{"id":13119,"date":"2009-01-04T20:00:00","date_gmt":"2009-01-04T20:00:00","guid":{"rendered":""},"modified":"2009-01-04T20:00:00","modified_gmt":"2009-01-04T20:00:00","slug":"zofenoprilis-uztikrina-sirdies-apsauga","status":"publish","type":"post","link":"https:\/\/www.pasveik.lt\/lt\/naujausi-medicinos-straipsniai\/zofenoprilis-uztikrina-sirdies-apsauga\/13119\/","title":{"rendered":"Zofenoprilis u\u017etikrina \u0161irdies apsaug\u0105"},"content":{"rendered":"

\u012eVADAS<\/font><\/strong><\/span><\/p>\n

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Renino ir angiotenzino sistema (RAS) yra centrinis \u0161irdies ir kraujagysli\u0173 bei inkst\u0173 funkcijos reguliatorius, kuris turi did\u017eiausi\u0105 reik\u0161m\u0119 \u012fvairi\u0173 \u0161irdies ir kraujagysli\u0173 lig\u0173 patogenezei. RAS sudaro keletas fermentini\u0173 reakcij\u0173, vykstan\u010di\u0173 plazmoje ir audiniuose (\u012fskaitant kraujagysles, \u0161ird\u012f ir inkstus), kuri\u0173 metu susidaro angiotenzinas\u00a0II. Pagrindiniai angiotenzino II patofiziologiniai poveikiai nurodyti 1 paveiksle<\/i>. Ry\u0161ys tarp renino ir angiotenzino sistemos (RAS) bei arterin\u0117s hipertenzijos komplikacij\u0173 patvirtintas klinikiniais tyrimais. Nustatyta, kad hipertenzija sergan\u010di\u0173 pacient\u0173, kuri\u0173 kraujyje yra padid\u0117jusi renino koncentracija, prognoz\u0117 daug blogesn\u0117 (i\u0161sivyst\u0117 \u017eymiai daugiau \u0161irdies ir kraujagysli\u0173 komplikacij\u0173), palyginti su pana\u0161aus laipsnio hipertenzija sergan\u010diais, bet normali\u0105 renino koncentracij\u0105 turin\u010diais asmenimis. Taigi RAS blokavimo nauda gydant arterin\u0119 hipertenzij\u0105 yra neabejotina. \u0160iuo metu skiriama plazmos ir audini\u0173 RAS, pastaroji lemia apie 90 proc. viso angiotenzin\u0105 konvertuojan\u010dio fermento (AKF) aktyvumo. Audini\u0173 RAS veikia parakrininiu\u00a0\/\u00a0autokrininiu b\u016bdu, o audini\u0173 AKF funkcijos slopinimas ne tik lemia veiksming\u0105 arterinio kraujosp\u016bd\u017eio suma\u017einim\u0105, bet ir pagerina endotelio funkcij\u0105, slopina kraujagysli\u0173 lygi\u0173j\u0173 raumen\u0173 l\u0105steli\u0173 proliferacij\u0105 ir migracij\u0105, ma\u017eina trombocit\u0173 agregacij\u0105, miokardo hipertrofij\u0105.<\/span> <\/span>\u00a0<\/span>Vienas i\u0161 AKF inhibitori\u0173 grup\u0117s atstov\u0173 yra lipofilin\u0117mis savyb\u0117mis pasi\u017eymintis sulfhidrilinis vaistas zofenoprilis, turintis i\u0161skirtini\u0173 savybi\u0173, pasi\u017eymintis \u0161ird\u012f apsaugan\u010diu poveikiu.<\/p>\n

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1 pav. Patofiziologinis angiotenzino\u00a0II poveikis<\/a><\/span><\/i>[H1]<\/font><\/a>\u00a0<\/span><\/span><\/span><\/p>\n

\"Zofenoprilis<\/span><\/span><\/span><\/p>\n

<\/stroke><\/f><\/f><\/f><\/f><\/f><\/f><\/f><\/f><\/f><\/f><\/f><\/f><\/formulas><\/path><\/lock><\/shapetype><\/imagedata><\/wrap><\/shape><\/p>\n

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Vasoconstriction \u2013 Vazokonstrikcija<\/p>\n

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SNS Activation \u2013 SNS aktyvinimas<\/p>\n

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\u2191 Aldosterone -\u2191 aldosterono<\/p>\n

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\u2191 Vasopressin – \u2191 vazopresino<\/p>\n

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\u2191 Extracellular matrix -\u2191 ekstraceliulin\u0117s med\u017eiagos<\/p>\n

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\u2191 Contractility – \u2191 kontraktili\u0161kumas<\/p>\n

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\u2191 PAI-1 \u2013 \u2191 PAI-1<\/p>\n

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Platelet Aggregation \u2013 Trombocit\u0173 agregacija<\/p>\n

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Oxidative Stress \u2013 Oksidacinis stresas<\/p>\n

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\u2191 Endothelin – \u2191 endotelino<\/p>\n

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Vascular smooth muscle growth \u2013 Kraujagysli\u0173 lygi\u0173j\u0173 raumen\u0173 augimas<\/p>\n

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Angiotensin II \u2013 Angiotenzinas II<\/p>\n

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Thrombosys \u2013 Tromboz\u0117<\/a><\/p>\n

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I\u0160SKIRTIN\u0116S ZOFENOPRILIO SAVYB\u0116S<\/strong><\/p>\n

Visi AKF inhibitoriai blokuoja AKF ir taip ma\u017eina RAS aktyvum\u0105, ta\u010diau priklausomai nuo chemin\u0117s formul\u0117s ir fizikini\u0173 bei chemini\u0173 savybi\u0173 skiriasi j\u0173 veikimas<\/span>. Kaip min\u0117ta, 90\u00a0proc. AKF yra audiniuose (\u0161irdyje, inkstuose, kraujagysl\u0117se), tik 10\u00a0proc. \u2013 kraujo plazmoje, tod\u0117l labai svarbu, kad AKF inhibitorius gerai patekt\u0173 \u012f audinius. Pastaruoju metu pabr\u0117\u017eiama, kad AKF inhibitorius tur\u0117t\u0173: 1) b\u016bti lipofili\u0161kas; 2) tur\u0117ti didel\u012f afinitet\u0105 audini\u0173 AKF; 3) ilgai veikti. Taigi lipofili\u0161kumas yra labai svarbi AKF inhibitori\u0173 savyb\u0117, nes padidina vaisto galimyb\u0119 patekti \u012f audinius ir slopinti AKF. Lipofili\u0161kum\u0105 nusako oktanolio-vandens pasiskirstymo koeficientas. Pavyzd\u017eiui, ramiprilato jis yra 4\u201310 kart\u0173 didesnis nei kaptoprilio ir lizinoprilio, o zofenoprilato \u2013 net 20 kart\u0173 didesnis u\u017e ramiprilato. Taigi zofenoprilatui b\u016bdingas didesnis lipofili\u0161kumas nei kitiems AKF inhibitoriams. Tiriant hipertenzija sergan\u010dius gyv\u016bnus nustatyta, kad zofenoprilis veiksmingiau ir ilgiau blokuoja AKF \u0161irdyje, palyginti su kitais AKF inhibitoriais (2).<\/p>\n

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Pagal AKF inhibitoriaus prisijungim\u0105 <\/a>prie AKF cinko jono<\/span><\/a>, skiriami trys \u0161ios grup\u0117s vaist\u0173 cheminiai pogrupiai. Sulfhidriline grupe prie AKF cinko jono prisijungia zofenoprilis ir kaptoprilis, karboksiline grupe \u2013 enalaprilis, benazeprilis ir dauguma kit\u0173, fosforiline grupe \u2013 fosinoprilis. Nustatyta, kad AKF inhibitoriai su sulfhidriline grupe, pvz., zofenoprilis, gerina kraujagysli\u0173 funkcij\u0105 ir ma\u017eina \u0161irdies nepakankamum\u0105 labiau nei nesulfhidriliniai AKF inhibitoriai. Eksperimentiniais tyrimais in vivo<\/i> ir in vitro <\/i>nustatyta, kad zofenoprilis ne tik veiksmingai ma\u017eina kraujosp\u016bd\u012f, bet ir pasi\u017eymi antioksidacin\u0117mis, \u0161ird\u012f apsaugan\u010diomis bei endotelio funkcij\u0105 gerinan\u010diomis\u00a0 <\/span>savyb\u0117mis (2 pav.)<\/i>. \u0160ios i\u0161skirtin\u0117s zofenoprilio savyb\u0117s gali suma\u017einti sergamum\u0105 ir mir\u0161tamum\u0105 nuo \u0161irdies ir kraujagysli\u0173 lig\u0173.<\/p>\n

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2 pav. Zofenoprilio \u0161ird\u012f po persirgto \u016bminio miokardo infarkto apsaugan\u010dio poveikio mechanizmas<\/span><\/span><\/i><\/p>\n

\"Zofenoprilis<\/span><\/span><\/i><\/p>\n

LR \u2013 laisvieji radikalai \u00a0<\/span>\u00a0<\/span>NO \u2013 azoto oksidas\u00a0\u00a0 <\/span>SH \u2013 sulfhidrilin\u0117 grup\u0117<\/p>\n

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Pagal Buikema H, Expert Rev Cardiovasc Ther. 2006;4(5):631-647.<\/p>\n

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TYRIMAS SMILE<\/i><\/span><\/b><\/p>\n

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Zofenoprilio \u0161ird\u012f apsaugantis poveikis \u012frodytas tyrimu SMILE (1). \u0160iame atsitiktini\u0173 im\u010di\u0173, dvigubai slaptame, placebo kontroliuojamame tyrime dalyvavo 1556 pacientai, sergantys priekiniu miokardo infarktu be ST segmento pakilimo. Papildomai prie standartinio gydymo vaistais pagal atsitiktini\u0173 im\u010di\u0173 princip\u0105 skirtas AKF inhibitorius zofenoprilis ar placebas. Pradin\u0117 zofenoprilio doz\u0117 buvo 7,5 mg 2 k.\/d., ji laipsni\u0161kai didinta iki 30 mg 2 k.\/d. (3). Pirmin\u0117 tyrimo SMILE i\u0161eitis buvo mir\u0161tamumas ar sunkus l\u0117tinis \u0161irdies nepakankamumas (L\u0160N). \u0160is rodiklis vertintas pacient\u0173 hospitalizavimo metu (7\u201315 dien\u0173), po 4 savai\u010di\u0173 ir gydymo pabaigoje (po 6 savai\u010di\u0173).<\/p>\n

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Per 6 gydymo savaites pirmin\u0117s i\u0161eities da\u017enis placebo grup\u0117je buvo 10,3\u00a0proc., o zofenoprilio grup\u0117je \u2013 3,6\u00a0proc. Did\u017ei\u0173j\u0173 \u0161irdies ir kraujagysli\u0173 sistemos nepalanki\u0173 \u012fvyki\u0173 santykin\u0117s rizikos suma\u017e\u0117jimas, skiriant zofenoprilio, siek\u0117 65\u00a0proc. (SR 0,35, 95\u00a0proc. PI 20\u201380\u00a0proc.; 2p=0,003). Kumuliacinis sud\u0117tinio rodiklio \u2013 mir\u0161tamumo ir sunkaus L\u0160N \u2013 da\u017enis per 6 gydymo savaites buvo reik\u0161mingai (p=0,017) didesnis placebo grup\u0117je, palyginti su zofenoprilio grupe.<\/p>\n

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Sunkaus L\u0160N da\u017enis po 6 gydymo savai\u010di\u0173 taip pat buvo reik\u0161mingai ma\u017eesnis (2p=0,006) zofenoprilio grup\u0117je (0,4\u00a0proc.), palyginti su placebo grupe (4,0\u00a0proc.) \u2013santykin\u0117s rizikos suma\u017e\u0117jimas 84\u00a0proc.<\/p>\n

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\u012evairiais tyrimais \u012frodyta, kad AKF inhibitoriai ma\u017eina \u0161irdies ir kraujagysli\u0173 ligomis sergan\u010di\u0173 pacient\u0173 mir\u0161tamum\u0105 (3 pav.)<\/i>. Tai pasakytina ir apie zofenopril\u012f: pacientai, kuriems 6 savaites skirtas gydymas \u0161iuo vaistu, i\u0161gyvendavo da\u017eniau, palyginti su gydytais placebu. Per 1 steb\u0117jimo metus placebo grup\u0117je mir\u0117 15,8\u00a0proc. pacient\u0173, o zofenoprilio grup\u0117je \u2013 tik 7,9\u00a0proc., t.\u00a0y. zofenoprilis statisti\u0161kai reik\u0161mingai (2p=0,036) 43\u00a0proc. suma\u017eino mir\u0161tamum\u0105.<\/p>\n

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Lengvo ir vidutinio sunkumo \u0161irdies nepakankamumo, kartotino miokardo infarkto,kr\u016btin\u0117s anginos da\u017enis po 6 savai\u010di\u0173 buvo pana\u0161us abiejose gydymo grup\u0117se. Nekardialinio mirtingumo da\u017enis buvo ma\u017eas tiek randomizuoto gydymo, tiek 1 met\u0173 sekimo laikotarpiu. Kaip ir tik\u0117tasi, kardialinio mirtingumo da\u017enis buvo didesnis nei nekardialinio ir didesnis placebo nei zofenoprilio grup\u0117je (P = 0,025 kardialiniam mirtingumui po 1 met\u0173). <\/p>\n

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3 pav. Miokardo infarktu sergan\u010di\u0173 pacient\u0173 mir\u0161tamum\u0105 ma\u017einantis AKF inhibitori\u0173 poveikis<\/span><\/i><\/p>\n

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\"Zofenoprilis<\/p>\n

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Trial \u2013 Tyrimas<\/p>\n

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Total No in Study \u2013 Pacient\u0173 skai\u010dius tyrime<\/p>\n

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OR \u2013 Santykin\u0117 rizika (SR)<\/p>\n

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OR and\u00a0 <\/span>95 proc. CI \u2013 SR ir 95 proc. PI<\/p>\n

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All trials \u2013 Visi tyrimai<\/p>\n

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Risk reduction 6,7 proc., p<0,006 \u2013 Rizikos suma\u017e\u0117jimas 6,7 proc., p<0,006<\/p>\n

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4,9 fewer deaths\/ 1000patients treated \u2013 4,9 ma\u017eiau mir\u010di\u0173 1000 gydyt\u0173 pacient\u0173<\/p>\n

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Skai\u010diuose vietoj ta\u0161k\u0173 kableliai<\/p>\n

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APIBENDRINIMAS<\/strong><\/p>\n

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Zofenoprilis yra lipofilinis, ilgai veikiantis AKF inhibitorius, turintis sulfhidrilin\u0119 grup\u0119. Pastaruoju metu vis didesnis d\u0117mesys kreipiamas ne tik \u012f vaisto kraujosp\u016bd\u012f ma\u017einant\u012f poveik\u012f, bet ir \u012f kitus naudingus veikimo mechanizmus. Klinikiniais tyrimais in vivo<\/i> ir in vitro<\/i> \u012frodyta, kad d\u0117l SH grup\u0117s zofenoprilis veikia kaip antioksidantas \u0161irdies audiniuose ir endotelyje. Endotelio l\u0105stel\u0117se jis skatina azoto oksido gamyb\u0105, slopina adhezijos molekuli\u0173 gamyb\u0105, gerina endotelio funkcij\u0105 ir stabdo ateroskleroz\u0117s progresavim\u0105. Skiriant \u0161io vaisto, dar labiau suma\u017einama ligoni\u0173 \u0161irdies ir kraujagysli\u0173 lig\u0173 rizika. <\/p>\n

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Tyrimu SMILE \u012frodyta, kad zofenoprilis ma\u017eina mir\u0161tamum\u0105 ir sunkaus l\u0117tinio \u0161irdies nepakankamumo da\u017en\u012f pacientams, sergantiems priekiniu miokardo infarktu, kai ST segmentas nepakil\u0119s (4). Sergamumo ir mir\u0161tamumo suma\u017e\u0117jimas, skiriant gydym\u0105 zofenopriliu, beveik nepriklaus\u0117 nuo sistolinio kraujo spaudimo suma\u017e\u0117jimo. Tai rodo, kad vaistas gerina pacient\u0173 prognoz\u0119 nepriklausomai nuo jo hemodinaminio poveikio. Zofenoprilis pasi\u017eymi \u0161ird\u012f apsaugan\u010diu poveikiu, nes saugo nuo infarkto zonos did\u0117jimo ir kairiojo skilvelio remodeliacijos po miokardo infarkto (5, 6). Jis taip pat slopina \u017ealing\u0105 neurohumoralin\u0119 aktyvavim\u0105 (7, 8), kuri b\u016bdingas pacientams, sergantiems \u016bminiu miokardo infarktu, ir kuris skatina vainikini\u0173 arterij\u0173 vazokonstrikcij\u0105, endotelio disfunkcij\u0105 ir miokardo i\u0161emij\u0105 (9). Visos \u0161ios zofenoprilio savyb\u0117s padeda dar labiau suma\u017einti pacient\u0173 sergamum\u0105 \u0161irdies ir kraujagysli\u0173 ligomis bei mir\u0161tamum\u0105 nuo j\u0173.<\/p>\n

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Pareng\u0117 gyd. E. RINK\u016aNIEN\u0116<\/p>\n

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Gauta: 2008-12-05<\/p>\n

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Pateikta spaudai: 2008-12-23<\/p>\n

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LITERAT\u016aRA<\/span><\/strong><\/p>\n

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  1. Claudio Borghi, Stefano Bacchelli, Daniela Degli Esposti, Ettore Ambrosioni. Effects of Early Angiotensin-Converting Enzyme Inhibition in Patients With Non-ST-Elevation Acute Anterior Myocardial Infarction. <\/span>Am Heart J. \u00a02006;152(3):470-477.\n<\/p>\n

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  2. Cushman DW, Wang FL, Fung WC, Harvey CM, DeForrest JM. Differentiation of ACE inhibitors by their selective inhibition of ACE in physiologically important target organs. Am. J. Hypertens. 2(4), 294-306 (1989).<\/span>\n<\/p>\n

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  3. Ambrosioni E, Borghi C, Magnani B. The effect of the angiotensin-converting-enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction. The Survival of Myocardial Infarction Long-Term Evaluation (SMILE) Study Investigators. N Engl J Med. 1995;332:80\u201385.\n<\/p>\n

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  4. Dekker JM, Schouten EG, Klootwijk P, et al.. ST segment and T wave characteristics as indicators of coronary heart disease risk: the Zutphen Study. J Am Coll Cardiol. 1995;25:1321\u20131326.\n<\/p>\n

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  5. Sargent CA, Sleph PG, Dzwonczyk S, et al.. Cardioprotection in ischemic rat hearts with the SH-containing angiotensin-converting enzyme inhibitor zofenopril: possible involvement of the ATP-sensitive potassium channel. J Pharmacol Exp Ther. 1993;265:609\u2013618.\n<\/p>\n

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  6. Frascarelli S, Ghelardoni S, Ronca-Testoni S, et al.. Cardioprotective effect of zofenopril in perfused rat heart subjected to ischemia and reperfusion. J Cardiovasc Pharmacol. 2004;43:294\u2013299.\n<\/p>\n

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  7. Walsh JT, Batin PD, Hawkins M, et al.. Ventricular dilatation in the absence of ACE inhibitors: influence of haemodynamic and neurohormonal variables following myocardial infarction. Heart. 1999;81:33\u201339.\n<\/p>\n

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  8. Omland T, Aarsland T, Aakvaag A, et al.. The effect of early converting enzyme inhibition on neurohumoral activation in acute myocardial infarction. Int J Cardiol. 1993;42:37\u201345.\n<\/p>\n

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  9. Borghi C, Bacchelli S, Degli Esposti D, et al.. A review of the angiotensin-converting enzyme inhibitor, zofenopril, in the treatment of cardiovascular diseases. Expert Opin Pharmacother. 2004;5:1965\u20131977.\n<\/p>\n

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    \u00a0<\/font><\/span><\/span><\/span><\/p>\n<\/div>\n<\/div>\n<\/div>\n

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    \u012eVADAS \u00a0 Renino ir angiotenzino sistema (RAS) yra centrinis \u0161irdies ir kraujagysli\u0173 bei inkst\u0173 funkcijos reguliatorius, kuris turi did\u017eiausi\u0105 reik\u0161m\u0119 \u012fvairi\u0173 \u0161irdies ir kraujagysli\u0173 lig\u0173 patogenezei. RAS sudaro keletas fermentini\u0173 reakcij\u0173, vykstan\u010di\u0173 plazmoje ir audiniuose (\u012fskaitant kraujagysles, \u0161ird\u012f ir inkstus), kuri\u0173 metu susidaro angiotenzinas\u00a0II. Pagrindiniai angiotenzino II patofiziologiniai poveikiai nurodyti 1 paveiksle. Ry\u0161ys tarp renino…<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[],"tags":[772,431,7,869,751,705,852,1140],"site":[],"post_item_type":[27345],"class_list":["post-13119","post","type-post","status-publish","format-standard","hentry","tag-grupeje-proc","tag-hipertenzija","tag-inhibitoriai","tag-inhibitorius","tag-placebo","tag-vitro","tag-vivo","tag-zofenoprilis"],"acf":{"post_sites":false},"aioseo_notices":[],"_links":{"self":[{"href":"https:\/\/www.pasveik.lt\/lt\/wp-json\/wp\/v2\/posts\/13119","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.pasveik.lt\/lt\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.pasveik.lt\/lt\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.pasveik.lt\/lt\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.pasveik.lt\/lt\/wp-json\/wp\/v2\/comments?post=13119"}],"version-history":[{"count":0,"href":"https:\/\/www.pasveik.lt\/lt\/wp-json\/wp\/v2\/posts\/13119\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.pasveik.lt\/lt\/wp-json\/wp\/v2\/media?parent=13119"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.pasveik.lt\/lt\/wp-json\/wp\/v2\/categories?post=13119"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.pasveik.lt\/lt\/wp-json\/wp\/v2\/tags?post=13119"},{"taxonomy":"site","embeddable":true,"href":"https:\/\/www.pasveik.lt\/lt\/wp-json\/wp\/v2\/site?post=13119"},{"taxonomy":"post_item_type","embeddable":true,"href":"https:\/\/www.pasveik.lt\/lt\/wp-json\/wp\/v2\/post_item_type?post=13119"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}