Antisense Oligonucleotides and Therapeutical Monoclonal Antibodies as a Basement for Novel Biological Lipidlowering Drugs

Афанасьева, О. И.; Ezhov, M.; Покровский, С. Н.

doi:10.15829/1560-4071-2018-8-99-109

Cited by 10 publications

(3 citation statements)

References 55 publications

(71 reference statements)

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“…Recent studies have shown that an increased level of PCSK9 is a marker of the presence and severity of atherosclerosis in coronary and peripheral arteries in patients with heterozygous familial hypercholesterolemia [ 3 ]. Therapeutic monoclonal antibodies (MABs) that inhibit the activity of PCSK9 initiated a new era in the treatment of severe lipid metabolic disorders [ 4 , 5 ]. Administration of PCSK9 inhibitors enables enhanced recycling of LDL receptors on the surface of hepatocytes and therefore promotes LDL clearance from the bloodstream.…”

Section: Introductionmentioning

confidence: 99%

Effect of Evolocumab on Lipoprotein(a) and PCSK9 in Healthy Individuals with Elevated Lipoprotein(a) Level

Afanasieva

Ezhov

Klesareva

et al. 2020

JCDD

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Background and aims: The aim of this study was to investigate the influence of a single injection of Evolocumab on the dynamics of Lp(a), fractions of apoB100-containing lipoproteins, PCSK9, and their complexes in healthy individuals with elevated Lp(a) levels. Methods: This open-label, 4-week clinical study involved 10 statin-naive volunteers with Lp(a) >30 mg/dL, LDL-C < 4.9 mmol/L, and a moderate risk of cardiovascular events. The concentrations of Lp(a), lipids, PCSK9, circulating immune complexes (CIC), and plasma complexes of PCSK9 with apoB100-containing lipoproteins (Lp(a)–PCSK9 and LDL–PCSK9) were measured before and each week after Evolocumab (MABs) administration. Results: After a single dose injection of 140 mg of MABs, the median concentration of PCSK9 in serum increased from 496 to 3944 ng/mL; however, the entire pool of circulating PCSK9 remained bound with MABs for 2–3 weeks. LDL-C level decreased significantly from 3.36 mmol/L to 2.27 mmol/L during the first two weeks after the injection. Lp(a) concentrations demonstrated multidirectional changes in different patients with the maximal decrease on the second week. There were no positive correlations between the changes in levels of Lp(a), LDL-C, and TC. The change in the amount of circulating complex of PCSK9–Lp(a) was significantly less than of PCSK9–apoB100 (−5% and −47% after 1 week, respectively). Conclusions: A single administration of monoclonal antibodies against PCSK9 (Evolocumab) in healthy individuals with hyperlipoproteinemia(a) resulted in a decrease of Lp(a) of 14%, a 5% decrease in PCSK9–Lp(a), a 36% reduction of LDL-C, a 47% decrease in PCSK9–apoB100 and a tenfold increase in total serum PCSK9 concentration.

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Section: Introductionmentioning

confidence: 99%

Effect of Evolocumab on Lipoprotein(a) and PCSK9 in Healthy Individuals with Elevated Lipoprotein(a) Level

Afanasieva

Ezhov

Klesareva

et al. 2020

JCDD

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“…Although Lp(a) is an independent genetic risk factor of various CVDs, there are no ways to manage it pharmacologically [ 27 , 28 ]. Therapeutic antisense oligonucleotides designed for these purposes are currently undergoing clinical trials [ 29 ].…”

Section: Resultsmentioning

confidence: 99%

A Sorbent with Synthetic Ligand for Removing Pro-atherogenic and Pro-inflammatory Components from Human Blood Plasma

et al. 2021

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Elevated levels of apoB-100 containing lipoproteins and markers of systemic inflammation are often observed in patients with cardiovascular diseases. The concentrations can be reduced by pharmacotherapy or extracorporeal treatment. The sorbent, which removes CRP and atherogenic lipoproteins, simultaneously reduces the bloodstream concentration of these components. The efficacy and selectivity of the designed sorbent were studied, desorption constants of CRP (Kd = 4.2 10-8 M) and LDL (Kd = 7.7 10-7 M) were distribution coefficients of CRP (Kc = 101) and Lp(a) (Kc = 38) were calculated, and the ability to bind large amounts of atherogenic lipoproteins (up to 32 mg of TC per mL of the sorbent gel) was demonstrated. Our sorbent can be recommended for performing complex removal of CRP and atherogenic lipoproteins from the blood plasma in patients with refractory hyperlipidemia and CVD that are accompanied by elevated levels of CRP.

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“…Коррекция гиперлипопротеидемии(а). Становится очевидным, что коррекция уровня Лп(а) необходима для все более широкой категории больных: уровень Лп(а) также не превышает 30%, включая препараты, блокирующие синтез апоВ 100 [67].…”

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Hyperlipoproteinemia(a) as a dangerous genetically determined violation of lipid metabolism and a risk factor for atherothrombosis and cardiovascular diseases

Афанасьева

Покровский

2019

Russ J Cardiol

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Липопротеид(а) (Лп(а)) представляет собой сложный надмолекулярный комплекс, принадлежащий к апоВ 100-содержащим липопротеидам. Лп(а) состоит из частицы подобной липопротеидам низкой плотности, в которой молекула апобелка В 100 ковалентно связана дисульфидной связью с уникальной полиморфной молекулой апобелка(а). Концентрация Лп(а) генетически контролируется, при этом варьирует в очень широком диапазоне. Повышенный уровень Лп(а) является независимым фактором риска атеросклероза коронарных, сонных и периферических артерий, ишемической болезни сердца и стеноза аортального клапана, сопутствующих сердечно-сосудистых осложнений, а также осложнений после операций реваскуляризации миокарда. Несмотря на это, уровень Лп(а) по-прежнему не учитывается в стратификации риска сердечно-сосудистых заболеваний. Отчасти это может быть связано с тем, что ни современная лекарственная терапия, ни новые поколения биологических гиполипидемических препаратов практически не влияют на концентрацию Лп(а), за исключением 20-30% снижения Лп(а) никотиновой кислотой и ингибиторами пропротеиновой конвертазы субтилизин-кексин 9 типа (PCSK9). Обзор освещает современные представления о Лп(а) как факторе риска сердечно-сосудистых заболеваний, возможности и целесообразности его определения, а также посвящен современным возможностям коррекции гиперлипопротеидемии(а).

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Antisense Oligonucleotides and Therapeutical Monoclonal Antibodies as a Basement for Novel Biological Lipidlowering Drugs

Cited by 10 publications

References 55 publications

Effect of Evolocumab on Lipoprotein(a) and PCSK9 in Healthy Individuals with Elevated Lipoprotein(a) Level

Effect of Evolocumab on Lipoprotein(a) and PCSK9 in Healthy Individuals with Elevated Lipoprotein(a) Level

A Sorbent with Synthetic Ligand for Removing Pro-atherogenic and Pro-inflammatory Components from Human Blood Plasma

Hyperlipoproteinemia(a) as a dangerous genetically determined violation of lipid metabolism and a risk factor for atherothrombosis and cardiovascular diseases

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