report-1 imatinib and ginseng
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Imatinib and Panaxginseng: A Potential
InteractionResulting in LiverToxicity
Naveen Bilgi, Kim Bell, Ashwin NAnanthakrishnan, and Ehab Atallah
Annals of PharmacotherapyMay 2010
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Philadelphia
Chromosome A shortened
chromosome 22
resulting from thetranslocation betweenchromosome 9 andchromosome 22
Produces BCR-ABLoncogene
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Structure of Imatinib (Gleevec)
Class: Phenylaminopyrimidines,
C30H35N7SO4
MW=589.7
CH3SO3HN
N
N
HN
HN
O
N
N
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Mechanism ofGleevec
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Side Effects
Mild: Nausea, vomiting, diarrhea,heart burn, headache, and musclecramps
Severe: Ascites, Pulmonary Edema,Neutropenia, Thrombocytopenia, etc
Uncommon: Hepatotoxicity(usually manifests within the first1-2 years of therapy
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Imatinib
Specifically targets an enzyme incancer cells, not normal healthy cells
Given orally instead of injections
Dosage 400 mg/day in Chronic Phase CML
600 mg/day in Accelerated/Blast
Crisis Metabolized in the liver via the
Cytochrome P450 system,
primarily by CYP3A4
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What is Ginseng? Low-growing, shade-
loving perennial herb oftheAralianceaefamily
(http://www.bccancer.bc.ca/PPI/UnconventionalTherapies/Ginseng.htm)
Latin name= Panax
The scientific names
Panax Ginseng
Derived from the Greek
word for cure-all,
related to the wordPanacea.
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Active Components Ginsenosides
or PanaxosidesMajor ginsenosides:
Rg1, Re, Rf, Rb1, Rc, Rg2, Rb2, Rb
Panaxans
Ginsenans
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Forms of Ginseng Root itself
Dried root
Teas, capsules, tablets,tinctures, powders.
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DosageWell tolerated orally
usually provide 100mg to400mg of dried extract
(equivalent to 0.5g to 2g of
ginseng root.)-A Cytochrome P450inhibitor
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Traditional and modern uses Improving the health of people
recovering form illness
Memory and energy
enhancement Heightens bodys response to
stress, fatigue, trauma and
anxiety
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Side Effects Bleeding disorders
Diarrhea Edema Headache Hypoglycemia
Hyperpyrexia Menstrual abnormalities Nausea and vomiting Nervous excitation
Palpitations Itchiness Dizziness Rose spots
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Side Effects (contd)Large doses over an extended period of
time
Diarrhea
Estrogenic effectHTN
Hypertonicity
Decreased libido
Insomnia
Menstruation in menopausal women
Nervousness
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Case Report
A 26-year-old man with CML (CP-MMR)
On Imatinib 400mg daily for 7 years withno complications
Presented with 2 day history of RUQ pain sharp, stabbing, exacerbated withmovement
(-)Heavy lifting, alcohol intake,acetaminophen ingestion
3 month history of using energy drink thatcontained Panaxginseng.
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Diagnostics
Liver enzyme tests - elevated
Abdominal and Pelvic CT scan -unremarkable
Hepatitis profile negative/non-reactive(NON-VIRAL)
Autoimmune work-up - negative
Enzymatic deficiency workup negative
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Liver Biopsy
Resolving or Late-Stage LobularHepatitis, Most likely
drug-induced
http://upload.wikimedia.org/wikipedia/commons/6/6d/Drug-induced_hepatitis_intermed_mag.jpg -
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Therapeutics
Both Imatinib and ginseng werediscontinued.
The patient was treated witha short
course of corticosteroids. Imatinib was later restartedat the same
dose, and liver enzymelevels remainednormal.
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Dilemma
Toxic Reaction:
Due to a previously tolerated drug?
Due to a newly added medication? Due to interaction of previously
tolerated drug and newly added
medication?
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Hypothesis
Hepatotoxicity due to ginseng-mediated inhibition of Imatinibmetabolism
Pharmacologic studies providesupport for this hypothesis
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What is known?
Imatinib is metabolized byCYP3A4, CYP2D6, 1A2, 2C9,
2C9Ginseng has an inhibitoryeffect on CYP3A4 but not onisoenzymes that play a role inthe metabolism of of
Imatinib.
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Pathophysiology of LiverToxicity
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What is known?
Imatinib is a P-GP Substrate
Ginseng has an inhibitory
effect on P-GP
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Pathophysiology of livertoxicity
http://www.drugdevelopment-technology.com/projects/tesmilifene/ -
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Conclusions
Importance of continuousmonitoring of liver function tests inpatients on Imatinib therapy evenafter several years
Importance of counseling patientsto avoid ginseng and any other
over-the-counter herbalsupplements that may interact withImatinib