Management of specific drug poisoning:

1

• Management of specific drug poisoning
• Antidepressants
• Barbiturates
• Benzodiazepines
• Dr. Satya Pal

University College of Medical Sciences GTB
Hospital, Delhi
2
Antidepressants drug poisoning

• Antidepressants most commonly divided into three
  categories
• Tricyclic antidepressants (TCAs)
• Monoamine oxidase inhibitors (MAOIs)
• Serotonergic drugs

3
Tricyclic Antidepressants

• Amitriptyline
• Amoxapine
• Clomipramine
• Desipramine
• Dothiepin
• Doxepin
• Imipramine
• Maprotiline
• Nortriptyline
• Protriptyline
• Trimipramine

4
Structure of TCAs
5
Tricyclic Antidepressants

• 3rd most commonly ingested medications after
  analgesics sedative-hypnotics. Also 3rd most
  common cause of overdose-related death.
• Accounts for 20-25 of fatal drug poisoning in
  the U.K. U.S.
• Deaths normally occur outside of hospital.
• Lethal dose 15-20 mg/kg (Amitriptyline).

6
Tricyclic Antidepressantsmechanism of action

• Blocking reuptake of norepinephrine and serotonin
• These effects are probably more important in
  combined overdose with selective serotonin
  reuptake inhibitors (SSRIs)

7
Tricyclic Antidepressants

• These drugs are pharmacologically "dirty" and
  bind to many other receptors
• Histamine (H1 H2) (sedation)
• a1 a2 (vasodilatation)
• GABAA (seizures )
• Muscarinic receptors (anticholinergic effects )

8
Tricyclic Antidepressantsmechanism of action on
heart

• These drugs block sodium and other membrane ion
  channels.
• The influx of sodium is the major event
  responsible for the zero phase of depolarisation
  in cardiac muscle and Purkinje fibres.

9
mv
Cardiac Action Potential
Phase 1
20
0
Phase 2
Repolarization
(Plateau Phase)
-20
Depolarization
-40
Phase 3
Phase 0
-60
-80
Phase 4
Resting membrane Potential
Na
-100
Na
ca
Na
ca
Na
Na
ca
Na
K
Na
K

m
ca
ATPase
h
K
Na
K
K
K
K
K
10
Tricyclic Antidepressants

• The duration of phase 0 in the heart as a whole
  is measured indirectly as the duration of the QRS
  complex on the ECG.
• Thus, blockade of the Na channel can be
  indirectly measured by estimating QRS width.

11
Tricyclic Antidepressants

• TCAs block voltage gated Na channels in a use
  dependent manner (i.e. block increases with heart
  rate).
• As the degree of Na channel block increases with
  use, the QRS width will increase with increasing
  heart rates.

12
Tricyclic Antidepressants

• Other cardiac effects reversible inhibition of
  the outward potassium channels responsible for
  repolarisation giving a mechanism for QT
  prolongation and arrhythmia generation
• Dose dependent direct depressant effect on
  myocardial contractility that is independent of
  impaired conduction
• alter mitochondrial function and uncouple
  oxidative phosphorylation

13
Tricyclic Antidepressantspharmacokinetics

• Highly lipid soluble.
• Rapidly absorbed
• Anticholinergic effects may prolong absorption.
• High volume of distribution.
• Protein binding gt 95
• May get saturated, increasing free fraction
• pH dependent
• Toxicity increase with acidosis
• Alkalinisation significant decrease in of free
  amitriptyline
• P450 Hepatic metabolism
• Long elimination half life eg.Amitryptiline 16
  hrs Nortryptiline 30 hrs Clomipramine 32 hrs
• Active metabolites

14
Tricyclic Antidepressants?CLINICAL EFFECTS

• Symptoms and signs at presentation depend upon
  the dose and the time since ingestion.
• Patients who are asymptomatic at six hours post
  ingestion of normal release medication do not
  normally develop major toxicity.

15
Tricyclic Antidepressants?

• There are three major toxic syndromes.
  
• -Anticholinergic effects
• -Cardiac toxicity
• -CNS toxicity
• Death in TCA overdose is usually due to CNS and
  cardiotoxic effects.

16
Tricyclic Antidepressants

• Anticholinergic Syndrome
• Hot as hell
• Blind as a bat
• Dry as a bone
• Mad as a hatter
• Thus, ask patients when they regain consciousness
  whether they're hearing or seeing anything
  strange
• A sensitive indicator for ingestion, but poor
  predictor for toxicity.

17
?Tricyclic AntidepressantsCardiac effects

• ECG changes
• Prolongation of QT interval
• Prolongation of PR interval
• Prolongation of QRS interval
• Right bundle branch block
• Right axis deviation
• Atrioventricular block
• Brugada wave (ST elevation in V1-V3 and right
  bundle branch block)

18
?Tricyclic Antidepressants

• ArrhythmiasSinus tachycardia due to
  anticholinergic activity and/or inhibition of
  norepinephrine uptake, heart blocks and
  ventricular tachycardia/ fibrillation.
• Hypotension
• Blood pressure elevated in early stages after
  overdose, due to inhibition of norepinephrine
  uptake. Later on,
• hypovolaemia,
• decreased peripheral resistance due to
  alpha-adrenergic blockade
• impaired myocardial contractility and cardiac
  output

19
?Tricyclic AntidepressantsCNS effects

• Rapid onset of decreasing consciousness and coma
  due to very rapid absorption of the drug
• Hyperreflexia , myoclonic jerks or seizure
  activity
• TCAs (eg.dothiepin, desipramine, and amoxapine)
  cause seizures more frequently and at lower drug
  concentration.
• Convulsions may lead to haemodynamic compromise.

20
Management of tca toxicity

• ?Supportive
• Resuscitation of patient.
• ECG monitoring
• ?GI Decontamination
• If patient is alert and co-operative and have
  ingested gt 5 mg/kg, charcoal may be administered
  orally at dose of 1-2 gm/kg .
• If the patient is unconscious , intubation to
  protect the airway and insert an orogastric tube,
  aspirate stomach contents then give single dose
  activated charcoal.
• Frommer, DA, Kulig, KW, Marx, JA, Rumack, B.
  Tricyclic antidepressant overdose A review. JAMA
  1987 257521.

21
Tricyclic AntidepressantsTreatment
of specific complications

• Seizures
• Diazepam 5-20 mg IV
• Phenobarbitone 15-18 mg/kg IV
• Phenytoin should be avoided ( sodium-channel
  blocking)
• Anticholinergic delirium
• Mild delirium Reassurance /- benzodiazepines
• Neuroleptics should be avoided (most of which
  have significant anticholinergic activity).

22
Tricyclic AntidepressantsBicarbonate

• Both sodium loading and alkalinisation have
  been shown to be effective in reversing TCA
  induced conduction defects and hypotension
• Dose 1-2 meq/kg
• Sodium bicarbonate is the drug of choice for the
  treatment of ventricular dysrhythmias and/or
  hypotension due to TCA poisoning
• Brown, TC, Barker, GA, Dunlop, ME,
  Loughnan, Anaesth Intensive Care 1971
  1203.Brown, TC. Med J Aust 1976 2380.Brown,
  TC. Clin Toxicol 1976 9255

23
Tricyclic Antidepressants
Intravenous Lipid emulsions A
new antidote of tca toxicity

• ILE decreased mortality from clomipramine
  toxicity by 80 when compared to placebo.
• Yoav G, Odelia G, Shaltiel C. A lipid
  emulsion reduces mortality from clomipramine
  overdose in rats. Vet Hum Toxicol 2002 44(1)30)
• ILE decreased the frequency of recurrent
  ventricular arrhythmia in a case of suspected
  imipramine overdose.

24
Monoamine oxidase inhibitors

• Low therapeutic index and potential for food
  (tyramine reaction) and drug (serotonin syndrome)
  interactions.
• Severe toxicity in overdoses.
• Includes
• Isocarboxazid
• Phenelzine
• Selegiline
• Tranylcypromine
• Moclobemide

25

• Used in refractory depression, social phobia
  disorder, panic disorder, PTST, OCD bulimia.
• MAO is intracellular enzyme bound to outer
  mitochondrial membrane which removes amine group
  from endogenous and exogenous biogenic amines
  (dopamine, norepinephrine and serotonin) by
  oxidative deamination.
• Reduction in systemic bioavailability of absorbed
  dietery biogenic amines eg. Tyramine
• MAO- A MAO- B
• Norepinephrine Dopamine
• Serotonin Tyramine

26
Mao inhibitors pharmacokinetics

• Rapidly absorbed in 1-2 hrs with 1-3 lt volume of
  distribution
• Bioavailability-50, Protein binding-50
• Metabolism- hepatic P-450
• Plasma half life- 2-4 hrs
• No significant active metabolite except selegiline

27
Mao inhibitors toxicityClinical presentation

• Lethal dose 4 - 6 mg/kg.
• Symptoms delayed 6 to 12 hours after ingestion
  but may be till 24 hours.
• Secondary to gradual accumulation of
  norepinephrine and serotonin in brain and
  peripheral sympathetic neurons leading to hyper
  adrenergic and hyperserotonergic state.
• Initial symptoms headache, agitation,
  irritability, tremor, nausea and palpitations.

28
Mao inhibitors toxicity

• Signs sinus tachycardia, hypereflexia,
  drowsiness, hyperactivity, mydriasis,
  fasciculations, hyperventilation, nystagmus, and
  generalized flushing.
• In moderate toxicity, opisthotonus, muscle
  rigidity, diaphoresis, hypertension, chest pain,
  diarrhea, hallucinations, confusion, hyperthermia
  PING-PONG gaze.
• Severe toxicity causes bradycardia, cardiac
  arrest, hypoxia, hypotension, papilledema,
  seizures, coma, and worsoning hyperthermia.

29
Mao inhibitors toxicity Tyramine reaction

• Dietary amine reaches more in MAO inhibited
  patients to systemic circulation and releases
  presynaptic stores of norepinephrine
• Most commonly by tranylcypromine than phenelzine
  or isocarboxid or levodopa
• More than 70 foods eg. aged cheese, broad (fava)
  beans, non fresh meat or fish, concentrated yeast
  extract
• Within 15-90 min after ingesting these foods.

30
Mao inhibitors toxicity tyramine reaction

• Hallmark severe occipital or temporal headache
• Hypertension, palpitation, diaphoresis,
  mydriasis, neck stiffness, pallor, chest pain
• Phentolamine is antiHT of choice. Avoid
  ß-blockers. Nitroprusside _at_ 1-4µg/kg/min
• Rapidly resolves. Asymptomatic discharged after 4
  hrs of observation.

31
Mao inhibitors toxicityManagement

• History of MAO inhibitor ingestion and
  hyperadrenergic symptoms.
• Identify hypoxia, rhabdomyolysis, renal
  failure, hyperkalemia, metabolic acidosis,
  hemolysis and DIC.
• I.V. line placement and cardiac monitoring.
• Single dose activated charcoal 1g/kg with gastric
  lavage.
• Phentolamine is antiHT of choice. 2.5-5.0 mg
  every 10-15 min continuous infusion _at_ 1-5 mg/hr.
  Nitroprusside infusion _at_ 1 µg/kg/min

32
Mao inhibitors toxicity

• Fenaldopam, short acting i.v. antiHT, acting as
  peripheral dopamine (D1 receptor) agonist, _at_
  0.05-0.1 µg/kg/min
• If hypotension, isotonic i.v. fluids
  10-20ml/kg. Norepinephrine vasopressor of
  choice
• Sinus tachycardia lidocaine, procainamide and
  phenytoin. Bradycardia atropine, isoproterenol
  and dobutamine.
• BZD anticonvulsant of choice.
• No role of hemodialysis

33
Serotonergic antidepressants

• Referred to as atypical, heterocyclic,or second
  generation antidepressants.
• Heterogeneous group of drugs
• GENERAL CHARACTERISTICS
• 1. Less cardiotoxic than TCA.
• 2. Do not inhibit MAO and not associated
  with tyramine-like reaction.
• 3. Have higher therapeutic index than MAO
  inhibitors and TCAs.

34
Serotonergic antidepressants

• 4. Mechanism of action poorly understood but
  due to inhibition of neurotransmitter uptake
  (except mirtazapine).
• 5. Unlikely to be removed significantly by
  extracorporeal mechanisms.
• 6. May interfere with metabolism of other
  drugs due to hepatic enzyme inhibition.
• 7. Not detected by standard drug screening
  tests

35
Serotonergic antidepressants trazodone

• MOA Combination of serotonin reuptake
  inhibition and antagonism of postsynaptic 5-HT2
  receptors.
• Moderately potent nonselective a1-adrenergic
  receptor blocker (five times affinity for a1 than
  a2) S/E. orthostatic hypotension
• Rapid and completely absorbed, highly protein
  bound with intermediate volume of distribution.
• Hepatic oxidation by CYT P50 with active
  metabolite, m-chlorophenylpiperazine(m-CPP).

36
Serotonergic antidepressants trazodone

• Serious toxicity if ingested gt2gm.
• Most common sign CNS depression. Other ataxia,
  dizziness, coma, and seizures with marked
  improvement in 6 to 12 hrs.
• In CVS, mostly orthostatic hypotension. Others
  are arrhythmias, conduction abnormalities or IHD.
  ECG marked prolongation of QTC interval.
• G.I nausea, vomiting and nonspecific abdominal
  pain.

37
Serotonergic antidepressantsmanagement of
trazodone toxicity

• I.V. access and cardiac monitoring should be
  started.
• Treat hypotension with fluids before initiating
  vasopressors.
• G.I. decontamination with early gastric lavage
  followed by activated charcoal.
• Coingested other drugs or ethanol leads higher
  incidence of coma, seizures and respiratory
  arrest.

38
Serotonergic antidepressantsnefazodone

• Inhibits serotonin reuptake and antagonizes
  postsynaptic 5-HT2 receptors.
• Rapidly absorbed, bioavailability of only 20,
  99 protein bound.
• Inhibit metabolism of terfenadine, astemizole,
  pimozideprolongation of QT interval and torsades
  de pointes. Symptoms includes drowsiness, nausea,
  dizziness and vomiting.
• Relatively safe, supportive care alone is
  sufficient
• Asymptomatic discharged after 6 hrs of
  observation

39
Serotonergic antidepressantsbupropion

• Inhibit reuptake of dopamine and to a lesser
  extent norepinephrine and serotonin.
• Rapidly absorbed, readily crosses BBB.
• Abrupt discontinuation Neuroleptic malignant
  syndrome due to dopamine agonist activity.
• Low therapeutic index, toxic dose more than
  450mg/day.

40
Serotonergic antidepressants bupropion

• Hallmark seizures and sinus tachycardia. Mild
  hyperthermia and hypertension may be seen.
• Peripheral I.V. line and cardiac monitoring
• Supportive care and G.I. decontamination if large
  overdoses.
• Benzodiazapines effective in stopping seizures.
• Observe asymptomatic pts. for 8 hr on monitored
  bed.

41
Serotonergic antidepressantsmirtazapine

• Instead blocks central a2-adrenergic receptor
  postsynaptic 5-HT2 and 5-HT3.
• Rapidly absorbed, 50 bioavailability due to
  significant 1st pass metabolism.
• Presents with sedation, confusion, sinus
  tachycardia and mild hypertension.
• Resolves over 24 hours with supportive care.
  Single dose activated charcoal for large overdose
  within 1 to 2 hours.

42
Serotonergic antidepressantsvenlafaxine

• Nonselective inhibitor of serotonin,
  norepinephrine and dopamine reuptake.
• Peaks in 2hrs with 27 protein bound and large
  volume of distribution, hepatic P-450 oxidation.
• 50 pts. asymptomatic. M.C. symptom drowsiness,
  progressed to coma.
• Sympathetic stimulation tachycardia,
  hypertension, diaphoresis, tremors and mydriasis

43
Serotonergic antidepressants venlafaxine

• Immediate evaluation , I.V. line and cardiac
  monitoring. 8 hrs observation is required.
• More aggressive G.I. decontamination with single
  dose activated charcoal within 1 to2 hrs.
• Benzodiazepines are anticonvulsant of choice.
• Sodium bicarbonate therapy if QRS widening
  gt100msec.

44
Selective serotonin reuptake inhibitors

• In CNS, serotonergic neurons found in brainstem
  regulating mood, personality, temperature,
  wakefulness
• 98 of body serotonin found peripherally
  regulate vascular tone, peristalsis and platelet
  activation
• SSRIs inhibit reuptake ? increasing stimulation
  of receptors.
• Includes
• -Fluoxetine -Citalopram
• -Sertraline -Escitalopram
• -Paroxetine
• -Fluvoxamine

45
Ssri pharmacokinetics

• Rapidly absorbed, reach peak within 6 hr
• High degree of protein binding
• Long elimination half life, with sustained
  biochemical activity due to active metabolites
• Metabolized in liver by cyt P-450, metabolites,
  renally excreted.

46
SSRI toxicity

• Compared with other anti-depressants, rarely
  produce fatality or serious sequelae
• Most fatalities reported with very high doses e.g
  x150 or because of coingestant.
• Unlikely to cause CNS depression or seizures
• Do not have significant cardiotoxicity (except
  citalopram, prolonged QTc)

47
SSRI toxicity

• Do not typically cause anti-cholinergic symptoms,
  significant sedation or hypotension
• May cause hyponatraemia (even at theraputic
  doses)
• Serotonin syndrome is rare unless mixed
  serotonergic ingestion or changes made in
  theraputic SSRI dosing

48
Serotonin syndrome

• Life-threatening
• Classical triad of mental status changes,
  autonomic instability and increased neuromuscular
  tone
• BUT actually spectrum from benign to lethal
• Increased serotonergic activity in CNS
• Seen with theraputic use, inadvertant
  interactions and intentional self-poisoning

49
Drugs that can precipitate serotonin syndrome

• Increases serotonin formation L-tryptophan
• Increases release amphetamines, cocaine
• Impairs reuptake cocaine, ecstasy, SSRIs,
  SNRI,TCA, St Johns Wort
• Inhibits metabolism ie MAOI linezolid
• Direct serotonin agonist triptans, LSD, fentanyl
• Increases sensitivity of receptor lithium

50
Management of ssri toxicity

• Supportive care.
• Single dose activated charcoal
• Use of sodium bicarbonate therapy if QRS
  prolongation.
• Administration serotonin antagonist
• Cyproheptadine 12mg (PO)2mg every 2 hr until
  clinical response
• ?Olanzapine, chlorpromazine
• BZD anticonvulsant of choice.

51
Barbiturates poisoning

• Originally introduced as sedative-hypnotics and
  anticonvulsants in early 1900s.
• Highest risk of morbidity and mortality among all
  sedative-hypnotics .
• Newer , relatively less toxic medication such as
  benzodiazepines largely supplanted its routine
  use.

52
Classification

• Ultra-short acting
• Thiopental Methohexital
• Short-acting
• Pentobarbital Secobarbital
• Butalbutal
• Intermediate-acting
• Amobarbital Aprobarbital
• Butabarbital
• Long-acting
• Phenobarbital Primidone
• Mephobarbital

53
Structure of barbiturates
54
Barbiturates poisoningPharmacokinetics

• Well absorbed orally
• Agents with long side chain such as thiopental
  have high lipid solubility, protein binding and
  potency, with rapid onset and short action.
• Undergoes complete hepatic metabolism then
  excreted renally.
• Concomitant ethanol or benzodiazepines enhances
  its sedative-hypnotic effect.

55
Barbiturates poisoningMechanism of toxicity

• Promote GABA binding to GABAA chloride channel
  complex, increasing duration of chloride channel
  opening.
• Chloride content in nerve cell,
• hyperpolarisation and depressed neuronal
  activity.
• Also reduces excitatory glutamate induced
  depolarization.
• May inhibit nicotinic neurotransmission in
  autonomic ganglia.

56
Barbiturates poisoning

• Depression of medullary respiratory center,
• Inhibition of myocardial contractility and
  conduction as result of membrane-stabilising
  action (i.e. fast Na channel blockade).
• Suppression of G.I. motility.

57
Barbiturates poisoningClinical presentation

• CNS depression Drowsiness, lethargy, sedation,
  ataxia, slurred speech and incoordination.
• Moderately severe depressed level of
  consciousness, slowed respiration, DTR (-).
• Severe coma, hypothermia, and circulatory
  collapse.
• Neurologic findings pupils-NR, loss of
  brainstem reflexes, absent DTR, Babinski sign ()

58
Barbiturates poisoning Anticonvulsant
hypersenstivity syndrome

• Idiosyncratic reaction to therapy with
  phenobarbital, phenytoin, primidone and
  carbamazepine.
• Reactive metabolic intermediates, not
  sufficiently detoxified , may bind covalently to
  cell membrane constituents and form neoantigens.
• Clinical features fever, malaise, pharygitis,
  cervical lymphadenopathy and cutaneous eruption.
  Visceral organ involvement hepatitis,
  myocarditis, pericarditis, nephritis, pneumonia

59
Management of barbiturates toxicity

• Aggressive airway management and ventilatory
  support.
• Administer i.v. fluids (1-2 L) if hypotension
  if no response, vasopressors (eg. Dopamine or
  norepinephrine).
• Vigorous rewarming measures for severe
  hypothermia.
• Administration of more than one enteral dose of
  activated charcoal.
• Urinary alkalization (Target urine pH 8) for
  moderate to severe phenobarbital overdose.

60
Barbiturates poisoning

• I.V. sodium bicarbonate 50-100 mmol/lit of 5
  dextrose _at_ 150-250 mL/hr.
• Hemodialysis and hemoperfusion to enhance
  elimination particularly long-acting ones.
• Indications includes not responding to
  supportive treatment and can not excrete
  barbiturates due to renal failure.
• Exchange transfusion for neonates.

61
Barbiturates poisoningCriteria for ICU admission

• Hemodynamic instability
• Requirement of mechanical ventilation
• Coma
• Severe hypothermia
• Presence of co-morbid medical conditions (severe
  CAD, CHF, RF).
• Requirement of hemodialysis
• Severe electrolyte disturbance or acidemia
• Actively suicidal tendency
• Increasing barbiturates level despite therapy

62
Barbiturates poisoningTake home massege

• Assessment and treatment based on patients
  clinical status, not just serum drug
  concentrations.
• Isoelectric EEG patterns can be present,
  diagnosis of brain death should not be based on
  EEG.
• Patients on long-term use may develop severe
  withdrawal syndrome if they are stopped abruptly.
• No role of forced diuresis.

63
Benzodiazepines

• Widespread use due to efficacy and safety unless
  used with other CNS depressant.
• Newer, higher potency BZD eg. Flunitrazepam more
  likely to cause life-threatening CNS depression
  and ventilatory failure.
• Zolpidem relatively recent addition, a nonBZD but
  act on same receptors.

64
classification
65
structure
66
Benzodiazepines poisoning pharmacokinetics

• Well absorbed orally, peaks in plasma approx. 1
  hour
• Several BZD first biotransformed to
  pharmacologically active intermediates in liver
  then degraded and excreted
• Thus, long-lasting benzos are so b/c both the
  parent drug and the intermediate are
  long-lasting/acting.
• Relatively high protein binding (60-95)

67
Benzodiazepines poisoning Mechanism of action

• Indirect GABA agonist enhancing binding to
  postsynaptic neuronal Cl- (GABAA)channel.
• Inhibit presynaptic uptake of adenosine which
  exert negative modulatory effect on presynaptic
  release of glutamate(excitatory).

68
Clinical presentation

• Mildly depressed sensorium to coma.
• Impaired psychomotor skill, somnolence
  dysarthria, nystagmus, ataxia, hyporeflexia and
  non life-threatening resp. depression.
• Hypoventilatory failure is unusual if present,
  it suggest another CNS depressant or co-existing
  disease eg COPD
• Retrograde and antegrade amnesia

69
Management of bzd toxicity

• Mainly supportive supplemental oxygen, dextrose
  or thiamine particularly if hypoxemia, altered
  mental status, hypoglycemia.
• Naloxone administration should be considered if
  hypoventilatory failure.
• Oral or nasogastric administration of a single
  dose of activated charcoal within 1-2 hr. after
  appropriate airway protective measures.

70
Benzodiazepines poisoning

• Flumazenil is a drug with antagonist activity at
  BZD binding site of GABAA chloride complex
  reverses CNS depressant effect.
• Dose 0.2 mg IV over 30 sec. repeat 0.5 mg
  every minute if needed.
• Uneventful recovery in 12-36 hrs after routine
  and supportive care, so extracorporeal
  enhancement not indicated.
• Significant withdrawal can occur so resumption of
  maintenance therapy.

71
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• Litovitz TL, White S, et al. Am J Emerg Med 20
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• Weinbroum AA, Scol O, Ogorek D, Flashon R. Eur J
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