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12/4/2010
1
Antiretroviral Pharmacology
Dept. Pharmacology & TherapeuticSchool of Medicine
Universitas Sumatera Utara
Different living organisms
Eucaryotes Mono or polycellular
Cell nucleus; DNA
May have cell wall
Sexual and/or asexual
replication
Animals
Plants
Fungi
Protocista (protozoea, algea)
Procaryotes Bacteriea
Monocellular, no nucleus –
DNA single strand
Cell wall, asexual replication
Virus RNA or DNA + protein coating
(not really a cell)
Use other organisms
ribosomes for protein
synthesis
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INFEKSI VIRUS
• PELEKATAN VIRUS DAN DINDING SEL
(DIHIDROLISA OLEH ENZIM VIRUS)
• DNA/RNA MASUK KE DLM SEL SEDANG CAPSID TIDAK
• VIRUS SEBAGAI PARASIT, MENGGUNAKAN PROSES ASIMILASI SEL � VIRION BARU
• ( PERBANYAKAN VIRION SAMPAI PUNCAK �GEJALA PENYAKIT )
Antiviral Drugs
• Amantadine and analogs
• Neuraminidase Inhibitors
• Nucleoside analogs - Antimetabolites
• Other comp. that interfere with replication
• Comp. that interfere with translation (protein synth)
• Interferon / interferon inducers
Specific retroviral drugs
• Reverse transcriptase inhibitors– Nucleosides (NRTIs)
– Non-nucleosides (NNRTIs)
• Protease inhibitors
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Klasifikasi Antivirus berdasarkanMekanisme KerjanyaMekanisme Kerja Antivirus
Menghalangi penetrasi γ Globulins
Menghalangi uncoating Amantadine & Rimantadine
Menghambat sintesis protein awal Formivirsen
Menghambat sintesis asam nukleat 1. Analog purin & pirimidin (Acyclovir, Valacyclovir, Famciclovir, Penciclovir, Ganciclovir, Idoxurudine, Sorivudine,Trifluridine, Cidofovir, Vidarabine, Ribavirine)
2. Pyrophosphate anorganic (Foscarnet )
3. NRTI (Zidovudine, Lamivudine, Stavudine
Didanosine, Zalcitabine, Abacavir)
4. NNRTI (Nevirapine, Delavirdine, Efavirenz )
Menghambat sintesis protein akhir Inhibitor protease (Saquinavir, Ritonavir, Indinavir, Nelfinavir, Amprenavir)
Menghambat perakitan Rifampin
Menghambat rilis Inhibitor neuraminidase (Zanamivir, Oseltamivir)
Menghambat penetrasi, uncoating, sintesis mRNA, translasi, perakitan,rilis
Interferon
RT
Provirus
Proteins
RNA
DNA
RNA
DNA
DNA
RT
RNA
RNA
DNA
DNA
DNA
Viral regulatory
proteins
Viral protease
Reverse
transcriptase
Viral integrase
Viral zinc-finger
nucleocapsid
proteins
Fusion
inhibition
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Antiretroviral Classes
�NRTIs (Nucleoside OR Nucleotide Reverse Transcriptase Inhibitors, aka “Nukes”)
�NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors, aka “Non-Nukes”)
�PIs (Protease Inhibitors)
�Fusion Inhibitors
�Chemokine Receptor Antagonists
�Integrase Inhibitors
Mechanism of Action of ARVs
NNRTI
NRTI
Protease
Inhibitor
Illustration by David Klemm
Fusion Fusion Fusion Fusion Inhibitor &Inhibitor &Inhibitor &Inhibitor &ChemokineChemokineChemokineChemokineReceptor Receptor Receptor Receptor AntagonistAntagonistAntagonistAntagonistIntegrase
Inhibitor
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NRTIs
(Nucleoside OR Nucleotide
Reverse Transcriptase Inhibitors)
Nucleoside Reverse Transcriptase Inhibitors
Nucleoside analogs without 3’ OH - DNA chain terminationPro-drugs - Phosphorylated by kinases in vivo
HN
N
O
O
O
HO
N3
Zidovudine (AZT)
Retrovir®Trizivir® Kombi prep.
HN
N
O
O
O
HO
Stavudine
Zerit®
N
N
O
O
NH2
HO
Zalcitabine (ddC)
N
N
O
S
O
NH2
HO
Higher bioavail. than ddC
Lamividine (3TC)
Epivir®Trizivir® Compivir ® Kombi prep.
Didanosine (ddI)
Videx®
HN
N N
N
O
OHO
in vivo N
N N
N
NH2
OOPPP
N
N N
N
HN
HO
H2N
Abacavir (ABC)
Trizivir® Kombi prep.
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NRTIs (Nucleoside OR Nucleotide Reverse Transcriptase Inhibitors)
Drug Std Dose Dosage forms Side Effects Elimination
Zidovudine
(ZDV/AZT)
Retrovir
300mg bid* 300mg tab,
100mg cap,
iv, oral soln
Fatigue, malaise, HA
myalgia, anemia, GI
Renal
Lamivudine
(3TC) Epivir
150mg bid* or
300mg qd
150, 300mg tab,
oral soln
Well tolerated Renal
Emtricitabine
(FTC) Emtriva
200mg qd* 200mg cap Well tolerated Renal
Didanosine
(ddI) Videx
400mg EC qd (≥
60kg)
250mg EC qd
(<60kg)*
125,200,250,
400mg cap,
pwdr for soln
Pancreatitis,
peripheral
neuropathy,
LA/HS
Renal
Stavudine
(d4T) Zerit IR
40mg bid (≥ 60kg)
30mg bid (<60kg)
15,20,30,40 mg
cap,oral soln
Peripheral
neuropathy,
Pancreatitis, LA/HS,
Lipoatrophy,
facial wasting
Renal
Abacavir
(ABC) Ziagen
300mg bid,
600mg qd
300mg tabs, oral
soln
hypersensitivity Hepatic by alcohol
dehydrogenase and
glucuronyl transferase
Tenofovir
(TDF) Viread
300mg qd* 300mg tabs Few SEs,
renal toxicity
Renal
NRTIsMechanism of Action
� Nucleoside analogs (like AZT below)� Analog of thymidine, cytosine, adenine, or guanine
� Triphosphorylated inside lymphocytes to active compound
� Incorporate into the growing HIV viral DNA strand by reverse transcriptase
� Nucleotide analog� Currently only tenofovir (TDF)
� Does NOT need to be tri-phosphorylated only di-phosphorylated to active compound
� After incorporation of
the NRTI, viral DNA
synthesis will be
terminated.
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NRTI Class Toxicities
• Lactic Acidosis– Damage to mitochondria in cells
– Elevated lactate, low pH/bicarbonate, N/V, shortness of breath, if untreated can lead to death
– Lactic acidosis can occur with any NRTIs
• Hepatomegaly with Steatosis– Build up of fat droplets
inside liver cells
– Enlarged liver
Non-nucleoside Reverse
Transcriptase Inhibitors
(NNRTIs)
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Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)
Efavirenz / Sustiva
Stocrin®
NH
NN
N
MeO
Nevirapin
Viramune®
O
NH
Cl
O
F3C
FDA 1998Already resistance
Binds directly to TR
NNRTIs
Drug Std Dose Dosage forms Side Effects Elimination
Delavirdine(DLV)
Rescriptor
400 mg tid 100mg tab, 200mg cap
Rash Potent CYP3A inhibitor; 3A4 substrate
Nevirapine(NVP) Viramune
200 mg qd x 14 d then200 mg bid
200mg tabs, Oral susp
Rash (SJ), hepatotoxicity
CYP3A inducer, auto inducer; 3A4, 2B6 substrate
Efavirenz*(EFV) Sustiva
600 mg qhs 50, 100, 200mg cap, 600mg tab
Vivid dreams, drowsiness or insomnia, rash (SJ), hyperlipidemia
CYP3A, 2B6 inducer; 2B6, 3A4 substrate
*Pregnancy Class D
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NNRTIsMechanism of Action
These agents directly bind to reverse transcriptase to inhibit transcription
NNRTIs do not
require
phosphorylation
to be active
RT
Protease Inhibitors (PIs)
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Saquinavir (green) bound to HIV-1 ProteaseHN
NH
OH
PhO
O
N
H
H
O
NH2
NHO
Saquinavir
Fortovase®
Indinavir
Crixivan®
Nelfinavir
Viracept®Amprenavir
Agenerase®
Lopinavir
Kaletra®
O
HN
NH
N
OH
PhO
PhO
NH
O
OH
O
HN
OHPh
N
N
N
O NH
HN
OH
S
Ph
O
OH
H
H
O NH
HN O
OH
PhO
ON
S
O O
Protease Inhibitors
Protease Inhibitors (PIs)Drug Std Dose Dosage forms Side Effects Metabolism
Atazanavir(Reyataz) (1)
400qd or 300/ rtv 100qd
100, 150, 200mg caps
Hyper-bilirubinemia, PR prolongation
3A substrate; 3A and UGT1A1 inhibitor
Fosamprenavir (Lexiva) (1)
1400mg bid; 700/100 RTV mg bid; 1400/200 RTV mg qd
700mg tabs (Agenerase-APV liq available)
Rash, GI intolerance, caution with sulfur allergy
3A4, Pgpsubstrate; 3A4 inducer/Inhibitor
Tipranavir(Aptivus) (1,2)
500/200 RTV mg bid
250mg caps Hepatotoxicity, Increased bleedingcaution with sulfur allergy
3A4, Pgpsubstrate; 3A4, inducer/inhibitor??; Pgpinducer
Darunavir(Prezista) (1)
600/100 RTV mg bid
300mg tabs Diarrhea, nausea, nasopharyngitis
3A4 substrate;3A4 inhibitors
Ritonavir(Norvir) (1,2)
Used as a PK booster 100-200mg
100mg caps; 80mg/mL
Nausea,vomiting, diarrhea, GI upset
2D6, 3A4, Pgpsubstrate; 3A4, Pgp inhibitor
(1) Take with Food; (2) Must be refrigerated
** All PIs except atazanavir can increase lipids and cause insulin resistance
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Protease Inhibitors (PIs):Mechanism of Action
� Protease enzyme cleaves HIV precursor
proteins (gag/pol polyproteins) into
active proteins that are needed to
assemble a new, mature HIV virus.
XHIV
� PIs bind to protease
preventing the
cleavage and inhibiting
the assembly of new
HIV viruses
Dose adjustments to consider
Renally-eliminated
NRTIs (except Abacavir)
Adjust for CrCl <50 ml/min or dialysis
Didanosine
Emtricitabine
Lamivudine
Stavudine
Tenofovir
Zidovudine
Reference: Drug product info and
DHHS guidelines (see tables)
Hepatic Metabolism
∼ NNRTIs
∼ PIs
Adjust for certain inducers, substrates, or inhibitors of P450 system
Adjust for insufficiency
Indinavir
Fosamprenavir
Atazanavir
Avoid
Amprenavir oral soln
Foasmprenavir (+/- ritonavir)
Tipranavir
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Fusion Inhibitor
• Fuzeon (Enfuvirtide, T-20)
See Kilby and Eron, NEJM 2003;348:2228-38
Fuzeon : Enfuvirtide (T-20)
• FDA-approved fusion inhibitor; 36 AA peptide
– Requires 106 steps to manufacture
• Dose: 90 mg sq bid
• side effects:
– injection site rxn, hypersensitivity (rare)
• resistance: changes in gp41 (cell surface protein)
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Chemokine Receptor Antagonists
• Marviroc (Selzentry®)
• CCR5 or CXCR4 receptors on cell surface
• Virus will bind to one of the 2 receptors
– Some patients’ virus will bind to either receptor
• Marviroc blocks viral entry at CCR5
• Dosed 300mg BID
– 150mg BID with P450 inhibitors
– 600mg BID with P450 inducers
Integrase Inhibitors
• Raltegravir (Isentress™)
• Dosed 400mg BID (1 tab BID)
• No induction or inhibition on CYP450 enzymes
or Pgp
• Metabolized by UGT1A1 (glucuronidation)
– Only affected by drugs that inhibit or induce UGTs
(ie, rifampin)
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Drug InteractionsDrug Interactions
ARV metabolism, induction, and inhibition
Drug Substrate Inhibits Induces
Efavirenz 2B6, 3A4 3A4 3A4, 2B6
Nevirapine 3A4, 2B6 3A4
Ritonavir 2D6, 3A4, Pgp 3A4, 2D6, Pgp 2D6 (at high doses only)
Saquinavir 3A4, Pgp 3A4
Nelfinavir 2C19 (M8→3A4) 3A4
Amprenavir 3A4, Pgp 3A4 (in vitro) 3A4 (in vivo)
Fosamprenavir 3A4, Pgp 3A4 (in vitro) 3A4 (in vivo)
Lopinavir/ritonavir 3A4, Pgp 3A4 2C9, 2C19, 1A2
Atazanavir 3A4, Pgp 3A4, UGT, 1A2
Tipranavir 3A4, Pgp 3A4 Other enzymes
Darunavir 3A4, Pgp 3A4
Maraviroc 3A4, Pgp
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Cytochrome P450: Non-Antiretrovirals
Cyp. Substrate Inhibitor Inducer
3A4 Macrolides,cyclosporine, CCB, statins, azoles, PDE5 inhibitors, aprepitant, midazolam, triazolam
Cimetidine, Macrolides, FQs, SSRIs, CCB, azoles, aprepitant
rifamycins, phenytoin, CBZ, St. John’s wort, aprepitant, garlic
2D6 nortriptyline, amitriptyline, tramadol, trazodone, opiates, paroxetine, metoprolol, propranolol, carvedilol
Haldol, SSRIs, cimetidine, amiodarone
rifamycins, phenytoin, CBZ, St. John’s wort
1A2 Amitriptyline, clozapine, caffeine, clozapine, imipramine, R-warfarin, theophylline, proprnaolol
FQs, azoles, macrolides,
rifamycins, phenytoin, CBZ, smoking, St. John’s wort
2C19 Omeprazole, phenytoin SSRIs, azoles, fluvastatin, omeprazole, topiramate
rifamycins, CBZ, phenytoin
2C9 S-warfarin, sulfonylureas, phenytoin, carvedilol
Amiodarone, SSRIs, azoles, amiodarone
Phenytoin, CBZ, rifammycins, aprepitant
Protease Inhibitors and Acid
Suppression
• Do Not combine Atazanavir and Proton Pump
Inhibitors
– May Combine ATV and Famotidine but dose
adjustments are REQUIRED
• May use Indinavir with PPIs but ONLY if
coadministered with RTV
• May use Fosamprenavir with Esomeprazole
– Separate FPV from H2 blockers if used
concomitantly
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Important Drug Interactions
• Do NOT use Simvastatin, Lovastatin, Antiarrthymics, Midazolam, Triazolam, Ergot derivatives, Rifamin, St. Johns Wort, or Garlic with most PIs or DLV
• Do NOT combine Rifampin with PIs
– LPV/RTV may be dose increased and combined with Rifampin
– Conflicting data with EFV and NVP
• Use other P450 inducers with CAUTION when combining with PIs and NNRTIs
• Do NOT use Fluticasone or Alfuzosin with Ritonavir
• Caution with Azoles, Clarithromycin, Oral Contraceptives, Phenytoin, Carbamazepine, Phenobarbital, Methadone, PDE5 inhibitors, Atorvastatin, Beta blockers, when combined with PIs
• Avoid Herbal Products with Known or Suspected Interactions
• When combining Protease Inhibitors, Often Dose Adjustments are Necessary
PI/ NNRTI/ Antidepressant
Drug Interactions Anti-
depressant
Potential for
Interaction
Effects Management
Amitriptyline ritonavir, lopinavir/r,
amprenavir,
Levels of amitriptyline may be increased
Start with lower dose (50%) of amitriptyline, adjust dose when addIng ritonavir. Monitor for side
effects
Fluoxetine ritonavir, lopinavir/r, all other PIs, efavirenz
Levels of both fluoxetine and
ARVs may be increased
As above
Sertraline ritonavir, lopinavir/r, all other Pis, efavirenz
Levels of sertraline may be increased. ARV levels
not likely to change.
As above
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PI Drug Interactions
• All PIs are metabolized all or in part by the
CYP3A4 enzyme system
• All PIs can inhibit CYP3A4 enzymes
– Ritonavir most potent inhibitor
– Saquinavir least potent inhibitor
• Ritonavir can also induce CYP1A2
ARV Interactions with Recreational Drugs
Effect Comments
Alcohol Abacavir AUC ↑ 41% Clinical significance unknown
Amphetamines RTV may ↑ amphetamine levels
Potential amphetamine toxicity
Barbiturates Potential ↓ levels of PIs and NNRTIs
Potential virologic failure/resistance
Benzo-diazepines ↑ Midazolam and triazolamlevels with PIs and delavirdine(levels of alprazolam and
clonazepam may ↑)
Potential benzodiazepine toxicity
λ-hydroxybutyrate(GHB)
Potential ↑ GHB levels Potential GHB toxicity
Heroin Potential enhanced heroin effect
Clinical significance unknown
Marijuana Minimal effect on IDV and NFV Interaction with ARVs
unlikely
3,4-MDMA (Ecstasy)
Potential ↑ ecstasy levels Potential ecstasy toxicity
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Dirgahayu negeriku
Dirgahayu FK USU
KEBANGGAAN INDONESIA UNTUK DUNIA
ANTIRETROVIRAL
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ARV dibagi dalam 6 kelas:
• Nucleoside reverse transcriptase inhibitors
(NRTIs)
• Nonnucleoside reverse transcriptase inhibitors
(NNRTIs)
• Protease inhibitors (PIs)
• Integrase inhibitors (IIs)
• Fusion inhibitors (FIs)
• Chemokine receptor antagonists (CRAs)
• Difosforilasi oleh enzim seluler untuk menjadi bentuk
aktif
• NRTI toksik terhadap hati kecuali Lamivudine dan
Abacavir
• Secara umum bekerja untuk menghentikan
pembentukan rantai DNA virus
• Monitoring kepada toksisitas oleh karena obat
Nucleotide Reverse Transcriptase Inhibitor
(NRTI)
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• Bentuk aktif berupa azido-deoxythymidine
monophosphate (AZT-MP)
• Bekerja menghalangi sintesis DNA
• Obat diserap dengan baik melalui oral, dapat
menembsu sawar otak
• SE: toksisitas sumsum tulang, sakit kepala
• Resistensi jarang terjadi
Zidovudine (AZT)
• Bentuk aktif berupa dideoxyadenosine
monophosphate
• Sama dengan AZT, ddl juga bekerja pada rantai
DNA
• Makan saat puasa,saat kondisi basa
• Dapat juga memasuki CSF, ttapi tidak seluas
AZT
• SE: pancreastitis
• Resistensi terjadi pada terapi yang panjang
Didanosine (ddl)
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• Digunakan bersama AZT
• Bentuk aktif berupa triphosphate
• Bekerja pada rantai DNA
• Penggunaan secara oral, hindari penggunaan
bersama antasida
• SE: Rash dan stomatitis, periferal neuropati
• Tidak boleh digunakan bersama pentamidine, dapat
menyebabkan pankreatitis
Zalcitabine (ddC)
• Bentuk aktif berupa triphosphate
• Bekerja menghentikan rantai DNA
• Diabdsorbsi dengan sangat baik tanpa dipengaruhi
makanan
• SE: periferal neuropati
Stavudine (d4T)
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• Dikombinasikan dengan AZT, tidak boleh digunakan
dengan ddC
• Menyebabkan terminasi sintesis rantai DNA virus
• 3TC dapat mengembalikan sensitiviras terhadap AZT
• Penggunaan secara oral
Lamivudine (3TC)
• Merupakan analog dari guanosine
• Penggunaan secara oral
• SE: gangguan pencernaan, sakit kepala, dan pusing
Abacavir
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• Analog nukleotid
• Menghambat reverse trankriptase
• Dimakan pada saat setelah makan
• SE: mual, muntah, diare
Tenovovir
• Derivatif dari lamivudine
• Menghambat reverse transkriptase
• Dikonsumsi secara oral
• SE: sakit kepala, diare, mual, dan kulit merah gatal
Emtricitabine
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• Tn H, harus segara cuci tangan debgan air dan sabun
serta melaporkan diri ke pihak rs dan segera
mengeluasi pajanan. Kode pajanan 3 dan status 2
dan diperlukan profilaksis obat AZT Zidovudin (3 kali
sehari 200mg ) dan dikombinasi dgn lamivudin
300mg/hari dan Idanavir 3 kali sehari 800mg per oral
dan nelvinapir 3 kali sehari 800 mg per oral.Tn H
harus lakukan follow up 3 bulan dan 6 bulan pasca
pajanan.
Nucleoside Reverse Transcriptase Inhibitors
� Abacavir (ABC, Ziagen)
� Didanosine (ddI, Videx)
� Emtricitabine (FTC, Emtriva)
� Lamivudine (3TC, Epivir)
� Stavudine (d4T, Zerit)
� Tenofovir (TDF, Viread)
� Zalcitabine (ddC, Hivid; no longer available in the United States)
� Zidovudine (ZDV, Retrovir; formerly azidothymidine [AZT])
Mekanisme kerja
� NRTIs menghambat replikasi HIV melalui inhibisi secara kompetitif HIV reverse transcriptase dan terminasi rantai DNA.
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Therapy of HIV Infection• Nucleoside-Analog Reverse Transcriptase Inhibitors (NRTI).
– These drugs inhibit viral RNA-dependent DNA polymerase (reverse transcriptase) and are incorporated into viral DNA (they are chain-terminating drugs).
– Zidovudine (AZT = ZDV, Retrovir) first approved in 1987 – Didanosine (ddI, Videx) – Zalcitabine (ddC, Hivid) – Stavudine (d4T, Zerit) – Lamivudine (3TC, Epivir)
• Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs). – In contrast to NRTIs, NNRTIs are not incorporated into viral DNA; they inhibit HIV
replication directly by binding non-competitively to reverse transcriptase. – Nevirapine (Viramune) – Delavirdine (Rescriptor)
• Protease Inhibitors. – These drugs are specific for the HIV-1 protease and competitively inhibit the
enzyme, preventing the maturation of virions capable of infecting other cells. – Saquinavir (Invirase) first approved in 1995 – Ritonavir (Norvir) – Indinavir (Crixivan) – Nelfinavir (Viracept)
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