Хронические цереброваскулярные заболевания (ХЦВЗ) – гетерогенная по механизмам возникновения группа синдромов, обусловленных стойким дефицитом кровоснабжения мозгового вещества, последствиями перенесенных острых нарушений мозгового кровообращения и их комбинацией. Формирование ХЦВЗ обусловлено вовлечением в патологический процесс сосудов, в первую очередь малого калибра, в значительной степени – нарушениями микроциркуляции и системной гемодинамики. Ключевыми принципами лечения пациентов с ХЦВЗ являются устранение факторов сердечно-сосудистого риска, при наличии соответствующих показаний – назначение антитромбоцитарных и антигипертензивных препаратов, статинов, контроль гликемии. Существенное направление при лечения таких пациентов – применение препаратов, обладающих способностью повышать мозговой кровоток. Важным эффектом их применения является не сама по себе вазодилатация, а повышение чувствительности сосудистой стенки к естественным регуляторам просвета сосуда. В связи с этим представляется вполне уместным использование термина «вазоактивные препараты». Одним из представителей таких лекарственных средств является Вазонит® (пентоксифиллин) – производное метилксантина. Рассмотрены данные о клинических эффектах препарата, вероятные механизмы его действия, возможность применения у пациентов с ХЦВЗ.
Chronic cerebrovascular disorders (CCVD) is a group of syndromes with heterogenic development mechanisms associated with a consistent deficit of brain tissue blood supply, consequences of acute cerebrovascular events and its combination. CCVD development is associated with involvement of vessels, primarily small vessels, in pathologic process and to a great extent with microcirculation and systemic hemodynamics disturbance. The key principles of patients with CCVD treatment include control of cardiovascular risk factors – the use of antiplatelet and antihypertensive therapy, statins and glycemic control in the case of appropriate indications. An important aspect in these patients treatment is the use of medications that improve cerebral blood flow. The most important effect of their use is not vasodilatation itself but the increase of vessel wall sensitivity to natural factors that regulate the inner diameter of the vessel. In this respect it appears to be appropriate to use the term “vasoactive medications”. One of these medications is Vasonit® (pentoxifylline) that is a derivative of methylxanthine. The article reviews its clinical effects, possible mechanisms of action and possibilities of use in patients with CCVD.
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[Zhetishev R.R., Mikhailova N.A., Kamchatnov P.R., Ivashchenko R.A. Asimptomnye infarkty golovnogo mozga: faktory riska i kognitivnye narusheniia. Zhurn. nevrol. i psikhiatr. im. S.S. Korsakova. Insul't. 2014; 3 (2): 3–7 (in Russian).]
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5. Cai Z, Wang C, He W et al. Cerebral small vessel disease and Alzheimer’s disease. Clin Interv Aging 2015; 10: 1695–704.
6. Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 2010; 9 (7): 689–701.
7. Blinder P, Tsai P, Kaufhold J et al. The cortical angiome: an interconnected vascular network with noncolumnar patterns of blood flow. Nat Neurosci 2013; 16: 889–97.
8. Nishimura N, Rosidi N, Iadecola C, Schaffer C. Limitations of collateral flow after occlusion of a single cortical penetrating arteriole. J Cereb Blood Flow Metab 2010; 30: 1914–27.
9. Sörös P, Whitehead S, Spence J, Hachinski V. Antihypertensive treatment can prevent stroke and cognitive decline. Nat Rev Neurol 2013; 9: 174–8.
10. Hilal S, Mok V, Youn Y et al. Prevalence, risk factors and consequences of cerebral small vessel diseases: data from three Asian countries. J Neurol Neurosurg Psychiatr 2017; 88 (8): 45–9.
11. Iadecola C. The pathobiology of vascular dementia. Neuron 2013; 80 (4): 844–66.
12. Cooper L, Woodard T, Sigurdsson S et al. Cerebrovascular Damage Mediates Relations Between Aortic Stiffness and Memory. Hypertension 2016; 67: 176–82.
13. Palacio S, McClure L, Benavente O et al. Lacunar strokes in patients with diabetes mellitus: risk factors, infarct location, and prognosis: the secondary prevention of small subcortical strokes study. Stroke 2014; 45 (9): 2689–94.
14. McLauchlan D, Malik G, Robertson N. Cerebral amyloid angiopathy: subtypes, treatment and role in cognitive impairment. J Neurol 2017; 264: 2184–6.
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16. Kollias A, Lagou S, Zeniodi M et al. Association of central versus brachial blood pressure with target-organ damage: systematic review and meta-analysis. Hypertension 2016; 67 (1): 183–90.
17. Barnes J, Harvey R, Zuk S et al. Aortic hemodynamics and white matter hyperintensities in normotensive postmenopausal women. J Neurol 2017; 264: 938.
18. Townsend R, Black H, Chirinos J et al. Clinical use of pulse wave analysis: proceedings from a symposium sponsored by North American artery. J Clin Hypertens (Greenwich) 2015; 17 (7): 503–13.
19. Webb A, Simoni M, Mazzucco S et al. Increased cerebral arterial pulsatility in patients with leukoaraiosis: arterial stiffness enhances transmission of aortic pulsatility. Stroke 2912; 43 (10): 2631–6.
20. Pase M, Himali J, Mitchell G et al. Association of aortic stiffness with cognition and brain aging in young and middle-aged adults: the Framingham third generation cohort study. Hypertension 2016; 67 (3): 513–9.
21. Davis K, Pearson H, Moat S et al. Acute hyperhomocysteinaemia affects pulse pressure but not microvascular vasodilator function. Br J Clin Pharmacol 2001; 52 (3): 327–32.
22. Plotnikov MF, Aliev OI, Nosarev AV et al. Relationship between arterial blood pressure and blood viscosity in spontaneously hypertensive rats treated with pentoxifylline. Biorheology 2016; 53 (2): 93–107.
23. Plotnikov MB, Aliev OI, Shamanaev AY et al. Effects of pentoxifylline on hemodynamic, hemorheological, and microcirculatory parameters in young SHRs during arterial hypertension development. Clin Exp Hypertens 2017; 39 (6): 570–8.
24. Brie D, Sahebkar A, Penson P et al. Effects of pentoxifylline on inflammatory markers and blood pressure: a systematic review and meta-analysis of randomized controlled trials. J Hypertens 2016; 34 (12): 2318–29.
25. Banihani SA, Abu-Alhayjaa R, Amarin Z, Alzoubi K. Pentoxifylline increases the level of nitric oxide produced by human spermatozoa. Andrologia 2018; 50 (2). DOI: 10.1111/and.12859
26. Dolatabadi H, Zarrindast M, Reisi P, Nasehi M. The Effects of Pentoxifylline on Serum Levels of Interleukin 10 and Interferon Gamma and Memory Function in Lipopolysaccharide-induced Inflammation in Rats. Adv Biomed Res 2017; 6: 110–5.
27. Bruno R, Marques T, Batista T et al. Pentoxifylline treatment improves neurological and neurochemical deficits in rats subjected to transient brain ischemia. Brain Res 2009; 13: 55–64.
28. Sari S, Hashemi M, Mahdian R et al. The Effect of Pentoxifylline on bcl-2 Gene Expression Changes in Hippocampus after Ischemia-Reperfusion in Wistar Rats by a Quatitative RT-PCR Method. Iran J Pharm Res 2013; 12 (3): 495–501.
29. Vakili A, Mojarrad S, Akhavan M, Rashidy-Pour A. Pentoxifylline attenuates TNF-a protein levels and brain edema following temporary focal cerebral ischemia in rats. Brain Res 2011; 1377: 119–25.
30. Xia DY, Zhang HS, Wu LY et al. Pentoxifylline Alleviates Early Brain Injury After Experimental Subarachnoid Hemorrhage in Rats: Possibly via Inhibiting TLR 4/NF-kB Signaling Pathway. Neurochem Res 2017; 42 (4): 963–74.
31. Vakili A, Khorasani Z. Post-ischemic treatment of pentoxifylline reduces cortical not striatal infarct volume in transient model of focal cerebral ischemia in rat. Brain Res 2007; 1144: 186–91.
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[Boiko A.N., Kamchatnov P.R., Chugunov A.V. et al. Patogeneticheskii podkhod k lecheniiu bol'nykh s vertebral'no-baziliarnoi nedostatochnost'iu. Vrach. 2005; 11: 7–13 (in Russian).]
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38. Teruya R, Fagundes D, Oshima C et al. Effects of pentoxifylline into the kidneys of rats in a model of unilateral hindlimb ischemia/reperfusion injury. Acta Cir Bras 2008; 23 (1): 29–35.
39. Rodriguez-Moran M, Guerrero-Romero F. Pentoxifylline is as effective as captopril in the reduction of microalbuminuria in non-hypertensive type 2 diabetic patients; a randomized, equivalent trial. Clin Nephrol 2005; 64 (2): 91–7.
40. Liu D, Wang L, LiH et al. Pentoxifylline plus ACEIs/ARBs for proteinuria and kidney function in chronic kidney disease: a meta-analysis. J Int Med Res 2017; 45 (2): 383–98.
41. Incandela L, Cesarone MR, Belcaro G et al. Treatment of vascular inner ear disease with pentoxifylline: a 4-week, controlled, randomized trial. Angiology 2002; 53 (Suppl. 1): S19–22.
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1. Zhetishev R.R., Mikhailova N.A., Kamchatnov P.R., Ivashchenko R.A. Asimptomnye infarkty golovnogo mozga: faktory riska i kognitivnye narusheniia. Zhurn. nevrol. i psikhiatr. im. S.S. Korsakova. Insul't. 2014; 3 (2): 3–7 (in Russian).
2. Debette S, Schilling S, Duperron M-G. Clinical Significance of Magnetic Resonance Imaging Markers of Vascular Brain Injury A Systematic Review and Meta-analysis. JAMA Neurol 2019; 76 (1): 81–94. DOI: 10.1001/jamaneurol.2018.3122
3. Zhang M, Chen M, Wang Q et al. Relationship between cerebral microbleeds and cognitive function in lacunar infarct. J Int Med Res 2013; 41 (2): 347–55.
4. Shi Y, Wardlaw JM. Update on cerebral small vessel disease: a dynamic whole-brain disease. Stroke and Vascular Neurology 2016; 1: e000035. DOI:10.1136/svn-2016000035
5. Cai Z, Wang C, He W et al. Cerebral small vessel disease and Alzheimer’s disease. Clin Interv Aging 2015; 10: 1695–704.
6. Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 2010; 9 (7): 689–701.
7. Blinder P, Tsai P, Kaufhold J et al. The cortical angiome: an interconnected vascular network with noncolumnar patterns of blood flow. Nat Neurosci 2013; 16: 889–97.
8. Nishimura N, Rosidi N, Iadecola C, Schaffer C. Limitations of collateral flow after occlusion of a single cortical penetrating arteriole. J Cereb Blood Flow Metab 2010; 30: 1914–27.
9. Sörös P, Whitehead S, Spence J, Hachinski V. Antihypertensive treatment can prevent stroke and cognitive decline. Nat Rev Neurol 2013; 9: 174–8.
10. Hilal S, Mok V, Youn Y et al. Prevalence, risk factors and consequences of cerebral small vessel diseases: data from three Asian countries. J Neurol Neurosurg Psychiatr 2017; 88 (8): 45–9.
11. Iadecola C. The pathobiology of vascular dementia. Neuron 2013; 80 (4): 844–66.
12. Cooper L, Woodard T, Sigurdsson S et al. Cerebrovascular Damage Mediates Relations Between Aortic Stiffness and Memory. Hypertension 2016; 67: 176–82.
13. Palacio S, McClure L, Benavente O et al. Lacunar strokes in patients with diabetes mellitus: risk factors, infarct location, and prognosis: the secondary prevention of small subcortical strokes study. Stroke 2014; 45 (9): 2689–94.
14. McLauchlan D, Malik G, Robertson N. Cerebral amyloid angiopathy: subtypes, treatment and role in cognitive impairment. J Neurol 2017; 264: 2184–6.
15. Nichols W, O’Rourke M. McDonalds’s blood flow in arteries: theoretical, experimental and clinical principles, 5th edn. Hodder Arnold Publishing, London. 2005.
16. Kollias A, Lagou S, Zeniodi M et al. Association of central versus brachial blood pressure with target-organ damage: systematic review and meta-analysis. Hypertension 2016; 67 (1): 183–90.
17. Barnes J, Harvey R, Zuk S et al. Aortic hemodynamics and white matter hyperintensities in normotensive postmenopausal women. J Neurol 2017; 264: 938.
18. Townsend R, Black H, Chirinos J et al. Clinical use of pulse wave analysis: proceedings from a symposium sponsored by North American artery. J Clin Hypertens (Greenwich) 2015; 17 (7): 503–13.
19. Webb A, Simoni M, Mazzucco S et al. Increased cerebral arterial pulsatility in patients with leukoaraiosis: arterial stiffness enhances transmission of aortic pulsatility. Stroke 2912; 43 (10): 2631–6.
20. Pase M, Himali J, Mitchell G et al. Association of aortic stiffness with cognition and brain aging in young and middle-aged adults: the Framingham third generation cohort study. Hypertension 2016; 67 (3): 513–9.
21. Davis K, Pearson H, Moat S et al. Acute hyperhomocysteinaemia affects pulse pressure but not microvascular vasodilator function. Br J Clin Pharmacol 2001; 52 (3): 327–32.
22. Plotnikov MF, Aliev OI, Nosarev AV et al. Relationship between arterial blood pressure and blood viscosity in spontaneously hypertensive rats treated with pentoxifylline. Biorheology 2016; 53 (2): 93–107.
23. Plotnikov MB, Aliev OI, Shamanaev AY et al. Effects of pentoxifylline on hemodynamic, hemorheological, and microcirculatory parameters in young SHRs during arterial hypertension development. Clin Exp Hypertens 2017; 39 (6): 570–8.
24. Brie D, Sahebkar A, Penson P et al. Effects of pentoxifylline on inflammatory markers and blood pressure: a systematic review and meta-analysis of randomized controlled trials. J Hypertens 2016; 34 (12): 2318–29.
25. Banihani SA, Abu-Alhayjaa R, Amarin Z, Alzoubi K. Pentoxifylline increases the level of nitric oxide produced by human spermatozoa. Andrologia 2018; 50 (2). DOI: 10.1111/and.12859
26. Dolatabadi H, Zarrindast M, Reisi P, Nasehi M. The Effects of Pentoxifylline on Serum Levels of Interleukin 10 and Interferon Gamma and Memory Function in Lipopolysaccharide-induced Inflammation in Rats. Adv Biomed Res 2017; 6: 110–5.
27. Bruno R, Marques T, Batista T et al. Pentoxifylline treatment improves neurological and neurochemical deficits in rats subjected to transient brain ischemia. Brain Res 2009; 13: 55–64.
28. Sari S, Hashemi M, Mahdian R et al. The Effect of Pentoxifylline on bcl-2 Gene Expression Changes in Hippocampus after Ischemia-Reperfusion in Wistar Rats by a Quatitative RT-PCR Method. Iran J Pharm Res 2013; 12 (3): 495–501.
29. Vakili A, Mojarrad S, Akhavan M, Rashidy-Pour A. Pentoxifylline attenuates TNF-a protein levels and brain edema following temporary focal cerebral ischemia in rats. Brain Res 2011; 1377: 119–25.
30. Xia DY, Zhang HS, Wu LY et al. Pentoxifylline Alleviates Early Brain Injury After Experimental Subarachnoid Hemorrhage in Rats: Possibly via Inhibiting TLR 4/NF-kB Signaling Pathway. Neurochem Res 2017; 42 (4): 963–74.
31. Vakili A, Khorasani Z. Post-ischemic treatment of pentoxifylline reduces cortical not striatal infarct volume in transient model of focal cerebral ischemia in rat. Brain Res 2007; 1144: 186–91.
32. Bath PM, Bath-Hextall FJ. Pentoxifylline, propentofylline and pentifylline for acute ischaemic stroke. Cochrane Database Syst Rev 2004; 3: CD000162.
33. Isakova E.V., Riabtseva A.A., Kotov S.V. Sostoianie mikrotsirkuliatornogo rusla u bol'nykh, perenesshikh ishemicheskii insul't. RMZh. 2015; 1: 1–5 (in Russian).
34. Tanashian M.M., Lagoda O.V. Profilaktika ishemicheskogo insul'ta u bol'nykh s aterotrombozom. RMZh. 2014; 6: 23–8 (in Russian).
35. Sha MC, Callahan CM. The efficacy of pentoxifylline in the treatment of vascular dementia: a systematic review. Alzheimer Dis Assoc Disord 2003; 17 (1): 46–54.
36. Boiko A.N., Kamchatnov P.R., Chugunov A.V. et al. Patogeneticheskii podkhod k lecheniiu bol'nykh s vertebral'no-baziliarnoi nedostatochnost'iu. Vrach. 2005; 11: 7–13 (in Russian).
37. Roman G. Perspectives in the treatment of vascular dementia. Drugs Today (Barc) 2000; 36 (9): 641–53.
38. Teruya R, Fagundes D, Oshima C et al. Effects of pentoxifylline into the kidneys of rats in a model of unilateral hindlimb ischemia/reperfusion injury. Acta Cir Bras 2008; 23 (1): 29–35.
39. Rodriguez-Moran M, Guerrero-Romero F. Pentoxifylline is as effective as captopril in the reduction of microalbuminuria in non-hypertensive type 2 diabetic patients; a randomized, equivalent trial. Clin Nephrol 2005; 64 (2): 91–7.
40. Liu D, Wang L, LiH et al. Pentoxifylline plus ACEIs/ARBs for proteinuria and kidney function in chronic kidney disease: a meta-analysis. J Int Med Res 2017; 45 (2): 383–98.
41. Incandela L, Cesarone MR, Belcaro G et al. Treatment of vascular inner ear disease with pentoxifylline: a 4-week, controlled, randomized trial. Angiology 2002; 53 (Suppl. 1): S19–22.