Domperidone

Domperidone, sold under the brand name Motilium among

others, is a peripherally selective dopamine D2 receptor
antagonist that was developed by Janssen Pharmaceutica
and is used as an antiemetic, gastroprokinetic agent, and
galactagogue.[1][6][7] It may be administered orally or rectally,
and is available in the form of tablets, orally disintegrating
tablets (based on Zydis technology),[8] suspension, and
suppositories.[9] The drug is used to relieve nausea and
vomiting; to increase the transit of food through the stomach
(by increasing gastrointestinal peristalsis); and to promote
lactation (breast milk production) by release of prolactin.[1][7]

Medical uses
It was reported in 2007 that domperidone is available in 58
countries, including Canada,[10] but the uses or indications of
domperidone vary between nations. In Italy it is used in the
treatment of gastroesophageal reflux disease and in Canada,
the drug is indicated in upper gastrointestinal motility
disorders and to prevent gastrointestinal symptoms
associated with the use of dopamine
Domperidone
agonist antiparkinsonian agents.[11] In
the United Kingdom, domperidone is
only indicated for the treatment of
nausea and vomiting and the treatment
duration is usually limited to 1 week.
Clinical data
In the United States, domperidone is Trade Motilium,
names
not currently a legally marketed human many
drug and it is not approved for sale in others

the U.S. On 7 June 2004, FDA issued a

AHFS/Drugs.com Micro
public warning that distributing any
Detail
domperidone-containing products is Consu
illegal.[12] Inform

Pregnancy AU: B2
Nausea and vomiting category
US: N (Not

There is some evidence that classified

yet)
domperidone has antiemetic activity.[13]
Routes of By mouth
It is recommended in the Canadian
administration
intramus
Headache Society's guidelines for
intraveno
treatment of nausea associated with
(d/c'd),
acute migraine.[14] rectal[1]
Drug class D2

Gastroparesis receptor
Gastroparesis is a medical condition antagonist;
Prolactin
characterised by delayed emptying of
ATC code releaser
the stomach when there is no A03FA03

mechanical gastric outlet obstruction. (WHO )

QP51AX24
Its cause is most commonly idiopathic,
(WHO )
a diabetic complication or a result of
Legal status
abdominal surgery. The condition
Legal UK: POM
causes nausea, vomiting, fullness after status
(Prescription
eating, early satiety (feeling full before only)
the meal is finished), abdominal pain US: Not
and bloating. approved for
use or sale
Domperidone may be useful in diabetic
Prescription
and idiopathic gastroparesis.[15][16] medicine (Rx
only):Pakistan,
However, increased rate of gastric India,
emptying induced by drugs like Australia,
domperidone does not always correlate Canada, Israel,
Belgium,
(equate) well with relief of
France,
symptoms.[17]
Netherlands;
over-the-
counter:
Parkinson's disease
Egypt, Ireland,

Parkinson's disease is a chronic Italy, Japan,

South Africa,
neurological condition where a
Switzerland,
decrease in dopamine in the brain
leads to rigidity (stiffness of China, Russia,
Slovakia,
movement), tremor and other
Ukraine[2]
symptoms and signs. Poor
Mexico,
gastrointestinal function, nausea and Thailand,
vomiting is a major problem for people Malta, South
with Parkinson's disease because most Korea, and
Romania[3]
medications used to treat Parkinson's
Pharmacokinetic data
disease are given by mouth. These
Bioavailability Oral: 13–
medications, such as levodopa, can
17%[1][5]
cause nausea as a side effect.
Intramusc
Furthermore, anti-nausea drugs, such 90%[1]
as metoclopramide, which do cross the Protein ~92%[1]
blood–brain barrier may worsen the binding
Metabolism Hepatic
extra-pyramidal symptoms of
(CYP3A4/5)
Parkinson's disease.
and
intestinal
Domperidone can be used to relieve
(first-
gastrointestinal symptoms in
pass)[1][4]
Parkinson's disease; it blocks Metabolites All
peripheral D2 receptors but does not inactive[1][4]
cross the blood–brain barrier in normal Elimination 7.5
doses (the barrier between the blood half-life
hours[1][5]
circulation of the brain and the rest of Excretion Feces:
the body) so has no effect on the 66%[1]
extrapyramidal symptoms of the Urine:
disease.[18] In addition to this, 32%[1]
Breast
domperidone may enhance the
milk: small
bioavailability (effect) of levodopa (one
quantities[1]
Identifiers
of the main treatments in Parkinson's
disease).[19] IUPAC name
5-Chloro-1-(1-[3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)p

Although these features make ropyl]piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one

domperidone a useful drug in CAS 57808-66-

Number  
Parkinson's disease, caution is needed 9

due to the cardiotoxic side effects of PubChem 3151

CID
domperidone especially when given IUPHAR/BPS 965
intravenously, in elderly people and in
DrugBank DB01184  
high doses (> 30 mg per day).[20] A
ChemSpider 3039  
clinical sign of domperidone's potential
toxicity to the heart is the prolongation UNII 5587267Z69
(lengthening) of the QT interval (a KEGG D01745  

segment of the heart's electrical ChEBI  

CHEBI:31515
pattern).[21]
ChEMBL ChEMBL21991

Functional dyspepsia
CompTox DTXSID1045
Dashboard
Domperidone may be used in
(EPA)
functional dyspepsia in both adults and ECHA 100.055.408
children.[22][23] InfoCard

Chemical and
Lactation physical data
Formula C H ClN O
22 24 5 2

The hormone prolactin stimulates Molar 425.911

mass
lactation (production of breast milk). g/mol g·mol−1

Dopamine, released by the 3D model Interactive

(JSmol)
image
hypothalamus stops the release of
Melting 242.5 °C
prolactin from the pituitary gland. point
(468.5 °F)
Domperidone, by acting as an anti-
dopaminergic agent, results in SMILES
Clc1cc2c(cc1)N(C(=O)N2)C5CCN(CCCN4c3ccccc3NC
4=O)CC5

increased prolactin secretion, and thus

InChI
promotes lactation (that is, it is a InChI=1S/C22H24ClN5O2/c23-15-6-7-20-18(14-15)25-
22(30)28(20)16-8-12-26(13-9-16)10-3-11-27-19-5-2-
1-4-17(19)24-21(27)29/h1-2,4-7,14,16H,3,8-13H2,
(H,24,29)(H,25,30) 
Key:FGXWKSZFVQUSTL-UHFFFAOYSA-N 
galactogogue). Domperidone
  (verify)
moderately increases the volume of
expressed breast milk in mothers of
preterm babies where breast milk expression was inadequate,
and appears to be safe for short-term use for this
purpose.[24][25][26] In the United States, domperidone is not
approved for this or any other use.[27][28]

A study called the EMPOWER trial was designed to assess the

effectiveness and safety of domperidone in assisting mothers
of preterm babies to supply breast milk for their infants.[29]
The study randomized 90 mothers of preterm babies to
receive either domperidone 10 mg orally three times daily for
28 days (Group A) or placebo 10 mg orally three times daily
for 14 days followed by domperidone 10 mg orally three times
daily for 14 days (Group B). Mean milk volumes at the
beginning of the intervention were similar between the 2
groups. After the first 14 days, 78% of mothers receiving
domperidone (Group A) achieved a 50% increase in milk
volume, while 58% of mothers receiving placebo (Group B)
achieved a 50% increase in milk volume.[30]

To induce lactation, domperidone is used at a dosage of 10 to

20 mg 3 or 4 times per day by mouth.[31] Effects may be seen
within 24 hours or may not be seen for 3 or 4 days.[31] The
maximum effect occurs after 2 or 3 weeks of treatment, and
the treatment period generally lasts for 3 to 8 weeks.[31] A
2012 review shows that no studies support prophylactic use
of a galactagogue medication at any gestation including
Domperidone.[32]

Pediatric reflux

Domperidone has been found effective in the treatment of

pediatric reflux.[33] However some specialists consider its
risks prohibitory of the treatment of infantile reflux.[34]

Contraindications
CYP3A4 inhibitors (e.g., triazole antifungal medications
such as ketoconazole, itraconazole, fluconazole; macrolide
 antibiotics such as erythromycin and clarithromycin;
grapefruit juice; other potent CYP3A4 inhibitors)
QT-prolonging drugs like amiodarone[35]
Prolactin secreting pituitary tumor (prolactinoma) or
hyperprolactinemia
Mechanical bowel disorders such as bowel obstruction,
gastrointestinal haemorrhage or bowel perforation
Moderate hepatic impairment (liver disease)
Severe renal impairment (kidney disease)
Cardiac disease

Side effects
Side effects associated with domperidone include dry mouth,
abdominal cramps, diarrhea, nausea, rash, itching, hives, and
hyperprolactinemia (the symptoms of which may include
breast enlargement, galactorrhea, breast pain/tenderness,
gynecomastia, hypogonadism, and menstrual
irregularities).[31] Due to blockade of D2 receptors in the
central nervous system, D2 receptor antagonists like
metoclopramide can also produce a variety of additional side
effects including drowsiness, akathisia, restlessness,
insomnia, lassitude, fatigue, extrapyramidal symptoms,
dystonia, Parkinsonian symptoms, tardive dyskinesia, and
depression.[1][7] However, this is not the case with
domperidone, because, unlike other D2 receptor antagonists,
it minimally crosses the blood-brain-barrier, and for this
reason, is rarely associated with such side effects.[1][7]

Excess prolactin levels

Due to D2 receptor blockade, domperidone causes

hyperprolactinemia.[36] Hyperprolactinemia can suppress the
secretion of gonadotropin-releasing hormone (GnRH) from
the hypothalamus, in turn suppressing the secretion of
follicle-stimulating hormone (FSH) and luteinizing hormone
(LH) and resulting in hypogonadism (low sex hormone (e.g.,
testosterone, estradiol) levels).[37] As such, male patients may
experience low libido, erectile dysfunction, and impaired
spermatogenesis.[37] Also in accordance with
hyperprolactinemia, 10–15% of female patients have been
reported to experience mammoplasia (breast enlargement),
mastodynia (breast pain/tenderness), galactorrhea
(inappropriate or excessive milk production/secretion), and
amenorrhea (cessation of menstrual cycles) with
domperidone treatment.[36] Gynecomastia has been reported
in males treated with domperidone,[38] and galactorrhea could
occur in males as well.[37]

Rare reactions
Cardiac reactions

Domperidone use is associated with an increased risk of

sudden cardiac death (by 70%)[39] most likely through its
prolonging effect of the cardiac QT interval and ventricular
arrhythmias.[40][41] The cause is thought to be blockade of
hERG voltage-gated potassium channels.[42][43] The risks are
dose-dependent, and appear to be greatest with high/very
high doses via intravenous administration and in the elderly,
as well as with drugs that interact with domperidone and
increase its circulating concentrations (namely CYP3A4
inhibitors).[44][45] Conflicting reports exist, however.[46] In
neonates and infants, QT prolongation is controversial and
uncertain.[47][48]

UK drug regulatory authorities (MHRA) have issued the

following restriction on domperidone in 2014 due to
increased risk of adverse cardiac effects:

Domperidone (Motilium) is associated with a

small increased risk of serious cardiac side
effects. Its use is now restricted to the relief of
nausea and vomiting and the dosage and
duration of use have been reduced. It should no
 longer be used for the treatment of bloating and
heartburn. Domperidone is now contraindicated
in those with underlying cardiac conditions and
other risk factors. Patients with these conditions
and patients receiving long-term treatment with
domperidone should be reassessed at a routine
appointment, in light of the new advice.

However, a 2015 Australian review concluded the

following:[45]

Based on the results of the two TQT (the

regulatory agency gold standard for assessment
of QT prolongation) domperidone does not
appear to be strongly associated with QT
prolongation at oral doses of 20 mg QID in
healthy volunteers. Further, there are limited
case reports supporting an association with
cardiac dysfunction, and the frequently cited
case-control studies have significant flaws. While
there remains an ill-defined risk at higher
systemic concentrations, especially in patients
 with a higher baseline risk of QT prolongation,
our review does not support the view that
domperidone presents intolerable risk.

Possible central toxicity in infants

In Britain a legal case involved the death of two children of a

mother whose three children had all had hypernatraemia. She
was charged with poisoning the children with salt. One of the
children, who was born at 28 weeks gestation with respiratory
complications and had a fundoplication for gastroesophageal
reflux and failure to thrive was prescribed domperidone. An
advocate for the mother suggested the child may have
suffered neuroleptic malignant syndrome as a side effect of
domperidone due to the drug crossing the child's immature
blood-brain-barrier.[49]

Interactions
Domperidone is almost exclusively metabolized by CYP3A4,
and for this reason, inhibitors and inducers of this enzyme
may alter the metabolism and concentrations of
domperidone. Moreover, domperidone has been identified as
a modest mechanism-based (irreversible) inhibitor of CYP3A4
(Ki = 12 μM), and it has been estimated that it may increase
the serum concentrations of CYP3A4 substrates by
approximately 50%.[50]

Itraconazole and ketoconazole, both used to treat fungal

infections, are potent CYP3A4 inhibitors and increase the
plasma concentration of domperidone.[51][52] In healthy
volunteers, ketoconazole increased the Cmax and AUC
concentrations of domperidone by 3- to 10-fold.[53] This was
accompanied by a QT interval prolongation of about 10–20
milliseconds when domperidone 10 mg four times daily and
ketoconazole 200 mg twice daily were administered, whereas
domperidone by itself at the dosage assessed produced no
such effect.[53] As such, domperidone with ketoconazole or
other CYP3A4 inhibitors is a potentially dangerous
combination.[53]

Erythromycin and certain other macrolide antibiotics are

CYP3A4 inhibitors and inhibit the metabolism of domperidone
(in vitro), thus increasing the concentration of domperidone
and potential side effects of the drug. This is of concern as
both drugs may be used to treat gastroparesis.[54]

There is evidence that domperidone should not be taken with

grapefruit juice, which is a known CYP3A4 inhibitor.[55]

Pharmacology
Pharmacodynamics

Domperidone is a peripherally selective dopamine D2 and D3

receptor antagonist.[7] It has no clinically significant
interaction with the D1 receptor, unlike metoclopramide.[7] The
medication provides relief from nausea by blocking D2
receptors in the chemoreceptor trigger zone (a location in the
nervous system that mediates nausea) at the floor of the
fourth ventricle (a location near the brain). It increases
motility in the upper gastrointestinal tract to a moderate
degree and increases[56] lower esophageal sphincter pressure
by blocking dopamine receptors in the gastric antrum and the
duodenum. It blocks dopamine receptors in the anterior
pituitary gland increasing release of prolactin which in turn
increases lactation.[57][58] Domperidone may be more useful in
some patients and cause harm in others by way of the
genetics of the person, such as polymorphisms in the drug
transporter gene ABCB1 (which encodes P-glycoprotein), the
voltage-gated potassium channel KCNH2 gene
(hERG/Kv11.1), and the α1D—adrenoceptor ADRA1D gene.[59]

Effects on prolactin levels

A single 20 mg oral dose of domperidone has been found to

increase mean serum prolactin levels (measured 90 minutes
post-administration) in non-lactating women from 8.1 ng/mL
to 110.9 ng/mL (a 13.7-fold increase).[7][60][61][62] This was
similar to the increase in prolactin levels produced by a single
20 mg oral dose of metoclopramide (7.4 ng/mL to
124.1 ng/mL; 16.7-fold increase).[61][62] After two weeks of
chronic administration (30 mg/day in both cases), the
increase in prolactin levels produced by domperidone was
reduced (53.2 ng/mL; 6.6-fold above baseline), but the
increase in prolactin levels produced by metoclopramide,
conversely, was heightened (179.6 ng/mL; 24.3-fold above
baseline).[7][62] This indicates that acute and chronic
administration of both domperidone and metoclopramide is
effective in increasing prolactin levels, but that there are
differential effects on the secretion of prolactin with chronic
treatment.[61][62] The mechanism of the difference is
unknown.[62] The increase in prolactin levels observed with
the two drugs was, as expected, much greater in women than
in men.[61][62] This appears to be due to the higher estrogen
levels in women, as estrogen stimulates prolactin
secretion.[63]

For comparison, normal prolactin levels in women are less

than 20 ng/mL, prolactin levels peak at 100 to 300 ng/mL at
parturition in pregnant women, and in lactating women,
prolactin levels have been found to be 90 ng/mL at 10 days
postpartum and 44 ng/mL at 180 days postpartum.[64][65]

Effects on TSH levels

Along with prolactin, domperidone has, to a lesser extent,

been found to increase the secretion of thyroid-stimulating
hormone (TSH), even in patients with hypothyroidism.[61] A
single 4 mg intravenous dose of domperidone produced peak
TSH levels of 1.9-fold above baseline and peak prolactin
levels of 23-fold above baseline (which occurred at 30
minutes post-administration) in women with
hypothyroidism.[61] Levels of TSH and prolactin decreased to
1.6-fold and 17-fold above baseline, respectively, at 120
minutes post-administration.[61]

Pharmacokinetics

With oral administration, domperidone is extensively

metabolized in the liver (almost exclusively by CYP3A4/5,
though minor contributions by CYP1A2, CYP2D6, and CYP2C8
have also been reported)[66] and in the intestines.[4] Due to the
marked first-pass effect via this route, the oral bioavailability
of domperidone is low (13–17%);[1] conversely, its
bioavailability is high via intramuscular injection (90%).[1] The
terminal half-life of domperidone is 7.5 hours in healthy
individuals, but can be prolonged to 20 hours in people with
severe renal dysfunction.[1] All of the metabolites of
domperidone are inactive as D2 receptor ligands.[1][4] The drug
is a substrate for the P-glycoprotein (ABCB1) transporter, and
animal studies suggest that this is the reason for the low
central nervous system penetration of domperidone.[67]

Chemistry
Domperidone is a benzimidazole derivative and is structurally
related to butyrophenone neuroleptics like haloperidol.[68][69]

History
1974 – Domperidone synthesized at Janssen
Pharmaceutica[70] following the research on antipsychotic
drugs.[71] Janssen pharmacologists discovered that some
of antipsychotic drugs had a significant effect on dopamine
receptors in the central chemoreceptor trigger zone that
regulated vomiting and started searching for a dopamine
antagonist that would not pass the blood–brain barrier,
thereby being free of the extrapyramidal side effects that
were associated with drugs of this type.[71] This led to the
discovery of domperidone as a strong anti-emetic with
minimal central effects.[71][72]
 1978 – On 3 January 1978 Domperidone was patented in
the United States under patent US4066772 A. The
application has been filed on 17 May 1976. Jan
Vandenberk, Ludo E. J. Kennis, Marcel J. M. C. Van der Aa
and others has been cited as the inventors.
1979 – Domperidone marketed under trade name
"Motilium" in Switzerland and (Western) Germany.[73]
1999 – Domperidone was introduced in the forms of orally
disintegrating tablets (based on Zydis technology).[74]
Janssen Pharmaceutical has brought domperidone before
the United States Federal Drug Administration (FDA) several
times, including in the 1990s.
2014 – In April 2014 Co-ordination Group for Mutual
Recognition and Decentralised Procedures – Human
(CMDh) published official press-release suggesting to
restrict the use of domperidone-containing medicines. It
also approved earlier published suggestions by
Pharmacovigilance Risk Assessment Committee (PRAC) to
use domperidone only for curing nausea and vomiting and
reduce maximum daily dosage to 10 mg.[9]

Society and culture

Generic names
Domperidone is the generic name of the drug and its INN,
USAN, BAN, and JAN.[75][6][76]

Availability

In 2007, it was reported that domperidone was available in 58

countries.[1] It is available over-the-counter to treat
gastroesophageal reflux and functional dyspepsia in many
countries, such as Ireland, the Netherlands, Italy, South Africa,
Mexico, Chile, and China.[77]

Domperidone is not generally approved for use in the United

States. There is an exception for use in people with treatment-
refractory gastrointestinal symptoms under an FDA
Investigational New Drug application.[1]

Formulations
 Formulations
Nation Manufacturer Brand Formulations

Australia Janssen–Cilag Motilium 10 mg scored tablets[35]

Belgium and the
- Motilium From 2013 only by prescription in Belgium.[78]
Netherlands

Bangladesh Square Motigut 10 mg scored tablets

Bangladesh Orion Pharma Cosy 10 mg scored tablets

Bangladesh Astra Pharma Domperon 10 mg scored tablets

Bangladesh - Ridon -

Canada - Motilium (1985–2002) Generic brands available

France Janssen Motilium 10 mg tablets only with prescription generic domperidone available

India Salius Pharma Escacid DXR pantoprazole 40 mg and domperidone SR 30 mg
India FDC Pharmaceuticals Pepcia-D Rabeprazole 20 mg and Domperidone SR 30 mg

India Rhubarb pharmaceuticals - domperidone 5, 10 and 20 mg tablets.

India Ipca Laboratories, Mumbai Domperi suspension domperidone 1 mg/ml, 30 ml suspension.[79]

India Torrent pharmaceuticals Domstal - [80]

Ozone pharmaceuticals and
India Pantazone-D 10 mg domperidone and 40 mg pantoprazole
chemicals
India Chimak Health Care Pancert D 10 mg Domperidone and 40 mg pantoprazole

India Draavin Pharma Draaci-XD Pantaprazole 40 mg and Domperione 30 mg

Iran Abidi Pharmaceutical Co. MOTiDON 10 mg tablet

Ireland McNeil Healthcare Motilium 10 mg orally disintegrating tablet (ODT)

Italy - Peridon domperidone 10 mg tablets; 30 ml suspension

Lithuania Johnson & Johnson Motilium -

Pakistan Barrett Hodgson Pakistan Domel

Pakistan Johnson & Johnson Pakistan Motilium-v domperidone 10 mg tablets; 30 ml suspension
Pakistan ATCO Laboratories Limited Vomilux domperidone 10 mg tablets

Pakistan Aspin Pharma (Pvt) Limited Motilium domperidone 10 mg tablets

Philippines Health Saver Pharma Abdopen -

Philippines United Laboratories, Inc. GI Norm -

Portugal Medinfar Cinet domperidone 1 mg/ml oral suspension (200 ml)

domperidone 10 mg film-coated tablets & ODT; 1 mg/ml suspension (100

Russia Janssen Pharmaceutica Motilium
ml)
- OBL Pharm Passagix domperidone 10 mg film-coated tablets & chewable tablets

- Dr. Reddy's Laboratories Omez D domperidone/omeprazole (10 mg/10 mg)

Saudi Arabia JamJoom Pharmaceuticals Dompy Domperidone 10 mg tablets

Spain Laboratorios Dr. Esteve, SA Motilium domperidone 1 mg/ml oral suspension (200 ml)
Domperidon Ebb
Sweden Ebb medical domperidone 10 mg ODT and peppermint
(2013)
Taiwan - Dotitone -
Thailand - Motilium M -

Turkey Saba Motinorm -

- GlaxoSmithKline Motinorm -

Research
Domperidone has been studied as a potential hormonal
contraceptive to prevent pregnancy in women.[81]

References
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W. (2007). "Domperidone: Review of Pharmacology and
Clinical Applications in Gastroenterology". The American
Journal of Gastroenterology. 102 (9): 2036–2045.
doi:10.1111/j.1572-0241.2007.01255.x . ISSN 0002-
9270 . PMID 17488253 .
2. "БРЮЛІУМ ЛІНГВАТАБС" [BRULIUM LINGUATABS].
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Ukrainian). 18 March 2014. Retrieved 29 May 2015.
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Turgeon, J. (2008). "Identification of the cytochrome
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16. Silvers D, Kipnes M, Broadstone V, Patterson D, Quigley
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(1998). "Domperidone in the management of symptoms
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quality-of-life outcomes in a multicenter controlled trial.
DOM-USA-5 Study Group". Clinical Therapeutics. 20 (3):
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Törnblom H, Van Oudenhove L, Simrén M, Tack J
(September 2013). "The relation between symptom
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External links
U.S. National Library of Medicine: Drug Information Portal -
Domperidone

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