ithnithmBookC_StringPrint_SetupTPrintStartupSound_TabLISTBook_PrefsAct List Scene Drawing_Model Draw_Specs diagram_struct_arrayDependentsScriptPad_ListManuscriptPlayPlay_PrefsModelSubscript_Set_ListSubscript_SetArraySimulation_ModelRun_Specsentity_struct_arrayentity_structint16_arraydouble_arraytoken_type_arraytoken_type run_handle_array!Draw_Index"Poster_Info#diagram_struct$Point_array%movie_attach&Picture_Tab'Pad(Model_Index_array)Button_Type*Condition+Play_Where,Movie_Tab-Model_Index.Picture_Data/AliasRecord0lid_info_array1lid_info2slider_type_array3slider_type4Log_Condn5Log_Page6Dependent_Entry7graph_type8curve_type_array9curve_type:table_type;table_var_type_array<table_var_type=SET>Panel?Sector_Specs@Sense_SetupAselect_struct_arrayBallow_struct_arrayCPicture_arrayDEntity_Controller_MapESection_ListFWindow_ListGModel_WindowHPad_WindowI<<$ccccc7<'dcxxHH@\HH@d'^~ pd>> ,,rc2c^c     cc    JJ@ drmd   $^N$]<<$\rcccc<cPP??A2    VV#c*c #c cwcc"<<6c 'dcO_&1 Dim_Name_1  jj@?əTime ~*!c @??@@????@?I dose_rateif ((MOD(TIME,spacing_between_cycles_in_hours) < hours_per_cycle) and (TIME < duration_of_dosing_regimen_in_hours)) then concentration else 00'=H  0 ,  '   =        !" #c@(? 1n?@(? 1n@(? 1n@(? 1n?d@rK?d@rK??? ?x- ?3?d@rK CFU_GM_population_relative_sizeCFU_GM/2000000000~ ~ / Ae  !" #c @@@?@@@@@???@? Iconcentration0 !"1 #s@Ҝ{{??@Ҝ{{@Ҝ{{:\(b:\(b????;0/z?2CP_in_periphery0 !" #s  @K??@K@K:F^~:F^~????;Js(?2 CP_in_blood0   !" #f5 @4+䦟B??@4+䦟B@4+䦟B;;%铉;0/z????2K2162.9*CP_in_periphery {from Cohen et. al., 1971, p.679}  @33 3333   !" #fG @5O<??@5O<@5O<;U6HE;=; ????2K12H4.2*CP_in_blood {per hour, from Table 1 of Cohen, Jao, and Jusko, 1971}  @   !" #f ?l{]???l{]?l{]:4:Q-Ϻ????2renal_clearance_of_CPKe*CP_in_blood     !" #s&?S;Bt???S;Bt?S;Bt:&T:&T????:ۼ!?3 'hydroxyCP_and_aldophosphamide_in_blood0  !" #f/?EtI???EtI?EtI:JϚn+q:@A????3 liver_MFO_metabolism0Kmet*hepatic_mixed_function_oxidase*CP_in_blood        !" #s????????????????3 hepatic_mixed_function_oxidase1    !" #f ??????3  creation!0*hepatic_mixed_function_oxidase      !" #f ??????3  degradation!0*hepatic_mixed_function_oxidase      !" #c?ěS?ěS???ěS?ěS?ěS?ěS?ěS?ěS???? ?ěS? 3Kmet0.262 {per hour, from Table 1 of Cohen, Jao, and Jusko, 1971. However, Sladek, page 315, suggests a plasma half life of about 7 hours (rate constant = 0.1) with a large interindividual variability}    ?ě S!"1 #c=?bM?bM???bM?bM?bM?bM?bM?bM?????bM?2Ke>0.032 {per hour, from Table 1 of Cohen, Jao, and Jusko, 1971}   ?bM !" #s @!ƂN??@!ƂN@!ƂN;!;_v;!;_v????;J6|?4phosphoramide_mustard_in_cells0 !-z !" #f (!??????3 oxidation)Kel*NAD_linked_aldehyde_dehydrogenases*0      !" #fa"@ ݔ_??@ ݔ_@ ݔ_:׾Ky:8????4cell_metabolismbcell_metabolism_rate*hydroxyCP_and_aldophosphamide_in_blood*tautomer_fraction_for_aldophosphamide       !" #c"%????????????????3#NAD_linked_aldehyde_dehydrogenases1 !" #s&???????3carboxyphosphamide0 !" #c(?%~06?%~06???%~06?%~06?%~06?%~06?%~06?%~06?????%~06?4cell_metabolism_rate3*0.08031/0.13 {see Sladek, p. 316. Production rate is based on discrepancy between actual and apparent elimination rates of PM and on assumption that PM is generated from 4hCP, which is present in about 1/(0.13 0.05) the concentration of PM, based on ratios of peak levels.}   ?% ~06!" #c%*???????????????? 4&tautomer_fraction_for_aldophosphamide1 {would be 0.05, from Table 5, p. 312 of Sladek, 1988, which shows about a 20:1 ratio of 4-hydroxyCP (cis and trans combined) to aldophosphamide. But other factor (cell metabolism rate) was calculated for combined form.} !"1 #s,@V_L0??@V_L0@V_L0@V_L0@V_L0?????4 acrolein0 !" #f!.@ ݔ_??@ ݔ_@ ݔ_:׾Ky:8????4beta_elimination"acrolein_fraction*cell_metabolism     !" #c0???????????????? 4acrolein_fraction1 !"1 #g2??????Parent Compound Module!" #g3??????Hepatic metabolism module 2!" #g4??????Cellular Metabolism Module!" #f5?"&???"&?"&:܆31:ۼ!????3Kel0.462*hydroxyCP_and_aldophosphamide_in_blood {per hour, calculated from a 1.5 hr. half life cited by Colvin and Chabner, p. 296. Half-lives in adults range from about 1 to 5 hours.}    ?ݑh r   !" #f 8@8Gq??@8Gq@8Gq;^,;J6|????4 elimination4*0.08031*phosphoramide_mustard_in_cells {adjusted from apparent, from mean phosphoramide half-life in plasma of 8.68 hours in human patients, cited by Colvin and Chabner, p. 295. But, see Sladek's discussion of apparent vs. actual half-lines, pp 316-317.}  * ?2 7    !" #f?> @??@@????@Iadministered_dose@if (AUC_of_admin_dose < target_total_AUC) then dose_rate else 0#"$$ # "       !" #s@@q??@q@q@q@q?????4 PM_AUC0! !" #f B@!ƂN??@!ƂN@!ƂN;!nqe;!;_v????4! PM_amountphosphoramide_mustard_in_cells  !" #c CAׄAׄ??AׄAׄAׄAׄAׄAׄ????Aׄ? I"target_total_AUC 100000000   Aׄ !"1 #sE@9333331??@9333331@9333331@9333331@9333331?????I#AUC_of_admin_dose0$ !" #fG@??@@????@I$dose_incrementadministered_dose# !" #gI??????%Administered Dose Sector !" #c K@??@@? ? ??????& sine_driver1 + SINWAVE(1, 24)    *   !" #cL@@??@@@@@@???@? I'hours_per_cycle2 !"1 #s PA73M!ATz|Z??A73M!ATz|ZA73M!ATz|ZA64HA64H@$??AP+ΐA]r?( cycling_HPCs4.9E7 +,-.1j*8+,-   A]r !" #s QA>FIIAPӅ??A>FIIAPӅA>FIIAPӅA|ui A|ui ????A@7F#ɮA?) resting_HPCs26.6E7*.1j+*   A !" #fRA\9"A> 0Z??A\9"A> 0ZA\9"A> 0ZA@7`n|A@7F#ɮ????AAL*recruited_into_cyclerecruitment_rate*resting_HPCs1)8)(  1 )  !" #f4S A\Q`UA-z ??A\Q`UA-z A\Q`UA-z A@讎A@}????AB +return_to_resting5max(0, (1-differentiation_fraction)*cycling_HPCs/10).(()(  .  (    !" #f(TA[.bA d+??A[.bA d+A[.bA d+A?~YrA?<@????@$ABCx,differentiated)differentiation_fraction*cycling_HPCs/10.(`( . (   !" #f FUAfJ??AfJAfJ< M / )  (       !" #c#[A_ A_ ??A_ A_ A_ A_ A_ A_ ????A_ ?/steady_state_HPCs$3.125E8 {PSC cells in steady state}.   A_ !" #c @^@^A L?A L@^@^@^@^???@^? I0 spacing_between_cycles_in_hours 24 {hours} !"1 #&c=_?A3?iʚMT???A3?iʚMT?A3?iʚMT?{`?{`?????W a?1recruitment_rate>k1*EXP(-v1*resting_HPCs-v1*cycling_HPCs) + k2*EXP(-v2*Z) + k353)(6427*G\ 5 3  )  3 (      6 4  2      7  !" #cDbBLzHRA{??BLzHRA{BLzHRA{BHq6BHq6????B>Nx?2ZE(signal_Z + CFU_GM) {= 3.208E9 + 3.469E10 + 12.8E10 in steady state}A~1  A ~  !" #c d>rN>rN??>rN>rN>rN>rN>rN>rN????>rN? 3v1 1.6955E-61   >r N!"1 #c e=$=$??=$=$=$=$=$=$???? =$? 4v2 3.1918E-111   = $!"1 #cf? =p ? =p ??? =p ? =p ? =p ? =p ? =p ? =p ????? =p ? 5k1.36 {per hour}1   ? = p !"1 #cg?zG{?zG{???zG{?zG{?zG{?zG{?zG{?zG{?????zG{? 6k20.04 {per hour}1   ?z G{!"1 #ch?bM?bM???bM?bM?bM?bM?bM?bM?????bM? 7k30.008 {per hour}1   ?bM !"1 #f oA\9"A> 0Z??A\9"A> 0ZA\9"A> 0ZA@7`n|A@7F#ɮ????AAL8cell_divisionrecruited_into_cycle*( *!" #c#t?????????????? ?? 9cytotoxic_potency_for_EHPC$0.1 {per cycling PSC cell per hour}-   ? !"1 #gx??????:Proliferative Sector!" #f {A㳵F|?x=Z2??A㳵F|?x=Z2A㳵F|?x=Z2A8EA2b????A0; precursorsto_maturation_pool< !" #s|B6iPTTA[??B6iPTTA[B6iPTTA[B-EFB-EF????AסkB'g?<maturation_pool5109E7?A;?   B'g !" #c# @i@i??@i@i@i@i@i@i???@i? I=$duration_of_dosing_regimen_in_hours 24 {hours} !"1 #sB=4A>.6S]??B=4A>.6S]B=4A>.6S]B<LB<L????A)B'?>marrow_reserve5123E7DA?D   B' !" #fFAcswvAE讯??AcswvAE讯AcswvAE讯AשBСAסk????ARt?maturedGmaturation_pool/transit_time_40_hr {fractional output = 1/40 per hour}<@<>  < @  !" #c@D@D??@D@D@D@D@D@D????@D?@transit_time_40_hr40 {hr}? (!" #c1BL0ѕA2N}??BL0ѕA2N}BL0ѕA2N}BHc BHc ????B=%?A signal_Z2proliferating_pool+maturation_pool+marrow_reserve<>j2  <  >  !" #g??????BEarly HPC & Stem Cell Sector!" #fAЅ@AE%DgL2??AЅ@AE%DgL2AЅ@AE%DgL2A+[a&A)????AP!uDrelease_to_bloodmarrow_reserve*release_rate>MK>Q  > M  !" #g??????ENon-Proliferative Sector!" #s@,ǝr??@,ǝr@,ǝr@,ǝr@,ǝr?????Fcumulative_aging_of_HPCs0JG !" #f?A3?iʚMT???A3?iʚMT?A3?iʚMT?zah?{`?????W aGHPCs_recruited_into_cyclerecruitment_rate1F 1!" #sB\&??B\&B\&B\&B\&????HAUC_Peripheral_Blood_Release0K !" #g??????IInternal Dosing Sector!" #c @,ǝr??@,ǝr@,ǝr@,ǝr@,ǝr?????JAge_Statisticcumulative_aging_of_HPCsF F!" #fAЅ@AE%DgL2??AЅ@AE%DgL2AЅ@AE%DgL2A+[a&A)???AP!uKnew_cells_into_bloodrelease_to_bloodDH D!" #f !A4AGνRA??A4AGνRAA4AGνRAAmV*AlZ???AԶmL blood_decay"peripheral_blood*blood_decay_rateQUQ  Q U  !" #c  ?N? Oǀ???N? Oǀ?N? Oǀ?*G?*G?????&`~?M release_ratek8-k9*EXP(-v3*GRF)VWXND( V W X  N      !" #s@ /?T??@ /?T@ /?T?yqwf?yqwf????_@(?NGRF12 {Steinbach et al. select the GRF scale to give a steady-state value of GRF = 10, but this appears to be low for dynamic consistency}MORO !" #f @h|???@h|?@h|??*Fd?_????333334O GRF_decayGRF*GRF_decay_rateNPN  N P  !" #c2??????????????? PGRF_decay_rate30.1 {per hour. From Steinbach et al., 1980, p. 7}O   ? !"1 #sDBY`nӷA}mp??BY`nӷA}mpBY`nӷA}mpB#s\B#s\???AlZB X?Qperipheral_bloodE1.39E10 {Steinbach et al., 1980, Table 1, p. 3 gives a value of 1.6}LRDL   B X!" #f@h?ͷG??@h?ͷG@h?ͷG?ǯQ.?Ƿ1i????`k|ڽRGRF_productionk10*EXP(-v4*peripheral_blood)TSQN  T S  Q     !" #c-=<|=<|??=<|=<|=<|=<|=<|=<|???=<|? Sv4.1.15*3.3E-10 {1.15 because F* = 1.4, not 1.6}R   =< |!"1 #cF@i@i??@i@i@i@i@i@i???@i? Tk10G200 {From Steinbach et al., 1980. p. 7, equation (22) and discussion.}R !"1 #c"??????????????? Ublood_decay_rate#0.1 {Steinbach et al., 1980, p. 6}L   ? !"1 #c@@??@@@@@@???@? Vk82M !"1 #cU??????????????? Wk9V1.9875 {k8 - k9 = .0125 --> k9 = k8 - .0125 = 2 - .0125. See Steinbach et al., p. 6}M   ? !"1 #c?D_n`^?D_n`^???D_n`^?D_n`^?D_n`^?D_n`^?D_n`^?D_n`^????D_n`^? Xv3 6.309E-4M   ?D_ n`^!"1 #b 8Ax*Dݜ3+??Ax*Dݜ3+Ax*Dݜ3+(2?[(2q"????+ qq3Y cell_death_19(CFU_GM_cytotoxicity_death_rate-new_birth_rate)*CFU_GM_1zj__ z j  _  !" #b 8A~7}OL_v{??A~7}OL_v{A~7}OL_v{0g0R:????2N893Z cell_death_29(CFU_GM_cytotoxicity_death_rate-new_birth_rate)*CFU_GM_2zjaa z j  a  !" #b 8A~SC??A~SCA~SC6h6Z????9qq3[ cell_death_39(CFU_GM_cytotoxicity_death_rate-new_birth_rate)*CFU_GM_3zjcc z j  c  !" #c&? =p? =p??? =p? =p? =p? =p? =p? =p????? =p?3\cytotoxic_potency_for_CFU_GM'0.13 {per proliferating cell per hour}z   ? =p!" #b 8A1J #Y7J??A1J #Y7JA1J #Y7J?nɷ4W?o OS????A893] cell_death_49(CFU_GM_cytotoxicity_death_rate-new_birth_rate)*CFU_GM_4zjee z j  e  !" #b 8A9ua`{rֵ??A9ua`{rֵA9ua`{rֵEssEJ????H;q3^ cell_death_59(CFU_GM_cytotoxicity_death_rate-new_birth_rate)*CFU_GM_5zjgg z j  g  !" #sA3y5AܪA9??A3y5AܪA9A3y5AܪA9A{9-FeA{9-Fe????AEWEA~?3_ CFU_GM_13.2E7Yb~`bY   A~ !" #fA[.bA d+??A[.bA d+A[.bA d+A?~YrA?<@????ABC3` inflow_1differentiated,_ ,!" #sA@Ѹ6DQ??A@Ѹ6DQA@Ѹ6DQAMAM????AM IA?3a CFU_GM_24.4E7Zd~bdZ   A !" #fAa-@5}T??Aa-@5}TAa-@5}TAElaAEWE????AHj3bflow_2CFU_GM_1/transit_time_10_i_a  _ i  !" #sA,ԃJ@wci??A,ԃJ@wciA,ԃJ@wciAu&PAu&P????AT)QAJ?3c CFU_GM_36.1E7[f~df[   AJ !" #fAh[@Y&Ӷc??Ah[@Y&ӶcAh[@Y&ӶcAMJl]-AM I????AP3dflow_3CFU_GM_2/transit_time_10aiac  a i  !" #sAǴlV@u%l.??AǴlV@u%l.AǴlV@u%l.AW9AW9????A\J苏zA^?3e CFU_GM_48.44E7]h~fh]   A^ !" #fApVvn@k%kd??ApVvn@k%kdApVvn@k%kdAT_AT)Q????AWE3fflow_4CFU_GM_3/transit_time_10cice  c i  !" #sAᇖ@REs?A?@REsAᇖ@REsAᇖ@REsAIAI????Acnb0A?3g CFU_GM_511.69E7^k~hk^   A !" #fAw*'V@@$W$??Aw*'V@@$W$Aw*'V@@$W$A\JINA\J苏z????A`3hflow_5CFU_GM_4/transit_time_10eieg  e i  !" #c, @$@$??@$@$@$@$@$@$????@$?3itransit_time_10-10 {hr for each of 10 compartments = 100 hr}bdfhknprt !" #3ca $?rt?qq???rt?qq?rt?qq?qq?qq?????qq?3jnew_birth_rateb0.1/(3 + min(0.2, k4*resting_HPCs+k4*cycling_HPCs) + min(0.2, k5*CFU_GM) + min(0.2, k6*signal_Z)){)(|~}AYZ[]^uvwxy$$  ?  ( ?ə { )  { (      ( ?ə | ~     ( ?ə } A      !" #fAGD #U@qR??AGD #U@qRAGD #U@qRAcmM:Acnb0????AfL3kflow_6CFU_GM_5/transit_time_10gigl  g i  !" #sA(?@5??A(?@5A(?@5AEAE????Ajo|?AO?3l CFU_GM_616.2E7nu~knu   AO !" #sA @ 6??A @ 6A @ 6A$A$????ArWSA?3m CFU_GM_722.4E7pv~npv   A !" #fA?z@ͧ& ??A?z@ͧ& A?z@ͧ& Aj{ :Ajo|?????An(3nflow_7CFU_GM_6/transit_time_10lilm  l i  !" #sAȉ@efh??Aȉ@efhAȉ@efhAVAV????AyF2FAz9?3o CFU_GM_831E7rw~prw   Az9 !" #fA?pW??A?pWA?pWArWjd"mArWS????Au\3pflow_8CFU_GM_7/transit_time_10mimo  m i  !" #sAаqZ6@fհ??AаqZ6@fհAаqZ6@fհAx[Ax[????A|A-?3q CFU_GM_942.96E7tx~rtx   A- !" #fA9x?բqO ??A9x?բqO A9x?բqO AyEAyF2F????A}\3rflow_9CFU_GM_8/transit_time_10oioq  o i  !" #s AֶZ@0B ??AֶZ@0B AֶZ@0B AĸAĸ????Ap`CA}`?3s CFU_GM_1059.5E7y~ty   A} `!" #fA0W?Gywn??A0W?GywnA0W?GywnA0jA|????A|$3tflow_10CFU_GM_9/transit_time_10qiqs  q i  !" #b 8A5+Vagic@??A5+Vagic@A5+Vagic@M)\MQ*u>????Q*3u cell_death_69(CFU_GM_cytotoxicity_death_rate-new_birth_rate)*CFU_GM_6zjll z j  l  !" #b 8AÔ\ p Gܗ??AÔ\ p GܗAÔ\ p GܗTa {TaQ] ????Wc83v cell_death_79(CFU_GM_cytotoxicity_death_rate-new_birth_rate)*CFU_GM_7zjmm z j  m  !" #b 8AAYl uϕm??AAYl uϕmAAYl uϕm\r=\4????`l83w cell_death_89(CFU_GM_cytotoxicity_death_rate-new_birth_rate)*CFU_GM_8zjoo z j  o  !" #b 8ArBx}t+@??ArBx}t+@ArBx}t+@cqQvcqN{????fҪ3x cell_death_99(CFU_GM_cytotoxicity_death_rate-new_birth_rate)*CFU_GM_9zjqq z j  q  !" #b 9AdyI0΂\??AdyI0΂\AdyI0΂\k(ޭk'Nʼ????o4883ycell_death_10:(CFU_GM_cytotoxicity_death_rate-new_birth_rate)*CFU_GM_10zjss z j  s  !" #c; ?|n???|n?|n:$R:R:$R:R?????3zCFU_GM_cytotoxicity_death_rate/Hg#EY>/Hg#EY??>/Hg#EY>/Hg#EY>/Hg#EY>/Hg#EY>/Hg#EY>/Hg#EY????>/Hg#EY? 3{k4X3.6418E-9 {from Steinbach et. al., 1980, p. 5, calculated from steady-state conditions}j   >/Hg #EY!"1 #cX=am^=am^??=am^=am^=am^=am^=am^=am^????=am^? 3|k5Y3.5476E-10 {from Steinbach et. al., 1980, p. 5, calculated from steady-state conditions}j   =a m^!"1 #cX=Fx=Fx??=Fx=Fx=Fx=Fx=Fx=Fx????=Fx? 3}k6Y6.9953E-12 {from Steinbach et. al., 1980, p. 5, calculated from steady-state conditions}j   = Fx!"1 #"cZ  A: A+.YU?A~nA+.YUA: A+.YUA: A+.YUAq6LpAq6Lp????Aޮ?3~CFU_GM[CFU_GM_1+CFU_GM_2+CFU_GM_3+CFU_GM_4+CFU_GM_5+CFU_GM_6+CFU_GM_7+CFU_GM_8+CFU_GM_9+CFU_GM_10_aceglmoqsj2L _ a  c  e  g  l  m  o  q  s  !" #g3??????CFU-GM Sector!" #f5A+qm?tgJ??A+qm?tgJA+qm?tgJAqhg6!Ap`C????A_/3to_proliferating_poolCFU_GM_10/transit_time_10sis  s i  !" #cH <? PS?fffffg??? PS?fffffg? PS?fffffg?fffffg?fffffg????? u?proliferation_birth_rateI0.07/(1 + min(0.6, y7*Z)) {Steinbach et. al., 1980, equation (16), p. 5}28  ? Q  ( ?33 3333  2      !" #c\==fqrRO=fqrRO??=fqrRO=fqrRO=fqrRO=fqrRO=fqrRO=fqrRO???? =fqrRO? y7]3.7289666E-12 {calculated from steady-state conditions described by Steinbach et. al., p. 6}   =fq rRO!"1 #b LIALɅ4??ALɅ4ALɅ4o8ho< '????tXjb~cell_death_11M(cytotoxicty_death_rate_for_proliferating_cells-proliferation_birth_rate)*P1      !" #b LKA9z}GZ??A9z}GZA9z}GZulf~uj2\|????{D}cell_death_12M(cytotoxicty_death_rate_for_proliferating_cells-proliferation_birth_rate)*P2      !" #b LMA|to;}??A|to;}A|to;}|կV$|҃J????/p8cell_death_13M(cytotoxicty_death_rate_for_proliferating_cells-proliferation_birth_rate)*P3      !" #c#&O? =p? =p??? =p? =p? =p? =p? =p? =p???? ? =p? $cytotoxic_potency_for_proliferating'0.13 {per proliferating cell per hour}   ? =p!"1 #b LPAT 0??AT 0AT 03&~6x????7<cell_death_14M(cytotoxicty_death_rate_for_proliferating_cells-proliferation_birth_rate)*P4      !" #b LRA]ft8^1??A]ft8^1A]ft8^1mk ????V$GIjcell_death_15M(cytotoxicty_death_rate_for_proliferating_cells-proliferation_birth_rate)*P5      !" #sSAT ׈?Zܖn??AT ׈?ZܖnAT ׈?ZܖnA6A6????AOIA`?P145.27E7   A `!" #fUA+qm?tgJ??A+qm?tgJA+qm?tgJAqhg6!Ap`C????A_/ inflow_2to_proliferating_pool !" #sVA| ?(Ʉ??A| ?(ɄA| ?(ɄAlHugAlHug????Aږ|oAT?P261.5E7   AT !" #fWA*..? ??A*..? A*..? 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