MAL

1. NUOVE STRATEGIE NEL TRATTAMENTO DELLA DISLIPIDEMIA Prof. Paolo de Caprariis MAL 1

2. Altered coagulation And fibrinolysis MAL

3. Lipoproteina

4. 2 Sets of Lipoproteins 0.95 ApoA1 Apo B 1.006 Density (g/mL) 1.02 1.06 1.10 1.20 5 10 20 40 60 80 1000 Diameter (nm) MAL

5. Atherogenic Cholesterol Load 0.95 1.006 1.02 Density (g/ml) 1.06 1.10 1.20 5 10 20 40 60 80 1000 Diameter (nm) MAL

6. Two Types of Lipoproteins are Atherogenic in Humans Apo B100 containing LDL Apo B48 containing Chylomicron Remnants B48 B100 CE TG TG Hepatic Intestinal TG CE Apolipoprotein B fragments Cholesteryl ester MAL

7. Atherosclerosis is linked to a Desequilibrium between Protective and Atherogenic Lipoproteins Apo B VLDL - IDL - LDL Atherogenic Transport Apo AI HDL Anti Atherogenic Transport MAL

8. Niacina, 1955 Resine sequestranti acidi biliari, 1961 Fibrati, 1967 Statine (inibitori HMG-CoA reduttasi), 1987 Inibitori dell’assorbimento del Colesterolo (ezetimibe), 2002 Terapia combinata, 2004-2005 FARMACI IMPIEGATI NELLE DISLIPIDEMIE

9. NIACINA o VITAMINA B3 o PP • Primo farmaco ipolipemizzante introdotto nel 1955. • COMPLESSO DELLA VITAMINA B IDROFILO • Sembra che agisca inibendo la lipolisi nel tessuto adiposo, con conseguente riduzione della sintesi epatica di VLDL • Effetti collaterali: vasodilatazione, prurito al viso ed alle parti superiori del tronco, eritema, vampate • Altri effetti collaterali importanti sono a carico del fegato, con aumento delle transaminasi e possibilità di ittero,dolore epigastrico,nausea,vomito, diarrea

10. Niacin is Available in a Number of Different Formulations According to the Speed of Drug Release. Formulations that Differ in Time of Release May Have Different Lipid Effects and Vary in their Adverse Reaction Profiles Efficacy Hepatotoxicity Flushing Knopp R. Am J Cardiol 2000;86:51-56

11. DRUG DESCRIPTION • NIASPAN (niacintablet, film-coatedextended-release), containsniacin, which at therapeuticdosesisanantihyperlipidemicagent. Niacin (nicotinic acid, or 3-pyridinecarboxylic acid) is a white, crystallinepowder, verysoluble in water, with the followingstructural formula: • NIASPAN isanunscored, medium-orange, film-coatedtabletfororaladministration and isavailable in threetabletstrengthscontaining 500, 750, and 1000 mg niacin. NIASPAN tabletsalsocontain the inactiveingredientshypromellose, povidone, stearic acid, and polyethyleneglycol, and the followingcoloringagents: FD&C yellow #6/sunset yellow FCF Aluminum Lake, syntheticred and yellow ironoxides, and titaniumdioxide.

12. Non Conjugated Pathway Conjugated Pathway

13. Comparison of the Effect of Niaspan and Immediate Release Nicotinic Acid on Plasma Lipids and Lipoproteins 8 weeks N=223 Carlson L.A. J.Internal Medicine 2005;258:94-114

14. Mechanisms of Action of Nicotinic Acid Knopp R. NEJM 1999;341:498-511

15. Flushing Out the Role of GPR109A (HM74A) in the Clinical Efficacy of Nicotinic Acid Pike N. JCI 2005;115:3400-3403

16. Vit E 800UI Vit C 1000mg Beta Carotene 25mg Selenium 100ug Simva 10-40mg Niacor 2000mg 34 39 33 40 N: Brown G.NEJM 2001;345:1583-1592

17. Brown G.NEJM 2001;345:1583-1592

18. Wolfe M. Am.J Cardiology 2001;87:476-489

19. Simcor • SIMCOR ® è indicato per ridurre elevate totale-C, C-LDL, Apo B, non-HDL-C, TG, o di aumentare il colesterolo HDL nei pazienti con ipercolesterolemia primaria e dislipidemia mista quando il trattamento con simvastatina in monoterapia o niacina monoterapia a rilascio prolungato è considerato inadeguato, e TG nei pazienti con ipertrigliceridemia quando il trattamento con simvastatina in monoterapia o niacina a rilascio prolungato in monoterapia è considerata inadeguata. http://www.drugs.com

20. Simcor Dosage and Administration Simcor should be taken as a single daily dose at bedtime, with a low fat snack. Patients not currently on niacin extended-release and patients currently on niacin products other than niacin extended-release should start Simcor at a single 500/20 mg tablet daily at bedtime. Patients already taking simvastatin 20-40 mg who need additional management of their lipid levels may be started on a Simcor dose of 500/40 mg once daily at bedtime. The dose of niacin extended-release should not be increased by more than 500 mg daily every 4 weeks. The recommended maintenance dose for Simcor is 1000/20 mg to 2000/40 mg (two 1000/20 mg tablets) once daily depending on patient tolerability and lipid levels. The efficacy and safety of doses of Simcor greater than 2000/40 mg daily have not been studied and are therefore not recommended. If Simcor therapy is discontinued for an extended period of time (> 7 days), re-titration as tolerated is recommended. Simcor tablets should be taken whole and should not be broken, crushed, or chewed before swallowing. MAL

21. RESINE LEGANTI I SALI BILIARI Sono disponibili due molecole: • COLESTIRAMINA • COLESTIPOLO CLORIDRATO • Dal punto di vista chimico sono resine che legano anioni • Meccanismo d’azione: Le resine legano gli acidi biliari scambiando ioni Cl- con cariche negative • Effetti collaterali: stipsi, nausea • Interazioni farmacologiche: diverse classi di vitamine anticoagulanti orali glicosidi cardioattivi diuretici β-bloccanti antibiotici

22. Colesevelam • Colesevelam is a bile acid sequestrant administered orally. It is developed by Genzyme and marketed in the US by Daiichi Sankyo under the brand name WelChol and elsewhere by Genzyme under the tradenameCholestagel. • Clinical use Colesevelam is indicated as an adjunct to diet and exercise to reduce elevated low-density lipoprotein cholesterol (LDL-C) in patients with primary hyperlipidemia as monotherapy and to improve glycemic control in adults with type 2 diabetes mellitus, including in combination with a statin. • Colesevelam is one of the bile-acid sequestrants, which along with niacin and the statins are the three main types of cholesterol-lowering agents. The statins are considered the first-line agents. This is because of side effects from the other two types, including bloating and constipation (bile-acid sequestrants) and skin flushing (niacin). These side effects often lead to low patient compliance. MAL

23. ConstituentsThe compounds which constitute the polymer colesevelam are: N-prop-2-enyldecan-1-amine; trimethyl-[6-(prop-2-enylamino)hexyl]azanium; prop-2-en-1-amine; 2-(chloromethyl)oxirane; hydrogen chloride; chloride.

24. How it works Colesevelam is part of a class of drugs known as bile acid sequestrants. Colesevelam hydrochloride, the active pharmaceutical ingredient in Welchol, is a non-absorbed, lipid-lowering polymer that binds bile acids in the intestine, impeding their reabsorption. As the bile acid pool becomes depleted, the hepatic enzyme, cholesterol 7-α-hydroxylase, is upregulated, which increases the conversion of cholesterol to bile acids. This causes an increased demand for cholesterol in the liver cells, resulting in the dual effect of increasing transcription and activity of the cholesterol biosynthetic enzyme, HMG-CoAreductase, and increasing the number of hepatic LDL receptors. These compensatory effects result in increased clearance of LDL-C from the blood, resulting in decreased serum LDL-C levels. Serum TG levels may increase or remain unchanged.It is not yet known how Colesevelam works to help control blood sugar in people with type 2 diabetes. However, it is clear that the drug works within the digestive tract, since it is not absorbed into the rest of the body.

25. Cholesterol Since Colesevelam can lower total and LDL cholesterol levels (along with raising HDL -- cholesterol), a person can decrease his or her risk of developing certain health problems in the future by taking it. In previous clinical research studies, people taking 3,800 mg to 4,500 mg of Colesevelam daily were able to: Reduce LDL cholesterol by 15 to 18 percent Reduce total cholesterol by 7 to 10 percent Raise HDL cholesterol by 3 percent. • The combination of Colesevelam with a HMG-CoAreductase inhibitor (known more commonly as a statin) can further lower cholesterol levels. MAL

26. DERIVATI DELL’ACIDO FIBRICO: CLOFIBRATO E GEMFIBROZIL • Riduzione dei livelli di VLDL • Modesto aumento delle HDL • Effetto variabile sulle LDL Il clofibrato attiva la lipasi a livello endoteliale • Farmacocinetica • Ben assorbiti per os. • Elevatissimo legame (95%) con l’albumina plasmatica. • Generalmente ben tollerati, con scarsi effetti collaterali gastrointestinali. • ATTENZIONE alla competizione con altri farmaci (es. anticoagulanti orali) per i siti di legame alle proteine plasmatiche

27. Fibrati FENOFIBRATO Steiner G. Atherosclerosis 2005;182:199-207

29. Rate of Rhabdomyolysis With Fenofibrate + Statin Versus Gemfibrozil + Statin Jones P. Am.J. Cardiol. 2005;95:120-122

30. Fenofibrate Resulted in a 33 Times Lower Rhabdomyolysis Reporting Rate than Did Gemfibrozil Jones P. Am.J. Cardiol. 2005;95:120-122

31. Grundy S. Am.J. Cardiology 2005;95:462-468

32. Structural Mechanism for Statin Inhibition of HMG-CoA Reductase Simvastatin Atorvastatin Type 1 Butyryl group Type 2 Fluorophenyl group MAL

33. Le statine inibiscono la biosintesi del mevalonato HMG-CoA HMG-CoA reduttasi STATINE Mevalonato Geranyl-difosfato Geranylgeranyl difosfato Dolicolo Farnesyl-difosfato Squalene Ubiquinone Colesterolo

34. R R R R Anti-hyperlipidemic Drugs - Statins

35. Anti-hyperlipidemic Drugs - Statins Atorvastatin Cerivastatin Fluvastatin Rosuvastatin Pitavastatin

36. HMG CoA substrate For example, Mevastatin Lovastatin Simvastatin For example, Fluvastatin Atorvastatin Cerivastatin Anti-hyperlipidemic Drugs - Statins Rationale – competitive binding

37. Anti-hyperlipidemic Drugs - Statins Pharmacokinetic properties of statins – case of cerivastatin Typically all statins possess side effects. The most dominant side effect, cited in the withdrawal of cerivastatin, is rhabdomyolysis (lysis of rhabdomyose) or weakening of skeletal muscles.

38. MECCANISMO D’AZIONE DELLE STATINE STATINE Riduzione attività HMG CoA reduttasi Deplezione del pool di colesterolo nell’epatocita Aumento espressione recettori LDL epatici Diminuita produzione di VLDL Alterata composizione delle VLDL Aumento clearance LDL circolanti

39. STATINE DI I GENERAZIONE MEVASTATINA e’ stata la prima sostanza scoperta, è stato isolata da colture di specie di Penicillum LOVASTATINA è un analogo della mevastatina, con aggiunto un gruppo metile E’ stato isolato da colture di Aspergillus. Molecola lipofila, emivita: 2-3 ore. PRAVASTATINA è anch’esso un analogo della mevastatina, con aggiunto un gruppo idrossilico. Molecola idrofila, emivita: 1 ora.

40. STATINE DI II GENERAZIONE SIMVASTATINA di derivazione semisintetica. Molto simile alla lovastatina. Indicata: • ipercolesterolemia primaria • Ipercolesterolemia familiare nella variante eterozigote • iperlipidemia mista (tipo IIa e IIb) • STATINE DI III GENERAZIONE • FLUVASTATINA è una molecola • sintetizzata chimicamente. • Molecola idrofila, ha una breve emivita.

41. STATINE DI IV GENERAZIONEATORVASTATINA di derivazione sintetica. Molecola lipofila, con una lunga emivita (13-16 ore).Indicata:- ipercolesterolemia familiare nella variante omozigote- ipercolesterolemia primaria- iperlipidemia mista (tipo IIaIIb) CERIVASTATINAdi derivazione sintetica. Molecola idrofila, emivita: 2-3 ore. E’ circa 100 volte più potente rispetto alle altre statine. Ritirata dal commercioperché si sono manifestati casi di rabdomiolisi mortale per sovradosaggio o per l’associazione con altri farmaci ipocolesterolemizzanti.

42. Prostata O Testicoli Ca (3R, 5S) H O Surrene O Tiroide O H Cervello Cervelletto trasporto attivo per alta affinità con un sistema organo-specifico (OATPs :Organic Anion Transport Proteins) F Occhio C H 3 Milza Ileo C H 3 Cuore Polmone N N Rene Fegato H C 3 N C H S 3 0,0 0,2 0,4 0,6 0,8 1,0 O O CLUptake(mL/min/g tessuto) ROSUVASTATINA • Gruppo polare metan-sulfonico • La più potente statina: 10-80 mg/dl riduzione LDL-C da 34%-65% e fino a 90% /2 sett. • Diminuzione apolipoproteina b e trigliceridi 10-35% • Aumento HDL da 9-14% • Basso rischio di interazioni con altri farmaci

43. SINTESI SIMVASTATINA

44. SINTESI SIMVASTATINA

45. SINTESI SIMVASTATINA

46. FARMACOCINETICASono somministrate per os ed hanno un assorbimento variabile. • Simvastatina:85% di assorbimento • Pravastatina:30% assorbimento • Fluvastatina:assorbita quasi completamente • Hanno tutte un esteso effetto di primo passaggio che, per la lovastatina e la simvastatina, serve per dare origine al farmaco attivo. • Sono strettamente legate alle proteine plasmatiche (50% pravastatina, 95% le altre) • Escrete quasi completamente per via intestinale. • Vengono generalmente somministrate in unica dose serale, perché la sintesi di colesterolo segue un ritmo circadiano, aumentando la notte.

47. Differenze farmacocinetiche delle statine:metabolismo epatico Pravastatina Lovastatina Rosuvastatina Simvastatina Cerivastatina Fluvastatina Atorvastatina 50 – 80% <5% CYP2C9 CYP3A4 CYP2C8 Prodotti di degradazione attivi o inattivi

48. FDA Approves LIVALO(R) For Primary Hypercholesterolemia And Combined Dyslipidemia Pitavastatin LIVALO(R) (pitavastatin), a potent HMG-CoA reductase inhibitor (statin). MAL

49. Livalo is a fully synthetic and highly potent statin engineered in Japan. Livalo differs from other, currently available statins in the U.S. in that it has a unique cyclopropyl group on the base structure. This cyclopropyl group contributes to a more effective inhibition of the HMG-CoAreductase enzyme to inhibit cholesterol production, and potentially affords greater low-density lipoprotein cholesterol (LDL-C) clearance and reduction of plasma cholesterol. Importantly, pitavastatin is only minimally metabolized by the liver through the cytochrome P450 pathway, through which many other medications are metabolized. • In pivotal Phase III trials, Livalo effectively reduced LDL-C and improved other parameters of lipid metabolism in special patient populations, including the elderly, patients with diabetes and patients at higher cardiovascular risk. The overall safety and tolerability of Livalo are consistent with other commonly prescribed statins.

50. Livalo is expected to launch in the U.S. during Q1 of 2010 and will be available in 3 low dosages (1 mg, 2 mg and 4 mg). After a thorough review of the statin market, KPA is also seeking a co-promotion partner in order to broaden the reach of KPA's rapidly growing internal sales force. Partnering with another organization to expand the sales efforts for this product is aligned with KPA's long-term vision to become a leader in the cardiometabolic therapeutic arena. • Since its launch in Japan, South Korea, Thailand and China, Livalo has been successfully used in these countries to treat primary hypercholesterolemia and combined dyslipidemia, and has accumulated millions of patient-years of exposure. It is frequently prescribed in these countries as first-line therapy for a broad range of patients including the elderly, patients with diabetes and those whose treatment is complicated by concurrent disease and concomitant medications.