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INR Elevation with Maitake Extract in Combination with Warfarin

INR Elevation with Maitake Extract in Combination with Warfarin
TO THE EDITOR: Maitake, Grifola frondosa,is an edible mushroom with
potential cancer benefits. Its potential benefits are thought to be associat-
ed with β-glucan (a protein-bound polysaccharide), which may stimulate
macrophages, cytokines, and natural killer (NK) cells, leading to im-
munostimulation.1In vitro, maitake has demonstrated enhancement of
murine hematopoietic stem cell proliferation and reduction in doxoru-
bicin toxicity.2,3 Additionally, maitake inhibits lung metastasis by activat-
ing NK cells and increases murine tumor cell cytotoxicity in vitro.4The
safety of maitake use in combination with other medications is un-
known. Warfarin has numerous drug interactions; however, an interac-
tion between maitake and warfarin has not been previously described.
In this report, a possible interaction between maitake and warfarin re-
sulting in an elevated international normalized ratio (INR) is described.
Case Report. A79-year-old man with newly diagnosed atrial fibrilla-
tion and metastatic bladder carcinoma began warfarin therapy.His medi-
cal history included benign prostatic hypertrophy, bilateral cataracts/
pseudophakia, diastolic heart failure/mitral valve regurgitation, dyslipi-
demia, hypertension, and insomnia. His medications included controlled-
release diltiazem, hydromorphone, tamsulosin, prednisolone ophthalmic
suspension, simvastatin, and eszopiclone. He did not receive chemother-
Warfarin was titrated to an INR goal between 2 and 3. The dose was
stable for 4 consecutive visits over 2 months (5 mg daily on Monday and
Friday and 2.5 mg on all other days). One week later,the patient self-ini-
tiated Grifron-Pro Maitake D -fraction (Maitake Products, Inc.) at the
recommended dose of 1 drop/kg in 3 divided doses for immunostimula-
tion effects. Product ingredients included maitake mushroom extract 22
mg (30% active proteoglucan), water, and vegetable glycerine.
One week after maitake initiation, an elevated INR of 5.1 was detect-
ed. The patient denied signs or symptoms of bleeding. He
also denied changes in his warfarin dose, medical condi-
tion, alcohol intake, and other medications. As a result of
his cancer diagnosis, his appetite had decreased. The
anorexia persisted while he was on warfarin therapy, and
he lost a small amount of weight over a 2-month period;
however, his diet with vitamin K–containing foods re-
mained consistent.
Warfarin was held for 2 days (7.5 mg total) due to the
elevated INR, resulting in an INR of 3.0. The patient
chose to continue taking maitake; therefore, another 2.5-
mg dose of warfarin was held. An 11% weekly dose re-
duction to 5 mg once weekly and 2.5 mg all other days
was made. Eight days after the initial INR elevation, his
INR was 1.8. One extra 2.5-mg dose was given, with no
permanent change to his weekly dose. The following
month, the patient began comfort care for his terminal
cancer. He discontinued warfarin and maitake at that
time. INR values over time are shown in Figure 1. Using
the Horn Drug Interaction Probability Scale,5apossible
relationship between maitake and warfarin, resulting in an
elevated INR, was indicated.
Discussion. Inthis case, our patient self-initiated the use of maitake.
Apossible interaction between maitake and warfarin, resulting in an INR
elevation, was reported. A MEDLINE search was conducted (1950
through August 2009), using key words maitake, β-glucan, Grifola fron-
dosa,warfarin, vitamin K antagonist, and INR. No published reports de-
scribing an interaction between maitake and warfarin were identified.
The mechanism of interaction between maitake and warfarin may be at-
tributed to the protein-bound polysaccharide, β-glucan, resulting in pro-
tein dissociation of warfarin, allowing for greater anticoagulation effect.
Clinicians should be aware of a possible interaction between maitake
and warfarin. Close INR monitoring upon initiation and discontinuation
of maitake should be considered.
Michele R Hanselin PharmD
PGY1 Pharmacy Practice Resident
Clinical Instructor
Department of Clinical Pharmacy
School of Pharmacy
University of Colorado Denver
Aurora, Colorado
Joseph P Vande Griend PharmD BCPS
Assistant Professor
Department of Clinical Pharmacy
School of Pharmacy
University of Colorado Denver
Mail Stop C238-L15
12631 East 17th Avenue, Room 1411
Aurora, Colorado 80045
fax 303/724-2627
The Annals of Pharmacotherapy n2010 January, Volume 44 n
Figure 1. Patient INR values from initiation of therapy to discontinuation. INR = in-
ternational normalized ratio.
Sunny A Linnebur PharmD FCCP FASCP CGP BCPS
Associate Professor
Department of Clinical Pharmacy
School of Pharmacy
University of Colorado Denver
Financial disclosure: None reported
Published Online, 29 Dec 2009,
DOI 10.1345/aph.1M510
1. American Cancer Society. Maitake mushroom.
ETO/content/ETO_5_3X_Maitake_Mushroom.asp?sitearea = ETO (ac-
cessed 2009 Aug 12).
2. Lin H, She YH, Cassileth BR, Sirotnak F, Cunningham-Rundles S.
Maitake beta-glucan MD -fraction enhances bone marrow colony forma-
tion and reduces doxorubicin toxicity in vitro. Int Immunopharmacol
3. Lin H, Cheung SW, Nesin M, Cassileth BR, Cunningham-Rundles S.
Enhancement of umbilical cord blood cell hematopoiesis by maitake
beta-glucan is mediated by granulocyte colony-stimulating factor pro-
duction. Clin Vaccine Immunol 2007;14:21-7.
4. Masuda Y, Murata Y, Hayashi M, Nanba H. Inhibitory effect of MD -
Fraction on tumor metastasis: involvement of NK cell activation and
suppression of intercellular adhesion molecule (ICAM)-1 expression in
lung vascular endothelial cells. Biol PharmBull 2008;31:1104-8.
5. Horn JR, Hansten PD, Chan L-N. Proposal for a new tool to evaluate
drug interaction cases. Ann Pharmacother 2007;41:674-80. Epub 27
Mar 2007. DOI 10.1345/aph.1H423
nThe Annals of Pharmacotherapy n2010 January, Volume 44
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Previous studies have indicated that MD-fraction (MDF), in which the active component is beta 1,6-glucan with beta 1,3-branches, has anti-tumor activity as an oral agent and acts as an immune adjuvant. Since some other beta glucans appear to promote mobilization of hematopoietic stem cells, the effects of a beta glucan extract from the Maitake mushroom "MD-fraction" on hematopoietic stem cells were examined in a colony forming assay. Here we report for the first time that MDF has a dose response effect on mouse bone marrow cells (BMC) hematopoiesis in vitro. Using the Colony Forming Unit (CFU) assay to detect formation of granulocyte-macrophage (CFU-GM) colonies, and the XTT cytotoxicitiy assay to measure BMC viability, the data showed that the addition of MDF significantly enhanced the development of CFU-GM in a dose range of 50-100 microg/ml (p<0.004). The mechanism of action included significant increase of nonadherent BMC viability, which was observed at MDF doses of 12.5-100 microg/ml (p<0.005). In the presence of Doxorubicin (DOX), MDF promoted BMC viability and protected CFU-GM from DOX induced toxicity. In addition, MDF treatment promoted the recovery of CFU-GM colony formation after BMC were pretreated with DOX. These studies provided the first evidence that MDF acts directly in a dose dependent manner on hematopoietic BMC and enhances BMC growth and differentiation into colony forming cells.