USOO7534455B2 (12) United States Patent (10) Patent No.: US 7.534455 B2 Cheng et al. (45) Date of Patent: *May 19, 2009 (54) HERBAL COMPOSITION PHY906 AND ITS (56) References Cited USE IN CHEMOTHERAPY U.S. PATENT DOCUMENTS (75) Inventors: Yung-Chi Cheng, Woodbridge, CT 4,618,495 A * 10/1986 Okuda et al. ................ 424,728 (US): Shwu-Huey Liu, Madison, CT 5,595,756 A * 1/1997 Bally et al. ................. 424/450 (US) 5,665,393 A * 9/1997 Chen et al. ........ ... 424/489 6,048,847 A * 4/2000 Ramadoss et al. ........... 514,169 (73) Assignee: Yale University, New Haven, CT (US) 6,630,176 B2 * 10/2003 Li et al. ...................... 424,728 (*) Notice: Subject to any disclaimer, the term of this 2003/0180395 A1 9, 2003 Bueter ........................ 424,725 patent is extended or adjusted under 35 U.S.C. 154(b) by 376 days. OTHER PUBLICATIONS This patent is Subject to a terminal dis Suzuki et al. Supressor Macrophages: A Role on the Growth of claimer. Transplanted Tumors and Regulation by an Extract of Licorice, Glycyrrhizin; Oncologia (Tokyo), 1987, 20(5), pp. 124-133; one (21) Appl. No.: 11/100,433 page Abstract from STN database only provided.* Raskin et al. Can an Apple a Day Keep the Doctor Away? Current (22) Filed: Apr. 7, 2005 Pharmaceutical Design, 2004, 10, pp. 3419-3429.* H.B. MacPhillamy: Plant Science Bulletin, Apr. 1963, vol. 9, Issue 2. (65) Prior Publication Data pp. 1-15.* US 2005/O196473 A1 Sep. 8, 2005 * cited by examiner Related U.S. Application Data Primary Examiner Patricia Leith (63) Continuation-in-part of application No. 10/220,876, (74) Attorney, Agent, or Firm—Cooley Godward Kronish filed as application No. PCT/US01/07353 on Mar. 8, LLP 2001, now Pat. No. 7,025,993, which is a continuation in-part of application No. 09/522,055, filed on Mar. 9, (57) ABSTRACT 2000, now abandoned. (60) Provisional application No. 60/625,943, filed on Nov. This invention provides herbal compositions useful for 9, 2004. increasing the therapeutic index of drugs, including those used in the treatment of disease, especially viral infections (51) Int. C. and neoplasms of cancer. This invention provides methods A6 IK 36/484 (2006.01) useful for improving the quality of life of an individual under A6 IK 36/725 (2006.01) going chemotherapy. Furthermore, this invention improves A6 IK 36/539 (2006.01) the treatment of disease by increasing the therapeutic index of A6 IK 36/65 (2006.01) chemotherapy drugs by administering the herbal composition (52) U.S. Cl. ...................................................... 424/725 PHY906 to a person undergoing such chemotherapy. (58) Field of Classification Search ....................... None See application file for complete search history. 4 Claims, 38 Drawing Sheets 150 100 50 -o-CONTROL (VEHICLE) -ve PHY 906 -o-FU/LV - y PHY 906 - FU/LV O 2 3 4 5 6 7 8 9 O DAYS AFTER CPT-11 TREATMENT U.S. Patent May 19, 2009 Sheet 1 of 38 US 7.534455 B2 ??ºldOON 6×6u)000||NEWIVEH1(£AWG)(8AWG) ON |NHWIWEBH1 (£AWG) 0 0/ HSM MOOTWILINO 39WINOld U.S. Patent May 19, 2009 Sheet 3 of 38 US 7,534.455 B2 FIG, 3 1800 500 -o-CONTROL (VEHICLE) -v-PHY 906 -- CP-1 -O-PHY 906 CPT-11 1200 P 900 O 2 3 4. 5 6 7 8 9 DAYS AFTER CPT-11 TREATMENT t-TEST CPT-11 CONTROL h P YY AT GENESPHY 906 CPT-11 p.6 PHY906 osso- 0.0027 0.0001 CPT-11 0.0027 - 0.0007 CPT-1 0.0001 0.000 0.0007 WITH PHY 906 U.S. Patent May 19, 2009 Sheet 4 of 38 US 7.534455 B2 FIG. 4 200 WBC 60 120 NNNNN SNNNN 60 40 O SÈN 200 60 RBC 120 8 TOHINOOHOE??)WINEOHEId 40 (No. 160 PLT 120 8 `N9 RN RNNs) DAYS AFTER CPT-TREATMENT CONTROL (VEHICLE) PHY 906 ZCPT-1 OPHY 906 CPT-11 U.S. Patent May 19, 2009 Sheet 5 Of 38 US 7.534455 B2 150 FIG. 5 100 50 -o-CONTROL (VEHICLE) -Ve-PHY 906 -o-FU/LV -v-PHY 906 - FU/LV 0 1 2 3 4 5 6 7 8 9 O DAYS AFTER CPT-11 TREATMENT U.S. Patent May 19, 2009 Sheet 6 of 38 US 7.534455 B2 FIG, 6 800 -o-CONTROL (VEHICLE) -v-PHY 906 -o-FU/LV 600 yePHY 906 - FU/LV A 7 w 400 200 1 2 3 4 5 6 7 8 9 DAYS AFTER CPT-11 TREATMENT U.S. Patent May 19, 2009 Sheet 7 Of 38 US 7.534455 B2 250 FIG, 7 200 150 100 50 O ÈN), HTT 250 §Nº. 200O R 150 TOHINOOJOESOVINE|0}}3d 1 OO 50 H)| O HOE H()| |NCN)| §), ?!), 250 200 50 100 50 O DAYS AFTER CPT-11 TREATMENTRNNs) CONTROL (VEHICLE) PHY 906 OPHY 906 - FU/LV U.S. Patent May 19, 2009 Sheet 8 of 38 US 7.534455 B2 FG, 8 H is 3000 -o-CONTROL (VEHICLE) 2500 -v- PHY 906 O -0- CPT-11 - FU/LV 22 2000 -O-PHY 906+ CP-11/FU/LV - s 1500 2 f 1000 2. CDC 21O Hale1. 500 a. 51 2. f O us-X he 0. 2 4. 6 8 10 12 14 DAYS AFTER CPT-11 TREATMENT U.S. Patent May 19, 2009 Sheet 9 of 38 US 7,534.455 B2 3000 CD L is 2500 -o-CONTROL (VEHICLE) 5 -V-PHY 906 S2000 -0-CPT-11 - FU/LV C -O-PHY 906 CPT-11/FU/LV s 1500 5 too V 9. 75 500 y L2 OQx: is: 0 E4XX DAYS AFTER CPT-11 TREATMENT U.S. Patent May 19, 2009 Sheet 10 of 38 US 7,534.455 B2 FG, 10 110 E > Y.Ni h 292Hi C o Y sH 4. ( R Z O s -o-CONTROL (VEHICLE) 1. -V-PHY 906 2 -0- CPT-11/FU/LV -O-PHY 906 CPT-11AFU/LV 80 O 2 4 6 8 10 12 DAYS AFTER CPT-11 TREATMENT U.S. Patent May 19, 2009 Sheet 11 of 38 US 7.534455 B2 FIG 11 S'EE -o-CONTROL (VEHICLE) st 700 -v- PHY 906 5 -0- 6PT-11 600E -- CPT-11+ PHY 906 l % 5 C X7 g 500400 ;A. 5300 O 3. 200 Y 5.E-2y 100e2 0 a 0 1 2 3 4 5 6 7 8 9 10 11121314 DAYS AFTER CPT-11 TREATMENT t-tist (PVALUE) CONTROL ATDAY 14 (VEHICLE) PHY 906 CPT-11 PHY 906 U.S. Patent May 19, 2009 Sheet 12 of 38 US 7,534.455 B2 10 FIG, 12 100 a 90 80 -o-CONTROL (VEHICLE) -v-PHY 906 -0- CPT-11 -O-CPT-11+ PHY 906 70 0 1 2 3 4 5 6 7 8 9 101112 1314 DAYS AFTER CPT-11 TREATMENT U.S. Patent May 19, 2009 Sheet 13 of 38 US 7.534455 B2 Hot - HQ - H- N M N H-SS H-H-(D- to bi-h-i- to E ----toW O a E Y. V H-Q- KH-t- - rt H&- - - - - 3. y V ?a He-H+ Hv Y O O S S o s () V GN few Jouni eugo effeueled U.S. Patent May 19, 2009 Sheet 14 of 38 US 7.534455 B2 ON-g?uðurgeºuL 000), 009 uffleMoun Ieugo effieueoled U.S. Patent May 19, 2009 Sheet 15 of 38 US 7.534455 B2 HQ - H Queu?eeuLON,c,… 002), 000), 008 009 ufeWJouneyulo effeueoled U.S. Patent May 19, 2009 Sheet 16 of 38 US 7.534455 B2 HO- N N N s H-S- te ' T 3 H-e- to s C s 5As O A. s g y o C. o r (e) s O U) E 9.G S SP>e H-6- aE O E y in 5 H. C. D. GN 5> 2O St O O O O C O O tS queS S. s ufew Jouni eugo effeueoled U.S. Patent May 19, 2009 Sheet 17 Of 38 US 7.534455 B2 819Gy£.Z ?uðu?eau,le???u?J???esÁed 00:21, 000), 008 009 007 00:2 ufem Oun Ieu Jo effeueoue U.S. Patent May 19, 2009 Sheet 18 of 38 US 7,534.455 B2 FG, 18 300 --CPT-11/FU/LV -O-PHY-906-6 0 so --too."" ceterre 20 B --CPT-1/FU/LV -O-PHY-906-6 s 2. 3 10 Z 92. 0 re- rto 12o so to go 2000 C --CPT-FU/LV d -o-PHY906-6-CPT-11/FU/LV D D 1000 C O - D . o, to TIME AFTER CPT-11/FUADMINISTRATION U.S. Patent May 19, 2009 Sheet 19 of 38 US 7,534.455 B2 FIG. 19 --CPT-1/FU/LV -o- PHY-906-6-CPT-11/FU/LV 0 600 1200 1800 2400 3000 (min) B --CPT-1/FU/LV -o- PHY-906-6-CPT-1/FU/LV O 600 1200 800 2400 3000 (min) C --CPT-1/FU/LV -O-PHY-906-6-CPT-111FU/LV Y O O 600 1200 1800 2400 3000 TIME AFTER Fuct ADMINISTRATION min) U.S. Patent May 19, 2009 Sheet 20 of 38 US 7.534455 B2 FIG. 20 --CPT-1/FU/LV -O-PHY-906-6+ CPT-11/FU/LV O 600 1200 800 2400 3000 (min) --CPT-1/FU/LV -O-PHY-906-6 CP-1/FU/LV O 600 1200 1800 2400 3000 TIME AFTER Fuca ADMINISTRATION U.S. Patent May 19, 2009 Sheet 21 of 38 US 7.534455 B2 600 400 ir control (vehicle de PHYoscomys -- Gemcitabine 150 mg/kg 200 - PHY-08500 mg/kg+ Gemcitabine songkg 1 2 3 4 5 6 7 8 9 10 11 12 Days After initial Treatment PHYgos N n Geractabine ? ? FIG.