Cennet GÜLTEKİN, Murat Çetin RAĞBETLİ, Ender ERDOĞAN, Nureddin CENGİZ

Simvastatin ve Amlodipin'in Hematolojik Parametreler ve Aorta Üzerine Etkilerinin Araştırılması

Bu çalışmada, modern toplumlarda sık olarak karşılaşılan hastalıklardan olan hiperlipidemi ve hipertansiyon durumlarında tercih edilen Simvastatinin ve Amlodipinin hematolojik parametreler ve Aort üzerine etkileri araştırıldı. Ratlara altı ay süreyle bu ilaçların verilmesiyle ortaya çıkan toksik etkiler hematolojik açıdan ve primer hedef organ olan aortanın histopatolojik analizleri ile belirlenmeye çalışıldı. Toplam 48 hayvan her gruptan 12 hayvan olacak şekilde dört deneme grubuna ayrılarak altı ay süreyle beslendi. Gruplar; Kontrol. Simvastatin lOmg/kg . Amlodipin 10 mg/kg . Simvastatin+Amlodipin Simvastatin 10 mg/kg + Amlodipin 10 mg/kg olarak belirlendi. Kontrol grubuna sadece yem ve su. diğer gruplara yem ve suya ilave olarak belirtilen dozlarda ilaçlar oral yolla verildi. Denemenin başında, üçüncü ayda ve deneme sonunda altıncı ayda her gruptan kan örnekleri alınarak hematolojik analizler RBC Alyuvar . WBC akyuvar . Hb Hemoglobin . Ht hematokrit , MCHC Ortalama eritrosit hemoglobin konsantrasyonu . Tromb. Trombosit . MCV Ortalama eritrosit hacmi . MCH Ortalama hemoglobin konsantrasyonu ve LY lenfosit gerçekleştirildi. Deneme sonunda her gruptan 8 hayvana otopsi uygulanarak aort makroskobik ve histopatolojik olarak incelendi. Hematolojik analizlerde üçüncü ve altıncı ayda yapılan ölçümler arasında paralel değerler elde edildi. Kontrolle karşılaşıldığında ilaç uygulanan tüm gruplarda Simvastatin. Amlodipin, Simvastatin + Amlodipin RBC. WBC. Hb. Ht. MCHC. Tromb. düzeylerinde artış görülürken. MCV. MCH ve LY düzeylerinde ise anlamlı düşüş gözlendi. Aorta örneklerinin makroskobik ve mikroskobik incelenmesi sonucunda ilaç uygulanan tüm gruplarla kontrol grubu arasında her hangi bir farklılık bulunmadı. Sonuç olarak, simvastatin ve amlodipinin yalnız ve kombine olarak ratlara altı ay süreyle verilmesi anlamlı hematolojik değişiklikler yapabilmesi ve bu ilaçların uzun süreli kullanım gerektirmeleri nedeniyle, klinik çalışmalarla da desteklenmesi gerekmektedir

Anahtar Kelimeler:

Simvastatin, Amlodipin. Hematolojik. Rat. Yan etki

Investigation of Effects on the Henıatological Parameters and Aorta of Simvastatin and Amlodipin

In this study hematological effects of Simvastatin and Amlodipin commonly used in developed societies were investigated. Side effects were determined hematological. macroscopic and histopathological analyses by giving these drugs to rats for six months single and in combination. A total of 48 rats were divided into 4 teratment groups each containing 12 and fed for six months. Groups are Control, Simvastatin 10 mg/kg, Amlodipin 10 mg/kg and Simvastatin 10 mg/kg+Amlodipin 10 mg/kg. Control group was fed only feed and water. Other groups were treated with drugs by orally with doses above and fed with basal diet and water. Blood samples total blood celi were taken from animals on third and sixth months of the treatment and blood hematological analyses were performed. Paraleli results were obtained in hematological analyses Hb Hemoglobin . Ht Hematocrit . MCHC Mean corpuscular hemoglobin consantration , RBC Red blood celi , WBC White blood celi . MCV Mean corpuscular volüme . MCH Mean corpuscular hemoglobin . Thromb Trombocyt and LY Lymphocvt between 3rd and 6,h months of the experiment compared to control. Hb. Ht. and MCHC values were observed higher than control. while RBC, WBC. MCV. MCH. Thromb and LY values were decreased in drugs treated groups Simvastatin. Amlodipin. Simvastatin plus Amlodipin . As a result. the uses of simvastatin and amlodipin single and in combination caused signifıcant hematological changes and degeneration in hemapoetik organs in rats given drugs for six months. At the end of the treatment eight animals were killed for makroskobik and histopathological analyses and aorta samples were analysed microscobically. However, especially. simvastatin can cause antiinflamatuar effects and prevent intimal thickening in aorta samples. but in our study there is no microscobic and histopathologic fındings. As a result. the uses of simvastatin and amlodipin single and in combination caused signifıcant hematological changes in rats given drugs for six months and hematological analyses should be repeated at spesific intervals.

Keywords:

Simvastatin. Amlodipin. Rat. Hematologic, Side effect.,

PDF

___

1. Ziversmit DB (1979) Atherogenesis: a postprandalphenemon,Cic\A
2. Marz W. Wollschlager II. Klein G, Nei BA and Wehling M (1999) Koroner kalp hastalığı bulunan bir hastapopulasyonıında siınvastatin ile karşılaştırmalı olarak atorvastatin ile sağlanan düşük dansiteli lipoprotein kolesterol düşürücü tedavinin güvenirliği (TARGET TANGİBLE Çalışması). The American Journal of Cardiology. 1999. Julv 1.84.1 -8
3. Isusi E. Aspichueta P. Liza M. Hernandez LM. Diaz C. Hernandez G and et ali (2000) Short and long ter m effects ofatorvastatin. lovaslatin and simvastatin on the cellular melabolisnı of cholesteryl eslers and VLDL secretion in hepotocytes, Atherosclerosis, 2000. 153. 283- 294.
4. Karaca I. Akbulut M, İlkay E. Üstündağ B, Özbay Y ve Arslan N (1999) Hiperlipidemik hastalarda simvastatinin etkinliği ve güvenirliği. T Klin Kardiyoloji 1999. 12. 100- 103.
5. Kayaalp O (2000a) Antihipertansif İlaçlar In “Rasyonel Tedavi Yönünden Tıbbi Farmakoloji ” Ed. by Hacettepe TAŞ Kitapçılık Ltd Şti, 1. cilt. 8. baskı 423-471
6. Çalışkan S, Çalışkan M. Kuralay F and Onvural B (2000) Effects of simvastatin therapy on blood and tissııe ATP /eveIs and erythrocyte membrane lipid composition. Res Exp Med(Berl), 2000. Feb, 199 (4), 189-194.
7. Sharifı AM and Schiffrin EL (1998) Apoptosis in vaskulatııre of spontaneoıısly hypertansive rats effect of an angiotensin converting emzyme inhihitor and a calcium channel antagorıist, American Journal of Hypertansion. 11. 1108- 1116.
8. Sparrow CP. Burton CA. Flernandez M. Mundt S, Hassing H, Patel S and et ali (2001) Simvastatin has anti-inflamatory and antiatherosclerotic activities independent of plasma cholesterol lowering. Arterioscler Thromb Vasc Biol. 21, 115- 121.
9. Mital S, Magneson A, Lake KE, Liao J. Forfıa PR and Ilintze TH (2000) Simvastatin actssynergistically with ACE inhibitors or amlodipine to decrease oxvgen consumption in rat hearts. J Cardiovasc Phannacol. 2000. Aug. 36 (2). 248-254.
10. Suzuki M. Yamanaka K. Nabata H and Tachibana M (1993) Long terin effects of aınlodipine on organ damage. stroke and life span in stroke prone spontaneously hypertensive rat s. Eur J Phannacol. Aprl. 228 (5-6). 269-274.
1!. Khemissa-Akouz F, Ouguergouz F. Şulem P. Tkoub el M and Vaucher E (2002) Amlodipine induced acııte hepatitis. Gastroenterol Clin Biol. Jun-Jul. 26 (6-7). 637-638.
12. KanathurN. Mathai MG. Bvrd RPJr. Fields CL and Roy TM (.2001) Simvastatin-diltiazem drııg interaction safely resulting in rhabdomyolysis and hepatitis. Tenn Med. 2001. Sep. 94 (9). 339-341.
13. Mehregan DR. Mehregan DA and Pakideh S (1998) Chelitis dne to treatment with simvastatin, Cutis. 1998. Oct. 62 (4). 197-198.
14. Lantuejoul S. Brambilla E. Brambilla C and Devovassoux G (2002) Statin-induced fibrotic nonspesific interstitial pnemonia, Eur Respır J. 2002. Mar. 19 (3). 577-580.
15. Koşay S. Oktay Ş (1992) Antihipertansifİlaçlar İn "Farmakoloji İlaç Uygulamalarında Temel Kavramlar” Ed by İsmet Dökmeci. Nobel Tıp Kitabevleri. 233- 241. Çapa, İstanbul.
16. Kayaaip O (2000b) Hipolipidemik ilaçlar In "Rasyonel Tedavi Yönünden Tıbbi Farmakoloji" Ed. by Hacettepe TAŞ Kitapçılık Ltd Şti. 1. cilt. 8. baskı. 567-587. Ankara.
17-Malaterre HR. Kallee K and Daver LMH (1999) Hvponatremia and amlodipine therapy, Cardiovascular Drugs and Therapy. 1999. 13. 171-172.
18. Kusus M. Stopleton DD. Lertora JJ. Simon EE and Dreischbach AW (2000) Rhabdomyolysis and acııte renal failure in a cardiac transplant recipient dne to mııltiple drııg interactions. Am J Med Sci. 2000. Dec. 320 (6). 394-397.
19. Mitani H. Bandah T. îshikawa J, Kimura M. Tatsuka T and Hayashi S (1996) İnhibitory effects of fluvastatin.a new HMG-CoA reduktase inhibitor, on the increase in vascıılar ACE activity in cholesterol-fed rabbits, Br J Phannacol. 1996.Nov. 119(6). 1269-1275.
20. Esper RJ. Machado R. Vilarino J, Cocharron JL, İngino CA. Guiııazu G and el ali (2000) Endothelium-dependent responses in patients yvith hypercholestrolemic coronary artery disease ıınder the effects of simvastatin and enalapril. either separatelv or combined. Am Heart J. 2000. Oct. 140 (4)’. 684-689.
21. Teo KK. Burton JR. Buller CE. Plante S. Catellier D. Tymchak W and et ali (2000) Longterm effects of cholesterol lowering and angiotensin-converting enzyme inhibilion on c o r on ary a thero sc l ero s i s i: The simvastatin enalapril coronary atherosclerosis trial(SCAT). Circulalion. Oct. 10. 102 (15). 1748-1754.
22. Azie NE. Broter DC. Becker PA. Jones DR and Hail SD (1998 ) 77te interaction of diltiazem xvith lovastatin and provastatin, Clin Phannacol Ther. 1998. Oct. 64(4). 369- 377.
23. Marumo H. Satah K. Yamamoto A. Kaneto S and Ichihara K (2001) Simvastatin and atorvastatin enlıance hypotensive effect of diltiazem in rats. Yakugaku Zasshi. 2001. Oct. 121(10). 761-764.
24. Marino MR. Vachharojani NN and Hadjilambris OW (2000) Irbesartan does not affect the pharmacokinetics of simvastatin in healthv subjects, J Clin Pharmacol. 2000. Aug. 40 (8). 875-879.
25. Meyer BH. Scholtz HE. Muller FO. Luus HG. Rey N, Seibert-Grafe M and et ali (1994) Lack of interaction betsveen ramipril and simvastatin, Eur J Clin Pharmacol. 1994. 47 (4). 373-375.
26. Marche P. Herembert T and Zhu DL (1997) Pharmocologic treatment of aterosklerozis: beyond lipid lowering therapy, Int. J. Cardiol, 1997, Dec 31.62(2). 17-22.
27. Palinski W (2001) Nexv evidence for benefıcial effects of statins unrelated to lipid lowering, ArteriosclerThrombVasc Biol. 2001.21.3-5.
28. Canadian Council on Animal Çare. Gıtide to the çare and tise of experimental animals, volume 1.86
29. NishimuraT. Faul JL, Berry GJ. Vazsar LT, Qiu D, Pearl RG and et ali (2002) Simvastatin attermates smooth muscle neointimal proliferation on pulmoner hypertension in rat s, American Journal of Respiratory and Critical Çare Medicine, 2002,166,1403-1408.
30. Fetkovska N. Ulicna L and Jakubouska Z (1993) İnhibition of trombocyte activity in atherogenesis and thrombogenesis using isrodipine and ot her calcium antagonists,Vnitr Lek. 1993. Apr, 39 (4). 326-333.
31. Nebe B. Halehausen C. Rychly J and Urbozsek W (2002) İmpaired mechanisms of leukocyte adhesion in vitro by the calciımı channel antagonist mibefradil. Cardiovaskuler Drugs and Therapy. 2002.16.183-193.
32. Pruefer D. Scalia R and Lefer AM (1999) Simvastatin inhibits leukocyte-endothelial celi interactions and protects against inflamatory processes in normocholesterolemic rats, Arterioscler Thromb Vasc Biol. Dec. 19 (12), 2894- 2900.
33. Kürşat T Veteriner Klinik Laboratuvar Teşhis, Eritrosit bozuklukları ve testleri. 18
34. Chen Z. Fukutomi T. Zago AC. Ehlers R. Detmers PA. Wright SD and et ali (2002) Simvastatin reduced neointimal thickening in low density lipoprotein receptor deficient mice after experimental angioplasty without changing plasma lipids. Circulation. 2002, Jul2,106(1). 20- 23.