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3. La productividad tiene una relación deficiente con los costos en:

This was tested in rabbits whose body temperature was increased by intravenously administered bacterial

pyrogen as described in the British Pharmacopoeia (1958).

Healthy adult rabbits (of either sex) each weighing not less than 1.5 kg and having a basal rectal temperature

ranging from 39.4 - 39.9 ° c were used. They were kept in the loboratory overnight to adjust to the rOO"­

temporature (20 - 22 ° c). Food was withheld from the rabbits overnight and water during the experiment only.

Rectal tCJT1perotures were measured with a clinical thermometer (clinical maximum thermometer) lubric3ted with paraffin oil and inserted into the rectum to a

depth of about 6.0 cm.

Temperatures were recorded at 30 minutes intcrv�ls for 60 minutes before the intravenous injection of 1.0 ug bactcri'll pyrogen. Temperature recording continued for

,.� hours aft,r pyrogon injection. At the end of 2½ h,

test rabbits \-:?re given drugo intraperitoneally !.n 2.0 ml propylene -glycol only intraperitoneally. Tcmperr,ture

recording continued for another 2 hours oftcr drug

adr.iinis tra t.lon . •

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-2.'12 Inhibition of Prostaalandin Synthesis in vivo It will be seen from the chapter on results that both OBA and Fagaramide inhibited rat paw oedema and

prostaglandin synthetase of guinea-pig lung and rabbit brain. Inhibition of prostaglandin synthesis could

account for the observed anti-phlogistic activity of OBA and Fagarrunide if it can be shown that these compounds

are active against prostaglandin synthesis in vivo.

This possibility was tested using the sponge exudate technique of Higg9 1 Harvey, Ferreira and vane (1976).

This model also afforded an opportunity to exllJlline the

effect of the drugs on leucocyte migration, histamine, 5-hydroxytryptamine content and protein exudation at the site of inflammation.

Procedure

Nylon foam sponges (2.5 x 1.2 x 1.2 cm) were cut from packing material. These were washed in distilled water dried 1nd sterilized by autoclaving. Fcmalo

albino c-ats 11eighlng between 180 g ond 250 g were

anilesthetizod with sodium pentobarbltone (30.0 m�/kg).

The flanks w,,re shaved and swabbed �,ith methyl .. t_d

spirit. An •. nclssion was made on one :.lcJc of the onimnli::'

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-flank and the subcutaneous space cleared. Sterile foam sponges were soaked in 2� (w/v) carrageenan

suspension in sterile saline. These were implanted, (one sponge into each animal) into the subcutaneous space. The would was closed up with silk thread and

('\

dusted with hibitane powder. The animals were allowed to recover from the pentobarbitone anaesthesia.

Eight hours aft�r implantation, the sponges were

removed under light ether anaesthesia. The sponges were immediately immersed in 10.0 ml heparinized saline

contained in a centrifuge tube and gently squeezed .

The sponges were then pinned across the top of tne centri-fuge tubes by means of a short piece of wire and centri­

fuged at 1,000 r.p.m. for 10 minutes. After centrifu-gation, the 'dry' sponges were re�ov�d and the volume of the remaining fluid was measured.

The total number of leucocyteo in the sponge exudate was counted with "Improved" ueubauer hi,emocytometcr .

The percentage of poly-morphonuclcar cells was deter­

rained by scanning a thin film of the exudate stnincd with Lcishmann stain and counting one hundred calls •

Prostngloncin content of the exudate was d,:tt..rmincd by subjecting the exucate to acid lipid extract-on �nd assaying the c�troct over supcrfuscd rat otomnch �trip

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-as previou�ly described.

Extraction of Prostaolandin •

The exudate was acidified to pH 3 with hydr�chloric acid and extracted twice with equal volumes of ethyl

acetate. The combined ethyl acetate fractions ,,,ere evaporated under reduced pressure at 40 - so 0 c. The

residue wus either taken up in Tyrode solution for

bioassoy or 1n 0.5 ml ethanol for thin layer chromato­

graphy.

Eff1cicncv of extraction:

The efficiency of the extraction procedure was estimated by determining the percentuge recovery of

trltiated PGP2a added to the fluid sample before extrac- tion.

o.os ml of 8 ng/ml solution of tritium labelled PCP2a wa� added to 10.0 ml of th� fluid sample. It

was well shaken and an aliquot of 0.5 ml was withdrawn.

The rest was then extracted os earlier described.

After �vaporating the ethyl acetat�, the residu� was then token up in 10.0 ml Tyrode solution and anc,thcr

aliquot o:: 0.5 ml '-<u& again withdrawn. To tho !epar, Le aliquots was added 5.0 ml of liquid scintillont (PFO:

- SO : 1 in toluene) and the radiooctivJ ty ,�of.

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-counted in a Packard Tr1-Carbl1quid Scintillation Spectrometer for 2 minutes. Efficiency of •

extraction waa cstirnftted by comphring lho count

in the extracted onmplo �ith thg count in tho porcnt solution of tritlntcd PGF2a.

Thin lnyer Chro::\atoarnphy

Prostaglandin-likc activity waa separated on glooo plates (S c:i x 20 C?:l) coated with ailico gel (Camo9,

Sv it:erland). Test and standard (PGE + PGF2 o) were

app11� on the sW-\e plates ond developed in A1 solvent

systeo (Ben:ene-Dioxane-�cetic acid in the rotio 20 : 20 : � of Green and S�uels�on (�964). After developing the

plates, �.O o:1 strips were scrapped off and extracted vi�h ':"yrodc ·�olution and assayed biologically on the

��e:fu�c� rot stcocch atcip.

Ar.' 1 o� h!c�--1nc

-Hi�t �!ne content of the opongo exudate wa& oasayed

!1ugrooc::r1colly uo1ng the �cthod oC Honkonaon ond

�·r..bec9 (1'l7<:).

f cov.:in wot.. J,r cl pi to tcd Hi t;}J S:C. Tr 1-ch loroacL t..lc --1d � v .. , , l h �"'n) . The mlxtur1.1 wno l• rt. in thr :f rid !ur 2 h ror !vll re c1p1t. l1on of I rot:oin. lt

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-was then centrifuged at 7,000 r.p.m. for 10 minutes.

The pH of the supernatant was adjusted to between

S.S and 6.5 with U/'10 sodium hydroxide solution.

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