness that increases with age, as well as in the presence of hypertension, diabetes, hypercholesterolemia and renal dysfunction.
Pentru a estima în ce măsură este activat fenomenul rigidizării arteriale la pacienţii cu HTA esenţială şi microalbuminurie am analizat indicii elasticităţii arterelor de calibru mare (C1), fig. 1., tab. 1 şi de calibru mic (C2) pe fundalul tratamentului cu Ramipril şi Eprosartan, fig. 2, tab. 2. Tabelul 1 In order to estimate the extent to which the phenomenon of arterial stiffening is activated in patients with essential hypertension and microalbuminuria, we analyzed the elasticity indices of large-caliber arteries (C1), fig. 1., tab. 1 and of small caliber (C2) against the background of treatment with Ramipril and Eprosartan, fig. 2, tab. 2. Table 1
Ponderea pacienţilor cu diverse categorii de elasticitate arterială în funcţie de medicaţie pentru C1, (nr. %) Share of patients with various categories of arterial elasticity depending on medication for C1, (no. %)
I lot (50 pct.) - Ramipril II lot (50 pct.) - Eprosartan Perioada (luni) Elasticitate Elasticitate redusă de limită norma redusă de limită norma Iniţial 1 (2%) 26 (52%) 23 (46%) 1 (2%) 23 (46%) 26 (52%) 3 luni 1 (2%) 19 (38%) 30 (60%) 1 (2%) 20 (40%) 29 (58%) 6 luni - (0) 20 (40%) 30 (60%) - (0) 20 (40%) 30 (60%) 9 luni - 19 (38%) 31 (62%) - 0 18 (36%) 32 (64%) 12 luni - 17 (34%) 33 (66%) - 0 16 (32%) 34 (68%) I batch (50 pts.) - Ramipril II batch (50 pts.) - Eprosartan Period (months) Elasticity Elasticity reduced limit norm reduced limit limit norm Initial 1 (2%) 26 (52%) 23 (46%) 1 ( 2%) 23 (46%) 26 (52%) 3 months 1 (2%) 19 (38%) 30 (60%) 1 (2%) 20 (40%) 29 (58%) 6 months - (0 ) 20 (40%) 30 (60%) - (0) 20 (40%) 30 (60%) 9 months - 19 (38%) 31 (62%) - 0 18 (36%) 32 (64%) 12 months - 17 (34%) 33 (66%) - 0 16 (32%) 34 (68%)
Rezultatele obţinute cu referire la arterele de calibru mare C1 denotă următoarele: la iniţierea studiului în ambele loturi preponderent s-au depistat cu categoriile de „limită” 26 (52%) şi 23 (46%) pacienţi şi de „normă” 23 (46%) şi 26 (52%) pacienţi în loturile I şi II respectiv. Odată cu administrarea medicaţiei numărul pacienţilor care au atins criteriile caracteristice pentru categoria de normă a sporit la 6 luni în egală măsură, câte 60% în ambele loturi. La continuarea tratamentului pacienţii atestaţi cu categoria „norma” pentru artere de calibru mare a sporit neesenţial - cu 2% şi 6% la 9 şi 12 luni la utilizarea Ramiprilului, 4% şi 8% la administrarea Eprosartanului, fapt care sugerează necesitatea continuării medicaţiei pentru o perioadă indefinită, fig. 1., tab. 1. The results obtained with reference to the C1 large-caliber arteries show the following: at the beginning of the study in both groups, 26 (52%) and 23 (46%) "limit" patients and "normal" 23 (46 %) and 26 (52%) patients in groups I and II respectively. With the administration of the medication, the number of patients who reached the characteristic criteria for the norm category increased at 6 months equally, 60% in both groups. During the continuation of the treatment, the patients certified with the "norm" category for large-caliber arteries increased non-essentially - by 2% and 6% at 9 and 12 months when using Ramipril, 4% and 8% when taking Eprosartan, a fact that suggests the need to continue the medication for an indefinite period, fig. 1., tab. 1.
Un alt tablou a fost elucidat pe artere de calibru mic C2. Iniţial majoritatea pacienţilor s-au încadrat în categoria „elasticitate redusă”- 62% în lotul I şi 54% în lotul II. Categoria „de limită” a fost semnalată la 24% şi 30% subiecţi şi „de normă” la doar 14% şi 16% în loturile I şi II respectiv. Odată cu administrarea remediilor la 3 luni de medicaţie prevalenţa subiecţilor cu „elasticitate redusă” a fost de 56% în lotul I versus 52% în lotul II; la 6 luni numărul pacienţilor cu „elasticitate redusă” a avut o tendinţă de descreştere de la 62% la 48% în I lot versus de la 54% la 38% în lotul II. Spre finele perioadei de supraveghere cu „elasticitate redusă” au fost depistaţi 8% în lotul I, iar în lotul II categoria de „elasticitate redusă” nu a mai fost documentată, categoria de „normă” constituind 92%, fig. 2, tab. 2. Another picture was elucidated on C2 small-caliber arteries. Initially, most patients fell into the "reduced elasticity" category - 62% in group I and 54% in group II. The "limit" category was reported in 24% and 30% of subjects and "normal" in only 14% and 16% in groups I and II respectively. With the administration of the remedies after 3 months of medication, the prevalence of subjects with "reduced elasticity" was 56% in group I versus 52% in group II; at 6 months the number of patients with "reduced elasticity" had a tendency to decrease from 62% to 48% in the I group versus from 54% to 38% in the II group. Towards the end of the surveillance period, 8% were detected with "reduced elasticity" in batch I, and in batch II the category of "reduced elasticity" was no longer documented, the category of "norm" constituting 92%, fig. 2, tab. 2.
Tabelul 2 Table 2
Ponderea pacienţilor cu diverse categorii de elasticitate arterială pe parcursul supravegherii în funcţie de medicaţie C2, (nr. %) The share of patients with various categories of arterial elasticity during the supervision according to medication C2, (no. %)
I lot (50 pct.) (Ramipril) II lot (50 pct.) (Eprosartan) Perioada (luni) Elasticitate Elasticitate redusă de limită norma redusă de limită norma Iniţial 31 (62%) 12 (24%) 7 (14%) 27 (54%) 15 (30%) 8 (16%) 3 luni 28 (56%) 12 (24%) 10 (20%) 26 (52%) 12 (24%) 12 (24%) 6 luni 24 (48%) 15 (30%) 11 (22%) 19 (38%) 15 (30%) 16 (32%) 9 luni 4 (8%) 11 (22%) 35 (70%) 2 (4%) 11 (22%) 37 (74%) 12 luni 4 (8%) 6 (12%) 40 (80%) - (0%) 4 (8%) 46 (92%) I batch (50 pts.) (Ramipril) II batch (50 pts.) (Eprosartan) Period (months) Elasticity Elasticity reduced limit norm reduced limit limit norm Initial 31 (62%) 12 (24%) 7 (14%) 27 (54%) 15 (30%) 8 (16%) 3 months 28 (56%) 12 (24%) 10 (20%) 26 (52%) 12 (24%) 12 (24%) 6 months 24 (48%) 15 (30%) 11 (22%) 19 (38%) 15 (30%) 16 (32%) 9 months 4 (8%) 11 (22%) 35 (70%) 2 (4% ) 11 (22%) 37 (74%) 12 months 4 (8%) 6 (12%) 40 (80%) - (0%) 4 (8%) 46 (92%)
Dacă analizăm dinamica valorilor absolute ale indicatorilor elasticităţii arteriale pe ambele categorii de artere (mari şi mici) de la iniţierea studiului constatăm o micşorare neînsemnată, comparabilă pe artere de calibru mare (C1), fig. 3 şi considerabilă pe artere rezistive (C2), fig. 4, tab. 3. If we analyze the dynamics of the absolute values of the arterial elasticity indicators on both categories of arteries (large and small) since the beginning of the study, we find an insignificant decrease, comparable to large-caliber arteries (C1), fig. 3 and considerable on resistive arteries (C2), fig. 4, tab. 3.
Pe parcursul aplicării formulelor terapeutice s-a urmărit o redresare comparabilă a valorilor indicilor elasticităţii arterelor de calibru mare (C1): la 3 luni 5,6% versus 5,7% (p>0,05), la 6 luni 7,4% versus 7,6% (p<0,05), la 9 luni 12% versus 12,5% (p<0,005) şi la finele supravegherii 14,9% versus 19% (p<0,005) în loturile I şi II respectiv, fig. 3. During the application of the therapeutic formulas, a comparable recovery of the values of the elasticity indices of large-caliber arteries (C1) was observed: at 3 months 5.6% versus 5.7% (p>0.05), at 6 months 7.4% versus 7.6% (p<0.05), at 9 months 12% versus 12.5% (p<0.005) and at the end of supervision 14.9% versus 19% (p<0.005) in groups I and II respectively, fig. 3.
Arterele de calibru mic (C2) au reacţionat mai convingător având o sensibilitate mai mare la remediile administrate. Deja peste 3 luni de medicaţie indicele elasticităţii arterelor de calibru mic a crescut cu 6,6% în lotul I versus 8,6% în lotul II (p<0,05). Totodată, 6 luni de administrare continuă a medicaţiei antihipertensive s-a soldat cu o creştere concludentă a elasticităţii în cazul administrării Ramiprilului 9% (p<0,05), pe când la utilizarea Eprosartanului acest indicator s-a ameliorat cu 15% (p<0,005), deci, practic dublu, comparativ cu IEC a AII. Această ameliorare progresivă a parametrilor indicilor de elasticitate a arterelor de calibru mic s-a confirmat şi mai mult la finele studiului: cu 80% în lotul tratat cu Ramipril şi cu 84,7% în lotul tratat cu Eprosartan (p<0,001), fig. 4. Small-caliber arteries (C2) reacted more convincingly, having a greater sensitivity to the administered remedies. Already after 3 months of medication, the elasticity index of small caliber arteries increased by 6.6% in group I versus 8.6% in group II (p<0.05). At the same time, 6 months of continuous administration of antihypertensive medication resulted in a conclusive increase in elasticity in the case of Ramipril administration 9% (p<0.05), while when using Eprosartan this indicator improved by 15% (p<0.005), so, practically double, compared to IEC of AII. This progressive improvement of the parameters of the elasticity indices of the small caliber arteries was further confirmed at the end of the study: by 80% in the group treated with Ramipril and by 84.7% in the group treated with Eprosartan (p<0.001), fig. 4.
În context, rezistenţa vasculară periferică a descrescut constant pe parcursul supravegherii, spre finele perioadei fiind constatată o reducere cu 37% în lotul I şi 39% în lotul II (p<0,001), fig. 5, tab. 3. In context, the peripheral vascular resistance decreased constantly during the surveillance, towards the end of the period, a reduction of 37% in group I and 39% in group II (p<0.001), fig. 5, tab. 3.
Tabelul 3 Table 3
Dinamica valorilor indicilor elasticităţii arterelor de calibru mare C1 şi mic C2 şi rezistenţa vasculară periferică pe fundalul medicaţiei, (M±m) The dynamics of the values of the elasticity indices of large C1 and small C2 arteries and peripheral vascular resistance against the background of medication, (M±m)
Varia-bila I lot (Ramipril) II lot (Eprosartan) C1 ml/mm Hg×10 C2 ml/mm Hg×100 RVP dină/s/cm-5 C1 ml/mm Hg×10 C2 ml/mm Hg×100 RVP dină/s/cm-5 Iniţial 10,7± 0,5 4,5± 0,3 2438±54 10,4± 0,4 4,6 ±0,3 2502±64 3 luni 11,3± 0,6* +5,6% 4,8± 0,4* +6,6% 1963± 50** -19,4% 11,0± 0,5* +5,7% 5,0± 0,3* +8,6% 1876±52,5** -25% 6 luni 11,5± 0,9* +7,4% 4,9± 0,3* +9% 1758±34,6** -28% 11,2± 0,6* +7,6% 5,3 ±0,3** +15% 1658±42,1** -33% 9 luni 12,0±0,4** +12% 7,0±0,2*** +55% 1635±32,5** -32% 11,7±0,3** +12,5% 7,1±0,2*** +54,3% 1643±23,4** -34,3% 12 luni 12,3±0,6** +14,9% 8,1±0,3*** +80% 1530±26,5*** -37% 12,4±0,7** +19% 8,5±0,2*** +84,7% 1509±22,9*** -39% Variable I batch (Ramipril) II batch (Eprosartan) C1 ml/mm Hg×10 C2 ml/mm Hg×100 RVP dyne/s/cm-5 C1 ml/mm Hg×10 C2 ml/mm Hg×100 RVP dyne/s/cm-5 Initial 10.7± 0.5 4.5± 0.3 2438±54 10.4± 0.4 4.6 ±0.3 2502±64 3 months 11.3± 0, 6* +5.6% 4.8± 0.4* +6.6% 1963± 50** -19.4% 11.0± 0.5* +5.7% 5.0± 0.3 * +8.6% 1876±52.5** -25% 6 months 11.5± 0.9* +7.4% 4.9± 0.3* +9% 1758±34.6** - 28% 11.2± 0.6* +7.6% 5.3 ±0.3** +15% 1658±42.1** -33% 9 months 12.0±0.4** +12 % 7.0±0.2*** +55% 1635±32.5** -32% 11.7±0.3** +12.5% 7.1±0.2*** +54 .3% 1643±23.4** -34.3% 12 months 12.3±0.6** +14.9% 8.1±0.3*** +80% 1530±26.5* ** -37% 12.4±0.7** +19% 8.5±0.2*** +84.7% 1509±22.9*** -39%
Legendă: * p< 0,05, ** p< 0,005, *** p< 0,001 comparativ cu iniţial. Legend: * p< 0.05, ** p< 0.005, *** p< 0.001 compared to baseline.
Aşadar, ameliorarea complianţei arterelor mari şi mici, tradusă prin normalizarea statistic semnificativă a indicilor elasticităţii acestora, este asociată cu reducerea valorilor tensiunii arteriale, ameliorarea profilului diurn în timpul de monitorizare automată ambulatorie a tensiunii arteriale (MAATA), a funcţiei renale şi diminuarea proteinuriei. Acest fenomen demonstrează cu certitudine rolul stiffness-ului arterial în geneza şi evoluţia hipertensiunii arteriale. Therefore, the improvement of the compliance of large and small arteries, translated by the statistically significant normalization of their elasticity indices, is associated with the reduction of blood pressure values, the improvement of the diurnal profile during automatic ambulatory blood pressure monitoring (MAATA), of renal function and the reduction of proteinuria. This phenomenon demonstrates with certainty the role of arterial stiffness in the genesis and evolution of arterial hypertension.
Normalizarea cifrelor tensiunii arteriale sistolice (TAS) poate fi patogenetic raportată la dinamica de creştere a indicelui elasticităţii arterelor de calibru mare, iar diminuarea valorilor tensiunii arteriale diastolice (TAD) ar fi preponderent dependentă de majorarea indicelui elasticităţii arterelor de rezistenţă. Poate fi remarcată şi corelarea cu dinamica rezistenţei vasculare periferice, valoarea căreia este în strictă concordanţă directă cu nivelul tonusului bazal al arterelor rezistive. The normalization of the systolic blood pressure (SBP) figures can be pathogenically related to the dynamics of the increase in the elasticity index of the large-caliber arteries, and the decrease in the diastolic blood pressure (DAD) values would be mainly dependent on the increase in the elasticity index of the resistance arteries. The correlation with the dynamics of peripheral vascular resistance can also be noted, the value of which is in strict direct agreement with the basal tone level of the resistive arteries.
1. Morgan T., Lauri J., Bertram D., et al. Effect of different antihypertensive drug classes on central aortic pressure. Am. J. Hypertens, 2004, №17, p. 118-123 1. Morgan T., Lauri J., Bertram D., et al. Effect of different antihypertensive drug classes on central aortic pressure. I have. J. Hypertens, 2004, №17, p. 118-123
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