Léčba dyslipidemie představuje velmi dynamicky rostoucí segment farmakoterapie včetně výroby biologických prostředků. Ty dnes cíleně míří na různé proteiny, které se podílejí na syntéze, transportu nebo metabolismu lipoproteinů. Sdělení podává přehled o současných možnostech biologické léčby dyslipidemií a o léčivých prostředcích, které mají potenciál rozšířit její spektrum v nejbližší době.
Dyslipidemia treatment represents a very dynamically growing segment of pharmacotherapy, including a production of biological agents. Nowadays, they are targeting at various proteins that are involved in the synthesis, transport, or metabolism of lipoproteins. This review provides a statement of current options for the biological treatment of dyslipidemias and for other products that have the potential to broaden its spectrum in the near future.
- Keywords
- inclisiran, evinacumab, volanesorsen, mipomersen,
- MeSH
- Anticholesteremic Agents therapeutic use MeSH
- Oligodeoxyribonucleotides, Antisense therapeutic use MeSH
- Biological Therapy * MeSH
- Dyslipidemias * drug therapy MeSH
- Humans MeSH
- RNA, Small Interfering therapeutic use MeSH
- Antibodies, Monoclonal therapeutic use MeSH
- Oligonucleotides therapeutic use MeSH
- PCSK9 Inhibitors MeSH
- Proprotein Convertase 9 therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
Farmakologická léčba dyslipidemií je považována za jeden z nejúčinnějších preventivních i terapeutických postupů v oblasti kardiovaskulárních onemocnění. Po objevu statinů a jejich zavedení do praxe v devadesátých Letech se zdálo, že vývoj hypolipidemik je u konce. Jediné nové molekule - ezetimibu chyběla data z velké intervenční studie a nové léky (inhibitory cholesterol-ester transportního proteinu [CETP], agonisté receptorů aktivovaných peroxisomovým proliferátorem alfa/gama [PPAR- α/γ]) přinášely spíše potíže a do klinické praxe se nedostaly. Další možnosti ovlivnění dyslipidemie potřebujeme pro pacienty netolerující statiny či ezetimib, pro ty, kterým současné možnosti léčby nedostačují nebo je u nich přítomno zmnožení na triglyceridy bohatých částic. K dispozici máme další perorálně podávané účinné látky (lomitapid, bempedová kyselina, deriváty omega-3 mastných kyselin). Výrazně se rozšiřuje spektrum parenterálně podávaných hypolipidemických terapií. K etablovaným inhibitorům proproteinové konvertázy subtilisin-kexin 9 (PCSK9) přibývají anti-sense terapie, oligonukleotidy blokující translaci proteinu, proti apolipoproteinu B, lipoproteinu (a) a angiopoetinu podobnému protein 3. Klinickým zkoušením prošel také první zástupce nového léčebného principu, používajícího sekvence malých interferujících RNA (short interfering RNA, siRNA) namířené proti PCSK9. Všechny nové terapie by měly být využitelné v kombinacích se zavedenými hypolipidemiky.
Pharmacological treatment of dyslipidemia (DLP) is considered one of the most effective preventive and therapeutic procedures in the field of cardiovascular disease. After the discovery of statins and their implementation in the 1990s, the development of hypolipidemic drugs seemed to be over. The only new molecule, ezetimibe, lacked data from a large intervention study, and the new drugs were more of a problem (CETP inhibitors, PPAR alpha / gamma agonists) and did not enter clinical practice. We need other options to control dyslipidemia for patients who are intolerant to statins or ezetimibe, for those for whom current treatment options are insufficient or have an increase in triglyceride-rich particles. We have other orally administered active substances (lomitapide, bempedic acid, derivatives of omega-3 fatty acids). The range of parenterally administered hypolipidemic therapies is significantly expanding. In addition to established PCSK9 inhibitors there are anti-sense therapies, oligonucleotides that block protein translation, anti-apolipoprotein B, lipoprotein (a), angiopoietin 3. The first representative of a new therapeutic principle using small interfering RNA (siRNA) sequences directed against PCSK9 has also undergone clinical trials. All new therapies should be useful in combination with established hypolipidemics.
- Keywords
- lomitapid, bempedová kyselina, mipomersen,
- MeSH
- Angiopoietin-like Proteins antagonists & inhibitors MeSH
- Anticholesteremic Agents administration & dosage pharmacology therapeutic use MeSH
- Oligodeoxyribonucleotides, Antisense therapeutic use MeSH
- Apolipoproteins B drug effects MeSH
- Benzimidazoles therapeutic use MeSH
- Dyslipidemias * drug therapy physiopathology MeSH
- Hypercholesterolemia drug therapy physiopathology MeSH
- Hypolipidemic Agents * administration & dosage pharmacology therapeutic use MeSH
- Dicarboxylic Acids administration & dosage therapeutic use MeSH
- Humans MeSH
- RNA, Small Interfering therapeutic use MeSH
- Antibodies, Monoclonal therapeutic use MeSH
- Fatty Acids, Omega-3 therapeutic use MeSH
- PCSK9 Inhibitors MeSH
- PPAR alpha agonists drug effects MeSH
- Proprotein Convertase 9 MeSH
- Hydroxymethylglutaryl-CoA Reductase Inhibitors adverse effects therapeutic use MeSH
- Carrier Proteins antagonists & inhibitors MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
Specific gene knockdown mediated by the antisense oligodeoxynucleotides (AODNs) strategy emerged as a rapid and effective tool for probing gene role in plant cells, particularly tip-growing pollen tubes. Here, we describe the protocol for the successful employment of AODN technique in growing tobacco pollen tubes, covering AODN design, application, and analysis of the results. We also discuss the advantages and drawbacks of this method.
- MeSH
- Oligodeoxyribonucleotides, Antisense metabolism MeSH
- Hypercholesterolemia epidemiology drug therapy MeSH
- Hypolipidemic Agents pharmacokinetics pharmacology therapeutic use MeSH
- Ezetimibe, Simvastatin Drug Combination therapeutic use MeSH
- Cholesterol, LDL metabolism drug effects MeSH
- Humans MeSH
- PCSK9 Inhibitors MeSH
- Proprotein Convertase 9 MeSH
- Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
Kardiovaskulární onemocnění stále představují celosvětově nejčastější příčinu úmrtí, především v průmyslově vyspělých zemích, včetně naší země. V České republice připadá kardiovaskulární onemocnění jako příčina úmrtí téměř na polovinu počtu zemřelých (více než 50 % žen a mužů lehce pod 50 %). Nejvýznamnějším krokem ke snížení kardiovaskulární morbidity a mortality je prevence, ovlivnění rizikových faktorů. Je to obecně akceptovaný směr v prevenci a léčbě kardiovaskulárních onemocnění. Farmakoterapie hyperlipoproteinemií a dyslipidemií je považována za jeden z nejúčinnějších preventivních i terapeutických postupů. Po objevu statinů a jejich zavedení do praxe v 90. letech minulého století se zdálo, že vývoj hypolipidemik je u konce. Jediné nové molekule, ezetimibu, chyběla data z velké intervenční studie (což se změnilo publikací studie IMPROVE-IT) a nové léky do klinické praxe nepostoupily. Teprve v posledních letech se možnosti ovlivnit plazmatické koncentrace lipidů a lipoproteinů velmi významně rozšiřují. Novými léky, které jsou cílené především na homozygoty s familiární hypercholesterolemií, jsou lomitapid a mipomersen. Za nejvýznamnější progresi a příslib v hypolipidemické léčbě považujeme dnes monoklonální protilátky nebo inhibitory proprotein konvertázy subtilisin/kexin typu 9 (PCSK9). Tyto parenterálně podávané léky snižují koncentraci LDL-choles- terolu o 50-60 %, i více, navíc snižují koncentraci apolipoprotinu B a dokonce i koncentraci lipoproteinu(a). Pro tuto nejnovější skupinu nemáme ještě data z kontrolovaných morbiditně-mortalitních studií. Přesto předběžná ale významná data z metaanalýz a sledování bezpečnosti svědčí pro pozitivní trendy ve snižování kardiovaskulárních onemocnění.
Cardiovascular diseases are still the most common cause of death worldwide, particularly in industrialized countries, including our country. In the Czech Republic, cardiovascular diseases accounts for almost half of all deaths (more than 50 % of women and men are slightly below 50 %). The most important step in reducing cardiovascular morbidity and mortality is the prevention an influence of risk factors. It is a generally accepted direction in the prevention and treatment of cardiovascular diseases. Pharmacological treatment of hyperlipidemia and dyslipidemia is considered one of the most effective preventive and therapeutic procedures. After the discovery of statins and their implementation in practice in 90 of those years, it seemed that the development of lipid lowering drugs is over. Only one new molecule, ezetimibe, is missing data from a large intervention trial (which changed in the publication of the study IMPROVE IT) and new drugs have not progressed into clinical practice. Just in recent years is the possibility to influence plasma lipid and lipoprotein greatly expanding significantly. The new drugs that are targeted primarily at homozygous familial hypercholesterolemia are lomitapid and mipomersen. The most significant progress and promise of lipid-lowering therapy is considered today a monoclonal antibody or PCSK9 inhibitors. Such parenterally administered drugs reduce LDL-C by 50, 60 percent or more, moreover, decrease the concentration of apolipoprotein B and even lipoprotein(a). For this particular group, we do not have the latest data from controlled studies of mortality morbidity. Nevertheless, preliminary, but significant data from meta-analyzes and safety monitoring suggest positive trends in reducing cardiovascular diseases.
- Keywords
- lomitapid, mipomersen,
- MeSH
- Anticholesteremic Agents pharmacology therapeutic use MeSH
- Oligodeoxyribonucleotides, Antisense pharmacology therapeutic use MeSH
- Benzimidazoles pharmacology therapeutic use MeSH
- Fibric Acids pharmacology therapeutic use MeSH
- Dyslipidemias * drug therapy MeSH
- Ezetimibe pharmacology therapeutic use MeSH
- Hypolipidemic Agents pharmacology therapeutic use MeSH
- Cardiovascular Diseases prevention & control MeSH
- Clinical Studies as Topic MeSH
- Cholesterol, LDL drug effects MeSH
- Humans MeSH
- Antibodies, Monoclonal pharmacology therapeutic use MeSH
- PCSK9 Inhibitors MeSH
- Proprotein Convertase 9 therapeutic use MeSH
- Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
- Keywords
- studie FIELD, studie ACCORD, studie IMPROVE-IT,
- MeSH
- Anticholesteremic Agents * pharmacokinetics pharmacology classification metabolism therapeutic use MeSH
- Oligodeoxyribonucleotides, Antisense pharmacokinetics pharmacology metabolism therapeutic use MeSH
- Apolipoproteins B MeSH
- Azetidines pharmacokinetics metabolism therapeutic use MeSH
- Cholestyramine Resin pharmacokinetics metabolism adverse effects therapeutic use MeSH
- Fibric Acids pharmacokinetics metabolism therapeutic use MeSH
- Dyslipidemias * drug therapy MeSH
- Cholesterol, HDL drug effects MeSH
- Hypolipidemic Agents * classification therapeutic use MeSH
- Cardiovascular Diseases prevention & control MeSH
- Clinical Trials as Topic MeSH
- Drug Therapy, Combination MeSH
- Cholesterol, LDL drug effects MeSH
- Humans MeSH
- RNA, Messenger MeSH
- Meta-Analysis as Topic MeSH
- Obesity physiopathology MeSH
- Proprotein Convertases economics pharmacokinetics pharmacology therapeutic use MeSH
- Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacokinetics classification therapeutic use MeSH
- Subtilisin drug effects MeSH
- Cholesterol Ester Transfer Proteins pharmacokinetics pharmacology metabolism therapeutic use MeSH
- Carrier Proteins pharmacokinetics pharmacology metabolism therapeutic use MeSH
- Triglycerides pharmacokinetics pharmacology metabolism therapeutic use MeSH
- Check Tag
- Humans MeSH
- MeSH
- Anticholesteremic Agents therapeutic use MeSH
- Oligodeoxyribonucleotides, Antisense MeSH
- Apolipoproteins B antagonists & inhibitors biosynthesis MeSH
- Atherosclerosis MeSH
- Azetidines therapeutic use MeSH
- Early Diagnosis MeSH
- Diet, Fat-Restricted MeSH
- Genetic Predisposition to Disease MeSH
- Hypercholesterolemia * diagnosis epidemiology etiology drug therapy genetics complications physiopathology pathology therapy MeSH
- Myocardial Ischemia mortality MeSH
- Humans MeSH
- Lipoproteins, LDL blood MeSH
- Antibodies, Monoclonal therapeutic use MeSH
- Plasmapheresis MeSH
- Proprotein Convertases MeSH
- Blood Component Removal MeSH
- Serine Endopeptidases MeSH
- Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use MeSH
- Lipid Metabolism, Inborn Errors * MeSH
- Life Style * MeSH
- Bile Acids and Salts therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Newspaper Article MeSH
- Geographicals
- Czech Republic MeSH
Snížená exprese ubikviterní NRl podjednotky NMDA receptoru v některých oblastech mozku osob trpících schizofrenií je dávána do souvislosti s jednonukleotidovými polymorfizmy (SNP) v genu pro tuto podjednotku (GRINl). Také neurovývojový (animální) model psychóze podobného chovaní SOdenního potkana (kmen Wistar, 50. PND), založený na intrakraniální infuzi kyseliny chinolinové (QUIN; 250 nmol/0,25 pL NaCl do každé z postranních mozkových komor) neonatálním potkanům (12. PND), charakterizuje pokles exprese proteinu ubikviterní NRl podjednotky v obou hipokampech, který provází porucha ve zpracování sensorických informací (deficit v prepulzní inhibici úlekové reakce) pozorovaná také u osob trpících schizofrenií. Protože však změnu v proteinu NRl podjednotky provázely 1 zmeny v expresi většiny NR2 podjednotek, nebylo možné prokázat přímý vztah mezi sníženou expresí NRl a změnami v prepulzní inhibici akustického úleku. Proto jsme do obou hipokampů potkana 50. PND infundovali antisense oligodeoxynukleotid (aODN) specifický pro NRl podjednotku. Za 24 hod. po infuzi jsme prokázali snížení exprese proteinu hipokampální NRl, ale prepulzní inhibice akustického úleku zůstala nezměněna. V práci se navrhuje další postup při vymezování úlohy NMDA-Rl v patofyziologii schizofrenie.
Decreased expression of ubiquitous NMDA-NR1 subunit in some schizophrenic brain regions has been related to several single nuc- leotide polymorphisms (SNP) in the subunit gene ( GRIN1 ). Also neurodevelopmental (animal) model of schizophrenia-like behaviour of 50-day-old Wistar rat males, which were neonatally treated with quinolinic acid (QUIN; 250 nmol/0.25 μL NaCl into each later al cerebral ventricle on postnatal day 12), exhibited a decrease in the hippocampal subunit NR1 protein together with a deficit in the sen- sorimotor gating (deficit in the prepulse inhibition of startle reaction) accompanying schizophrenia. Because changes in the su bunit NR1 protein went with changed expression in most of NR2 subunits, it was impossible to reveal a direct relation between the dec reased expression of NR1 protein and changed prepulse inhibition of the acoustic startle. Therefore, we infused bilaterally a single d ose of antisense oligodeoxynucleotide (aODN) specific for NR1 subunit into ventral hippocampi of 50-day-old rat males. Twenty four hou rs later we found decreased hippocampal levels of NR1 protein, but prepulse inhibition of the acoustic startle remained unchanged. We discuss further study course delimitating the role of NMDA-R1 subunit in pathophysiology of schizophrenia.
- MeSH
- Oligodeoxyribonucleotides, Antisense genetics MeSH
- Research Support as Topic MeSH
- Financing, Organized MeSH
- Hippocampus physiology drug effects MeSH
- Disease Models, Animal MeSH
- Rats, Wistar physiology genetics MeSH
- Receptors, N-Methyl-D-Aspartate genetics drug effects MeSH
- Reflex, Acoustic physiology genetics MeSH
- Schizophrenia etiology genetics MeSH
- Reflex, Startle genetics drug effects MeSH
- Blotting, Western methods utilization MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
The effectiveness of antisense (AS) phosphorothioated oligodeoxynucleotides (AS-ODN) targeted to the angiotensin (ANG) type 1 (AT1) receptor, was studies in Ren-2 transgenic rats (TGR), whose ANG II-dependent hypertension can be attributed to the insertion of a single mouse renin gene. Our results show that a single intraarterial bolus injection of AT1-AS in 30-day-old rats results in a prolonged lowering of systolic blood pressure (SBP) for a period of 18 days with an average difference in SBP of 30 mm Hg between AS-treated and untreated TGR. No effect of AS therapy on SBP has been observed in control HanSD animals. However, at the end of the experiment, i.e. on day 100 of age, there were no differences in mean arterial pressure, proteinuria or cardiac hypertrophy between AS-treated and untreated TGR. Thus, no persistent effect of this therapy was observed after a single bolus injection. Collectively, the data show a prolonged antihypertensive effect of AT1 receptor antisense oligonucleotides during the developmental phase of hypertension in TGR when applied as a single treatment in prehypertensive animals which, however, does not persist up to the maintenance phase of hypertension in adulthood.
- MeSH
- Oligodeoxyribonucleotides, Antisense administration & dosage therapeutic use MeSH
- Angiotensin II Type 1 Receptor Blockers therapeutic use MeSH
- Financing, Organized MeSH
- Animals, Genetically Modified MeSH
- Hypertension drug therapy MeSH
- Hypertrophy, Left Ventricular prevention & control MeSH
- Rats MeSH
- Disease Models, Animal MeSH
- Rats, Sprague-Dawley MeSH
- Proteinuria drug therapy MeSH
- Receptor, Angiotensin, Type 1 genetics MeSH
- Renin genetics MeSH
- Systole drug effects MeSH
- Thionucleosides therapeutic use MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
