MAL

1
NUOVE STRATEGIE NEL TRATTAMENTO DELLA DISLIPIDEMIA
Prof. Paolo de Caprariis
MAL
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2
Altered coagulation And fibrinolysis
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)
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)
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
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
8
FARMACI IMPIEGATI NELLE DISLIPIDEMIE

• Niacina, 1955
• Resine sequestranti acidi biliari, 1961
• Fibrati, 1967
• Statine (inibitori HMG-CoA reduttasi), 1987
• Inibitori dellassorbimento del Colesterolo
  (ezetimibe), 2002
• Terapia combinata, 2004-2005

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 20008651-56
11

• DRUG DESCRIPTION
• NIASPAN (niacin tablet, film-coated
  extended-release), contains niacin, which at
  therapeutic doses is an antihyperlipidemic agent.
  Niacin (nicotinic acid, or 3-pyridinecarboxylic
  acid) is a white, crystalline powder, very
  soluble in water, with the following structural
  formula
• NIASPAN is an unscored, medium-orange,
  film-coated tablet for oral administration and is
  available in three tablet strengths containing
  500, 750, and 1000 mg niacin. NIASPAN tablets
  also contain the inactive ingredients
  hypromellose, povidone, stearic acid, and
  polyethylene glycol, and the following coloring
  agents FDC yellow 6/sunset yellow FCF Aluminum
  Lake, synthetic red and yellow iron oxides, and
  titanium dioxide.

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
N223
Carlson L.A. J.Internal Medicine 200525894-114
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Mechanisms of Action of Nicotinic Acid
Knopp R. NEJM 1999341498-511
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Flushing Out the Role of GPR109A (HM74A) in the
Clinical Efficacy of Nicotinic Acid
Pike N. JCI 20051153400-3403
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Vit E 800UI Vit C 1000mg Beta Carotene
25mg Selenium 100ug
Simva 10-40mg Niacor 2000mg
34
33
39
40
N
Brown G.NEJM 20013451583-1592
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Brown G.NEJM 20013451583-1592
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Wolfe M. Am.J Cardiology 200187476-489
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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
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• 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 (gt 7 days), re-titration as
  tolerated is recommended. Simcor tablets should
  be taken whole and should not be broken, crushed,
  or chewed before swallowing.

21
RESINE LEGANTI I SALI BILIARI

• Sono disponibili due molecole
• COLESTIRAMINA
• COLESTIPOLO CLORIDRATO
• Dal punto di vista chimico sono
• resine che legano anioni
• Meccanismo dazione
• 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
• ß-bloccanti
• antibiotici

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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 tradename Cholestagel.
• 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.

23
ConstituentsThe compounds which constitute the
polymer colesevelam are
N-prop-2-enyldecan-1-amine trimethyl-6-(prop-2-e
nylamino)hexylazanium 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-a-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-CoA reductase, 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.

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• 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-CoA
  reductase inhibitor (known more commonly as a
  statin) can further lower cholesterol levels.

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DERIVATI DELLACIDO 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 lalbumina
  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 2005182199-207
28
(No Transcript)
29
Rate of Rhabdomyolysis With Fenofibrate
Statin Versus Gemfibrozil Statin
Jones P. Am.J. Cardiol. 200595120-122
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Fenofibrate Resulted in a 33 Times Lower
Rhabdomyolysis Reporting Rate than Did
Gemfibrozil
Jones P. Am.J. Cardiol. 200595120-122
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Grundy S. Am.J. Cardiology 200595462-468
32
Structural Mechanism for Statin Inhibition of
HMG-CoA Reductase
Simvastatin
Atorvastatin
Type 1 Butyryl group
Type 2 Fluorophenyl group
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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
Anti-hyperlipidemic Drugs - Statins
35
Anti-hyperlipidemic Drugs - Statins
Atorvastatin Cerivastatin

Fluvastatin
Rosuvastatin
Pitavastatin
36
Anti-hyperlipidemic Drugs - Statins
Rationale competitive binding
37
Anti-hyperlipidemic Drugs - Statins
Pharmacokinetic properties of statins case of
cerivastatin
Bioavail. Dosage (mg) Protein Binding Metabolites
Atorvastatin 14 10 80 gt98 Active
Cerivastatin 60 0.2 0.3 gt99 Active
Fluvastatin 24 10 80 98 Active
Lovastatin 5 10 80 gt95
Pravastatin 17 10 40 50
Simvastatin 5 10 - 80 95
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.
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MECCANISMO DAZIONE DELLE STATINE
STATINE
Riduzione attività HMG CoA reduttasi
Deplezione del pool di colesterolo nellepatocita
Aumento espressione recettori LDL epatici
Diminuita produzione di VLDL Alterata
composizione delle VLDL
Aumento clearance LDL circolanti
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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 anchesso 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 IIa IIb)
CERIVASTATINA di derivazione sintetica.
Molecola idrofila, emivita 2-3 ore. E circa 100
volte più potente rispetto alle altre statine.
Ritirata dal commercio perché si sono manifestati
casi di rabdomiolisi mortale per sovradosaggio o
per lassociazione con altri farmaci
ipocolesterolemizzanti.
42
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.

• Simvastatina85 di assorbimento
• Pravastatina30 assorbimento
• Fluvastatinaassorbita 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
lt5
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).
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-CoA reductase 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.

51
Selected Drugs That May Increase Risk of
Myopathy When Used Concomitantly with Statins
Adapted from Corsini A. Pharmacol.Ther.
199984413-428
52
INTERAZIONI FARMACOLOGICHE CON LE STATINEle
principali classi di farmaci a rischio

• INTERAZIONI FARMACOCINETICHE
• Inibitori CYP 3A4 Ciclosporina, Eritromicina,
  Ritonavir, Fluconazolo, fluoxetina, pompelmo (gt
  la concentrazione plasmatica delle statine)
• Induttori CYP 3A4 Barbiturici, Carbamazepina,
  Fenitoina, Rifampicina (lt la concentrazione
  plasmatica di statine)
• Inibitori CYP 2C9 Amiodarone, Cimetidina,
  Isoniazide, Chetonazolo
• (gt concentrazione plasmatica di
  fluvastatina)
• Induttori CYP2C9 Barbiturici,Carbamazepina,
  Fenitoina, Rifampicina
• (lt concentrazioni plasmatiche fluvastatina)
• Antibiotici macrolidi Eritromicina,
  Claritromicina
• Antifungini azolici ketoconazolo
• Calcio-antagonisti
• Acido nicotinico
• Benzodiazepine Diazepam, Midazolam
• Anticoagulanti cumarinici warfarin
• INTERAZIONI FARMACODINAMICHE
• Gemfibrozil fibrati

53
Altre formulazioni combinate

• Co-somministrazione statina niacina
• Advicor ( Nicostatin) combinazione di
  lovastatina e niacina
• ltLDL del 47
• gtHDL del 41
• Aumento glicemia e acido urico con
  conseguenti anomalie
• Co somministrazione statina resine
• Effetti collaterali gastrointestinali
  costipazione, gonfiore, flautolenza, dolori
  addominali
• Co-somministrazione statina fibrati
• Gemfibrozil gt concentrazione statine nel
  sangue alzando il potenziale di tossicità si
  sostituì con il fenofibrato.
• Controllo periodico
• Alanina aminotransferasi (ALT)
• Aspartato aminotransferasi (AST)
• Creatina kinasi (CK)
• Usare cautamente un trattamento combinato in
  pazienti con età superiore a 70 anni
• Se appaiono sintomi muscolari sospendere la
  terapia
• Non somministrare in pazienti con insufficienza
  epatica

54
Whole Body Cholesterol Homeostasisis Maintained
Through 3 Major Pathways
Intestinal Absorption
LDL-C
Biliary Excretion
de novo Synthesis
Bays H. Expert Opin. Investig. Drugs 2002 11
1587-1604
55
Intestinal Cholesterol Absorption is a Multistep
Process that is Regulated by Multiple Genes
Lumen
Enterocyte
Lymph
Sterol Influx Transporter
Lammert F. Gastroenterology 2005129718-734
56
Complementary Actions of Statins and Selective
Cholesterol Absorption Inhibitors
57
Assorbimento di Colesterolo nellIntestino
300700 mg
1000 mg
Plant stanols
NPC1L1

58
Ezetimibe Parametri Farmacocinetici

• Assorbimento
• Rapido,dopo somministrazione orale
• Picco di concentrazione plasmatica di metabolita
  attivo in 12 ore
• Metabolismo
• Rapidamente metabolizzato a metabolita attivo
  ezetimibe- glucuronide
• Eliminazione
• attraverso le feci
• Emivita
• 22 ore / dose giornaliera

Ezetimibe
OH
OH
N
F
O
Glucuronidazione
F
OGluc
OH
N
F
O
Glucuronide
F
59
Synthesis Ezetimibe
60
Effetti dell Ezetimibe sull Assorbimento del
Colesterolo
80
54 Riduzione dellassorbimento di colesterolo
con lezetimibe
70
60
49.8
50
Assorbimento Colesterolo 2 settimane
40
30
22.7
20
Individuali livelli di assorbimento
Principali livelli di assorbimento
10
0
Placebo
Ezetimibe
61
Effetti dell Ezetimibe sull Aterogenesi
Sezione trasversale dellarteria coronaria
Control
Ezetimibe 5 mg/kg/day
62
Nuovi approcci Ezetimibe

• La associazione di Ezetimibe con statina agisce
  attraverso la duplice inibizione della sintesi di
  colesterolo a livello epatico e di assorbimento
  di colesterolo a livello intestinale.
• La associazione di Ezetimibe 10 mg con qualsiasi
  statina al dosaggio di 10 o 20 mg produce una
  riduzione di LDL-colesterolo sovrapponibile a
  quella ottenibile con il dosaggio massimo della
  statina.
• Oltre il 70 dei pazienti che non hanno raggiunto
  lobbiettivo terapeutico in monoterapia con
  statine, lo raggiungono se si associa Ezetimibe

63
Efficacy of LDL-C Lowering with
Ezetimibe/Simvastatin Compared with Simvastatin
Alone In Patients with Primary Hypercholesterolemi
a
64
INEGY

• Inegy è indicato come terapia aggiuntiva alla
  dieta in pazienti con ipercolesterolemia primaria
  (eterozigote familiare e non-familiare) o con
  iperlipidemia mista ove sia indicato luso di un
  prodotto di associazione
• ? Pazienti non controllati adeguatamente con una
  statina da sola.
• ? Pazienti già trattati con una statina ed
  ezetimibe. Inegy contiene ezetimibe e
  simvastatina.E stato dimostrato che la
  simvastatina (20-40 mg) riduce la frequenza degli
  eventi cardiovascolari (vedere paragrafo
  5.1).Non sono stati completati gli studi per
  dimostrare lefficacia di Inegy o di ezetimibe
  nella prevenzione delle complicazioni
  dellaterosclerosi. Ipercolesterolemia familiare
  omozigote (IF omozigote) Inegy è indicato come
  terapia aggiuntiva alla dieta in pazienti con
  ipercolesterolemia familiare omozigote.I
  pazienti possono essere sottoposti anche ad
  ulteriori misure terapeutiche (per esempio,
  laferesi delle lipoproteine a bassa densità
  LDL).

65
INEGY

•  Gruppo  farmacoterapeutico  altri
   ipocolesterolemizzanti  ed  ipotrigliceridemizzan
  ti.  Codice  ATC C10A X Inegy 
   (ezetimibe/simvastatina)   è   un   prodotto 
   ipolipemizzante   che   inibisce 
   selettivamente lassorbimento intestinale del
  colesterolo e dei relativi steroli vegetali e
  inibisce la sintesi endogena del
  colesterolo. Meccanismo dazioneInegyIl
   colesterolo  plasmatico  è  derivato
   dallassorbimento  intestinale  e  dalla
   sintesi  endogena.  Inegy contiene   ezetimibe 
   e   simvastatina,   due   composti 
   ipolipemizzanti   con   meccanismi   dazione
  complementari.

66
Omega-3 Fatty Acids The Basics

• What are Omega-3 fatty acids?
• What are common dietary sources?

67
AHA Recommendations

• For patients with documented CHD, about 1g of
  EPADHA per day
• Capsules
• Low Potency - 300 mg EPADHA/g (Typical
  drug store capsules)
• High Potency - 500-700 mg EPADHA/g (CardioTabs,
  Triomega, OmegaRx)
• Pharmaceutical 850 mg EPADHA/g
• (Omacor, Reliant Pharmaceuticals)
• Cod Liver Oil
• 1 tsp (RDA for Vit. D 2x RDA Vit. A)

68
OMACOR (omega-3-acid ethyl esters) reduced
triglycerides by a median of 45 while raising
HDL-C by 9 OMACOR reduced nonHDL-C by 14
overall,) The placebo group had no significant
changes from baseline for any of the above lipid
parameters Every attempt should be made to
control serum TG levels with appropriate diet,
exercise, weight loss in overweight patients, and
control of any medical problems (such as diabetes
mellitus and hypothyroidism) that may be
contributing to the patients TG abnormalities.
69
Combination Lipid Therapy Options
Vasudevan A. Curr. Athero. Rep. 2006876-84
70
While cholesterol is necessary for many
biological functions, too much of it increases
our risk of cardiovascular diseases. Most of us
have an unfortunate appetite for foods rich in
cholesterol and some of us are genetically
predisposed to handle it worse than others, so
the scientific community is working hard to help
us control cholesterol levels.  As cholesterol
is insoluble in blood, it must be carried around
in the form of lipoproteins. One particular type
of transporter, HDL (high-density lipoprotein),
has been the focus of many research groups. HDL
carries cholesterol away from arteries to the
liver, where the cholesterol can be excreted or
reused. Having more HDL is beneficial to the
cardiovascular system, but raising HDL levels is
difficult.
71
HDL with surface proteins and cholesterol. 
Current drugs that induce our bodies to boost
HDL concentration have negative side effects,
leading some scientists to focus on mimicking HDL
with synthetic nanoparticles instead. However,
creating nanoparticles with the dynamic
activities of HDL is a serious challenge.
Scientists at Northwestern University report in
an advanced issue of the Journal of the American
Chemical Society that they have solved some of
the problems involved in creating a synthetic
HDL. Their idea was to use gold nanoparticles as
the inner cores. The gold nanoparticles act as a
scaffold that can be given the appropriate
dimensions to resemble HDL. Apolipoproteins and
phospholipids, which are present in natural HDL,
can then be layered onto the nanoparticles to
create a surface similar to HDL. With this in
mind, the researchers created synthetic HDL
nanoparticles with a diameter of about 18 nm,
making them similar in size to the biological ones
Each nanoparticle contained between 2 and 5
apolipoproteins and 80 to 160 phospholipids
chemical composition analysis showed that this
surface constitution is analogous to natural HDL.
The nanoparticles are also soluble in water,
suggesting they can dissolve in blood and move to
and from cells. To determine how well the
synthetic HDL can bind cholesterol, the
scientists used a fluorescent analogue of
cholesterol for their studies. When the
cholesterol analogues are in water, they are
weakly fluorescent when they are bound to the
synthetic HDL, their fluorescence is increased.
Using the fluorescence signal as an indicator,
the authors determined that in a 5 nM solution of
synthetic HDL, the binding affinity to
cholesterol has a dissociation constant of 3.8
nM. This is the first time that a research group
has published a value in this range for a
synthetic HDLno value is known for natural HDL,
so it's impossible to make comparisons. The
authors' approachcreating a nanoparticle that
mimics the size and functions of biological
HDLis a good starting point for further
investigations. The next steps in this line of
research include determining how well this
synthetic HDL transports cholesterol to the
liver, testing the toxicity of the nanoparticles,
and finding methods of introducing them inside
the body.
Journal of the American Chemical Society, 2009
72
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73
Anacetrapib

• Anacetrapib (codenamed MK-0859, Merck) is a CETP
  inhibitor being developed to treat
  hypercholesterolemia (elevated cholesterol
  levels) and prevent cardiovascular disease. It
  has been in Phase I clinical trials preliminary
  results appear encouraging, although long-term
  safety data are lacking.
• At the 16th International Symposium on Drugs
  Affecting Lipid Metabolism (New York, Oct 4-7,
  2007), Merck reported on a Phase IIb study. The
  eight week study reported dosage correlated
  reduction in LDL-C and increases in HDL-C levels
  with no corresponding increases in blood pressure
  in any cohort. The increase in HDL was
  particularly significant, averaging 44 percent,
  86 percent, 139 percent and 133 percent at doses
  of 10 mg, 40 mg, 150 mg and 300 mg.