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The effect of meta-iodo benzyl cinnamate on the course of experimental tuberculosis in the guinea pig Horn, Howard J. 1935

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T i l l mWBGf OF IIETA-iODO BEHZYI ClfflMMAT OH THE COURSE OF E X P E R l E E I f A I fUBERCULOSIS IK THE GUI SEA PIG.  hj  Hofard J . Horn* B'.A.  A t h e s i s s u b m i t t e d f o r the "Degree o f Master o f A r t s i n the ' Department o f B a c t e r i o l o g y  September 30., 1955.  1.—Introduction*  In a discussion on various attempts at chemotherapy i n Tuberculosis Galmette makes the following statements; "It must he recognized, that un to the present, despite the great number of attempts made to discover among chemical agents a substance capable of arresting the developement of experimental tuberculosis i n the -guinea pig a»d the rabbit, these e f f o r t s have been i n v a i n , a reason for discouragement.  But- this i s not  Certain attempts among those  which we have c i t e d deserve further attention*--  I t will  be desirable, f o r example, to give f u r t h e r consideration to those with iodized compounds which, i f they do not appear f u l l of promise, give, nevertheless, some d e f i n i t e l y favorable r e s u l t s . -7e must always  tf  i t may  remember that i t i s useless, perhaps  be, dangerous, to ia.|ectat random, as has been too  often dose, such and such a.chemical into patients with the vague hope of discovering a s p e c i f i c a c t i v i t y , i s a practise- which should be condemned. alone, methodically  This  Experimentation  conducted upon animals sensitive to  t u b e r c u l o s i s , w i l l enable us to explore with p r o f i t the  im-  mense perspectives that chemotherapy o f f e r s . " • The Department of Chemistry at this University has f o r several years, been building up different combinations  of c e r t a i n of the compounds which seem to have given -promise  o f cheraotherapeutic v a l u e i n tuberculosis. These  compounds Include .urea, b e n z y l a l c o h o l , -oinnamyl.-.-- c h l o r i d e , iodine, and a l l i e d compounds.  The papers of the Department  o f Chemistry discuss i n f u l l the eojapottnds -synthesized -and the methods of synthesis employed. . i'Jae Department of'Bacteriology was then approached with a view to determining the therapeutic value of the drugs synthesized.  T h i s paper.being,  i t i s hoped, the f i r s t  of a series on the behavior i n vivo of these compounds, i s largely devoted.to a description of the.technique and methods employed, although a complete description of the behavior of one drug i s included. B e a r i n g i n mind the t e n e t s o f Calciette i t was determines to cover the ground s l o w l y and thoroughly.  It was  decided t o use large p o p u l a t i o n s of g u i a e a p i g s f o r the experiments , rather than inoculating a few at random, and a l s o to use a number of controls equal to that of the test population. There v/as- f i r s t to "be discovered the best method by which to administer the drugs*  Method of Administration of Chemicals: The  chemicals to he used i n a preliminary series were  benzyl einnamate, aeta-iodo benzyl cincarnate, and ethyl meta-iodo cinnamate.  -These compounds (as can be found by  reference to the papers of the Chemistry Department on their preparations) are a l l solids at room temperature (2S C) and Insoluble i n water. 6  Their s o l u b i l i t y i n sub-  stances usually employed as solvents f o r injection i s very low.  EmuIs i f i ea t i on without the use of an emulsifying  agent vns not possible:  thus i t was thought best not to  use the drug i n emulsified form as the protective c o l l o i d used as the emulsifying agent might very easily interfere with the action of the drug i t s e l f * It was found, however., that although the drugs did not  melt u n t i l considerably above Dlood heat (37°C) they  could be cooled while molten to blood heat without s o l i d ifying.  I t was therefore decided to inoculate the pure  drug i n molten state at 38°C. thus making sure that the e f f e c t s , i f any, would be due to the chemical and to that alone, Intracardiac inoculation was f i r s t t r i e d as being the most direct method. however  Two d i f f i c u l t i e s were encountered,  which rendered this system impractical.  The f i r s t  d i f f i c u l t y was that although recovery of uninoculated guinea  p i g s from the anaesthetic used, whether e t h e r of.chloroform , was normal, the recovery of guinea p i g s inoculated, w i t h the drug w h i l e under a n a e s t h e t i c was very slow, and o f t e n unsuccessful.  Since these drugs are highly soluble  i n both ether and chloroform this phenomenon may have been due to some sort of loose .chemical., or even physical, combination between the drug and the anaesthetic. Certain i n d i v i d u a l guinea, pigs, however, did recover from inoculations of as much as 0,» 75c. c, benzyl cinnamate or inetaiodo benzyl cinnamate or 0.5 e.c. ethyl raeta-iodo• cinnamate-* The other d i f f i c u l t y encountered., however, was such as to majce t h i s system of inoculation unsatisfactory.  The needle  of gauge l a r g e enough to pass the solten chemicals was not s s s a l l enough i n outside diameter to ensure that the heart muscle wou!.d close the puncture, and the deaths by hemorrhage were thus f a r too frequent to laajfce practicable inoculation by this method.  The necessity f o r a needle of  large, gauge also made intravenous inoculation, impossible. Intraperitoneal inoculation of the various compounds was then atteiapted and found to be highly satisfactory.. The guinea pigs stood inoculations of up to L o c c * each of the chemicals without any loss of weight or other.:symptoms of distress.,  The technique was as follows."  the chemical to he  inoculated was p.laced i n a s t e r i l e container and heated at 60°C» u n t i l l i q u i d *  The molten drug was then drawn up into  a s t e r i l e syringe with a needle of 22 gauge and inoculated intraperitoneally into the guinea p i g .  The guinea p i g had  previously been prepared by clipping a space about one inch square on i t s abdomen and wiping with both alcohol and ..iodine solution* In f i n a l l y determining the route by which the drug was to be administered, consideration was also given to the fact that the drugs are highly insoluble.  I f the i n t r a -  cardiac or intravenous route were chosen, the t o t a l amount of comparatively insoluble material which could safely be given was obviously very small and the r e s u l t i n g assimilation of the s o l u b l e portion, i f any, into  the system would be  negligible.', On the ether hand, i f injections were given iatraperitonealiy large quantities of the drug could he administered, with the result that a greater t o t a l amount might possibly be assimilated into the system. ;  Care of Experimental Guinea Pigs. The experimental guinea pigs were jcept In individual cages and .weighed,, fed, and cleaned at regular intervals. In t h i s group of experiments i t was decided f o r convenience' salce to perform these operations on Hon days, 9A.M.  Vfed-  needays 1 :%r> i>.M,,  and Fridays 5:30  .The ration, given  P.M.  a f t e r w e i g h i n g consisted of SQOgms.  g r e e n f e e d (moist)-~lettuce, cabbage, and cauliflower l e a v e s . an'd' 85 gms. crushed oats. :  Bo water was given as the fresh"*"*'""  greens were found to be s u f f i c i e n t as a source of moisture. The cages i n every case ivere cleaned and washed thoroughly a f t e r each.weighing but before feeding. I t was found that by feeding at longer intervals than one day, the weights d i d not show as great a day-to-day v a r i a t i o n , since there was time f o r evacuation o f the i n t e s t ines after feeding. Preparation of Myc. tuberculosis f o r Inoculation. The t u b e r c l e b a c i l l i used were from a virulent c u l t ure , freshly isolated from sputum at the Vancouver General Hospital through the kindness of Dr. H . K . 7- i t t s , Director of the laboratories.  The cultures were a l l grown on Petra-  gnani's medium a t 37 C . A 15--day culture was washed off the medium•with s t e r i l e saline <0>87?f-) » using, a s t e r i l e Pasteur pipette..  The  suspension wss well mixed by continued drawing up and exp e l l i n g with the p i p e t t e , and then allowing the large lumps to settle out before removal from the tube.  The resulting  suspension was then transferred to another s t e r i l e tube and diluted w i t h s t e r i l e saline to a turbidity equivalent to Mac Par land Standard #4-  After much experimentation i t was  found that 0.25 e.c, of a 1/20 d i l u t i o n o f t h i s  turbidity  i n o c u l a t e d i n t r a o e r i t oneally would cause the death o f a guinea p i g a f t e r a p - p r o x i l a t e l y 6 weeks. the  i n f e c t i n g dose used f o r the p r e l i m i n a r y t e s t s . For  was  T h i s , t h e n , was  the aere conclusive experiment the culture used  f r o a the T r a n q u i l i e Sanatorium, i s o l a t e d from pleural  f l u i d , t h i r d subeultui-e.  This was a more slowly growing  o r g a n i s m and necessitated the use of an 86 day culture f o r maximum growth. A f t e r further t x p e r i m e n t a t i o r i t was found best t o a l l o w the suspension of t u r b i d i t y #4 to settle f o r exactly ]0  minutes and then make the 1/20 d i l u t i o n from the super-  natant suspension.  T h i s removed the majority of clumps o f  b a c i l l i , and gave a much f i n e r s u s p e n s i o n , thus i n c r e a s i n g the p e r i o d before death t o approximately-12 weeks-,  This  therefore gave any possible therapeutic powers o f the drug a much b e t t e r  opportunity.  Inoculation, whether of drug or tubercle b a c i l l i , was for at  convenience' sake always given before feeding, a period which the intestines would be c o m p a r a t i v e l y empty. Preliminary Experiments. To determine i f the drugs had any p r o p h y l a c t i c Prop-  e r t i e s i t was d e c i d e d t o i n o c u l a t e s m a l l numbers o f g u i n e a p i g s w i t h the drug and t u b e r c l e b a c i l l i  siauItanenasiy. I t  8. -was thought t h a t t h i s perhaps would g i v e some l e a d as t o •' t h e r e l a t i v e v a l u e of the drugs and h e l p t o decide which -:f s e v e r a l s h o u l d he used i n t h e snore extensive • experiment • .. $h& f o l l o w i n g t a b l e shows the detail® of the p r e l i m i n a r y 4  experiments-  .  ••  jaurobcr of  Co impound  Quantity of  g u i n e a (jigs  inoculated  compound  ' quantity of s u s p e n s i o n of t u b e r c l e  bacilli  inoculated Benzyl  1o Oc.c .  0,<> S5 c. e.  1. 0 6*0* '  0 •». &j «5 c * c »  einnamate 4 "  Meta-iodo benzyl einnamate  4.  E t h y l metai o d o einnaaiate Hone—C on t r o 1 s  Of the controls, three averaged 47. days before death; the remaining control, however, remained alive f o r 77 days. 'Theguinea' pigs inoculated with ethyl meta-iodo oincarnate also l i v e d f o r an average of 47 days after inoculation. The animals inoculated with benzyl einnamate averaged 62  days, one remaining a l i v e f o r 73 days.  The guinea pigs  inoculated with metafiodo b e n z y l eiimamate gave by f a r the most promising r e s u l t s , averaging 62 days, one however, r e maining a l i v e f o r 93 days. Due 'co the one control which was l i v i n g at 77. days a f t e r inoculation these results did not seem to be even i n dicative of any conclusions. This guinea p i g , however, on autopsy, showed.an ear-puncture, proving that at some time t h i s animal had been ear-tagged.  After a check-up of animals  i t was found that this was a guinea pig which had been tagged when inoculated i n t r a c a r d i a l i y 71 clays previous to the inoculation with tubercle b a c i l l i with 0.7 c.c. benzyl einnamate f o r a t o x i c i t y test. ion  of t h i s animal:  This, then, caused the eliminat-  thus the experiments gave some Indications  of s l i g h t l y better prophylaxis from meta-Iodo benzyl ciruminate  than from benzyl airnamate. Such inconclusive r e s u l t s d e f i n i t e l y upheld, the necess-  i t y of employing much larger populations f o r the next experiment try  For the large scale experiment i t was decided to  aeta-iodo benzyl eizmamate a s i t had given some indication  of s l i g h t l y better prophylaxis then benzyl cinnaraate. I t was also thought that i t would perhaps combine the supposed therapeutic properties of both benzyl ciunamate and iodine. The f i r s t method used by the Chemistry Department f o r  the s y n t h e s i s o f t h i s drag was s u c c e s s f u l f o r s m a l l q u a n t i t i e s only.  As i t was c a l c u l a t e d t h a t a t l e a s t 100 gn;s. of the  compound would be r e q u i r e d , the w r i t e r a s s i s t e d the i n v e s t i g a t o r i n the Department of Chemistry f o r s e v e r a l months  i n d e v i s i n g a new method f o r q u a n t i t y p r o d u c t i o n . P i n a l Experiment w i t h Meta-iodo  Benzyl  Gianaifiaie. Mgthpu of .Becording  u i n e a I;ig Weights^  l u e t o the h i g h l y i n c o n c l u s i v e r e s u l t s with s i a a l l e r p o p u l a t i o n s i n the p r e l i m i n a r y worfe i t was d e c i d e d t o use ^ p o p u l a t i o n o f 20 g u i n e a p i g s f o r the f i n a l experiment, w i t h an a d d i t i o n a l £0 g u i n e a p i g s f o r the c o n t r o l .  Each pop-  u l a t i o n c o n s i s t e d of S males and 12 females, the  a n i m a l s a v e r a g i n g 424 gms.  control  and the t e s t a n i m a l s 419 gms.  It  s a y be w e l l t o g&y here t h a t the p r o p o r t i o n of males t© f e males was not due t o any s t a t i s t i c a l requirement, but t o the f a c t -that t h e young a n i m a l s on hand happened t o be so d i v i d e d . ;  The a n i m a l s were t o be f e d and weighed., f o l l o w i n g the normal r o u t i n e f o r a c o n s i d e r a b l e p e r i o d w i t h o u t any  inoculations.  The average. weight o f each p o p u l a t i o n a t each weighing t o be c a r r i e d i n t o a moving average. following manner—for  was  T h i s was done i n the  each p o p u l a t i o n the t o t a l weight I s  d i v i d e d by the number of g u i n e a p i g s , g i v i n g the weight of the average g u i n e a p i g f o r t h a t day.  These weights wore then  .1.1.. added i n over lap M ng groups rf  t h r e e and the mean t a r e n ,  t h u s g i v i n g a moving average.  T h i s method tends t o smooth  out the c u r v e , s i n c e I t e l i m i n a t e s t o a l a r g e e x t e n t the d a i l y fluctuations,,  The moving averages of the two pop-  u l a t i o n s were p l o t t e d a g a i n s t the time on s e m i l o g a r i t h m i c paper.  The complete experiment l a s t e d from Oct. 22,  19S4  Ino c u l a t i ons. With Meta-iodo B e n z y l In  Cinnamate,  o r d e r t o g i v e the drug every p o s s i b l e chance i t  was d e c i d e d t o i n o c u l a t e the drug i n 0.5 c c . q u a n t i t i e s at  several d i f f e r e n t periods.  The guinea p i g s were tons  i n o c u l a t e d w i t h the drug 14 days, 7 days, and 3 days before r e c e i v i n g the i n o c u l a t e n of tne t u b e r c l e baci H i and 2, 9. a n d 16 days a f t e r . I t i s I n t e r e s t i n g to note on trie curve t h a t the drug aaa seemingly no e f f e c t , up to the time of the i n o c u l a t i o n w i t h My c. t u b e r c u l o s i s * .On r e c e i v i n g the t u b e r c l e b a c i l l i . , the a n i m a l s immediately,began  t o drop i n weight, r e c o v e r i n g  s l i g h t l y and t h e n d r o p p i n g a g a i n a t each f u r t h e r i n o c u l a t i o n w i t h the drug*.  I t was f o r t h i s reason t h a t the drug  a i s c o n t i n u e a 16 days a f t e r the t u b e r c l e b a c i l l i  was  inoculation,  as the guinea p i g s were becoming r o u g h - h a i r e d and  emaciated  and shewing f u r t h e r s i g n s of d i s t r e s s . WItb "tPuberele B a c i l l i As d e s c r i b e d before the i n o c u l a t i o n used f o r both  12. • p o p u l a t i o n s was 0.25  c„c.  of a 1/20  d i l u t i o n of a t u r b i d i t y  eq.ua! t o Mac P a r l a n d #4, u s i n g tiie s u p e r n a t a n t l i q u i d f o r d i l u t i o n a f t e r 10 minutes  settling.  Results S t a t i s t i c a l l y the r e s u l t s were e n t i r e l y n e g a t i v e . E l e v e n of the t r e a t e d a n i m a l s d i e d of t u b e r c u l o s i s before  m  days, whereas o n l y e i g h t of the c o n t r o l s d i e d over the same period.  The r e m a i n i n g guinea p i g s were then i c i l l e d and aut op-  s l e d , a l l showing d e f i n i t e symptoms of t u b e r c u l o s i s . The .knowledge t h a t these deaths were s p e c i f i c a l l y due t o t u b e r c u l o s i s i n f e c t i o n , i s owing t o the k i n d c o - o p e r a t i o n of Dr. JI.il. P i t t s , P a t h o l o g i s t and D i r e c t o r of l a b o r a t o r i e s a t the Vancouver G e n e r a l H o s p i t a l .  Dr. i - i t t s performed  autopsy  and h i s t o l o g i c a l e x a m i n a t i o n on a l l g u i n e a p i g s used I n the experiments« I t would seem therefore,, f r o m t h i s , t h a t the drug Is of no v a l u e i n t u b e r c u l o s i s p r o p h y l a x i s . of  I n f a c t , from a study  the weight c u r v e s i t would seem t h a t the drug has a d e t r i -  mental e f f e c t i n the presence of t u b e r c u l o s i s , as e x p l a i n e d i n the p r e v i o u s s e c t i o n . In every c a s e , i t vias found t h a t the t r e a t e d guinea p i g s on autopsy showed e x t e n s i v e i n t r a p e r i t o n e a l adhesions., whereas the uhdrugged g u i n e a p i g s d i d n o t .  The adhesions t h e r e f o r e  were d o u b t l e s s due to the i r r i t a t i n g a c t i o n of the drug. Discussion. The one v a l i d c o n c l u s i o n which may be d r a m from t h i s  -  experiment i s t h a t a e t a - i o d o b e n z y l cinnamate i s of no ypeutie v a l u e i n experimental t u b e r c u l o s i s ,  thera-  large populations  were used; a minimal inoculum of tubercle b a c i l l i was  given;  drug inoculations were so spaced as to g i v e ample opportu n i t y f o r both p r o p h y l a c t i c  and  therapeutic a c t i o n .  I t i s I n t e r e s t i n g , however, t o s p e c u l a t e upon the mechanism of the r e a c t i o n of the drugged p i g s f o l l o w i n g i n o c u l a t i o n of the t u b e r c l e  bacilli.  It- i s obvious t h a t t h i s cannot be the r e a c t i o n of d r u g on t u b e r c u l o u s l e s i o n s as such.  It might be  by a c c u m u l a t i v e traumatic effect of c o n t i n u e d  the  explained  inoculations  upon the peritoneum of the g u i n e a p i g . On the o t h e r hand i t i s p o s s i b l e s e n s i t i z e d the t o the  animals to the  t h a t the drug  t u b e r c u l o u s t o x i n s or- even  a c t u a l p r o t e i n of the organism.  " S e n s i t i z e d " i s used  here i n the sense of 'a c h e m i c a l s e n s i t i z a t i o n r a t h e r w i t h any  had  than  reference t o a l l e r g y . Beferenees.  S i n c e t h i s paper, i n the main, concerns the a c t i o n a c h e m i c a l compound Which has references-alluding  not been h i t h e r t o p r e p a r e d ,  d i r e c t l y to the s u b j e c t  n a t u r a l l y unobtainable,  of  matter are  For r e f e r e n c e s to work of a s i m i l a r  n a t u r e , the r e a d e r i s r e f e r r e d to the f o l l o w i n g  sources;—  14. I n d e x - C a t a l o g u e o f the L i b r a r y of the Surgeon G e n e r a l ' s O f f i c e , U n i t e d S t a t e s Array:  T h i r d S e r i e s , ¥.pl.Z 1932  See  5  T u b e r c u l o s i s ( E x p e r i m e n t a l , Treatment of.) rs.527. T u b e r c u l o s i s {Pulmonary., Treatment of ) p . 5 S l — 5 8 3 . T u b e r c u l o s i s (Buinonary., Treatment o f ) w i t h c a l c i u m u. 592. T u b e r c u l o s i s (Pulmonary, Treatment o f ) by ohemotherapy p. 5 9 2 — 5 9 3 . T u b e r c u l o s a s (Pulmonary, Treatment o f ) by g o l d s o l u t i o n s p. 593 T u b e r c u l o s i s -(Pulmonary, Treatment o f ) by i n h a l a t i o n t h e r a p y , p.596 .Tuberculosis (Pulmonary, Treatment o f ) w i t h ie&ine.p. 59 6 T u b e r c u l o s i s (Pulmonary, Treatment o f ) w i t h s a n o c r y s i n . p.. 599. T u b e r c u l o s i s (Pulmonary, Treatment o f ) w i t h s i l i c i c acid. ;p.60Q» T u b e r c u l o s i s (Pulmonary, Treatment o f ) w i t h sugar p.. 600*  A u t h o r i s e d E n g l i s h l a i t i o n - - T u b e r e l e B a c i l l u s -Infection and f f  T u b e r c u l o s i s i n Man and A n i m a l s  11  by A l b e r t c a l r o e t t e —  W i l l i a m s and W l l k l n s Go., B a l t i m o r e , 1 9 2 3 . — w i t h s p e c i a l r e f e r e n c e to C h a p t e r XKEII-  "Attempts a t chemotherapy  In  Tuberculosis" Z u r Jodbehandlung der lungentubericulose ; A* S y l l a ; B e i t r . a. K l i n . d» Tuberlc.  May, 1932, lxxx,51..  The use o f I o d i n e and c e r t a i n I o d i n e compounds i n exper-  XI3 •  imental tuberculosis. l  s  G. K a i a y s i , J . I n f . M s . March, 1 9 3 2  r  261.  Treatment o f pulmonary t u b e r c u l o s i s on l i n e s o f mineral' deficiency.  IC. Fraser, B r i t . M. J . May 24, 1930, #3620, 946.  Affpgndix^ S i n c e there appear t o be several m o d i f i c a t i o n s of Petragnanl s !  medium f o r the c u l t i v a t i o n  of Hye. tubereulosi  i t was &®emea a d v i s a b l e t o g i v e here the f o r m u l a i n t h i s p a r t i c u l a r experiment,  followed  i'he s t r a i n s o f Iiy_c. tuberc-  u l o s i s used would g i v e satisfactory growth on t h i s medium 1 l e s s than one-half the time required on any of the more common media f o r tubercle b a c i l l u s JrVL3- J L I C *  . t?  e  • P &»» 9  c « & « » » * * » n  ,« * « # - 9 0 0 0 < G fl  P o t a t o ' f l o u r . . ..  5 6 grass  Peptone  .........  1 otato — e g g - s i z e d p i e c e s . . . , - . Eggs--who.] e .........  o©  x i'i© • * « DO* o * * J. .  Malachite  6 grams 6  . 24  Egg y o l i c s . . . . . . . . . . . . . . . . . . . . . 0  cultivation.  6  £1***1 i' 70  o «o *  green-—aqueous  s oXufcJ. 0 2 1 « « » w  *»«*•«•-*»  »•«0- * »  «*>««  6 0  c«c p  Grind potatoes with fine meat g r i n d e r . gredients.  Mix a l l i n -  This m i x t u r e i s fcept i n a b o i l i n g water b a t h  :  16.  with, frequent s t i r r i n g u n t i l i t "becomes sticky. i t i s l e f t In the water hath f o r 1 t o 2 hours.  After t h i After,  c o o l i n g to*.50 O.add 24 whole eggs and 6 egg y o l k s and 70 c glycerine-green.  Then add 60 c c , 2<P aqueous s o l u t i o n m a l a c h i t e  The whole mixture I s f i l t e r e d through s t e r i l e  gauge, .tubed f o r slants and p l a c e d i n an A r n o l d i n a s l a n t ing p o s i t i o n . I n e u b a t e — f i r s t day 1/2 hour a t ?Q t o 75 i„ n e x t day 1/2 hour a t 80 Q* l a s t day 1/2 hour a t 80 0-  

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