Non-Cumulative Portion of Final Exam

Opioid PRN for Breakthrough Pain

10-20% of daily dose q 1-2h for cancer pain
10-20% of daily dose q 4h for chronic pain

Codeine

Metabolized to active form (morphine) by CYP2D6.
Treatment of mild to moderate pain.
Duration of Action: 2-4 hours

Morphine

MS Contin = sustained release
Dosed q 12h or q 8h.
Metabolism not significantly affected by cirrhosis.
Active metabolite accumulates if CrCl < 30 ml/min.

Morphine Metabolite Toxicity

Accumulation of morphine-6-glucuronide: drowsiness, nausea & emesis, coma, and respiratory depression

Accumulation of morphine-3-glucuronide: impaired cognitive function, myoclonus/seizure, hyperalgia

Oxycodone

OxyContin = sustained release

Dosed q 12h or q 8h.

25-50% more potent than morphine
Safe in renal insufficiency.

Hydromorphone

5-10 x more potent than morphine
Dosed q 3-4h.
No extended release available.
Safe in renal insufficiency.
Less histamine release than morphine (less itching/wheezing).

Hydrocodone

Half the potency of morphine.
Metabolized to morphine by CYP2D6

Oxymorphone

More potent than morphine.
Less likely to induce histamine release than morphine.

Fentanyl

100 x more potent than IV morphine
high lipophilicity and short half life
Dosage Forms: lozenge, patch, injectable
Safe in renal insufficiency.

Transdermal Fentanyl

change patch q 72h or q 48h.
Takes 24-48h for onset of effect.
1 mg/hr IV of morphine = 25 mcg/hr patch

Fentora Dosing (=ODT)

Dosing is not based on equianalgesic conversion from other opioids.
Initial dose is 100 mcg
titrate to effect
once titrated to effective dose, limit to ≤ 4 units a day
Indicated for breakthrough cancer pain in opioid-tolerant patients only.

Actiq

Start with 200 mcg, wait 15 min.
If no relief take another dose.
If still no relief, increase to 400 mcg lozenge for next episode of breakthrough pain.

Methadone

Long metabolic half-life (-24h)
Dosed every 8-12h (may accumulate and caused delayed toxicity.
Safe in renal insufficiency.

Meperidine

Short half-life → dosed q2-3h (IV or SC)
not recommended for chronic pain
has a toxic metabolite (normeperidine) = tremors/seizures
Renally eliminated.
Drug interaction with MAOI's.

Typical PCA Dose

50-100% of hourly CI

Side Effects of Opioids

Constipation and Urinary Retention
Nausea/Vomiting
Confusion/Delirium
Pruritis(urge to scratch)
Myoclonus(twitching)

Prevention of Constipation 2/2 Opioid Therapy

Senokot 2 tab PO HS + Docusate 300 mg PO d (both ATC)
Titrate as needed...
Max dose of senokot = 4 tabs BID
Max dose of docusate = 500 mg d
Dulcolax may be added to regimen if no BM in 48-72h

Treatment of constipation if no BM for several days...

Lactulose 30 mL PO q4h till BM
Magnesium citrate 8 oz PO
Fleet enema
Haley's magnesium hydroxide

Methylnaltrexone

New treatment for constipation caused by opioid therapy. Acts as a peripheral opioid antagonist. Blocks peripheral side effects (constipation) while not crossing the BBB to block desired effects.

downside = SC injection

Opioids for Patients with TRUE Morphine Allergy

Methadone
Fentanyl
Meperidine

Treatment of Pruritus/Rash 2/2 Opioid Therapy

Hydroxyzine
Diphenhydramine
*Should note that this is not an allergic reaction due to histamine release.

Treatment of Sedation 2/2 Opioid Therapy

Psychostimulants: Dextroamphetamine 5-10 mg BID
Use Precaution with Co-morbitities: Hypertension, Glaucoma, Seizures, Psychotic Patients, Cardiovascular Disease

Treatment of Confusion/Delirium/Hallucinations 2/2 Opioid Therapy

Occur in the first 24-48h of opioid initiation or significant dose increase.
Tolerance usually develops with 2-3 days.
If side effects continue: Haloperidol 0.5-1 mg PO BID or TID

Treatment of Myoclonus 2/2 Opioid Therapy

Usually occurs with high dose of opioids.
Switch to a different opioid and/or add clonazepam 0.25-0.5 mg PO TID

Treatment of Respiratory Depression 2/2 Opioid Therapy

Withhold 1-2 doses of opioid until symptoms resolve.
Resume opioid with 25% dose reduction once symptoms resolve.
*If patient is hard to arose or respiratory rate is < 8 breaths/min give naloxone IV

0.4 mg drug + 9 mL NS --> administer 0.5 mL over 2min
if no response, continue to max 20 mL
may need to redose 30 min later du to short half-life

Adjuvant Analgesics

Bone Pain

Bisphosphonates
Radiopharmaceuticals
Corticosteroids

Neuropathic Pain

Tricyclic Antidepressants (TCA)
Anticonvulsants
Corticosteroids *not commonly used

Metastatic Bone Disease (MBD) Pain Management

Opioid *not best agent for bone pain
+ IV bisphosphonate
+/- Anti-inflammatory (corticosteroid or NSAID)
Radiopharmaceuticals

Bisphosphonates Mechanism and Indications

Bind preferentially to bone at site of active bone metabolism.
Inhibit osteoclast activity and survival. (reduce bone breakdown)
Indications: osteoporosis, hyohercalcemia, complications of MBD
*** onset of analgesia = 8-12 weeks of regular dosing

Pamidronate (Aredia)

2nd generation Bisphosphonate
Dosing: 90mg over 1-4 hrs IV q 3-4 weeks

Zoledronic Acid (Zometa)

3rd generation Bisphosphonate
Dosing: 4mg over 15 min q 3-4 weeks

Adverse Effects of Bisphosphonates

IV: renal toxicity & acute phase reactions

Oral: GI toxicity

Osteonecrosis of the Jaw

Caused by prolonged Bisphosphonate therapy.
Reverses after therapy is discontinued.

Denosumab (Xgeva)

Fully human monoclonal antibody that binds and neutralizes receptor activator of NF-kB ligand (RANKL).
Dosing: 120mg SC q 4 weeks.
Safe in renal and hepatic dysfunction.
Administer with 1000 mg calcium and 400 units of vitamin D.
Correct any hypocalcemia before administration.

RANKL

RANKL binds RANK receptor on osteoclast precursors, promoting their differentiation.

Strontium 89 & Samarium 153

Radiopharmaceuticals for bone pain
pain relief within 1-4 weeks
analgesia lasts 3-6 months
may be administered at 3 month intervals
may cause thrombocytopenia or neutropenia

Prednisone And Dexamethasone

most commonly used corticosteroids for short term relief of bone pain
onset of effect 24-28 hours
side effects increase with dose and duration of therapy: psychosis, hyperglycemia edema, fungal infection, GI ulcers

Treatment Options for Neuropathic Pain

Opioids
Antidepressants

Tricyclic antidepressants (TCA)
Serotonin & Noradrenaline reuptake inhibitors (SNRIs)

Anticonvulsants
Topical anesthetics

TCA Antidepressants

Tertiary Amine (should not be used for NP): Amitriptyline & Imipramine

Secondary Amine (less side effects): Nortriptyline & Desipramine

TCA Antidepressant MOA

reuptake inhibition of serotonin and norepinephrine as spinal cord receptor sites
reuptake inhibition of dopamine
blockage of potassium, calcium and sodium channels
antagonism of the N-methyl-D-aspartic acid (NMDA)-receptor

TCA Dosing

Start with the lowest dose: 10-25 mg HS
Increase by 10-25 mg a day q 2-7 days
max dose = 75-150 mg a day

TCA Antidepressant Onset of Analgesia

Should be on drug for 6-8 weeks to assess for efficacy.
Should be on drug for 1-2 weeks at maximum tolerated dose.

Side Effects of TCA Antidepressants

Anticholinergic Effects: dry mouth, constipation, burred vision, urinary retention, dizziness, tachycardia, memory impairment, delirium
less severe with secondary than tertiary

Most Commonly seen Anticonvulsants used for NP

Gabapentin
Pregabalin

Stevens-Johnson Syndrome

Skin & mucous membrane reacts severely to drug or infections.

Flue-like symptoms
Painful red or purplish rash that spreads and blisters
Eventually top layer of skin dies and sheds

*Can be caused by Lamotrigine

Gabapentin (Neurontin) Dosing

start at 100-300 mg HS
increase by 100-300 mg a day q 1-7 days
maximun dose = 3600 mg a day

give TID
effective dose is usually 1200-2400 mg/day

titrate for 3-8 weeks and 1-2 weeks at max dosage to assess analgesia

Pregabalin (Lyrica)

start as 75-150 mg HS
increase by 50-150 mg weekly
max dose = 600 mg a day

give BID or TID
effective dose is usually 150-600 mg/day

titrate for 3-8 weeks and 1-2 weeks at max dosage to assess analgesia

Capsaicin

Topical used for Neuropathic Pain
Burning, stinging pain and redness initially and subsides after about 72h.
Pain Relief: 14 days, up to as long as 4-6 weeks.
Use everyday, apply 3 to 4 times a day as directed; duration of action is 4-6 hours

5% Lidocaine Patch

Topical used for Neuropathic Pain
Starting dose = max 3 patches daily for a max of 12 hours a day
12 hours on / 12 hours off
no titration needed
use for at least 2 weeks to assess for efficacy

Glutamate and Aspartate (seizures)

Both of these excitatory amino acids are found in increased level extracellular shortly after traumatic injury resulting in seizures.

Febrile

Type of seizure provoked by fever which occurs in one of of 20-50 children.
Increased excitability due to inflammatory mediators, increased temp, elevated pH, and altered NT receptor assembly.

General Seizure Model

An increase in excitatory glutamatergic activity through recurrent connections
A reduction in the activity of the normally inhibitory GABA-ergic projections.

Petit Mal

Generalized Absence Seizures.
Altered normal oscillatory rhythms of thalamo-cortical network.
During the first cycles of the seizure the cortex drives the thalamus, while therafter cortex and thalamus drive each other to produce recurrent waves.

Possible Molecular Mechanisms (seizure)

increased junctions (inc. excitatory)
decreased junctions (dec. inhibitory)
abnormal sodium, calcium, or potassium channels
inc. sensitivity to Ach

Role of GABA in seizures

GABA mediates inhibition of glutamate decarboxylase binding to GABA-A and benzodiazepine sites.
Reduced levels of GABA have been reported in studies of post epileptic brain tissue.
Many AED's work by enhancing GABA-mediated inhibition (i.e. reuptake inhibition/metabolism inhibition).

Glutamate (seizures)

Increased levels of glutamate release is observed during seizures.
Glutamate and selective agonists of glutamate channels can cause convulsions.

Different types of Glutamate Receptors

NMDA
kainate
AMPA
ibotenic acid

Ways to reduce neuronal excitability...

altering ion channels (esp. Na, K, Ca, Cl)
promoting inhibitory mediated signals or reducing excitatory mediated signals

Phenytoin AED MOA

Main mechanism is to block frequency-use and voltage-dependant neuronal sodium channels, limiting repetitive firing of action potentials.
***At usual doses there is little to no change in "normal" firing patterns (selectively targets abnormally firing neurons) = less side effects

NA channels AED mechanism

AED prolong the inactivation of the Na channels by increasing the time that the inactivation gate is closed, rather than blocking the channel itself.

Ca channels AED mechanism

AED drugs induce reduction of current(flow) through T-type Ca channels.

GABA Metabolism

Glutamate is metabolized to GABA via Glutamate decarboxylase (GAD).
GAD is Vitamin B6 dependent.
Therefore, low levels of B6 reduce GABA synthesis.

What type of receptor is GABA?

Increases Cl and Ca conductance into cell.

Effect of GABA Binding

Usually is inhibitory.
Receptor site A = Cl conductance
Receptor site B = Ca conductance

Gabapentin MOA

Increases GABA and blocks Ca channels

not a direct agonist
may also block glutamate release
also used in neuropathic pain

Pregabalin is a close analog to gabapentin.

Vigabtrin (Sabril)

inhibits GABA-T

approved for epilepsy and infantile spasms

Tiagabine (Gabitril)

GABA uptake inhibitor.

Felbamate

Inhibits NMDA, potentiates GABA.
May also inhibit glycine binding to NMDA receptor.
Stabilizes desensitized state of receptor.

Valproate

Increases GABA levels
decreases aspartate levels and release (excitatory neuron)
inhibts high frequency Na channel discharge
dec. Ca channel activity
inc. K conductance
Dec. GHB (can produce coma and seizures) = date rape drug

Topiramate

blocks sodium channels
enhances GABA at site different from BDP and barbs
blocks kainate receptor
blacks Ca channel

Seizure Classification

Partial Seizures: Simple & Complex
Generalized Seizures: Tonic Clonic (Grand Mal)
Absence Seizures: Petit Mal
Myoclonic
Status Epilepticus

Partial Seizures

simple partial seizure: consciousness is maintained
complex partial seizure: consciousness is lost
can spread and become partial seizures with secondary generalization

Absence Seizures

consciousness is maintained
usually occurs in children and is outgrown

Myoclonic Seizures

occurs usually in the morning due to lack of sleep

Lennox-Gastaut Syndrome

occurs in children
defined by triad: multiple seizure types, distinct EEG pattern of slow spike and wave discharges, usually impaired cognitive function, associated with CNS disease
poorly controlled form of epilepsy

Epilepsy in Women

Enzyme-inducing AED's can cause oral contraceptive treatment failure.
Need to treat women with a high hormonal dose of OCP and use supplemental birth control
25-30% of women have increased (or decreased) seizure frequency in pregnancy

Status Epilepticus

Seizures recur/persist within a short period of time.
baseline consciousness not regained between seizures
lasts at least 30 min
can leade to systemic hypoxia, acidemia, hyperpyrexia, cardiovascular collapse and renal shutdown

Normal Neuronal Activity Requires...

Adequate supply of: glucose, oxygen, Na, K, Cl, Ca, AA and normal pH

Important Enzymes in AED Metabolism

CYP2C9 CYP2C19 CYP3A4 CYP1A2
Glucuronyltransferase substrates: UGT1A9 UGT2B7 UGT1A4
***Gabapentin and Pregabalin are 100% renally eliminated

Penytoin Metabolism and Interactions

Metabolized by CYP2C9 and CYP2C19
Inhibitors: valproate, ticlodipine, fluoxetine, topiramate

Carbamazepine Metabolism and Interactions

Metabolized by CYP3A4, CYP1A2 and CYP2C8
Inhibitors: ketoconazole, fluconazole, erythromycin, diltiazem

Lamotrigine Metabolism and Interactions

Metabolized by UGT
Inhibitor: valproate

Pediatric AED Dosing

Neonate: often lower per kg doses

low protein binding and metabolic rate

Children: higher, more frequent doses

faster metabolic rate

Goals of AED Therapy

Ultimate = patient has a normal QOL
maximize seizure control
minimize AEDs associated risks
prevent emotional and behavioral problems

Partial Seizures (newly diagnosed) First-Line Drugs

CARBAMAZEPINE, GABAPENTIN, LAMOTRIGIN, OXYCARBAZEPINE, PHENOBARBITAL, PHENYTOIN, TOPIRAMATE, VALPROIC ACID

Partial Seizures (refractory monotherapy) First-Line Drugs

LAMOTRIGINE, OXYCARBAZEPINE, TOPIRAMATE

Partial Seizures (refractory adjunct) First-Line Drugs

GABAPENTIN, LAMOTRIGIN, LEVE, OXYCARBAZEPINE, TIAG, TOPIRAMATE, ZONISAMIDE

Generalized Seizures Absence (newly diagnosed)

LAMOTRIGINE

Primary Generalized Seizures (Tonic-Clonic)

TOPIRAMATE, VALPROIC ACID

Carbamazepine AED

Liver Metabolized (CYP3A4) 98-99% of a single dose
Major metabolite = 10-11-epoxide (active)
autoinducer (non-linear PK)
titration take 21-28 days and rapidly reverses if d/c

Carbamazepine Dosing

200 mg BID with meals
time to peak conc =2-24 hours (lvls = 4-14,cg/ml)
increased in 200 mg increments every other day
usual effective range: 600-1600mg/day, rarely 2000-3000mg/day

Oxcarbazepine AED

prodrug converted to 10-monohydrate derivative (MHD) =active form
prodrug metabolized by non-inducible cystolic ketoreductases to MHD
Protein binding: MHD>>>Oxc
MHD is inactivated by glucuronide conjugation and eliminated via kidneys

Oxcarbazepine Dosing

Start at 300-600mg/day
time to peak = 4-6hrs
max dose: 24-3000mg/day
patients being converted from CBZ, typical dose of OXC is 1.5 times the CBZ dose

Phenytoin AED

Has very slow absorption, dissolution is rate limiting step.
Metabolism: CYP2C9 and CYP2C19
Drugs can displace PHY by competing for binding sites on albumin

Phenytoin and Food

Decreased bioavailability in the presence of tube feeds
EtOH (acute): ↓ phenytoin metabolism
EtOH (chronic): ↑ phenytoin metabolism

Phenytoin Dosing

2-5mg/kg PO (200-400mg)
15-200mg/kg loading dose
max dose= 500-600mg

When to get Phenytoin Levels?

Acute/hospital setting: within 2-3 days of initiation/change, than at 6-7 days, then once weekly
Maintenance: monitor level every 3-12 months as needed
Any time an AED or CYP affecting drug is added or removed measure within 2-3 days

Lamotrigine

Rapidly absorbed (not effected by food) and almost fully metabolized by liver
Half-life dec with PHY and CBZ and increased with VPA
Watch out for the fatel Stevens-Johnson Syndrome!

Lamotrigine Dosing

Initial Dosing: 25-50 mg/day

25mg/day if on VPA

Maintenance Dosing: 300-500mg/day

100-150mg/day if on VPA

Gabapentin

Substrate of I-amino acid carrier protein in the gut system --> varies considerably among individuals i.e. dosing
eliminated exclusively by the kidneys

Gabapentin Dosing

300mg HS on the first day, increasing to 900mg/day over 3 days
should be given at least four times/day

Valproic Acid

metabolized rapidly and extensively by conjugation and beta-oxidation in the liver

Valproic Acid Dosing

Initiate 10-15 mg/kg/day
increase at weekly intervals by 5-10 mg/kg/day
max 60mg/kg/day
ER can be given once a day, convert to ER by inc 8-20%

Valproic Acid Levels

Draw a trough: 2-5 days after start or change in dose or when adding/subtracting another AED (PHY)
Therapeutic range 50-100 mg/L (total)
displaces PHY from binding sites when >700mg/L

Topiramate & Dosing

minimal protein binding
minimal hepatic transformation
25mg BID, titrate by 50 mg/day at 1 week intervals to 200-400mg/day

Phenobarbital

T1/2=2-6d
potent inducer of CYP1A1 CYP2C CYP3A
adults: 100-300 mg/day at bedtime
not used in humans as much anymore, mostly doggies.

Pregabalin

add on treatment for epilepsy
dosing: 150mg/day divided BID or TID Max= 600mg/day
can cause withdrawal symptoms upon stopping

insomnia, nausea, diarrhea

Lacosamide

add on therapy for partial seizures >17 y/o
dosing: 50mg BID inc. weekly by 100 mg/day to a target dose of 200-400mg/day
CYP2C19 substrate

Vigabatrin

Used for refractory partial seizures in adult patients whom benefits outweighs risk of possible permanent vision loss
irreversible inhibitor of Y-GABA
causes plasma dec. of PHY by 16-20%

Vigabatrin Dosing

initial: 500mg BID, increase by 500 mg incrememnts at weekly intervals depending on response
recommended dose: 1.5g BID

Alternative Generalized Seizure Therapy for Absence and Tonic Clonic

Absence: Ethosuximide & VPA
Tonic Clonic: LMT & VPA

AED Drugs that appear NOT to induce or inhibit CYP enzymes

Gabapentin GaLaLePreTiZo
Lamotrigine
Levetiracetam
Pregabalin
Tiagabine
Zonisamide

Anticoagulants & AED

PHY and Phenobarb increase metabolism of anticoagulants

Birth Control & AED

Most AEDs incease metabolism of birth control

*OCP enhance the clearance of LMT

Statins and AEDs

AED's likely to reduce effects of statins, use rosuvastatin

Antacids, PPIs and AED's

Antacids and PPIs chelate or block absorption of AEDs, enhance side effects, platelets and osteoporosis

most common dose related adverse effects of AED's

neurological/psychiatric (most common)
also, sedation/fatigue, dizziness, tremor, parasthesias, meed swings, libido changes, blurred vision

when can someone stop AED therapy

seizure free for 2-4 years
complete seizure control within 1 year of onset
onset after age 2 but before age 35
normal EEG

0-10min treating status epilepticus

IV Benzos

10-30min treating status epilepticus

IV phenytoin or fosphenytoin

30-60min treating status epilepticus

additional phenytoin or fosphenytoin
IV phenobarbital

refractory status treating status epilepticus

IV pheno, VPA
general anesthesia

treatment of status-acute

IV Benzo for immediate cessation of seizures
0.1 mg/kg lorazepam at 2 mg/min or...
0.2 mg/kg diazepam at 5 mg/min
repeat every 5 min if seizures don't stop

benzo dosage forms

oral: clonazepam and clorazepate
oral and parenteral: diazepam and lorazepam

termination of status-prolonged

phenytoin IV 15-20 mg/kg: max rate 50 mg/min
fosphenytoin IV 15-20 mg/kg: max rate 150 mg/min

Relapse-Remitting (RR)

clearly defined by acute attacks with full or partial recovery

Secondary Progressive (SP)

MS with an initial RR course followed by progression of variable rate that may include occasional relapses and minor remissions

primary progressive (PP)

MS is characterized by disease showing progression of disability from onset, without plateaus or remissions or with occasional plateaus and temporary minor improvements

progressive-relapsing (PR)

MS shows progression from onset but with clear acute relapses with or without full recovery

Favorable Indicators in MS

age of onset < 40 years
gender: female
initial symptoms: optic neuritis or sensory symptoms
attack frequency: low
disease course: relapse/remitting

Unfavorable Indicators in MS

age at onset > 40 years
gender: male
initial symptoms: motor or cerebellar symptoms
attack frequency: high
disease course: progressive

Diagnosis of MS

must demonstrate "lesions separated in space and time"
two distinct episodes in different areas of the CNS at different times

acute management of MS

steroids are often used to decrease edema in area of demyelination

hastens recovery
transiently restores BBB

mild case = no therapy
severe case = IV methylprednisolone

Interferons MOA in MS

inhibits INF-gamma activity
inhibits upregulation of adhesion molecules
inhibits production of MMP 6 and 9
inhibits transmigration of inflammatory cells across BBB

Beta-1b dosing and monitoring

dosing: 250 mcg every other day SC
monitoring

if ANC < 750/mm³ stop therapy

Beta-1a (Avonex)

dosing: 30 ug IM once weekly, no titration

Beta-1a (Rebif)

dosing: 44 ug SQ 3/week
initial 8.8 mcg 3 times/week x 2 weeks
titration: 22 mcg 3 times/week x 2 weeks
final dose: 44 mcg 3 times/week

Nab Development

All INFB's can cause Nab but rates very.
Bataseron(31%) > Rebif(15%) > Avonex(2%)
patients who remained Nab negative for at least 24 months of IFNB therapy were unlikely to develop Nab positivity

Beta-1b (Betaseron/Extavia)

dosing: 250 ug SC every other day

Glatiramar Acetate (Copaxone)

synthetic polypeptide: Glutamic acid, Lysine, Alanine, Tyrosine
may serve as T-cell decoy / blocks myelin specific autoimmune rxn
heart attack like symptoms upon injection will pass and have no risk
dosing: 20 mg SC daily

natalizumab (Tysabri)

monitored strictly due to multiple cases of progressive multifocal leukoencephalopathy (inc risk if taking immune suppresion meds)
reserved for patients who can't tolerate other therapies
recombinant humanized IgG antibody

natalizumab (Tysabri) dosing

infusion of 300 mg IV every 4 weeks

alemtuzumab (Campath)

being tried now off label to treat relapsing MS
dosing: 24 mg administered on 3-5 consecutive days annually

mitoxantrone (Novantrone)

can be used in combo with other therapies
dosing: 12 mg/m2 infusion 5-15 min every 3 months

fingolimod (Gilenya)

first oral for MS
can cause bradycardia, AV block, and other serious side effects, should be limited to patients who can't tolerate injections or break through disease on other approved therapies

Side Effects of INFB

flu-like symptoms (can be treated with APAP/NSAID or steroids)
Asymptomatic Liver Dysfunction

increased alanine aminotransferase (ALT)
betaseron=rebif > avonex

Non-Cumulative Portion of Final Exam

Pharmacy 3040 with Jeffery at University of Connecticut

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