{UTF-8}
********************************************************
	.oseltamivir hydrolyse-effekt
********************************************************~
		Simulation: Peter Bützer
	|

Abstand=
	8
	~	Hour [0,12,1]
	~		|

Anteil=
	0.9
	~	Dmnl [0,1]
	~		|

Anzahl Dosen=
	10
	~	Dmnl [0,10,1]
	~		|

hydrolysieren=
	Anteil*kh*Prodrug
	~	mg/Hour
	~	Die Konzentrationsabhängigkeit vom Prodrug gilt nur, falls genügend \
		Enzyme vorhanden sind
	|

Dosis=
	75
	~	mg [0,300,75]
	~		|

relativer Effekt=
	Konzentration/(LC50+Konzentration)
	~	Dmnl
	~	Occupationstheorie
	|

Darm= INTEG (
	dosieren-ausscheiden-resorbieren,
		0)
	~	mg [0,150]
	~	Normale Tablette: 75 mg
	|

Dim=
	1000*1
	~	ng/mg*l/ml
	~	Anpassung der Einheiten
	|

dosieren=
	Dosierungsintervall*Dosis
	~	mg/Hour [0,8000]
	~		|

Dosierungsintervall=
	PULSE TRAIN(0, 0.5 , Ende/(Anzahl Dosen/2) , Ende )+PULSE TRAIN( Abstand, 0.5 , Ende\
		/(Anzahl Dosen/2) , Ende )
	~	1/Hour [0,4,1]
	~		|

Prodrug= INTEG (
	resorbieren-entfernen-hydrolysieren,
		0)
	~	mg
	~	Von Oseltamivir wurde  cmax von den meisten Patienten innerhalb 1–2 \
		Stunden erreicht
	|

Ende=
	120
	~	Hour [12,120,12]
	~		|

entfernen=
	(1-Anteil)*kh*Prodrug
	~	mg/Hour
	~		|

LC50=
	127
	~	ng/ml [110,140]
	~		|

Konzentration=
	Drug im Blut/Volumen*Dim
	~	ng/ml
	~		|

Volumen=
	25
	~	l [0,10]
	~		|

ausscheiden=
	kr*(1-Biologische Verfügbarkeit)*Darm
	~	mg/Hour
	~		|

resorbieren=
	kr*Biologische Verfügbarkeit*Darm
	~	mg/Hour
	~		|

Biologische Verfügbarkeit=
	0.9
	~	Dmnl [0.7,1]
	~	Verfügbarkeit 80%, Die Bioverfügbarkeit ist ca. 80% für Drug und Prodrug zusammen.
		Craig Charles R., Stitzel Robert E., Modern pharmacology with clinical \
		applications, Lippincott Williams and Wilkins,  6th Ed., 2003, S. 576
	|

kh=
	0.15
	~	1/Hour [0,1]
	~		|

Drug im Blut= INTEG (
	+hydrolysieren-eliminieren,
		0)
	~	mg
	~		|

ke=
	LN(2)/HWZe
	~	1/Hour
	~		|

eliminieren=
	ke*Drug im Blut
	~	mg/Hour
	~		|

HWZe=
	2
	~	Hour [1,2]
	~	Nach intravenöser Verabreichung beträgt die Halbwertszeit des aktiven \
		Metaboliten knapp 2 Stunden.
	|

HWZr=
	0.4
	~	Hour [0,1]
	~	Normale HWZ für Medikamente ca. 0.3-1 Stunden. The Cmax for oseltamivir \
		was reached within 1–2 h in most patients, Robson Richard, Buttimore \
		Adrian, Lynn Kelvin, Brewster Mike, Ward Penelope, The pharmacokinetics \
		and tolerability of oseltamivir suspension in patients on haemodialysis \
		and continuous ambulatory peritoneal dialysis, Nephrol Dial Transplant, \
		21, 2006, 2558
	|

kr=
	LN(2)/HWZr
	~	1/Hour
	~		|

********************************************************
	.Control
********************************************************~
		Simulation Control Parameters
	|

FINAL TIME  = 120
	~	Hour
	~	The final time for the simulation.
	|

INITIAL TIME  = 0
	~	Hour
	~	The initial time for the simulation.
	|

SAVEPER  = 0.5
	~	Hour [0,?]
	~	The frequency with which output is stored.
	|

TIME STEP  = 0.1
	~	Hour [0,?]
	~	The time step for the simulation.
	|

\\\---/// Sketch information - do not modify anything except names
V300  Do not put anything below this section - it will be ignored
*View 1
$192-192-192,0,Times New Roman|12||0-0-0|0-0-0|0-0-255|-1--1--1|-1--1--1|96,96,100,0
10,1,Prodrug,499,105,34,18,3,131,0,52,0,0,0,0,0-0-0,0-192-255,Arial|12|B|0-0-0
10,2,Drug im Blut,681,105,34,19,3,131,0,52,0,0,0,0,0-0-0,255-0-0,Arial|12|B|0-0-0
1,3,5,2,4,0,0,22,0,0,0,-1--1--1,,1|(620,102)|
1,4,5,1,100,0,0,22,0,0,0,-1--1--1,,1|(558,102)|
11,5,556,589,102,5,6,34,3,0,0,1,0,0,0
10,6,hydrolysieren,589,119,55,11,40,131,0,48,-1,0,0,0,0-0-0,0-0-0,Arial|12|B|0-0-0
1,7,8,2,100,0,0,22,0,0,0,-1--1--1,,1|(734,104)|
11,8,220,759,104,5,6,34,3,0,0,1,0,0,0
10,9,eliminieren,759,121,44,11,40,3,0,48,-1,0,0,0,0-0-0,0-0-0,Arial|12|B|0-0-0
1,10,2,8,1,0,0,0,0,64,0,-1--1--1,,1|(722,79)|
10,11,HWZe,641,39,25,11,8,3,0,48,0,0,0,0,0-0-0,0-0-0,Arial|12|B|0-0-0
10,12,HWZr,344,41,23,11,8,3,0,48,0,0,0,0,0-0-0,0-0-0,Arial|12|B|0-0-0
10,13,kr,417,48,10,11,8,3,0,48,0,0,0,0,0-0-0,0-0-0,Arial|12|B|0-0-0
1,14,12,13,1,0,0,0,0,64,0,-1--1--1,,1|(381,33)|
10,15,ke,743,57,11,11,8,3,0,48,0,0,0,0,0-0-0,0-0-0,Arial|12|B|0-0-0
1,16,11,15,1,0,0,0,0,64,0,-1--1--1,,1|(696,30)|
1,17,15,8,1,0,0,0,0,64,0,-1--1--1,,1|(761,80)|
12,18,48,827,103,10,8,0,3,0,48,-1,0,0,0,0-0-0,0-0-0,Arial|12|B|0-0-0
1,19,8,18,4,0,0,22,0,0,0,-1--1--1,,1|(790,104)|
10,20,Darm,334,98,32,16,3,3,0,48,0,0,0,0,0-0-0,0-0-0,Arial|12|B|0-0-0
1,21,23,1,4,0,0,22,0,0,0,-1--1--1,,1|(442,100)|
1,22,23,20,100,0,0,22,0,0,0,-1--1--1,,1|(387,100)|
11,23,348,414,100,5,6,34,3,0,0,1,0,0,0
10,24,resorbieren,414,117,46,11,40,3,0,48,-1,0,0,0,0-0-0,0-0-0,Arial|12|B|0-0-0
1,25,13,23,1,0,0,0,0,64,0,-1--1--1,,1|(438,73)|
10,26,kh,537,51,12,11,8,3,0,48,0,0,0,0,0-0-0,0-0-0,Arial|12|B|0-0-0
1,27,26,5,1,0,0,0,0,64,0,-1--1--1,,1|(579,68)|
1,28,20,23,1,0,0,0,0,64,0,-1--1--1,,1|(393,72)|
1,29,1,5,1,0,0,0,0,64,0,-1--1--1,,1|(546,72)|
10,30,Biologische Verfügbarkeit,429,198,55,19,8,3,0,48,0,0,0,0,0-0-0,0-0-0,Arial|12|B|0-0-0
12,31,48,337,203,10,8,0,3,0,48,-1,0,0,0,0-0-0,0-0-0,Arial|12|B|0-0-0
1,32,34,31,4,0,0,22,0,0,0,-1--1--1,,1|(334,177)|
1,33,34,20,100,0,0,22,0,0,0,-1--1--1,,1|(334,131)|
11,34,48,334,154,8,6,33,3,0,0,4,0,0,0
10,35,ausscheiden,393,154,51,11,40,131,0,48,-1,0,0,0,0-0-0,0-0-0,Arial|12|B|0-0-0
1,36,20,34,1,0,0,0,0,64,0,-1--1--1,,1|(354,127)|
1,37,30,34,1,0,0,0,0,64,0,-1--1--1,,1|(358,180)|
1,38,30,23,1,0,0,0,0,64,0,-1--1--1,,1|(449,160)|
1,39,13,34,1,0,0,0,0,64,0,-1--1--1,,1|(389,123)|
10,40,Volumen,796,182,36,11,8,3,0,48,0,0,0,0,0-0-0,0-0-0,Arial|12|B|0-0-0
10,41,Konzentration,674,210,57,11,8,131,0,48,0,0,0,0,0-0-0,0-0-0,Arial|12|B|0-0-0
1,42,2,41,1,0,0,0,0,64,0,-1--1--1,,1|(691,155)|
1,43,40,41,1,0,0,0,0,64,0,-1--1--1,,1|(735,172)|
12,44,48,497,203,10,8,0,3,0,16,-1,0,0,0,0-0-0,0-0-0,|12|B|0-0-0
1,45,47,44,4,0,0,22,0,0,0,-1--1--1,,1|(497,179)|
1,46,47,1,100,0,0,22,0,0,0,-1--1--1,,1|(497,137)|
11,47,48,497,157,8,6,33,3,0,0,4,0,0,0
10,48,entfernen,544,157,39,11,40,3,0,48,-1,0,0,0,0-0-0,0-0-0,Arial|12|B|0-0-0
1,49,26,47,1,0,0,0,0,64,0,-1--1--1,,1|(541,132)|
1,50,1,47,1,0,0,0,0,64,0,-1--1--1,,1|(513,133)|
10,51,Anteil,555,194,24,11,8,3,0,48,0,0,0,0,0-0-0,0-0-0,Arial|12|B|0-0-0
1,52,51,47,1,0,0,0,0,64,0,-1--1--1,,1|(522,183)|
1,53,51,5,1,0,0,0,0,64,0,-1--1--1,,1|(596,164)|
12,54,0,276,479,250,171,3,188,0,32,1,0,0,0,0-0-0,0-0-0,Arial|12||0-0-0
Konzentration
10,55,Dim,806,238,17,11,8,3,0,48,0,0,0,0,0-0-0,0-0-0,Arial|12|B|0-0-0
1,56,55,41,1,0,0,0,0,64,0,-1--1--1,,1|(745,206)|
10,57,Dosierungsintervall,154,160,48,19,8,131,0,48,0,0,0,0,0-0-0,0-0-0,Arial|12|B|0-0-0
10,58,Anzahl Dosen,239,203,56,11,8,131,0,48,0,0,0,0,0-0-0,0-0-0,Arial|12|B|0-0-0
1,59,58,57,1,0,0,0,0,64,0,-1--1--1,,1|(164,188)|
12,60,48,131,98,10,8,0,3,0,48,-1,0,0,0,0-0-0,0-0-0,Arial|12|B|0-0-0
1,61,62,60,100,0,0,22,0,0,0,-1--1--1,,1|(183,95)|
11,62,48,231,95,5,6,34,3,0,0,1,0,0,0
10,63,dosieren,231,112,42,11,40,3,0,48,-1,0,0,0,0-0-0,0-0-0,Arial|12|B|0-0-0
1,64,57,62,1,0,0,0,0,64,0,-1--1--1,,1|(171,132)|
10,65,Dosis,266,165,24,11,8,3,0,48,0,0,0,0,0-0-0,0-0-0,Arial|12|B|0-0-0
1,66,65,62,1,0,0,0,0,64,0,-1--1--1,,1|(255,125)|
10,67,Ende,60,202,22,11,8,131,0,48,0,0,0,0,0-0-0,0-0-0,Arial|12|B|0-0-0
1,68,67,57,1,0,0,0,0,64,0,-1--1--1,,1|(71,170)|
10,69,Abstand,62,123,34,11,8,3,0,48,0,0,0,0,0-0-0,0-0-0,Arial|12|B|0-0-0
1,70,69,57,1,0,0,0,0,64,0,-1--1--1,,1|(133,121)|
1,71,62,20,4,0,0,22,0,0,0,-1--1--1,,1|(269,95)|
10,72,LC50,632,265,22,11,8,3,0,48,0,0,0,0,0-0-0,0-0-0,Arial|12|B|0-0-0
10,73,relativer Effekt,788,287,57,11,8,131,0,48,0,0,0,0,0-0-0,0-0-0,Arial|12|B|0-0-0
1,74,41,73,1,0,0,0,0,64,0,-1--1--1,,1|(753,240)|
1,75,72,73,1,0,0,0,0,64,0,-1--1--1,,1|(669,260)|
12,76,0,800,480,261,170,3,188,0,0,1,0,0,0
relativer_Effekt
///---\\\
:GRAPH Oseltamivir
:TITLE Oseltamivir
:X-AXIS Time
:SCALE
:VAR Blut
:LINE-WIDTH 2

:GRAPH Konzentration
:TITLE Konzentration
:X-AXIS Time
:SCALE
:VAR Konzentration
:DATASET 8-Stunden
:LINE-WIDTH 2
:VAR Konzentration
:DATASET 12-Stunden
:LINE-WIDTH 2

:GRAPH relativer_Effekt
:TITLE relativer Effekt
:X-AXIS Time
:SCALE
:VAR relativer Effekt
:DATASET 8-Stunden
:LINE-WIDTH 2
:VAR relativer Effekt
:DATASET 12-Stunden
:LINE-WIDTH 2
:L<%^E!@
1:8-Stunden.vdf
1:12-Stunden.vdf
9:12-Stunden
23:0
15:0,0,0,1,0,0
19:100,0
27:2,
34:0,
4:Time
5:Abstand
24:0
25:119.999
26:119.999