THE IMPROVED EULER METHOD AND RELATED METHODS

Phamacokinetics and metabolirm of �� 220G2-c ¹⁴ 1-1cro studied ⁱⁿ Rh sue monkeyc IIRAlR (19iS). The averege whol�

blood and pla:;ma levcl.G pcalced rc,,£pect1vcly to ¹ ,07ug/r,l and 2.87 ug/ml nt 4 hours after on I orally odoinister d doce of 301 .. g/ltg. The µ\o:.ma U, of the 111ajor log - linear

elilllination phase of the drug wac 7 hours . Aporoxir.iot�ly 781 of the adainictortd dose wat ol1minat�d 1n the urine and faeces toget�er in 1S d ye �ith feeceo being the predooinant route of elimination.

Concorn1ng organ distribution, , high concontration of

(C- ¹ 4 r1>d1oect1vity of WR33063-C ¹⁴ wtre found in the liver, lung, cerebru�, kidney ll.lld heart. Lower !evcla were

detected in ell ot�or ^tiaau•a ar�� y�d. Artounta of

rod1ooctiv1ty 1n the gaatro--inte tinal tracto w�re con�1ftL�nt

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-77-Stulliell invol\·ing I u n ha'lc b� n cerri�d uut .ilso an':!

there hnc been o rcpid nb�orption following an oral do&c.

Pollowing 400r:19 oral do&c containing 50uC1, 4-6 hours after dosin9�p-1k level& ^of rudiooct1v1ty c:curcd ⁱⁿ rl.ilillla

and red c<·ll v rtlng frc� G-1 g/1 ln plasmo to 1.Smg/1 in red c ell.

Pll,\�,, 1-.C-C ( .OGlC.\T I.CTTC1/S

In comparative te�ts on.!!.• ber ^hi infections in �ice CUC"atlvc activity wee noted �t ⁶⁴⁰ ng/1:g when ^W:?33063

woe acl!:iinintercd or�lly. The coeipCJUnd w�& moot cffcctiv� whon given oubcutancounly and intrapcriton�olly with ao�o curoc

at doues as low as 20mg/kg. A 27-fold crosa rPsistnnco was noted when ^t ntcd agoin:;t the chloroquin�- resistant

-atra.ln of - ^I'. bcr ^{hc1. tlo} crocs-resi .. ^tancc was not.,rJ Yh"n tented again,t the oulphone, triozin or pyC"ii:toth �inc resist nt ntraint. h'Rl30G3 d11 not ^provide rroph�·lnctic

protect101, 1191110:at ::poro.:.ni 1nducco Jnf'c-ct1ons \lith ^P.

cynomolgi 1n tteccco ^cul11tn when given orally at 100m9/kg

daily for acven d11yo (R�c·c .ind llo9h11r�on 1972, IF'AIR). Dll.ily dose of �OO�g/kg ^{C,iled to} curo in!cctlona ^{with thfo}

chloroquine suaccptiblc U94nda Palo Stroin of P, - fulci aruM 1n Aotu'l tr1yirg to'i rnd wi-re borely curatJvo with tho.

chloroquine re1.iatant Vietnal!I >lontcrcy :ltrain (Sclv�idt, 1972, \,"lV,IR)

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-78-Canfield et al (1973) tcoted WR33063 and WR30090

on u.s. coldicre with acute falcipaC'Ulil malaria in Vietnam.

The radical cuce rbtr for WR33063 wac 92t(23/25) and for WR30090 was 98% (23/26). Other p tic, ¹³ with r�crudesccnt

infcclio110 were 1111 cured by one or othc.r of these new (1974) Gtudiod 'ncigenouc pat! nt- in llorth- t �hbilond �- found a cure r tc of 921.(23/25) for WR33063 =d 94� (24/25) for quinine.

Quinin,. wee co.11parcd \tith :nt 33063 and lffl30090 for t.h trcnt111cnt of 207 potient, wilh falc:i1 ^w uri alrHJ" In

Southcac. �h,iland. Cuininc orAlic L perao.1.t ,.n 1 (uv t 9e

70 hour ) more rapidly th n it.her t:R30090 ( 72 hours) or IIR 33063 ( 77 houro). But :r.tJ3063 had w hi�hcr cu::.::- r ^tQ

(9�) th n W:l30090 (861-) or quinint> ^{(8� ).} Th .. l!!c,1n

durotion of fever .u1<.1 of ;u,rd 1tae 1 .. ",..r( comblnod with lhc failure r•tc to fori:i an orbitr ry �fflcocy index. Using

thia concl!;>t WR 33063 woa thc cioot effrctivc drug. Cllall, Segal, Pearlman, Phintuyothin, 1975).

A a.-ioll sc.ile trlul of ',:R 3306" ,a:, un,1crtakcn to dej:crmine its prophylactic 'tJlue 1n n r:. Two voluntcer1t

were challenged with th� Vietnu.i Z�ith Slrnin of P, tnlc! - ^t"U�

(aensit1vn strain).

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-oo-,WRAIR (1968) conduct.ad an acute oral and intraporit.oneal toxicity at.udioa in male albino mice using WR]] 063. The

acut.a oral and intraporilonoal Lo50wora cst.imatod ¹¹¹ being leas t.han 10 ¹ 000 m9/kg and greater than 21S0::ig/kg of body woight, rcapoctivcly. Pollowing an oral doao, no

Pharmacological or toxicological cffecta were obsorvod in any of the animal• uced at any docn level oxccpt for a very

alight doproasion in the animals at 10,000!llg/kg that

disappeared by one hour post do3119e. Thia was sinlilor to intrapcritoneal adminiot.rotlon.

A sub-ncut� toxicity toct waa carried out in malo monlcoyo (by the aa�c Laboratoriua). Clinical l�boratory studios rovcolod occocional increased white blood cell counts and increased

segmented noutroph1ls at tem1nation in two aale monkey3 given

62. Smg/ke/day. 141..! ^\ial:\ and .w11 l la� ,: 'AAIR, 196 7) h vc demonatratt>d t.hc phototoxic effect of ^WR33063 1n ,1ce. The treated albino

mica showed photosona1t1zation with gross intl 1.111111ation in the akin of the oors and tail. Thoce cutonooun loo1ona varied frOl'l orythema to necrosin doponding upon the rclattvo degrco of

photo toxicity.

Cardio-pulmonary &ffecta, The cardio-pulmonary effects of WR33063 and other phcnanthrcnc mothanols have been

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In document Elementary Differential Equations with Boundary Value Problems (Page 118-128)