梦幻120无级别国标刀能卖多钱啊？加21力_梦幻西游_你问我答
您的当前位置： &
梦幻120无级别国标刀能卖多钱啊？加21力 来源： http://361t.net|人气：9974 ℃|时间： 17:38:03
前天帮人过剧情，死了，很伤心郁闷，赌气拿出1500W攒买果子的钱买了本120刀书和铁，赌气一鉴定，是个无级别，加21力，值多少钱啊？是个国标。我不懂价 楼主你好，120级无级别刀能卖人民币块的样子.不过这也得参照你们区的玩家人数和物价。希望对你有帮助，谢谢 追问：谢谢乐啊，我以为能卖个几百块，我还有个猴子，中将给的。看看能卖700块吧，补充：神兽猴子的话要看下级别，如果是69带的话可以卖块人民币.如果是等级在130以上价格在人民币左右. 希望对你有帮助，可以的话设个最佳谢谢。
1000RMB左右、 补充：区不懂也会有差异。比如我们区90无级别都3000RMB- -。超级变态- -
根据目前各区的物价，和各区有钱人的情况而定。普通价格在3000---5000之间，这是我根据我们区的价格定的。RMB100=1400MHB，市场价。
最少8000块。。那东西好啊。还加21力量，那就不属于国标伤害了！ 送蓝色泡泡，升级奖励箱送400W经验200W储备金 有需要的朋友请加QQ (39 39 45 778)QQ(79 76 6 17)
按你区的物价而定的，如果是极品区就贵，一般区就比较便宜了。还得按伤害和命中....你的1500W是只赚不赔的，最低也能赚400W左右。
||||最新更新Laterodorsal tegmentum interneuron subtypes oppositely regulate olfactory cue-induced innate fear. - Abstract - Europe PMC
Europe PMC requires Javascript to function effectively.
Either your web browser doesn't support Javascript or it is currently turned off. In the latter case, please turn on Javascript support in your web browser and reload this page.
Search worldwide, life-sciences literature
Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Key Laboratory of Neurobiology of Zhejiang Province, Zhejiang School of Medicine, Hangzhou, China.
[):283-289]
Journal Article, Research Support, Non-U.S. Gov't
10.1038/nn.4208
)- subscription required
Show all items
Show all items
Show all items
Show all items
Show all items
Show all items
Show all items
Show all items
Show all items
Show all items
Show all items
Show all items
Show all items
Show all items
Show all items
Show all items
CitePeer Related Articles
Chemicals (1)
Diseases (2)
Gene Ontology (1)
Genes/Proteins (2)
Organisms (2)CANCER TREATMENT
WIPO Patent Application WO/
The treatment of cancer by the concurrent administration of at least three, preferably four, and most preferably all of the following agents: (1) angiogenesis inhibitors, (2) tumor suppressor gene stimulants, (3) multidrug resistant pump inhibitors, (4) anti-inflammatory agents, and (5) non-angiogenesis chemotherapy agents.
Inventors:
VAN DYKE, Knox (106 Morgan Drive, Morgantown, WV, , US)
Application Number:
Publication Date:
09/25/2014
Filing Date:
03/12/2014
Export Citation:
CBA PHARMA, INC. (670 Perimeter Drive, Lexington, KY, 40517, US)
International Classes:
A61P35/00; A61K31/47; A61K31/513
View Patent Images:
&&&&&&PDF help
Domestic Patent References:
WOA1N/AWOA1N/A
Foreign References:
EP11401926962927
Attorney, Agent or Firm:
MITCHELL, James, A. (Mitchell Intellectual Property Law, PLLC1595 Galbraith Avenue S, Grand Rapids MI, 49546, US)
L A method' for tsmb eaacor comp sing. &e tacun*ai admimstoiion of at leasi t&ree .of he entitfe* seleoi d from the f lowiag
{ I ) .m og& 3/4 s 3/4 esi s loblbdors,,
(2) i nm s oppress r gen*/
3/4 :muams,
(3) mis!tidmg resstoi p m fMDfl)
1/2 Mbilors,
( ) nila m t (R)Q i$ . m4
(5 ) it ofr-ang .ogeaesi s cbemother apy agents .
2. T 3/4 e method of sMm I m fekii said turner s ressor gesse siimdants ae M AC L The method of daii 2 In whic . s&kl MO ia biP&rs are selected from tiie giro p of :d- leiraKloos family m m es,
method of claim 3. in in h s d arst-lo! ammsiOi agents selected S'om- the- ' f h oil, anto dants, HS.AI.Ds, aa^mlammaor steoids (R)%d NF-KB .mliibi Ts,
5. l 3/4 e m 3/4
od of clam whk comprises the coocurrem admmistration of si teas! foisr of said smmes.
6. Too method of claim 4 wttieh. t mpm nc tr t Mmimmt i&n of all ive of said entites.
7 7, The met od of d n I m whch said MDR Ej&l toirs sxe■ seleced from the aroop of d-
L The-. method of claim J. txi whleh saki mi- I 3/4 mm%t&?r are selected from he group consisting. (R)t hah olh anii ?xklams;? SAIDs., d.~isifl :m 3/4 Miw siemkls id NF-K inhibitors,
9. The met od of claim 1. which, comprises, the co 3/4 cii EUR
3/4 dmi 3/4 fetajkn of at leas four o said colds as.
10. The method of claim 9 in which sai ivm su pressor gen stm ftS' ape MQAC inhibitors.
I ! , The method of c itn 10 k which said MD' i&hi 3/4 itors are selected 'fk>>m the ro of d- tetxa>>dnne faodJy members,
12; The method of claim i ! ia ieh said a>>ti: afi iB>>tat.&& agents re selected fiom the .group consisting of: ish. oil. amt-oxidaats, NS IDa, a 3/4 i-hiflatr 3/4 m?iiiofy ceroids sad NF-KB inhibitors.
?. The■ meth d -of claim 1 which .c mprises eomare adnaii stea&a of all five of said eatities. 14 The method ofclawfc ! &&r treating gastric cancer by the c Pewcoo admmistetiorx csC: the JiOB-ais io eBie caneer ^riigs X to!a -(c 3/4 i§o$a 3/4
3/4 e) and dspi drsv
th i xm: up ress r ^imulao! valproic acki,
at teast oae aab-angiogerbc drug, and
&i leasi one bi^enxyl k<< #< 1 , admi istraion
the mn- 3/4 a kg(R) k- cancer drugs ilmlldora ii.de md the stero de.* me 1/2< at least ne: astb&ngiogemc
at e st ope bis< 16.. The metfeod of claim 1 for treatk multiple testicular cascer by t e coi 3/4 currot 3/4 t admimstrsiioB
.at least one of the oo-aogiogeme cseee drags Ifex (i&sam e), ?epeslde:{etopos e&- Vei a 3/4
( in lastine sulfate), Bk< a least a m g g n dim tod
at leas ite
toxl ig^uinoJi&s MD.R:
3/4 jtor<< 7, The method of claim I fa ir 3/4 afeg multiple cervical caaeer by tb concurred admmstr km of:
.the tog Avas&n (Bevacmsnab),
Ihe >>< the t mor sup r ssor stmulant valproc &csd, mid
at east one fe- enssyl Iso usmdire Dil kblbd r.
IS, The m t d ο? m ? fo tratin m<< p!.e reast o&aeer by b.e c
sal least &m
3/4 04i~aagcsgmk csaiswr drug selected fern the g u■co sistin essental oft m xiftw, raloxfene, aoasdEUR&zofc and fclroEOle,
ihe mor .o ressor stimulant valpmk- acid,
at l ast urn afcfi ^giogenic dr 3/4
at le st one bis-ben 3/4 i isoquns !me MDEio oitoo
19, The- -method of clam 1 fo treatmg adYaoced breast areer by the cciocwrenl
3/4 gio nesk inhibitor Avssord^ (hevacmmiafe),
a o-on-angiogerdc career drug coektad of Ta &sirsi smd Wercepiip, with eitherEUR 3/4 φ&??η or Ciu op latin.,.
h< at least ooe l.s-b tz l fsoqumeiioe ' i R fehib or.
20. llso method of claim 1 comprisin the c jicisrreo admitdstraiioo of the coiifoioadon of at kutei. two a i-imgk eo ss drygs, the I-IDAC inhibitor Valproic acid, as die tumor s< Description:
C lA CE TRE T ENT
C OSS RE ER NCE TO RELATEB APPLICATIONS
P | ! 3/4 ? s 3/4 sen* application, dainss the enefit of IIS, t sm &mt, A feslo N&*.
61/79SJ07, so l . CANCER REATMENT, filed n March IS, 2Q13, the entire contents of which are !ru&t oralcd by lofdence.
FI?LD AN(R). BACKGROUND OF ill INVENTION
P002| "Hi present invention- relates t>> i e treatment of cexieer, Ca>>oe* chemotherapy s partially affective kt only a o< SfiM AEY OF THE INVE TION
[0003] is too pesen i. sod B caocer is treated by the concurent mini raiicm of three or oe of the .following agents: 0) m angiog sie 3/4 :is iid:h itor (2) m HDAC kbibltop (3) a multidrug resstant pmnp rnbibdor, (4) at aoii-ioSammai y, and (S) a o n- n iogeoedB chemothea y ageot.
DESCEIFTION OF HE F E E REI) ISM OI&I E TS
[01504] lo the preferred emkKfctest eascer is reaed with the cooe n^ot admmLstatio.u of a least three, prolmbly ioor, and i preferably
3/4 j of e low!ng ssoots:
(1.) asgiogeuc^k inhibtors ;
(2) aunor suppressor gese stim'ol arris.
(3) multidrug resistaai puitep irdh itors,
(4) -miMftilamn ory r^eots, md
(5) m-mgio im ch mohera y agents. [0005] Hie am COBOIMTC adsxdslstratiori Is used broadly to reifet to ttte.use of all of hee dra s, duriog a gives cycle of tre meM t & m. . T 1/4
various agent might be idmb sered serially or sim ltane usy. Preferably, tfecy (R)rv all administered suc that ooe m mom of the drags remains bo the pabcsfs system -wfei each additional drug is adroir sewd. The dosage levels for the ari us drugs which ibil mix) th& above Eve categories have een ap roved by the FDA. m are listed m 2 3/4 g P clw '$ i sk iefere .
pOCiJ Th multi eom^l<>HSy 3/4 ergs .as originally proposed by Mil Bererb&uur 3/4
in Pka stsc&hgs i Mev ws, 4 'b pp 93-141, I9S - b a re ious pate t (6,962, 27); have o ser ed synergistic a s cancer aebvity th, combinations of doxomhielb -md mate the IvIO , drug t 3/4 sistath cance cell m re Semitc to .certa li- cancer drugs tk 3/4
drug seoshiv aTU.i-EUR 3/4 ncer cells, ito er, m im m fet reside m ysmm orleo have their t mor suppressor gei 3/4 e§ ciiv ed<< By osing substarsces tha eoritroi oncogenes md . activate . im i suppressor genes slmnitarscously n com s ioft with the action of auiieuueer i 3/4
me<< ami MQR pump inhibios, the dormant eaneet cell which is mo ly imoruoe '-maa drugs should beoorue a vicim of this mom multiply effective and seleobve acti n, A TI-ANGK)EURE ESiS I IIEURS
[80OTJ The followin drugs have been approved to
1/2 hi'hii impog iesfs (blood vossel f rrnah if), which is consdered past of the .oncogene, .
1. Avosik (Bovaek mah) -Vascular etKiolhelial rowh factor Inhibitor (VEGF);
2. Cet ximub- lohibitioo f epldcrrual growth hetor receptor (BOFRH
3/4 ay 3/4 r (Soralh<<3b)-Ki<>dotfec*fM .gro h factor (V IGF) nni pate i- firived gro fe facto (P.DGi 3/4
5,. Olte oitedies to vascular endothelial growth factor (VEG ) aod fibroblast growth factor. TUMOR SIIFFilESS O ^g STIMULANTS
SOSJ Hixkme degeeyhi.se (HDAC) inhbit r are a cl ss of a nts that mixiu e gene cxpr
3/4 ;-.- by ioereasiag .histone acety!atiarL Hisioae acetyl&tioo stooo ie* the expression of h ior pprsssiori factors by some rum r sappesarori genes, Bcc ase these age a able to r gulate the c nro of specific geocs, mc!odm loaior sup ess r genes, the are viable candidates for uso
coo ear ireatmersL
[0009] Valproic acid, a owerful HDAC inhibitor, relieves re resson of traoacriprioo f cos, causng hyperaeetyaticfo of h nes hrtdhiiing tumor growth and .metast sis The origina use of valproic acid Inhbitors to io ibii Msteoe deacet lssse (HDAC) was by Martin. Ciottlicher of Germany where be published ""Val ic acid defines a nov l class of HDAC inhibitors" in EMBQJour l 2$, pp S, 2001.
[691 ClJ Other historic deacety!ase inhibitors, may be used as therapeutic agents for cancer aimem, four of the most edeeb e BDAC Inhibitors in addition n- valproic acid are "J Yiehostaho. A,, butyric acid and BfVfL-210. However, th m are many ohers that may also be effective. These include six categories of 0DA.C is hi biters:, short-chain &tty acids (e,g. phc y!baiynito id vaipn:; ttil hydroxamic acids (e.g.. saberoyJao lido hydroxamic acid, trkhosi&dos, SAHA arxl derivative^ oxatrdlahrp ABHA... senpiaid. pyfoxaralde, propeg 1/2 zm&k$}, cyclic tetmpeptides (e,g, oaioxkrs, iIC ox 3/4 y cbhmydocin, di eis e idp F-3161, C I-1 and Cyi- 3/4
oo~epixyl(etooe-coofaaiog cyclic tetrapeptidea (e<<. F. 901228, apieidm, cyclic peptides (C AFsT ber&amk!e$ feap MS~27:\ Cl~ :i , olh r be^^de analogs) ami ld r mlsceHaa ous slnsetures (e,g. depudecb depsipepide ami org^osulfur cem oaiKkf
MUL IPLE Wt!IEUR R SIS ANT ( I) 3/4
3/4 011 J One of the major causes of .multi-drug resistaaee Is the MDR pirmp mec sm(s) by wliich an MD eaacer keeps or pumps- therapeutic drugs mi of the c&aeer cells. Various MDR ump laMbdess are kas o ara! available,
[Q 3/4 12J E e lary DF p inhibitors i.aclede TT- 3/4 s? !T-! BE-- i5Y-- yefiai:td e: P!i--p 1/4 OB-- ΓΛ- &figchim&-i<> ibaliearpke. Especially r ferred are members of the d-dri.ne fendi? having fee fowiag ckemc ! sitact re:
where R.= md ii (R) the same or diifeeat sh rlch 3/4 l 3/4 sd ssrboB based Hgao keludfeg without limitation, CHj. COjCH? nd l&feCIb or Calls aed
Is O-E and where he chemical stmc&u-(C) hw the "S" someric co ilgiaamkm at t e C-l ' eblraf cafes locati n
[ 13J The d,
3/4 nd:r 3/4 e fmily members have been f md effective im treatin mrdibdas msixiasice: In a a et of iseases d con itions, ieeluding cancer. See U.S, Patents 5,025,020: 5,332,747; 6,528 19 6 J1L454; 6A24J 15 aod 6,962,927. The preiOTed mem ers o dre d- erandrine family isdode the follo ing r resenative examples, w efe are >>ot iBt
dAeiraaddrie, isoietiaaddae, he.m3mle.:dee., beibarmae, . yaamk^ phaea hiae, dba gne ethyl | 3/4 gc 3/4
1/2 o1 3/4 e and iarsgpbiaoldm t'n all of d 3/4 sp axam tes, K\ md { eoaistitate the mta 3/4 y! gro . V grqap occurs m thai
tmy mmiitnia- either a meibyl groap or bydtofeip aadthe isooietrie e <> of the etaB oorid t t e CM. -md C-Γ chtf-sl esrboo posiboos in either jf 3/4
(rectus) or S (sinister). The reloa t 3/4 r R md S coirhguratkm can be found m oms∞ arsd Boyd, Orgmk- Ckemkiry^ m Edkio 3/4
copyright 1913 by Al!ya aa.d-Bacot 3/4 y-at p, 13 -14L As aoted aio e, tte ehirai eonfigaradoa ai CMf is ';"$'?; for members of the d-tetraaddee famdy, la addition, befnandeaine mel des a raetboxy group at dte C-5 position.
|DCH J The most preferred meaiber of the dairoed tetraaddits fa ily is d-tstrattdrme. Methods for exmtef g apd/or p rifymg d-te&aaddne are disclosed in U.-S..'Patent. d-,2I S,5 l apd m Poblished Patent Appiieadoo N , 201 W1057S.S.
|0O1 §1 These are. drags that ..inhibit the MDR. |?? 3/4 ρ.?? do a t l t the metabolism of the m&~ eaaeer drug, and are i ms
fi 3/4 e& b the P4-5 s stem aad bkh probably eoatpeta for the AT. pampiag medmasra srace they work at lower aad rioaoxle doses. This places them *; generatio three drdbdors since they are selective d aeiaid are effective clinkally (see Cancer Biologies of Aateriea) at Lexmgtoo eMueky.
[8016| In a ddioo, there are a variety of
3/4 ah&ge:aa 3/4 d dero^ es of the forgoing drugs ih&t: eo.otaio chloine* bromine, iodid -or dooride hich' act sbrblary. Some f these derivatives htdode 5 bo iotetaodnpe, 5, I4 bro^oioxnddpe, S chtpratemndnrse ami 5, 14 ebloroterirnddoe aa wed as the arous hd geaateA Ι 3/4 ι 3/4 << 3/4 ??οΙΙβ(C)^. [0017J Tbe fbdo iog cheraotherap^irge drags which are kno a ty be im ed by the R multiple dru osiaboice pump,
boteobairhigtooiee, krdposide, !orxbeea 3/4 , yju&i&siine- < POISJ The ddstraiidriric family msoi er tbe oilier agents osed cm be I nm atsd a eil<< mio a .single form l , ibey cm bo formulated separately aod bnmi ne sl o sufficie tly close togethe that the ca ce cells are exp sed, w l 3/4 e drugs as formulated separately m be s ld as past of* a
3/4 ?.Τ the usage tio Of de d-ieiraudnu iamiiy member t a rinci le txm-angloge le cancer treahng drugfs) il vary from p tieet to pabeol aod >> iuocll rs of the principle
3/4 o 3/4 -a:n
3/4 i>> esIo cancer treating dtugis) used, A dra tsect mt m -a an e &il 1/4 m about 0,04 to &hmi t7(L more typically fern about I to 100.
flfHS] il is bef levod thai the optlmom dosa e procedure would bo to adminter the d-idri o famly moliMfUg teslsiaace revorser in cod d^s of Jkan about SO to about lilb rog per o s re ererer per day, more preferably 250-700, mil roost preferably about 500, (pto aMy in two to four doses per day) over a period of boos, a bins 4 u- about 14 days, The dosage level tor the d- tetrandrbae family member will vary from cose to case, based on the patient aad on tbe primary anthcaacer drug(s) io 3/4
3/4 i The principle noa-anglogeak cancer treating drug/s) is (are) tbea adorabstered t usu l dosage levels (possibly somewba less in view of die ot ibi d ri effect of tbe resistance revorser) once or mote daring tbe ourse of tbe esisanc reveter d smg, box e ample, daring. four day period :;i doetrarairine adorsaiistnitioo.. the principle eoo-aobogeoic caocor reatng dragfs) would bo administered on the beginnin of tbe thiol day. Over a.1 da period, ik primary blRSA. drug or drags: might be diidrdstered on. day 5 day ! 0>> or on da s 4.8 nd 12.
02?} The dTerBdn e ik&i!y hbe 3/4 2 3/4 1.is qumo!ines h & two tikiogm lo aions and hence e s exist m the free bas orm, or as n mono or di-acld mil Bee ase of the eahanoed solebility of the salt forrn of pfcan< [§§21] The preferred !domiktio 3/4 s comprise a mem r of the d-tetrasdrine family eembiaed with a suitable pharmaeeniioal carder, The pharmaeexbical carder can be a liquid or a solid cornposhbom A liq id carder will preferably comprise watep possibly with addidona! higredieras su h as .25% ca 3/4
3/4 xy:ai.erbylceiiuiose, The solid carder or ddaeni used m 3/4 y bo pregelahmscd starch, mkrt^rystaTiine eefloPse or the like, it aaay a3s>> be ibr olafed with other ingredients, such as colloidal sdiecnae dioxide, sodi arn mr i aulhae and magnesium s^ rte. P822J A :2 -'.mg solid or l d dosage ferrnuiahoa is most preferred. The m st preferred dose erf' abou 500 aig/squsre uieter/d&y h rcntg y 1000 g. per day for a 1 0 pound patteftt six. feet tall Such a. patient can i !, the dosage reqthremenis by faking live capsules daing the coarse of the day, for easrn le tlsxee in the morning and two in die evening, pr one at a time spaced orb over the day, A smaller person weighing 125 poands at a height of five feet six inches would require fmt 200 ng eapsniesdaring the corase of the clay. AH I ^fI,AM ATOa? AGENTS
addition to t 3/4 iy cds -sacfe as fish oil and lMsxi nts which, ad to tnhi ti fiammsti yn, non-st$oj
3/4 I a<>?-sn 3/4 atory drugs ( SAlDS),. am- dlaoo^arc<<'y ster ids aod/ or alter oueie r kappa-b (NF>>iiB) .inhibitors assist .in re e ting iv ammati a, hc d i es c ncerous growth. Bxem l&ry aoi-R!lamm tor NF-&B
Drug Molecular targets- (MF- B-d iked} Qraieid Activity
Ismwm p s ii
3/4 ui dou 3/4
KIC ICS 3/4
IJdom I do I KB lo Mtkm M AID , CL3L various solid ismors Macro 1 ides Ik.Ou sabilization NA
!KKIi inhibition
Pr isiisome h 3/4 !obkors
B rtezottiib Protc-asome Inhibtion MMANSCLC MCE
Ρ?-0052 ieasome io hidori MA
3/4 c Irloxid ! K i loFlbpiors solid tumors
ami.m ei 3/4
IK I ii ii&itios NA
PS- 1145 NA
B S-34SS4! I K khibiboo MA
CHS-S2S 1 KK.& loMhitioo NA
ACHF IKK.B mhlhiiion NA.
A 6 2g0§ IKKSbsbibitioo MA
Bloddng peptides IKK. complex assembl NA Ge 3/4 e tlierapy
siENA. Decreased 65 expressieai
Decoys Inhibition of ONA-bladmg
Exem p!aro ai-kiammsioiy sterol ci & mo 1 sde:
A ailable Pr partons of Attooeoiical Steroids sad Their S ntheik Anal gs
'Nonproprietary Narac I Apes of Nonpropriear Name Types of
(Tr de -' FrepamiiAis (I E 3/4 de nan&;.-) Preparations
Oral, injectable
T cal Oral, Erpleal
Injectable
To kaF oph- rhalrs!C. otic. injectable Topical
Oral hi 1/2 Iadon Topical
Topical Ophthalmic
Ophthalmic
Topic a! 1 opkui Cortisol (hydrocortisoiic Oral Me&ysoiie {nm& UQi LM)
cyplorsate ( 3/4 g'tBF) Mcthylpredisi 3/4 alono (MHOROS,) Oral
Cortisol ( ycito &fttSi&m8) Ipfteobk ed !predmso!ooe &eei 3/4 ?& Topk-aLm- s di m phosphate &EIO- RD O L, VR!DROl jecisblc {e:VD 3/4
:: R1Y) i: H S. iiATE} ACETATE, odtefs)
Cor sol (hydrocorn ime) sodum beeO ie Met hy I f d nis l one sodium
socebsaA? (A-.HViiRm'DRt SOLO- SUCdaate ( A- ETMAFRED..
Topical- Prod o i SoJ te (DELTA -CO TEF) Oral IVIamck Io e (A sR7 3/4 :EUR0] 3/4 'i
PrednAdeae acetate (EC KOP EX), EUR&p h&b>>k\ ! 3/4 a 3/4
o !ofts aeetoidde TopkaL sri- others) injectable ( - OLiXL othes) ala on, h-
P^msolone sodi m phosphate Oral, Tiajncrs l no, di aceUrte Oral inject- (p.EO^AP i:?, ot ers}' ophhalmic, (AR!$1tX&RT, E ACORT able
D ACETA'TH. others)
Pred s&tee eb stc fcjeetab Tn (R) ei a kase hexaeetonide hbeetahte {HYOELTRA-T.s.A., others) i -A CilOGl ISIS INHiBlTI G ANTICANCER I IiGS f The foll in a< Alkylating A rogeo mustards Meohlotcdiamiae HcAi kfoA disease.. o nAfedgkinA
geois fyombo 3/4 m
Cyc lophos pbaa ode Acute and chrooe 'lymphocytic leukemia,
Bodgkk dsease on-H rie ro blasi ma breast, maty, img cancer, Wilms' cervix, soA tissoo saxcoTH
Mdphalaa {!^s&rco- ldpte mydom& hreaA; !yAo) ChloramChronic
bucil rnacfoglobO- ModgkinA dsease
o n- llodgkm A '!ymp om R
Ethy ienci mines nd Ovarian cance
meh lmelM oes TMotepa. Bladder, breat vamm cancer Meth l draxme PrjCiirba2ise ( - !fcdgfcioA disease
dors vali ve Antimetabolites
hl bd } Products- blsstie fcnkenb& in obddnen
To ote an, sneo- Qvs& enneer, smeibcell lun cncer teoa<< colon and Sung carreer
Antibiotics ChorloearelBO Wilms" rhab? (aetmomycin D) Ka osi's sarc ma Doxou icin Acme myelogenous am! acue lympho? (daiaimnyerry cytic leukemia
nibk rnycin)
Di.>>x∞ cm SoflAis-sue, osteogenic, and .oilier
IfcdgkinA disea e: mm- Hodgkin's !yp 3/4 phos< Acute myelogenous leukemia, east and rosate cancer
Bleomycin I'estls, and cervic&I cancer, i!odgkirbs diseas . nm^Hod kir , ym homa Mitonweb (mil - Stootaeb, anal, and han eauce fnyein C;
Acute lymphocytic teukernia
Miscellaneous
ageais SabAiteted Hydroxyurea C rome
sse tial ibrsanbooytesis DbfecnbiUio agents T.. arsenic Acute pmmyeocytic leukemia
Protem tyros e Iniaiua b Chronic gastm- kinase inhibitor intestinal stromal: hyper- eosiooph!la sy>>dfOs>>C .
Non-small -eel! lung eaaee*
Proteasome m- Bortemunb Multiple n^ eloma
Boi&gica! re nse <<16ΓΙ 1/2 \ΓΗ&.1Ι 3/4
H Kaposi's modfiers intede kis 3 carcinoid: renal cell
oon-IIodgkio 3/4
lympho &itiple. chrod
m lg a t melaeom
Antibodies
Hormon s and:
Adxcraocortica! M ioiane & .;&. '-DDD) Adrenal cortex cancer
su pressants Amiriog teildirdde Breas cancer
A drenoeon :&.c- Prednisone (several Aeuie artd
noo- sterods other e uivalent pre- ! !odgki breast paratlons avail ble) ea e
Prog dsis H dfasL' r gester- Endometrial breast cancer OOO ψθ ηθ. seetate, meg str l
Pstropens Breast, pr state ancer
ethnyl esiradkri
iod-er pe aid oas
Anti-estrogens Tam.oKii 1/2 ii; orsrnk Breast, cancer
Ar(HTsaia?5<< inhibitors
Aolkandmges
MoBOcIona! Antibodies Ap roved .:f .r ikaatopoleiic ami Solid Tumors
m per* dr i Tuns r Amigen Fractal Naked AMi bodies Radiost e- Cell Targets ase Anbbodtes Antibo es
reced d'e s
Afebreviaikai&; C1..L. chi e l 3/4 FR, pi idermal growth factor receptor, NSCLCk 000-srsta. VEG'F. f5scii!ar-eadoth< Drug Dose and Sdaedu!e Major Toxic Ivy
Euoxmab32 ADCC: C;X: 375 rowariV infusion
es y for 4 < a opiosls W .3 times pes* eek .
followed by 30 msCtrr
3 times per week ids 4 io
e ADCC: atop 3/4
sk: Loading dose of 4 apCkg C USIOB- mhi itionof HER2 j faskm fbdowed by 2 related ioxkity
ss o almg with Ch < inhi ton of ECFR Losdog dos of 400 m&%? t'<<$kR-rekt 1. toxicity skh sksa Bs: a oMosis:
ADCC ~ ' " :
Bevadm b* Inhibiti n o anso- pe 3/4
3/4 $:sAies *"
vascula zation
DemktAin di im.i ' s Ysrraeted iipteheria
toxin widt ik
h i hid oo of pmtei n
3/4 u i.gb: o 3/4 y ou l IMA. strand 2 d ses of 9 sgfei^ I Irs i 1/2 aroie ied: gamlekC- reaks apoptosis beraa
oleosa! heoatie ( VO.D1; andskfa toxicit
Targeted radiotherapy OAfoCkkg IV I-Iei 3/4
ts. mve- lodyplasia'
Targeted, T 3/4 dk&lberafy Pabeat-s eedk dosimetry H myc~
lodyplasia'
Abbrevl.;doos: ADCC ankkody "depeodcoi
CDC, e mpleme i-de^ -BGf'R, epidermal gr ivth, faeior receptor* VOE-ζ wm& eh iw disease
EXEMPLARY COMBINATIO S
|0 2S] There are various, tr tm nts currently impiemaaied. for dfferent forms of c reers. The com d doital Steatn 3/4 ent proposed hemk s oold be com aible' with all the various forms oFcaaeer ireafmera. Be w (R)zs examples okC detailed csaoer tre 3/4 Pm eats e< .ato the ooorapbiJIfy f oar tresitment wkh a wide ra ge of currerit e 3/4 aeer teataveP^ aad i& isot
3/4 & Eorrs adbidi wdh ooly the .few caece teaimesits Ksted below. Any &( m$≠. pfmlmd pr t c ls cm be gi vers with the addition of off additional new txe me ts, The cornblnaboo of old and af addkkmd new substnces stayald be giv cshnuha e nsly at the start of cancer treatment. For xam le the fbllowiag protocol examples of how the treaimeb could be integrated.
3/4 6J Xdoda o!oda (ea ed ine) lus elsplatm are carysndy Its Phase 111 trials for the ireaim.ern of advanced, gastric o&neer. This combi at has proven to has;e higher overall res onse rales t n aO the aaitrent ireafaeuis available for gastrc cancer, This combhtatioa for gasirle cancer could be further c< when t mm%& ko contact with a nainraity occurring rotei called thymidine phosphory!asa is converted into 5- fi aoroia-acil which acts s a cytotoxic drag, Caaa: e.o; gcooaily hav iglier. levels of th mi ine phospbca-yl se, so 5-iIwoarci! is targeted txtmof more than other tisanes, Cisplatiri Inhibits mitosis I rapidiy dlvldmg cods by erosidinking DMA* therefore in b!ting the rapidly dvdng eaiieer cells, Xe s!is md ck Wm .target cancer -cells in two dlifeem wnys-doy eytoxkaty
3/4 d .inMbinoa of mhosia, 27| If t ese two tucalu rn were farther eornhined with substaoees that target cancer cells in ways other than Xdoda and oiaplafin, the comhio dotj should be . ever* m re ei!eetive reatment. Addition of a tumor sunpreasof gone stinaalaoh aa oncogene inhibito arsd m SViDR penip inhibitor would impede ahernaiive sonroes sapplyisg the tonaor ceils. Valproic acid, acs as a tomor suppressor gene abrral flb which inhibits the proli!eratioo of im f ceils before Cboy are transcribed from NA. by hlhibiting histonc dcacotykses. The addition araiangiogenie drags,, which play a role in nhibiio of the aacogene. oold: act to inhibit. t 3/4 e blood, su ply to the r cell Any combio hoo of two of Ibo: s iooglogeoic drugs bsted ab ve would be effective to preveoi vascularization of the tumor cell A fisrd . si&nce hat, eooid combat multiple drug resstance C I&R bo inhibiting tbe MDR ump would allow the eorrettt esucer teatmens to be more eitectivc by peventing the drugs fmm beng pumped ou and allowing ihzm ' i ftger activt- the eeJL y 000 of tbe vadous bis- eaiwi isoquiooung MI1R om inhi itos listed above would be effective in tlui combinational treatment.. However ietr%sitdr 1/2 e and s:oueioootdoo are llkoiy the r ws eoectwe. Tibs ws' iasioml treatment, m addition to Xolodo and ekplat , would act to target alternatve ooe!sarssEas thai allow iho oaooer to prolslemte, 1'Ms would allow the current ireatroetu to be even more elective by targebng the cancer is. more ways.
Exampl 2: sii!ipfe
Multiple isydoma, a. saucer of tbe booe uuurow', cm bo treated by a combination of thalidomide and tbe steroid: doxameihasone. 'lds combination was recently discovered t have a synergistic effect when taken together. rkiwever, mdividuuby tbe drags were inflecive agaiosi multiple mydorna. T Is thought to redu e hone n uro tumors associated with multiple nweionsO-s .by i 3/4 ve 3/4
< i>>eehaaiisms sed bf die eam r celts proliferate. This combio fea -would wmk by Pie s me . ect oisms s in gastric cancer.
xample 3s T^tSc<<1a 0&i*c< 130301 bde t3n 3/4 §: ee se rsl drags approved, by tise Food - d Dreg Adfma 3/4 ir i D? no stagle drug is effective for all testicular cancers. Drugs ap oved, ibr treai eni iae!ode If (ilbsamide), Vepetiie (etopoiddef V lbm (vinblastine $ι & Bk x m (hhomyew suitors) end C spktra). Usy 3/4 ily aeombkatiors dl'&ese drugs $t& m ckplatm, ctoposide, and bleomydif : 3/4 ?! Ο will be ased m treat testicular cancer.
?00311 In addsikm to t ese drugs, the eomPiaadonai Irsahoeot of valproic acd, two aitiaogiogeok drugs and a is-taz !
>>?<<οΗκ MDR pump irddbdor eou . be added to make the current areatrneots mote o 3/4 eth/e. The aok!tiioa of these sabsiaaees cowid hove a synergisbe eObc eo die current ieaimeaOe See tJSFBA ftla,gov.. 3/4 kc
Ex e 4j C rvlcs! Caaeer
?0&32J idder current: cervical, eaocer treatme.nL 90 eaces! of recurrent cervical cancer patients die -wilHu. live years, However, :reeead? a study using Av:a 3/4 tm (Bcva umab) m mhtmim with 5-!loooasey Pes proveo w have dmmate eileets advanced ce dcid meer pade ls, Many of the padenis saw as?gm'11caat dec ase in t mo shte r elimnation of the tumor completely. A\ 3/4 sik5 oaie of the above listed aadaogiogeofc drags,, aets to inhibit the
1/2 mai 3/4 &5 of od essels s pplying the iuiisor. If Avasiln bibds nly a prseebsge of the fbrojadoo of blood vessels, the addfdoo of ooiber a iaoglogeaie drug ifeat works possibly via a di 3/4
3/4 resat mechansm aaay furdor inhibit sogi eae$ 3/4 .. The addition of valproic
3/4 ckl .or other MDAC inhibitor end a bis-- 3/4 ri: 3/4 d. isorpimidJoe MDR. pump m b r could also hroteaso the <a<< am r tw? tmmi:msd may ima se the nornbe of sk&ts with coaipte elminaton of ten rs.
xampe Bi &r$miEUR 3/4 >>cer Preventive
[P§S 3/4 ] C ax 3/4 oprever 3/4 tsors Is used prior to di gn ss of creers hel rdaee the risk of csttesr io health people. Women at. ItK-reosed r k for breast c ncer ca? treated, with, drugs such as lmoxifeo or raJoxiiene, or ih
3/4 roWase r&biiOsrs arsasr zo!e or 1ein& 3/4 ote.
p|$ a combina'dors of valproic add or other IdDAC iotsi i r, tw ardiaogiogeme drops arid a ss-b ozvl jsoquirsohoe MDR .pimp inhi itor coo!d be added to roake the ean^ot treatroeits more effective. The combi ation of thse subsances with the eheaioprevetrioo hora could have a higher efficacy in "more i nts, nd could provide a s nergitc effect in the treatrneM of areas! career or other cancers.
E^as& fc Advaaeeg Breas : Career
PJOISJ Advanced with staiKiard chemotherapy prcd< 3/4 g to the atona Cancer Institute oews-2i 3/4 B MCi trews -see NCI wehslto at v ^ .caoeeratov. TMs new combination doubles the survival of patients who respond Avasbn mtlmgiiigmicx or an inhibitor of Mood vessel rbro'satioro and Avasbn inhibits VBGP or Vascular eodoihelial. growth .factor...
3S The addition of v lpoic acid and or derivati ves arsd a bis- eaayl isoqois linv MDR.
omp nhibitor e.g. tetraiidrl e. 'The details of dosing ith iotrBiidlrse are covered m our previous patent on bis-ahen 3/4 yl isoqtdoeitnes inhibiting rno!hpte drag resistant carseer in humiffis (eum 3/4 si dosbig 300-609 mgday of tetrandnne. to the Avasflrs s 3/4 md&rd ebemmber&py would Increase the efficiency or elkacy of ihe ehoniodiera y.. lo addtion a sudy t at used Taxotcre aad Wereepdn with eithe Cisptatm or Carbopls n as highly effective 51 advanced breast " cancer since response ales were extrap iii& .
Exampl 7: Nonspecific Exam l OUST] The oil mg s
m^-sp cbk career example of a eombmadon of aH five and-eaoeer
I, A so 3/4 E ESIS I H 18 i ? >>? S
A co.mbim.iion of at least hvo &tfxmgiegcnk drugs to inhibit vascalar adaihsbbd growth fac r (VKGF) or other growth, isetors e.g.. epbbebat cell gro * factor (ECGF) and thereforfe inhibit the blood supply to de immyr eelL
Z. TUMOR P ^ ^SS S a ?■ t. STS UL A N S :
3/4 dd or other lsone de 3/4 eets 3/4 se inh mjrs (listed above) as tumor suppressor gene xtlmidaots,
T!ie use of one bis- benzl oqeko!ioe such as t iisodrme or isotetraftdr e to irihibb the multiple dug resistant (MDE).pump
4 Λ Y AGENTS*
Am xsdaiHS s ch as fish, oil and gr ea ea.
5, H-A C^OG?P5 3/4 !S ACINI'S:
A ooniblaapon of ca cer type s ec! H drugs to combat specific eaaces- (See HoHsod a d FreL 'wurr Medicine M edition, B.C, Becker Ese 2000, p SS6-5 3/4
ibr specific cancer teas^ e t com inations } . The precedin ex mples wer just a few f the hsrsdreds o treatareois ot orato c ncer chem therap which coul bese t by the addti n: of a hiapsae deaeerylase inhibitor like valproic acid nd to many derivatives esters o salts, batyrle acid and its S IW esters or derivatives mcksdiag various salts and trichosiatin A aad its imy deri vatives. The ottfce. list of these dr gs' is delineated in. other parts of this ap lieatiCHL The addition of a b!sderszyi isoqainolirie um
3/4 M it r aad derrvadves such as delineated m the seeders raaM drug resistance (M'PR) pump inhibitors that block the DR exit pump would prevent aj st aodcaace 'drags si provided above) tm being pumped or extruded imta t!ie cancer ccIL S 1/2 ce this ATP-udeui: protein pump i>> m icibk, the longe the c reer cell Is treated th maay anti-cancer drags, the more pantps ar produced md. the reater the resistance to the drug becomes. Once die -pump is inhibited, the cell that t eatens to ksCame restsia to the aetl-ea o- drug -actually become more aeHSdlve to the aittl-caaioor drag.
CO CLUSION
3/4 e use of antiaivgiogeme drugs, as oncogene lohihiters or conroilera to posvenl the mereased v sci 3/4 lari 3/4
k of tem ts charscteristic of many earteets. The addhioa f any t o differera roMbiiofs of the abcrve listed .aniiangiogefck' 'i g$ mil he efibetlve mhihitmg vascidarlzakm of the tumor cell., T his will include ai of the a i-aogiogemc drags currently available aud the ones to be developed..
use of one or more lastone deaceylase CHI5AC} ie b.lt&?rs (as ddfaesed in the previous, .section oa hisfoite deacetylase la Mtors HDAC Inhibitors) to activate transcription of tataot suppressor genes, Aw of the above listed IIDAC inhibitors should be e fective in activating, tamor sup ressor ems. However,. Valprehc acid lias proven to be i\ powet blDAC i -Mtor, so It may be the Hi) AC Inhibitor of choke, for many c&iRoer ireiproorsts.. Valproic acd or lis s b - osier derivatives are cog nly FDA ap r ed for epilepy aed bipolar disease asd have oodergotte extensive clinical trials domoBStratlng those IHIAC jd.d d r t xn sup ressor siminl to be effective, in ixmassk See appendix fx details of ie d!flore (val rokaeid derivatives r ints) aad salts with, the correct d e.se Assy of die available Mstoae deaoetylase InMbdors coaid be meksdod in this gr p including those slid to be developed. The list Is Bterdy to indicate examples.
ijp041] The use of one muliple dmg resistant {MBRJ pump inhibitor w increase the efficacy of t e c ren cance chemotherapy teatme . Aay of the above listed DE puoip in ibitos coald be effective against MDR, B cver tetr 3/4 mdri-ac and Isotctrandrine currently seem to be the m st effective of the MIIR iahlfeitors fOKt a ehoieal perspeetlve. The d ses of these dr 3/4 g.s m -vary with the weight of the iodlvldnal. bin $k& generally In ihe dQ-h 3/4 § .r gd 3/4 y range. Most of the drug hidleated on the 0& list can be mclttded specially those still to be. developed,.
p042| 1"he co>>c<> i B(R)mmdkwy steroids eg, preehnsone, prednisolone or o!esaneihasone (see anti- inilapmmtory .d sgs previo sly Usiedf . This list Is mi xcteive bat merely indicates exaaples that cook! be ased, la addiloop absi BCcs thai i i opclear. bheior kappa b that are not steroids ss listed above uld be used aioneor added: to steroids merrhoned above. Arsii-nEafHntatory steroids also Inhibit noek&r j 3/4 etor b as mil m strotiskte die roduction of de inhibitory factor known as i-kappa h,. alpha or tela etc. Doses of these drags are listed
? The Phy ician's Desk Refir ce (PDR)-bbih. edition.. For other xamples of $ 3/4 ese atdHirfl& matory dru s consult the :a<>matory -serod drugs lsted t ikKtim&n. & Oilman's, t e Pkarm a gic Basis of Therape tics eleventh edhloa (FOR) lsted on age M02, This. list eooialre? drugs top wo as D ARDS or disease modifying drugs s< [0043] The ase of eaerrt arsii-carcar drugs :aod aad-earicer drug eomfe 3/4 a 3/4 oos -for .can. These rugs, or eomMoa oo will fee ased combination with two aobangiogeme dra s, ooe or mom HDAC inhihfers, oae Μ? pomp iothoitst & a -mxture of ao -i nas: 3/4 o-sap&fy subsfaocss aodfor stemkfs.
[0044] l 3/4 e dosages of the above iBdicaied drags arid o tames which have beers, approved by the FDA are listed in the 60th Edition of
a ove iadiated dregs or $ 3/4 r 3/4 staoees not approved by the FDA mast he determned on m dlvidoa patkni bask a d/or approved fbr pafeiis a heroic bss for us ,
@4S| ! 3/4 e -foregomg is offered primarily for ur oses of ilh &tlofi. it will be readily apparent to those- of ordinary skill-, hi the tat that the o ea ng eonddiossL materi , proeedmal ste s arsd other parameters of the mveappn escri ed herein may be ferther modified or sobsdimed Io varkms ways wihout depart g from i e spird and scope of the iave icst for exam le, the .invention has heeo described with human patients, hat veiem y use Is coni&mpIar&T Th s the preceding description of the ireveatioo shook! oof he viewed s h mid rrg bat merely exemplary.
|0046] Although the lovearion has beea described with reference to pre!ers-ed. eaibodirs-soois and exaarp!ea thereof, fee scope of tire present hweistl o Is not hoslted only to those preferred emb dl ie is. As wl be a parent o perscms skilled llbe art modI& 3/4 :tk*ns and adaptatons to the above-des ribed im-emiors c be made
the spirt a d scope of the 'iaveotcsr
& 2004-. All rights reserved.