A COMPARISON OIt SOME UI TEE
ERGOT ALKALOIDS.
being
a Thesis
Presented for the Degree of
Doctor of Medicine
Edinburgh University
by
Adam Cairns White, ßß.B., Ch.B., Ph.D.,
Wellcome Physiological Research Laboratories,
Langley Court, Beckenham, Kent.
INS,
September, 1939. Com-parison alLome FrEot Alkaloids. A-
Section I. Contents.
Introduction pp 1-8
General Toxic Symptoms in:-
Monkey pp. 8 - 27
Fowl pp. 27 - 34
Canary pp. 34 - 36
Ct pp. 36a - 43
Rabbit pp. 43 - 44
Guinea Pig pp. 44 - 45
Mice pp. 45 - 55
Frog p) 55
Discussion of Toxic Symptoms pp. 55 - 60
Actions on Temperature Regulation in:-
Mice pp. 60 - 76
Rabbit pp. 77 - 96 -1-
The ergot alkaloids, other than those that are
molecular compounds, fail into two groups, a laevorotatory physiologically active group, and a dextrorotatory group which is considerably less active. Smith and Timmis drew attention to this fact in their paper on isoergine and isolysergic acids (1).
In Table l I have assembled the ergot alkaloids in descending order of the number of constituent carbon atoms, and given, where possible, their rotations in chloroform.
The figures are obtained from the papers of Smith and Timmis
(1) (2). The decomposition products, ergine and isoergine have also been included. -2-
200
Table 1. (« } 5461
Ergotoxine C35114105N5 -226e
Ergotinine 035H4106N5 +446°
191 Ergotinine C35H4106N5 +513°
Ergotamine C33H3505N5 -1810
Ergotaminine C33113505N5 +4500
Ergosine C30113705N5 -1930
Ergosinine C30H3705N5 +5220
Ergotnetrine C19x2302N3 -
Ergometrinine C19i-12302N3 . +5200 isoErgine C16H170 N3
Ergine C10170 N3 +598° -3-
Since the publications of Smith and Timis (1) (2),
Stoll and Burckhardt (3) have reported the isolation of yet another large moleculed pair of alkaloids, ergocristine and ergocristinine C35H3905N5 (this is the same gross formula as they give for ergotoxine) for which they have
rotations (el )p in chloroform of -186° and +365e respectively.
Ergometrine and isoergine are too insoluble in
chloroform to give a rotation figure but Smith and Timmis
(1) give a series of figures for p aridine. (Table 2.) -4-
Table 2 200
(a ) 5461
Ergorrletrine c19H2302N3 -16°
Ergometrinine 02N3 +596o
isoErgine C19H170 N3 +25°
Ergine C10170 N3 +6350
Lysergic Acid C16H1602N2 +490 isoLysergic Acid C16H1602N2 +3650 -5-
The rotations for ergometrine and ergometrinine in pyridine show analogous differences to those found for the alkaloids with the higher molecular weights in chloroform
solution. Ergosine and ergosinine are two new alkaloids
(2) (4), but they also (as will be shown in this communication) fall into line. The ergine and lysergic
acid series, while showing considerable differences in rotation do not show quite such marked differences in physiological action as is the case with the alkaloids of higher molecular weights. It should be noted that ergine
belongs to the ergotinine ergometrinine series whereas
lysergic acid belongs to the ergotoxine ergometrine series.
That this differentiation in the nomenclature has arisen is
unfortunate but it was a consequence of the historical
sequence of isolation of these substances by Smith and
Timis (5) and Jacobs and Craig (6) respectively. These
lists include all the alkaloids definitely characterised
as pure substances, as well as the breakdown products of -6-
the erg;ine, and lysergic acid series. Sensibarnin (7)
and ergoclavin (8) have been excluded. These two have been
.characterised by Stoll (9) as mixtures, sensibarain as an
e::¡juimolecular mixture of ergotamine and ergotarninine and
ergoclavin as a mixture whose components are still under
investigation. In a later paper he further states that
Kftssner's (8) ergoclavin is composed of a dextro- and laevo-
rotatory fraction. Smith and Tiinmis (2) reported leucine
to be one of the products of acid hydrolysis of ergosinine
and also report analytical figures strongly suggesting
ergoclavin is a mixture of ergosine and ergosinine. Jacobs
and Craig (11) report the presence of leucine as a product
of the acid hydrolysis of ergoclavin.
Kftssner himself (12) has also recognised that his
ergoclavin is a mixture of two alkaloids. Further evidence
of the non -unity of ergoclavin has been brought forward by
Kofler and Kofler (13) who conclude that ergoclavin may
possibly consist of two compounds, one of ergosine and -7-
ergosinine, the other of ergotamine and ergosinine.
Stoll and Burckhardt's (3) first isolation of ergocristine was from a double compound found in the mother liquors of ergotoxine from Spanish and Portuguese
ergots the other component of which was ergosinine. These authors remarked on the analogies of this compound with
erg=,oclavin. A. Kofler (14) has now described and characterised at least fourteen such molecular addition compounds between ergot alkaloids of opposing rotations.
Provided suitable conditions are obtainable the list of such
possible compounds is not yet exhausted. (L. Kofler) (15).
So far, no compounds have been described between different
ergot alkaloids with similar rotation. Very little is known of the quantitative or qualitative pharmacology of
these compounds, and it will require prolonged and accurate
comparisons if any results of value are to be obtained.
A number of the ergot alkaloid pairs have not so far
been examined together, and it is the purpose of this paper
to extend these comparisons as far as my material allows. -8-
The comparison of the activities of the various alkaloids
and their decomposition products will perhaps be simplified
if instead of describing the action of each pair as a whole,
the actions of all pairs on a given species or physiological system are described together.
GENERAL TOXI C SYMP'rO NbS .
( a ) Symptoms in the iVionkey .
ERGOSINE.
The same type of monkey was used in all our experiments
with the ergot alkaloids, namely, silenus rhesus. The
highest dose of ergosine given to a monkey was 4 mg.
intramuscularly. The earliest symptoms were, pallor of
the face and ears, and the animal was obviously ill at ease.
The pupil was slightly contracted. The hair was roughened
and the animal appeared to maintain its balance with great
difficulty. Then the pupils were found to be dilated and
did not react to light. Respiration was rapid and now and
then a purposeless stretching out of the hands was observed. -9-
At other times it sat all huddled up and ground its teeth frequently. When the animal partly lost its balance, it recovered with a convulsive shiver; this might be accompanied by twitching of the wrists. When the eyelids were raised, the pupils were seen to be very dilated. The huddled up position was disturbed every now and then by twitching of the muscles of the forelimbs, giving rise to
a beating type of movement (clonus) with the wrists flexed.
Four hours later the animal was found slightly more awake,
but when the head was kept erect for a short time it finally fell jerkily forward and downward into the huddled up position, accompanied by a few twitches of the forearms.
half an hour later, on being given a lump of sugar it was
observed that the animal held it more awkwardly than usual
and was still very timid. At the end of six hours it had
largely recovered. The next day the animal was found to be
slightly jumpy and was scratching itself more than normally.
An attempt was made to induce chronic ergosine poisoning in a monkey, and between the 16th November, 1936, -10-
and the 8th January, 1937, a total of 45.5 mg. was injected
intramuscularly, at first in daily doses of 0.5 mg. and then
after about three weeks the dose was doubled. A week later
the dose was increased to about 2 mg. No symptoms of
chronic poisoning were observed during or after the
experiment and our supply of the drug did not justify
proceeding further to determine the effect of higher doses
of ergosine. The animal was apparently able to destroy
moderate amounts of the drug without showing any chronic
sympi oms. Whether this was due to the gradual developing of
a tolerance to the drug or entirely due to insufficient
dosage could not be determined. The develop?ient of
tolerance to some of the other ergot alkaloids has already been noticed in the literature.
RGOSININE .
With large doses (il mg.), on intracardiac injection, the animal immediately became unconscious, gave a few dyspnceic gasps, became limp, assuming no characteristic -11-
attitude and then died. Smaller doses (2 mg.) showed a
much slower effect, the animal became less sure footed,
and its movements were slower. At the end of twenty minutes,
the animal was sitting in a corner supporting its body with
its forelimbs (c.f. Fig. 1. where 5 mgm. had been given);
it seemed dazed. It got up onto its perch, and had a
great struggle to keep its position. The movements,
however, were much slower than usual. The gripping power
of the hind limbs was also reduced. The animal seemed, as
it were, half awake. It was able to make a sudden rapid
movement, but was unable to maintain am attitude or steady
level of activity, for instance, when sitting, in the
corner, it lay half on the side of its rump using its
forelimbs to support the upper part of its body, the head would then slowly fall down and then be jerked back into its
original position, (recalling the movements of the head when
the human subject nearly drops off to sleep while sitting in
a chair) . Fast movements were distinctly clumsy. A very
characteristic attitude the animal adopted in this state was -12-
a sort of Landseer lion attitude. At times, too, purposeless slow movements of the forelimbs were observed.
Figure 1 shows the stage of the effects of 5 mg. ergosinine
intracardiac in one of the monkeys. -13-
Figure 1.
Fig. 1. Monkey No 7. 2.6 kg S 5 mgm. ergosinine intracardiac. EkGOTOXINE IN T T PrTOIirï FY
One monkey was injected with 2 mg. ergotoxine ethane
suiphonate intracardiac, to serve as a comparison with
ergosine. The first symptom was immediate collapse as if unconscious, the eyes were closed, but the pupils were
normal and the corneal reflex was present. The chest
seeped full of fluid and respiration was increased. The
animal lay on its side with its hands flexed. Then the
chest cleared of fluid and the pulse rate increased. Later,
on being handled the animal opened its eyes. At the end of
an hour the animal was recovering, sitting up, but
distinctly drowsy, and had difficulty in preserving
the sitting upright position. Finally it completely
recovered. Fig. 2 shows the effect of 2.2 mgm. ergotoxine
ethane sulphonate in another monkey. Figure 2.
Fig. 2. Monkey. 3.7 kg. ? 2.2 mg. erEotolLine ethane sulphonate intracardiac seven minutes after injection. -16-
ERGOCRISTINE IN THE MONKEY.
2.93 mg. ergocristine (acetone) were injected
intracardiac into a mala monkey 2.4 kg. (silenus rhesus).
Within two minutes the animal was flat out on the floor
as if asleep. When the eyes were open the corneal reflex
was iuite active. The respiration was 36 per minute and
regular: all tone had gone from the voluntary muscles.
On raising the eyelid the pupil was found to be, if
anything, dilated. The face became pale. Fifteen minutes
later the pulse was 120 and the rebpirat:ion 38 per minute and
it was still lying on its side as if asleep. At the end of
twenty minutes the rectal temperature was found to be 37.10 C
and during the disturbance necessary to take the temperature
the animal woke up and put up a small amount of resistance.
During this period the corneal reflex was brisk the pupil
dilated but reacted to light. The chest sounds were clear.
At the end of thirty five minutes the animal shifted into an
apparently more comfortable position with its haunches flat -17-
supporting the main part of the body with its forelimbs, the
head retracted and the eyelids half open. The animal
remained in this position for quite a time and at the end of
fifty five minutes still showed retraction of the head. The
toes of the left hind foot were clenched. When disturbed he
showed a short period of rapid activity which was rapidly
succeeded by the development of fatigue and if left undisturbed he again reverted to his original position.
This semi erect position supported by the fore limbs
persisted for some time longer. The animal would swing from
side to side, he would suddenly recover and then the whole cycle
would repeat itself, the eyelids gradually closing to reopen suddenly with the sudden recovery movement. In addition there was also a repeated drawing up of the hand
(wrist flexed, fingers extended). The animal then gradually recovered, his movements became less clumsily
jerky and at the end of an hour and a half he had practically recovered. The next day he was perfectly normal.
Figure 3 shows the symptoms after a large dose of ergocristi.ne acetone injected intramuscularly. This shows the typical drowsiness seen after mush smaller doses injected intracardiac. -18-
LIEure 3.
Fig. 3. Monkey 3 k,. * , 4 mg. + 4 mg. ergocristine intramuscularly. -19-
ERGONE Tip INE .
2 mg. ergometrine.injected into the heart did not cause
any very striking changes. The general movement and
activity of the monkey was unimpaired. Some seven
minutes after the injection the animal would pass its hand
over its nose in a wiping type of movement. The animal
became distinctly timid. No other symptom were noted. In
another monkey 12 mg. were injected intracardiac (3.43
mg. per kilo) . The animal proceeded to crawl about on all
fours, was dyspnoeic, but showed no signs of rage. It
looked as if it would have fallen asleep if it had been left
completely undisturbed. It was unable to grip things and
lay prone in a flaccid flexed position. The pupils were dilated but reacted to light. It was timid, but too feeble to react. Almost twenty minutes after the injection,
the animal suddenly jumped up and clung to a nearby pipe for a second or two and then rushed off again on all fours into
the corner where again it lay flexed and prone. The pupils
were still dilated. Ten minutes later it tried to sit up on -20-
its haunches, but it could not support itself and finally
flopped onto its side. It is of interest to note that the
animal was capable of sudden but not sustained effort. About
this time too, fluid was noted at the nostrils. When held
up, the animal kept the fore limbs and hands fl::xed. At the
end of forty minutes it was still lying huddled half
sideways on the floor as if nearly falling asleep, trying to
keep its head in position. Its mouth was open as if dyspnoeic.
The pupils were now less dilated. At the end of ninety
minutes the animal's condition was improving.
The toxic symptoms of poisoning by the ergot alkaloids
in the monkey, illustrated by the various photographs are
all very similar, one could have obtained a similar series
of photographs using one alkaloid only. In that the exact
toxicity ratios of these drugs the one to the other could not
be determined with any accuracy - ( insufficiency of
experimental animals and drug) all that can be done is to
stress the essential similarity of the symptoms in the cases
illustrated. Figures 4 and 5 show two stages of -21- ergomet.ri_ne poisoning in the monkey.
Figure 4.
Fig. 4. Monkey 3.4 k. 7 ac. erEometr i_ne acetone intracardiac, 18 minutes after injection. -22-
Fire 5.
Fig. 5. (Same monkey as in Figure 4) 18 minutes later
(i.e. 36 minutes after injection). ISOERGINE.
5 mg. Isoergine suspended in 16% g.r;. acacia was
injected into the heart into a female monkey weighing approximately 3.4 kilos. The effect was immediate,
the animal became limp before being put back into its cage.
The hind limbs apparently lost all power and the animal
tried to support itself by pulling with its fore limbs on
the floor or sides of the cage. Respiration was dyspnoeic
and the movements were jerky. The general jerkiness was
due to the sudden attempts of the animal to recover its
balance and in its efforts it kept striking itself against
the walls of the cage. It might be described as resisting
the onset of sleep or struggling against the loss of bodily
tone. At the end of thirteen minutes it lay huddled in the
corner of its cage supported mainly by its forelimbs with
its head dropping frequently and this drop of the head
being followed by a jerky recovery movement. This was
followed by a series of violent spasmodic twitches. The
hind limbs were extended forwards under the prostrate body, -24-
the head tended to fall and the fore limbs grasped the wires of the cage bottom in an effort to keep at least ser d
erect. It then gave the impression of being overcome by a
strong desire to sleep as the monkey's head dropped the eyelids
closed but as the head perked back to a more erect position
the eyelids opened again. The fore limbs were used mainly
as props as the grip of the band was found to be very feeble.
The grip actually became stronger during the general jerky
recovery movement. These jerky recovery movements recurred
about eighteen times a minute. At this stage the animal
did not appear specially susceptible to external stimuli.
Several of the more violent spasms were accompanied by soft grunts. During the whole of the intoxication the mouth was kept open and the tongue partially protruded and the face was paler than before the experiment. The animal had largely recovered. by the end of three hours. Fourteen hours later
the animal was still a little drowsy but recovered during the next few hours. -25-
0.6 mg. Ergine intramuscularly caused no special
syniptorrs in the monkey.
In another experiment a female monkey of about 3 kg.
weight received 1.2 mg. ergine Hydrochloride in 12% acacia
intracardiac. The respiration increased in frequency and for
hours the next three ranged between 45 and 60 respirations per-
minute. Within eight minutes of the injection the animal was lying prone on the bottom of the cage with its head lying on its bands. It looked as if the animal wanted to go to sleep but it was still fairly easily disturbed by outside noise.
The face became pallid. This drowsy condition persisted during the whole three hours of the observation. At times
the animal lay prone at other times it lay on its side.
Every now and then there would be as it were a convulsive jerk generally in the direction of increased flexion and for
a while it was noted that movement was mainly confined to the hind limbs, the fore limbs taking no part remaining with hand and wrist flexed under the chest. Most of the -26-
movements seemed to be conditioned by sorte external stimulus
such as a fly alighting on the animal and when attercpt was
made to reach the site of irritation the accuracy of the
movement of the fore limb was very considerable. In some
cases we could not trace any external agent actin; as cause
of the movements. The pupils were sli_gtly dilated.
LYSERGIC ACID.
2.1 mg. were injected. intramuscularly. No symptoms of
any kind were noted, neither coarse nor fine movements
were affected and no drowsiness supervened.
ISOLYSERGIC ACID.
Here also 2 mg. were injected intramuscularly and again
no symptoms due to the drug could be observed.
In anot1:er experiment 10 rng. isolyser ;ic acid in 0.01 N
NaOh suspended in 11% gum acacia was injected into 3.4 kg. female monkey intracardiac. The symptoms observed were less
marked than those observed with smaller quantities of the
larger moleculed alkaloids but were of a similar character. -2`7-
Within five minutes however slight salivation and general
drowsiness was noted an( for a short time it sat in the
corner of the cage hunched up and look ng, very drowsy. It
was quite sensitive to eAtraneous sounds and when any occurred
it would look up in the general direction from which the sound came.
Then it lay down on the floor of the cage as if going to sleep but
still wasAeasily disturbed by exterrrmal sounds. Later in the
experiment it simply lay on the floor cf the cage for as
lone as twenty five minutes looking very sleepy but not
actually going off to sleep: the eyes remained open during
this period. It had complete, ly recovered by the end of the
three hours.
(b) Sylgtoms in the i;'owl.
ERGOL-,INE.
The symptoms of ergosine poisoning in the fowl closely
resemble those produced by ergotoxine (16) and ergotamine (17).
The earliest symptom was a circumocular and comb pallor. This
weL. followed by slight salivation and dyspnoea, then the comb _2g_
started to become vyanosed, and a patchy cyanosis appeared
on the wattles, and often the animal would stand perfectly
still with the wings drooping. The respiratory rate on
occasion. was extremely high. The rectal temperature rose
also. On one occasion, when a fatal dose of ergosine was
given, the rectal temperature at the moment of death was
45.60 C. The symptoms with a fatal dose$ were much more
intense. The animal, in one case, adopted what might
be described as a "nose dive" position, salivation and
dyspnoea were marked -- walking was impossible, it lay on its
side while the limbs showed intermittent walking movements, accompanied by flapping movements of the wines. The dyspnoea became more narked, respiration finally slowed down and all movement ceased. The corneal reflex was present until just
before the exitus.
In addition, the effect of chronic poisoning on the comb
was investigated in tyro fowls. In one case, a total of
6.5 mg. was given intramuscularly over a period of six days.
No gangrene of the tips of the comb appeared, and in view -29--
of the small amount of the drug then at our disposal this
experiment was di scon.tin.ucd. Th results with the other
fowl, however, were definite. Here 15.1 mg. were given over
a period of eleven days, mainly in mill gramme doses. 3y the
sixth day the comb and wattles were cyanosed before the
injection, and in the succeeding five days, a dry gangrene
of the tips of the posterior serrations of the comb developed.
This persisted after the cessation of the drug. Eighteen
days after the drug had been stopped , the last two small gangrenous points on the serrations were picked off, leaving a
clean bloodless line of separation. in its action on the
comb therefore, erg,osine presents a complete analogy with
ergotoxine. An exact : ua.ntitat.ive comparison of the gangrene producing action of these two alkaloids was not ale.
Kreitnair's description (18) of the symptoms of ergoclavin poisoning in the fowl closely resemble those described for ergosine above, and also for ergotoxine and ergotamine. It
is interesting to mote that he found 2 mg. per kilo
ergoclavin intramuscularly fatal in 30 hours, whereas in the -30-
fatal case of er ;osine intoxication described above 2.67 mg.
per kilo killed in ninety minutes.
ERWHNINE.
1.56 mg. per kilo intramuscularly produced in a hen
circum.octsl..ar and comb pallor, followed later by cyanosis.
The respiration increased in rate, and the wings dropped. The
conditions gradually inpooved. In another cae, 2.67 mg. per
kilo injected intravenously was not fatal, nor for that
matter was a similar dose given intramuscularly, whereas
2.67 mg. per kilo ergosine intravenously proved fatal.
ERGOCRISTINE.
A hen weighing 2.5 kg. was injected intravenously with
1.5 mg /kg ergocristine. Within two minutes the comb and
re ;imn round the eyes had become paler than normal and the wings and tail began to droop. At the end of four minutes the comb was becoming dusky. Thirteen minutes after the
injection the comb was moderately dusky - the anima walked
around slowly and its head was tending to droop on occasion. -31-
±t looked extremely dejected. The respiration increased
in rate, the comb and wattles became cyanosed and the
feathers generally ruffled. The recul temperature in this
case at least did not show any significant change under the
influence of the drug. The cyanosis gradually wore off -
the last parts to clear being the serrations of the comb. The'
next day the animal appeared completely normal.
ERGOM MININE.
Doses ranging from 20 to 27 mgm. per kilo intravenously
had very little effect. With 27 mg. per kilo no symptoms
were observed during an observation period of five hours; the
comb and wattles showed no discolouration and there were no
disturbances of behaviour. In only one case were there any symptoms noted and these were certainly due to the reaction of the solution injected, but recovery thereafter was rapid and at the end of an hour no symptoms were observable.
In contrast to the activity of ergometrine (19) in the
fowl, ergometr_i_nine is practically inactive, at least in the
doses used here. -32-
Firther evidence of the practival inactivity of ergometrinine has also been given by Chen, Swanson and
Hargreaves (20) who have reported that ergometrinine assayed
by the U.S.P. methods, and using 17 birds showed about
C.4iw 0.7 per cent. of the activity of ergotoxi maleate.
ISOMGINE.
In this case 1.21 mg. per kilo was injected intravenously
into a white leghorn cockerel. The earliest symptom noticed
was a ruffling of the neck feathers and the wings and tail began
to droop and the comb became slightly paler than before the injection.
The anim -Al lay on the floor almost in a "nose- dive" position
with its tail slightly elevated and grubbing aimlessly
at the floor with its beak. Vvithin two minutes the comb and
wattleswere cyanosed, the anix :.l was gaping and quite unable to stand, the feet sprawling out too widely. Every now and then the
tail jerked upwards and the animal attempted to right itself by drawing its feet together. Eight minutes after the injection the rectal
temperature was 42.9° C and the cyanosis of the comb and wattles was intense. Twenty minutes later the animal was still pecking aimlessly at the bottom of the cage and the respirations were 114 per minute. Twenty minutes later still the
general condition was improving, the animal was now better
able to hold up its head and the respirations were 60 per
minute and it was still showing cyanosis of the comb and
wattle -S the rectal temperature was 42.1 °C. At the end
of 70 minutes the rectal temperature was 41.70 C. the
animal was able to stand and the anterior portion of the
comb was less cyanosed. At the end of two hours the comb
was still slightly dusky, but the animal had otherwise
clay recovered, and the next a ìiIrial was apparently normal.
ERGINE .
1.21 ig. per kilo ergine was injected intravenously into a white leghorn cockerel. 'hithin three minutes the wings were drooping and the beak gaping. Within six minutes there was a slight circumocular pallor, and two minutes later
the posterior part of the comb began to darken and the tail was no longer held erect, the animal remaining perfectly still with a respiratory rate of 72 per minute. The animal -34-
found difficulty in keeping e.;uilibrium when disturbed..
At the end of thirty minutes the respiratory rate had
fallen to 36 per minute, the rectal temperature was 41.6 °C.
The posterior serration of the comb was cyanosed. At the end
of seventy minutes the animal was still gaping but its
hour movements were more active, and at the end of the secondAit
could be described as having recovered.
LYSERGIC ACID.
A dense of 1 mg. Lysergic Acid intravenously in a white leghorn cockerel only caused a transitory slight cyanosis of
the comb.
ESOLYSERGIC ACID.
1 mg. per kilo Isolysergic acid intravenously in a. white
leghorn cockerel caused e fluctuating cyanosis of the posterior portion of the comb and a. slight drooping of the wings. The rectal temperature was unaffected.
(c) S.02.1ptoms in the Canar .
FRGOSIM. -35-
The eauliest symptom is an incapability of the bird to
sit on its perch. Then it found difficulty in hopping, the
legs took a wider base. As the animal progressed forward,
the bead often hit the ground and then it would get jammed into
the corner of the cage and showed marked dyspnoea, accompanied
by convulsive flapping of the wings, and frantic efforts to
keep upright. Later the bird was unable to keep erect, and
lay prone on the bottom of the cage and respiration slowed
down to the final exitus. With small, non -fatal doses,
the stillness of the bird was very striking, suggesting a
catatonic state, the wings drooped and there was also
polypnoea, but not so marked. There was a sugg ?scion that salvation was also one of the symptoms of poisoning, and
from the movements of the animal, it would appear that in the
toxic cases at least, vision was probably impaired, 0.4 mg.
intramuscularly killed all of five canaries of 12 - 16 :m. in
weight, and 0.2 mg. intramuscularly killed four of six
canaries of 13 - 18 ms. in weight. With the higher dosage,
four of the birds were dead within an hour receiving their -36-
injection.
ExGOszNTlVii.
The symptoms here were considerably slower in onset and
progress than was the case with ergosine. ;ven with the
largest doses e;rLployed, the sympttme were slower than with
ergosine. Otherwise, the picture of poisoning with this
alkaloid was indistinguishable from that of its isomeride.
there was the same catatonic like attitude, with the
smaller doses, the same dyspnoea and drooping wings and
inability to walk and the same type of exi tus . 1.0 mg.
intramuscularlyy killed all of seven birds between 14 and 19
gm., three of them 2 to 3 hours after injection, the rest
ov might. 0.5 mg. intramuscularly, killed five out
of six canaries of 13 - 17 gin. in weight. Death took
place overnight, i.e. within 17 hours. Two canaries, each
of 15 gm. weight, survived 0.2 and 0.4 mg. ergosine
intramuscularly. Ergosinine is less toxic and slower in its toxic action than ergosine. `_' IN '1.'rE GAT. (d) SY iul
RGOCRISTINE Poisoning in the Cat.
The animal was given ,1 mg/kg ergocristine acetone iritra-
the injection the animal was very cardiac. Immediately after
and the hind legs began to frightened - the pupils were dilated
drag. Salivation began and the animal crawled about dragging i s
belly along the ground. There was no true paralysis but mainly
The a paresis. e head was kept nearly at ground level.
respiration increased in rate. l'be pupils remained dilated for
about thirty minutes while the salivation diminished. the ears
twitched intermittently and the head was always tending to fall
towards the floor. Any loudish sound made the animal start and
jump away. During the phase of dilatation of the pupil near vis on was
obviously disturbed. No marked erection of the hair was noted.
After the lapse of about half an hour the pupils began to
constrict and the animal tended now to be quiet as if asleep -
but when disturbed would slink away for a few steps and then
sink down to the floor again. At the end of two hours while the
animal's condition was improving, the pupils were still
unequally constricted and the fear of sound and movement was r
When left quiet , it still tended to show Still exaggerated.
attitude. Sixteen hours later the animal had the Landleer lion
completely recovered.
LRGNE.
The symptoms of ergosine poisoning in the cat are very like
those described for ergotoxine. 1 mg /kg. injected intracardiac
caused an immediate dilation of the pupils, the hair roughened,
the front; legs sprawled and the animal became hypersensitive to
sound. Then the hind limbs also sprawled, and finally the heat,
dropped towards the bench and the animal lay on its side with its
hind limbs stretched forwLird. The pupil began to contract, they_
ceased to react to light, secretion on the cornea obscured the view
of the fundus; salivation also occurred. After a slight
convulsive spasm, the animal died. 'lhe pupil constriction
was by no means as marked as one finds with ergotoxine. Post
mortem, the heart was found in systole. The cat in which these symptoms were observed was slightly emaciated. In another cat in a much healthier condition, this dose was not fatal, and the continual stimulant symptoms were much more evident. -38-
MGOSININE
2.3 mg /kg. injected intracardiac brought about a very
definite train of symptoms. The pupils dilated and the
animal fuffed on being touched. In approximately fifteen
minutes it was not able to walk, the muscles were
twitching and it dragged itself along on its belly. The head
tended to flop to the ground. The hair became erect and the
hind quarters were splayed along the floor. The nose was
also resting on the floor. On slightly tapping the floor
the cat leapt into the air head over tail, but landed on its
similar feet. A second, stimulus was much less effective. On milk
being brought toward it the animal growled. Salivation
appeared, and then at the end of thirty minutes, the cat convulsed, then lay on its side showing walking movements of the limbs; the pulse was 120 per minute, and the corneal reflex was present. On being stimulated, however, the animal still sprang up and fuffed. When undisturbed for twenty minutes the animàl just lay on its side, and by now
the pupil was no longer dilated (pulse 144, respiration 30). -39-
The pupil was not responsive to light. The pulse and the
respiration became even slower and at the end of 22ti hours
the pulse was 84 and the respiration per minute, the
plastic tone was still present and twitching was observed in
the muscles of the shoulder and pelvic girdle. The pupil
was more contracted than ever. Sixteen hours later the
animal had. recovered.
JGODiETRININE.
The symptoms of poisoning were crush less dramatic than
those observed with ergonetrine. Sham ra`,e was entirely
absent with doses of 4 - b mg /kg intracardiac, with these
doses all that was noted was dilation of the pupils and ex-
opthalmos and an increased timidity, Even with 10 mg /kg.
intracardiac no Biggs of so- called sham rage were apparent -
only dilation of the pupil and exophthalmos (pupil did not
react to light) , and slight weakness of the hind limbs.
SYMPTOMS OF ISOI RGINE POISONING IN THE CAT.
2.29 prig. per kg. were injected intraauscularly.. Within t;.vo -40-
minutes the pupils dilated and by the end of ten minutes
the animal showed paresis of all four limbs. It tended to
keep all four limbs splayed out, and moved along on its
belly more or less dragging its hind limbs. At the end of
fifteen minutes it was quite timid and started if the floor
were scraped by the shoe some six feet away from it.
If its face touched any thing it started back. At the end
of twenty three minutes it was crouching in a corner and fuffed
on being touched. At the end of half an hour the animal had great difficulty in keeping the fore part of its body off the ground. If its head came in contact with anything the animal started convulsively. The pupils were maximal dilated.
The difficulty the animal had in keeping its head up (the
head fell gradually toward the ground and then as it neared
the ground was jerked back up again) reminded one of the
evolutions of the human head when its owner falls asleep
upright in a chair, a type of symptom already remarked upon in the monkey. At the end of three hours the animal had
largely recovered although the pupils were still dilated. -41-
The animal showed no abnormality on the following day.
Three days later this animal was used as the subject of the
ergine experiment described next.
sy 1PTOMS OF ERGINE POISONING IN THE CAT.
2.2 mg per kg. were injected intramuscularly. ¡Marked
salivation occurred within five minutes of the injection,
the animal vomited, the pupil was dilated but reacted
to light. At the end of nineteen minutes the cat was hypersensitive to external stimuli and timid, the
salivation was less marked. Six minutes later it was
reacting violently to external stimuli mainly as if afraid.
On its being taken out of its cage it was found that the move-
ments of the hind limbs were incoordinated. It fled to a corner and remained there. This condition persisted for about another hour, but at the end of the next thirty
minutes it was possible to stroke the animal, the pupils were still dilated but the animal was still timid. At the end of four hours the animal had recovered. -42-
THE ACTION OF ISOLYSERGIC .ACID IN THE CAT.
4 mg. in suspension in 1 c.c. were injected intracardiac
(1.54 mg /kg.) into a 2.5 kg. cat ( ). There was no
immediate reaction. The animal was easily handled. Within
six minutes, however, the gait had become atoxic. It kept
its head down and lifted its hind le=gs in a high steppage
gait. This phase only lasted a few minutes. Thereafter
the cat moved about with a slight ataxia (legs spread out on a vide base. At the end of thirty minutes the pupils were considerably constricted but reacted to light. This constriction lasted about an hour and then gradually faded away. The animal was completely recovered by the next
day.
THE ACTION OF LYSERGIC ACID ON THE CAT.
4 mg. Lysergic acid in suspension in 1 c.c. was injected
intracardiac into a 2.2 kg. cat ( ). Within five
minutes there was a slight ataxia of the hind limbs, which gradually passed off within fifteen minutes. The pupils were -43-
considerably constricted at the end of fifty minutes, but
responded to light. Thereafter the constriction gradually
wore off.
(e) ERGJSINE IN THE RABBIT.
After 1 mg. per kg. of ergosine injected intravenously
the rabbit's ears and back where it had been shaved,
reddened. This later became less marked. The respiratory
rate increased, in the latter part of the experiment this
was so rapid that it wati: not possible to take the pulse. The
rectal temperature also rose. In one case it was 42.7° C.,
two hours after the injection. Ales were heard in the
chest; the gait was lumbering and there was a slight
weakness in the hind limbs. Exophthalmcs was also noted;
the normal secretion on the cornea appeared as if dried. The animal finally recovered.
ERGOSININE IN THE RABBIT.
1.7 mg/kg. ergosinine intravenously in the rabbit caused
polypnoea. The pulse when it could be counted, was of the -44-
order of 150 per riinute . The pupils dilated, and were
insensitive to light. The animal recovered. The dilation
of the pupils was slow in onset.
ayETOMS OF ERGOSINE POISONING IN THE GUINEA-PIG.
4.6 mg. ergosine per kilo, intracardiac, caused an
immediate dyspnoea with signs of fluid in the upper air passages and convulsive spasm of the hind limbs, thereafter
it became very quiet as if asleep, but still dyspnoic, the heart rate was still rapid, but there was a slight increase
in the lachrymal secretion. By the end of half an hour, the twitching had reappeared and was becoming more frequent.
Later the forelimbs were mainly involved. Three hours
later the animal was still restless, showing a jerky head
movement and tended to run in circles. The next day it had completely recovered. Small doses, 1.7 mg /kg. caused similar symptoms, but not so intense. These symptoms recall
Rothlin's (20} description of ergotamine poisoning in the
ergotamine poisoning in the guinea pig. -45-
ERGOSININE IN THE GUINEA -PIG.
8.9 mg. per kg. intracardiac brought about a paresis
of the hind limbs. The animal ran on its belly, with its
hind 'limbs splayed out. Within four minutes of the injection
a series of convulsions started; the legs were drawn
higher and then shot sharply back into the old splayed
position. This extensor spasm occurred in the beginning
at least at the rate of thirty -two per minute. The eyes
seemed to recede. The spasms did not lead to any
progressive movement, but tended to make the animal go round
in a circle. This was observed persisting for seventy minutes when the observations were discontinued. Sixteen hours later the animal was found completely recovered. In
in the earlier stages of the Jtoxication, there was evidence of
increased fluid secretion in the nose.
General To i1sIty L sures and Symptoms on Intravenous In 'ection
ofErgot alkaloids in Mice.
Tables 1 and 2 and figures 6 and 7 show the toxicitmes -46-
of ergotaxine ethane sulphonate and ergotamine tartrate
respectively on intravenous injection into mice.
Table 1.
Toxicity of Ergotoxine Ethane Sulpronate on Intravenous injection into mice.
Mortalitl Date of Dose 24 hrs. Experiment mg./ 20 gm.
17.3.36 1.5 22/30 73.3
1.0 13/30 43.3
0.67 30/30 100.0
0.44 5/30 16.7
030 3/30 10.0
0.2 0/30 0.0
0.13 0/30 0.0
22.6.36 1.2 18/30 60.0
0.96 15/31 48.5
0.77 9/30 30.0
0.61 16/30 53.3
0.49 10/30 33.3
0.40 8/ 30 26.7
0.32 10/30 33.3 -4.6- a-
Emgure 6.
" n t 1 _ { m/.::a::t:/r::/:H nn'ux N x 't ¡-41 ' ± nn.:° :t:t:g/ , E :: N ' g :: pCr:iñt.ut' Ex C/.. , i Rm. NNlp x... // %YNéN :.m/ñE ; t/rnt/tNNMBNtx C NNAt :gN H t NIN: ttéui : :! N N ! :Ca l u / t gill...... : i/n::óC .agg tN ' g :u . g :¡óúa Nt::gExn=xnuNtu :w ; H :g NifiCC t. ;iú ' ttNn/mNt " t r ú:uNKNtNVCú:: d 5° . x é ,r,.kt:t...t ":CC:.N éN i 1../N Plier-d- g E pimp!. ; lrCt. i ..... EEaii I x ETlCtFi/tC .N .=mi i.... ! :C:i :.... i. 1 m.Ntw. :i i....!: I/nnH. .t l, E :RrN ::: N...gt; I:m'%:H:;m'amm.'r.;mH..- _i° i :C gE t.i: iwH é ; i :éxñn:ï üüü . : ..... adz: xtx. C . : : uInumu: ggggg g.; ! n:m:t g; .. . ! u xiiiúntéx im óx /x :.0 ;WM; tu;tntu tN/rtKtú évtI : N tN : tut \Cl: xuum ;; t HN r ttttttxtúil: irii:=m R:: :wpm,tt ügi:t ..t iN..tnui . . Pawl C.. ll. g. gi:igg:'i: x $ E ;gg ii ilgE E:g =i:::Cggng A h. EEliE .N; g pi i = , i g E "u:ro : gg xE nN : ttr t:ux;.t:: ii.i$;p:nN;;ttt.tt t t g'g:Ñégg :'i:::l: uitt.N qCÿi g i . i :R: g . :ig OiR: é.p giNE'EEiig gEi;g . -.iÉ::gtti:tn g;:. t::.. ... : 9 gN . iiC.:. E : C= lgi ; ::E:!i :taat . t nxx: xi g ggnt ti:n.0 ..g .: E' g: '/t 1E ü gN;ü : E i
Fig. 6. Toxicity of Ergotoxine ethane sulpbonate on intra-
venous injection into mice.
Ordinate, percentage, mortality.
Abscissa. Los. dose in ricrogrammes per 20 gm. mouse.
. figures for experiment of 17.3.36.
figures for experiment of 22.6. . -47- Table 2.
Toxicity of Er amine Tartrate on intravenous In ' ection into
Mice.
Mortality Date of Dose 24 hours ¡o Experiiment 20 .
20.12.37* 2.0 15/20 75.0
1.33 12/20 60.0
0.89 1/20 5.0
0.59 2/20 10.0
0.395 1/15 6.7
0.263 0/15 0.0
30.12.37 2.5 10/10 100.0
1.67 12/20 60.0
1.10 2/20 10.0
0.74 4/20 20.0
0.49 3/20 15.0 0.z2 i/o0 S'U 0.33 1/20 5.0
0.15 1/30 3.3.
* Specimen used was at least 7 years old. -47a-
F i_fu r e_ 7 .
N. N N ...../nNN..N.N .gq /.NN. N +, :..N/= CCNSCC.,/N N::C::wm ' ___....s=i::::C :C.:.N'::::::C °C .N:" .. C : ./ :1 /. ./ : q.N.N. u... uq : : =C::iii:Cs/,N g ' :C:i ir..n.nt. NNNNg... q/ qmN q.Nq. Mg 1/rin. ..N..q/.qM / .. :C:.C:::CCC.°.0..... S.=.q°:::CC'C:ÑCC: :,g,=..N...... NC::Ng/....r.ñ°,G=:::CC::'CS:CCCCCCC C .:CCC:': C.:HCC.N.,CCCC::CÑCCCCCNC C CCCCCC" CC::C L!JIllhh ...... C.=C:::Có:C t N/..:s.....\i: .::Cú nonnt..Nm n.N :::/w..qq Ñ/.//NC :....N n..../tn NNt. .qn Cs::.q.'s:: rA° CtNt CCCC:::Ni'iC.4, : u--- :C g'CC:::CC ././tN.NqC:C°'C:C...N..N/ y ::.= :_.. NC:: L: C: N s: "'C::SC:C.....C... :: :: NÑ;.:N ..nN : ./. ír /. s .. : ...n 8 rcC:::::: ..../...q.:..ó.q.á . :.g../g../W /.q:: ::.... :...... ' N .. ..
:C": . :.....gN en....NN.N.\C ±I!i!I .Nt://Nq..N...... q:..:N.N':..,C.N:::::z:s. :::NCCC.NNC/ : .:nu. :C:CCd::"M!''G' .. :.: .N.:NN.CC°.Ó:: : .....::::C::'N:=CE:Ç...... r:
Fig. 7. Toxicity of ergotamine tartrate on intravenous
injection into mice.
Ordinate : percentage mortality.
Abscissa: Log. dose in micrograrr,mes per 20 gm. mouse.
x = experiment of 30. 12. 37.
= experiment of 20. 12. 7. -48-
The results given here suggest that the 50% lethal dose
of ergotoxir,e calculated as base is about 33_mg /kg. and that
of ergotamine also calculated as base 52 mg/kg. These
results for ergotoxi_ne, as Barger remarked after I had communicated them to him (22) agree more with those of
Kreitmair (18) and Rothiin (23) than with those of Brown and
Dale (19) . The cause of this discrepancy is &lrnost
certainly due to the fact that the latter authors used (24)
bii.t a small number of mice for their determination. Rothlin
(25) in a more recent paper has confirmed my results. His
most recent figures although based on fewer mice are 35 mg /kg
for ergotoxine as base and 51.5 mg/kg for ergotamine as base.
It ..s also interesting to note that the first specimen of
ergotamine tartrate I used was at least seven years old. It
had lain in the laboratory in a sealed tube as it had come
from the manufacturer's for at least that period, yet despite
this the results obtained with the two different specimens
of ergotamine tartrate do not appear to be significantly
different, at least they make a toiicity curve with no more -49-
scatter than is shown in the ergotoxine curve, where
there was no such difference in age bet-:,ceri the specimens
of ergotoxine ethane sulphona{te used
ACTION OF ERGOSINE IN ME MOUSE.
Only a. few animals were injected and these were
injected intravenously. One mouse died with 0.5 mg.
ergosine per 20 gms. The symptoms were exophthalmos
erection of the hair, general tremor, gasping, dyspnoea,
paresis of the limbs and then death. Lower doses showed
similar symptoms, but they recovered. In some of these
a tendency to run in circles was observed.
ACTION OF ERGOSININE IN THE MOUSE.
The symptoms on intravenous injection were not rapid
in onset. The usual course of the symptoms was as follows:
exopthalmos, dyspnoea, sometimes followed by polynoea, a
tendency to run in circles, ruffling of the hair, paresis
of the hind limbs and death, i.e. the symptoms were similar
to those of ergosine. -49a-
The following figures give a rough idea of the toxicity
of ergosinine in the mouse on intravenous injection.
INJ EC`HON INTO JiICE. TOXICITY Ole GOSININE ON INTRAVENOUS
Dose Mortality at % Mortality. mg/20 48 hours.
1.0 9/10 90.0
0.67 E/10 50.0
0.44_ 5/10 b0.0
0.30 3/10 30.0
0.20 0/10 0.0 (1). ERGOJ11ETRININE POISONING IN ;.;ICE.
The animals show. a preliminary stage of poylpnoea, and
sprawling of the hind limbs, the respiration then becomes
slower, exopthalmos is seen and the tail is erected.
Convulsive twitchings of groups of muscles at different
times is noted. In the later stages the animal stays
quiet as if asleep and the hair may be rough. Ergorrietrinine
is more toxic to mice than ergometrine, the following
table shows this. -51-
TABLE 3.
TOXICITY OF ERGONIETRIla AND ERGOIvEETRININE ON INTRAVENOUS
INJECTION INTO l'E CE .
Dos___ e in Er11,metr ine Ergomet_rinine 20 m. (14.3.36) (10.3.36) Mortalitl
1.0 0/10 9/10
0.67 0/10 7/_1C
0,44 0/10 0/10
0.30 0/10 3/10
0.20 - 4/10 -52-
A later experiment confirmed the fact that ergometrinine
was more toxic to mice than. ergometr:ine. This experiment
also is free from the objection of the comparison not
having been carried out at the same time with each isomeride.
TABLE 4.
TONICITY OF ERCOMETRINE AND ERGOL TRININE NITRATE ON
INTRAVENOUS INJECTION INTO MICE.
Dose in Ergometrine 24 hours 26.1.38. mortali. Er ometrinine Nitrate. 26.1.38.
1.28 1 /10
1.0 6/10
0.64 0/9
0.5 0 /10
0.25 1/10 -53-
In a comparison of the toxicity of er obesine and
ergotamine Rothlin. (26) gives the following figures for
white mice on intravenous injection 2.9 .mg/20 gm. for ergometrine and 0.9 mg / 20 for ergotamine. These figures support my findings that ergometrinine is more toxic than
erg,ometrine in that they place the toxic dose at an even
higher level than any amount I inject,eü. But no explanation
can be offered for this result.
The intravenous toxicities of ergortiamine and ergotarriinine in mice were also compared with the following
result. -54-
TABLE 5.
TOXICITY OF ERGOTAMININE AND ERGOTAMINE TARTRATE ON
q INTEAVENOUS INJECTION INTO ALICE. ( lÉ . .r ) .
24 hours mortality.
Dose in Ergotamine Erutarr.:.inine Tartrate LIELEL.12-
0.4 1 /10 0 /10
0.6 3/10 1/l0
Ergotaminine unlike ergometri.nine is not more toxic
to mice than its enantiomorph.. -55-
SYMPTOMS IN ThI; FROG.
0.5 mg /20 gm. ergometrinine did not produce any
symptoms. in the frág.
Ergosine and ergosinine only produce lethargy in the frog
-In this they resemble ergotoxine, no convulsions were
observed; iobert's cornutine (27) is still a mystery.
DISCUSSION OF GENERAL TOXIC SYMPTOMS.
Very few authors seem to have tried the effect of ergot
or its alkaloids in the monkey, despite the great clinical
and historical interest of convulsive and gangrenous
ergotism. Pentschew (28) fed three monkeys with varying
amounts of crude ergot, and obtained a fatal tesult in one
case and a subacute poisoning in another case: the post
mortem findings did not throw any light upon the pathology
of ergotism in the human subject.. This author did not try
the effect of giving any of the pure ergot alkaloids
although. he did try the effect of repeated doses of
ergotamine tartrate in the rabbit. Stockman (29) also -56-
failed to produce convulsive ergotism by feeding monkeys
with lightly baked ergotised rye oatmeal cakes and
ergotised rye. In my experiments with .monk.,eys j;he animals were kept on their usual type of fruit diet and no attempt was made to deprive them of any special vitamins.
One interesting point however arose early in the experiments,
namely, the great difference in intensity of the effect following the intracardiac and intramuscular administration
of the alkaloids. ,411ile such e. difference was to be
expected it was much. greater than I had expected.
my experiments on monkeys I generally used the intracardiac
route of injection for two reasons, namely, ease of
execution and the greater intensity and rapidity of onset of symptoms for a given dose; intravenous injection was
mucb more difficult and required anaesthesia. It is
interesting to note that the figures 4, 7, and 8 of Stock- man's (22) paper obtained. after rye deeding and the administration of rye and wheat phytate show poisoning symptoms like those mentioned and figured here for the -57-
fol the pure ergot alkaloids.
The action of these various alkaloids in causing a
sleep -lixe condition in the monkey is very interesting. A similar type of effect has been obtained in other animals using special routes of injection. Marinesco,
Sager and Kreindler (30) reported that the injection of 1 mgm.
of ergotamine in 0.1 c.c. into the lateral ventricle
caused sleep in dogs. A similar type of effect was noted by
Hess (24) in cats on injecting ergotamine in suspension in a
small volume into the lateral ventricle or the third
ventricle. Incidentally one has observed even with
ordinary intracardiac injection in cats that a sleep like
condition may be induced when external disturbances are
reduced to the minimum. Of course, if the external disturbances exceed a certain threshold level the animal will "start" into activity and show that train of symptoms designated as "sham rage." This type of reaction can also
be described as a fear or start reaction as it may not necessarily be directed definitely against the stimulating -58-
agent which may be a loud sound, and it shows considerable analog to the "start" the human subject may show when he hears some unexpected sudden loud noise or is suddenly wakened from sleep. A narcotic effect was also noted
by Barger and Dale (32) in ti; e it description of the effects
or large doses of ergotoxine in the cat. The sleep
symptoms described by Hess (31) were much more prolonged
tan those observed by us even in monkeys. Uur cats were
much more easily disturbed than appears to have been the
case with the intraventricular injection of the precipitated
base probably as a result of the more intense local
concentration near the centres underlying the `bird
ventricle where it could exert its maximum action. Our
results with ergometrine in the cat injected intracardiac
did not show any marked drowsiness but the "sham rage"
reaction could be reduced to an absolute minimum by excluding
the possibility of external stimuli.. Under such conditions
the animal might lie quietly for prolonged periods. The
activity of such a relatively inactive sympathicolytic -59-
isomeride as ergosinine in producing a sleep like condition
in the monkey is of considerable interest. The sympathicolytic activity of ergosinine is considerably
smaller than that of ergotoxine or ergosine but yet it
has quite a powerful action on the monkey. Erf__ometrine too
which has practically no sympathicolytic action also causes
ti
drowsiness in the monkey. kn ; intere,s ding point as regards t
action of ergometrine in the human subject is th 4. »+ +,ta
41q. the case of a woman who was receiv ng the usual therapeutic dose of ergometrine complained that this dosage
.made her drowsy and a reduction of dosage was recommended.
(Trevan 34). Similarly ergine and isolysergic acid cause
in tmvnKey drowsines2 These/ facts suggest that whatever `roupings in the molecule are responsible for sympathicolytic activity
these groups are not necessarily involved in the central action of these drugs. Certain clinical results with
ergotamine in migraine suggest a similar train of thought.
The case quoted by Lennox (33) where bilateral
syïripathectomy failed to relieve migranous headaches which -60-
were cut short by ergotamine does not support a sympathicolytic theory as a necessary explanation of the
benefic_iall action of ergotamine in such conditions.
THE ACTION OF ERGOT ALKALOIDS ON TEMPEPATURE REGULATION.
This was investigated on an extensive scale in mice
and rabbits. The first section will deal with the effect
of the various ergot alkaloids on the rectal temperature
in mice. ks a rule three series each of ten mice were
used ,, one series each to the isomerides under comparison
and one control series. In each case, three mice, one
from each group, were kept in the same container, to
make conditions as comparable as possible. If only one isomeride was being tested then only two series were used, one for the isomeride and one for the control. The rectal
temperature was determined by means of a thermocouple inserted into the rectum, and inserted the same distance in every case. The temperatures recorded for the different times before and after injection are nearly all of them the
average of ten readings in ten animals. -61-
The following table shows the results obtained comparing ergotoxine ethane sulpbonate and ergotinine. It
will be observed that the ergotoxine is the more active
drug of the pair. The point of interest, however4i from
this experiment is that here the temperature falls under
the influence of the active substance, whereas in the rabbit
the effect is the reverse. TABLE 6.
The effect of 0.05 mm;.L0 rm. Er -,off toxine Et} ane Sulphonate and Eroótinine in 0.5 c.c. saline intravenously on the rectal temperature of mice. Control mice received an ecual amount of saline alone. The ergotinine was in partial suspension. (Ten mice in each group).
Experiment of 3.9.37.
Ergotoxine Ergotinine Controls Ethane Sulphonate Time in Av. 'Temp..Q°C. A.V. r °C. Av. Te °C. minrtes oC Temp. `'C oC
0 33.45 0.91 33.3 0.80 33.4 0.97
30 32.40 0.62 34.3 0.54 34.2 0.49
60 32.20 0.98 34.6 0.75 34.35 0.42
90 33.00 0.88 34 . 4 0.80 3440 0.41
210 32.90 1.20 34.0 0.78 33.8 0.73.
Standard error of the difference of the ergotoxine and
ergotinine means at 30 rninut.es is 0.26. -63-
The method we adopted to determine the more active of
any pair of isomerides was to drop the effective dosage to such
a level that a dose was found where one was active and the other
not. By this means significant differences were more easily
observed than would have been the case if one of the isomerides
had showed a moderate act ivity, since the individual readings
snowed a considerable individual scatter which would have
meant a much larger series of experiments to obtain a
significant result. In the case of e ±gotoxine and ergotamine
we were fortunate enough to strike a dose shoing a suitable
difference in a single experiment.
Anot er series of mice were injected with ergotamine and
ergotaminine, the results of this experimentent are given below. -64-
TABLE 7.
EFFECT OF 0,..0Lruil. of ERGOTAA1NE TRRTRATE AND MINACvIININE IN 0.5 c.c. SALINE INTRAVENOUSLY ON THE RECTAL TEMPLRATURE OF AraCE. CONTROL MICE REC -,IVttD AN EQUIVALENT AMOUNT OF SALINE ALONE (TEN MICE IN EACH GROUP) .
Ixraent of 2.9.37. ELEotamine Ergotaminine Controls Tartrate (r°C °C Time in Av. Av. U' Av. 4'' °C min utes Temp. Temp. Temp. oc oC °C
0 34.8 0.50 34.6 0.36 34.5 0.69
30 33.3 0.72 34. 7 0.93 35 . 0 0.65
6 0 33.7 1.00 34.7 0.95 35.1 0.86
90 34.5 0.98 35.1 1.07 35.1. 0.52
120 34.6 1.09 34.8 0.83 35.2 0.61
240 33.7 0.99 34.1 0.66 33.8 0.35 -65-
The standard error of the difference of the Ergotamine
and Ergotaminine means at 30 minutes was 0.37. Here again,
the laevo -rotatory alkaloid is the more active. With this pair of isomerides a differentiating dose was also found early in the experiments 0.025 mg. per 20 gm. mouse showed
both isomerides to be inactive.
Yet another series was done on the two isomerides
ergosine and ergosinine with the sa e tjpe of result, namely the more active isomeride was the laevo- rotatory one. The
res-alts are to be found in Table 8 below. -66-
TABLE 8.
EFFECT OF 0:05 . 20 ::m. of ERGOSINE AND ERGOSININ:E IN 0.5 cc SALINE INTRAVENOUSLY ON THE RECTAL TEMPERATURE OF MICE. coma MICE RECEIVED AN EkUIVAGENT AïviOUNT OF SALINE ALONE.
) . ( TEN MICE IN EACH GROUP
Experiment
Ergosine Ergosinine Controls
Time in Av. 0.0C.. Av. c oC Av. o- minutes Temp. Temp. Temp. oC oC. oC
33.9 0.69 33.7 0.72 33.3 . 0.90
30 32.9 0.37 33.7 0.41 34.15 0.86
60 32.4 0.60 33.8 0,37 34.15 064
90 32.4 0,77 33.7 0.62 33.55 0 87
1.20 32.7 0 84 33.4 0.50 33.55 0.91
240 33.65 0.85 33.6 0.48 33.50 0.95 -67-
The standard error of the differences between ergosine
and ergosinine at 60 minutes was 0.235.
It took much longer in this case to find a dose of the
two isomerides at which the difference in activity could be
shown. 0.0125 mg. per 20 or.. was effective with both isomerides in one experiment and ineffective in another, and
0.025 mg. per 20 gm. was found to be effective in that
ergosine reduced the temperature whereas ergosinine failed to
do so.
Action of Ergometrine and E ;gometrinine on the RRctal Temperature in Mice.
As in the other experiments, three groups of ten mice
were used, 0.2 mg. /20 gm. ergometrine and 0.2 mg. /20 gm.
erorietrin s.ne being injected intravenously each into a group
of ten mice, the other group being injected with saline as a
control.
The following results were obtained:- -68-
TABLE 9.
Dgeriment 5.10.37. Ergometrine ErUometrin_i_ne Controls
Time in Av. cr oC Av. ß-oC Av. v-oC minutes Temp. Temp. Temp. oC oC oc
0 34.0 1.05 33.7 0.95 33.75 0.70
30 33.2 0.88 34.2 0.37 34.2 0.59
60 33.85 0.68 34 . 3 0.51 34 .1 0.58
90 34.0 0.55 34.4 0.59 34.3 0.37
210 33.5 0.95 33.5 0.55 33.55 0.26 -69-
Trie standard error of the difference between ergometrine
and ergometrinine is 0.303, and between ergometrine and the
control mice 0.036. Both these differences are significant.
This result falls into line with the others, namely the
laevo- rotatory alkaloid of this pair is again the more active.
Ergometrine to be active in reducing the temperature in the
mouse requires a greater dosage than is the case with the
larger moleculed alkaloids.
ACTION OF ISOERGINE AND ERGINE ON THE RECTAL TEMPERATURE IN MICE.
Three groups each of ten mice were also used in this experiment. In the experiment shown in the following Table 0.75
mg. /20 gra. isoergine was injected intravenously into one group;
0.75 mg. /20 gm. was injected intravenously into the other group, while the control group were injected with an equivalent amount of saline. -70-
TABLE 10.
9.10.37.
Isoereine Ergine Controls
e" . C Time in Av __._0C cr ° Av. d' °C minutes Temp. Temp. Temp. °C
0 34.1 0.d4 34.05 0.5 0,.0 0.77
30 31.75 0.69 33.2 1.15 34.2 0.73
60 32.4 0.95 33.7 0.99 33.7 0.51
90 32.8 1.02 33.5 1.17 33.55 0.70
120 33.05 0.59 33.25 0.55 33.4 0.67. -71-
The standard error of differences of the means of ergine
and isoergine, ergine and control, isoergine and control
at thirty minutes are 0.424, 0.317 and 0.430 respectively.
The differences are significant in each case.
In this experiment while ergine showed itself to be less active than isoergine it will be noted that even here ergine was active in reducing the temperatures of the mice.
another experiment where 0.1 mg. per 20 gm. was injected
ergine was inactive while isoergine was active in reducing the temperature. It is interesting also to note that the
ergine seems to be more active than ergometrine.
ACTION OF ISOLYSERGIC AND LYSERGIC ACIDS ON THE RECTAL
TEMPERATURE IN NICE.
A. series of two groups of ten mice were injected
intravenously on the morning of 23.8.37, 0.2 mg. /20 gm. lysergic acid in the one grogp and an equivalent amount of
saline alone in the other and the following result was obtained. -72-
Table 11.
Lysergic acid Controls Time in Average C oC Average or °CC. minutes Temp. Temp. °C oC
0 33.2 0.92 32.9 0.69
20 33.8 0.64 33.6 0.48
40 33.7 0.`sí0 33.4 0.66
60 33.3 0.78 33 . 3 0.40
80 33.6 0.91 33.6 0.47
100 33.5 0.67 32.9 0.52. -73-
At this dosage level lysergic acid has no action on the mous. temperature. In the afternoon of the same day the action
of isolysergic acid in the same dosage as above was determined on the mouse temperature with a similar result.
Only nine mice were used for each group as one of the ten injected with isolysergic acid died. -74-
Table 12.
Isóse_rgic aced Controls
Time in Average 6- oc Average ®-oC m? nui,-3,s Temp. Temp. oc oc
0 33.0 0.49 33.0 0.45
20 33.0 0.46 33.6 0.64
40 33.4 0.51 33. 8 0.71
60 33.3 0.49 33.5 0.54 -75-
Isolyser ;ic acid in a dosage of 0.2 mg. /20 gm. intravenously had no action on the mouse temperature.
Figure 1 .is included to show the effect of larger doses ergosine and ergosinine on the temperature of mice. These actual results are the averages of the observations of nine
mice in each group. The higher dosage results in a
prolonging of the temperature reducing action of the drugs.
Similar results were noted with all the others examined ergotoxine, ergotamine, ergometrine, isoergine and ergine.
Our results with the lysergic acids, confined to one experiment cannot be correlated with these findings.
The following tables summarise all our results with the various alkaloids on mice. The results shown are all of them statistically significant. -75 a-
rigure 7a
xpt. 25.8.37.
The effect of the intravenous injection of 0.2 mg ergosine and
0.2 'mg ergosinine in 0.5 cc. per 20 gm. on the rectal temperature of mice.
(There were 9 mice in each group and the curves give the
average temperatures of the groups at the times stated.)
Ordinate. Rectal Temp. °d.
Abscissa. Time in hours.
---E = ergos ine _...,. _ . = ergos i.nine = control -76-
Tab1 13.
SUMMARY OF LEVELS AT WHICH DIFFERENCES IN EFFECTIVENESS OF THE
VARIOUS ISOMERID-ES W.ERE FOUND.
Date Drug Dose in No. of Effect mice on in temper - group ature
3..9.37 Ergotoxine 0.05 10
Ergotinine 0.05 10 0
2.9.37 Ergotamine 0.05 10
Ergotaminine 0.05 10 0
31.8.37 Ergosine 0.025 9
Ergosinine 0.025 9 0
5.10.37 Ergometrine 0.2 10
Ergometrin- ine 0.2 10 0
9.10.37 Isoergine 0.075 10
Ergine 0.075 10
23.8.37 Isolysergic
Acid 0.2 10 0
Lysergic
Acid 0.2 10 0
- = Full in Temperature
0 = No effect. -7? -
EFFECT OF THE ERGOT 1%T,KLOIBS ON THE TEMPERATURE OF THE RABBIT.
In contradistinction to their effects on the rectal temperature in mice, the ergot alkaloids all tend to raise
the rectal temperature in rabbits. The extent of this temperature rise subsequent to any given dose varied considerably. the large moleculed alkaloids we often found that those animals, which either survived or did not show any excessive rise in temperature when such might be expected, showed a very marked polypnoec. This suggests
that in such cases respiratory activity was sufficiently
stimulated to compensate in whole or in part, the rise in
temperature. This could serve at least as a partial explanation for our scattered results. It also served as
a warning that a very considerable number of experiments
would be required if accurate comparative activities of any
two alkaloids were to be determined. The temperatures -in these rabbits were recorded every two minutes by means of a
calibrated thermopile kept in the rectum throughout the whole experiment. The drugs were all given intravenously and no -78-
rabbit ever received a second injection of any of these drugs. By only using the rabbits once any effects due to cumulation or the development of tolerance etc. were avoided.
The following table (Table 14) summarises Our results with varying doses of ergotoxine ethane sulphonate injected
intravenously into the rabbit and the subsequent fi ?_sure
(Fig. 8) shows the actual course of the temperature changes when 1.6 mg. per kilo were given. The table shows up
clearly the great variation in the extent of the temperature change and even in the question of actual survival with any
given dose that may occur; a result that can also be seen with the other large moleculed alkaloids. -79-
TABLE 14.
ERGOTOXINE ETHANE SULPHONMTE ( INTRA:Vú'NOUS ) .
Deste Wt. of Sex Dose Effect on temperatura of rabbit MLLE- rabbit. k. 15.10.37 2.5 a 3.2 Rise: death
18.10.37 2.5 Z 3.2 Rise: survived
18.10.37 2.5 $ 3.2 Rise; death
4.1.38 2.5 ti 1.85 Rise
5.1.38 2.5 Zi 1.85 Delayed rise and death
6.1.38 2.3 6 1.85 Gradual rise.
6.1.38 3.7 1.85 Rise and early death
19.10.3? 2.75 3 1.6 Rise: death
19.10.37 2.7 2 1.6 Rise: death
20.10.37 2.7 $ 1.6 Rise: death
20.10.3? 2.2 $ 0.8 Gradual rise
22.10.37 2.3 0.8 Rapid rise: death
25.10.37 2.5 $ 0 4 Nil
26.10.37 2.8 1 0.4 Slight initial fail, them rise; death
27.10.87 2.8 a 0.4 Gradual rise: death
27.10.37 2.7 a 0.2 Gradual slight rise
29.10.3? 3.0 3 0.2 Mil
1.11.37 2.7 a 0.2 Nothing significant
2.11.37 2.8 $ 0.1 Initial fall, gradual recovery
3.11.37 2.5 a 0.1 Slight initial fall; recovery
4.11.37 2.8 a 0.1 Slight fall with later rise (probably insignificant).
5.11.37 ,S 0.1 Fall (no recovery when th experiment was abandoned. 2 hours after the injection). -79a-
Figure 8.
p C r.:::aiT....i i:: i =' _ : :. "_ . : : :...... :;
_:'__
. : . u. i7 :.H. :hilw::: .x=xN - .//xx.Nx f i :::i':it°::i:"'x'Yt::' I .. j H: 1t. ' . 1.r/.... .H .t ...VP=I.0 : : _ :..x ,:l:Ñ,::::i3a::yq i : :YNH: .r,/.. .%. s..::t:ÑN. ': s = :...... :..HNxH.: Na.x.. x ::1: =:. . ::=Ö.=' 3 as : : : ::: a;: _ .... , : ::: . . ?a .9 1 ; t. ... H :.... ,...... r. . : . tH . . e.a...Y1...:.ípi/::9s.0 '_u .:.:':: srá6-.:::_::::' . .- ,,.. x ...... x. . .. ;. UM':`:i...: sa.:.... :...W . ... . ii, ..N'i'iY::Ñ. .._itw...... x::: : .. .:-'.i/.i.t.:x= " ï s ...... : :si_':g.a':ii° '.1%'::s gr: G =¡i :_ ï . ::' : = H ..... :N ° ., Oggga:"': Á:::: ::.Ñ::::r:::::tl :.::..\.:: : :.N.. : ' :::": ::/:_::::::Ó:":::x.. xtl,. . On.... .r. .n_.. .i=.:a.:::;:.=aa..:. ss ..t :_ ...... :s:::: . . :e::s ::?:.....?. r,. i ::s:::.:sssE:.:: 4...... :r Jl r ( -- . `6 /yJ . \.l :./H a. r: : : .H .c-. . ìo a :. c ::íi. i::.xrN.:::: ...x x. : ': i.'i' i ' ...... /...:.: ..u.ru:: :: .. x... °ii..u:íi:..tí t:n ..:,iú: .I..,.rlII ar =r..x...:_ : :_.,li1.a....H:ñ=':t..m./...... :. :. .e=.:::' I.Hx..H....:=%,Ì:IaÌ, ::: .HxxN.N .nHN i,,,NNH nH. 1 :._ kid::ss::::: ; a rrJ. ....:..ss=s:a....?:.::é..N. ::=:=s::. .... alti9 : _..:..x.... '`:,: ::Aiá ::ll . . i . . . . terkmuligir : .....:i....:.a ...... 3i ---- -3- -:.-.-.-.-..:. -.-.-=-e -.-.-.-:-..-..-..-.. -:-.-.-.-.-.-s-. -:-..-..-. -.--.- I. : ss ':°::: : r 7x.tx:::::I _ '__:: ' :::i' w:::iúiilï
Fig. 8. The effect of the intravenous injection of
ergotoxine ethane sulphonate 1.6 mg. per kilo on the rectal
temperature in rabbits.
Ordinate: Rectal Temperature °C.
Abscissa: Time in hour:.,
+ animal died under experiment. -80-
The next table (Table 15) shows some of our results with
ergotamine tartrate intravenously in the rabbit. Here again.
considerable variation in response may be seen, a fact
also illustrated in Fig. 9 which shows the effects on the recta temperature of 2.5 mg. per kilo intravenously. -81-
Figure 9.
Fig. 9. The effect of the intravenous injection of2.5 mg. per kilo of ergotamine tartrate on the rectal temperature of the rabbit.
Ordinate. Rectal Temperature °C.
Abscissa. Time in hours.
Animal died under experiment. -82-
TABLE 15.
Date Ergotamine Tartrate (Intra- Effect on venous). temperature of Wt. of Sex Dose rabbit rabbit mg /kg
kam;. 4.1.38 2.7 " 1.85 Nil
5.1.3.8 2.5 a 1.85 Short initial rise followed by steady fall 6.1.36 2.0 3 1.85 Slight gradual fall
6.1.38 3.5 a 1.85 Delayed rise and later, death
10.1.38 3.4 2.5 Rapid rise and deat7
10.1,38 3.7 a 2.5 Rise and death
14.1.38 3,9 2.5 Rapid rise and death
14.1.38 3.6 2.5 Nil
18.1.38 3.4 a 2.5 Rise and death
18.1.38 3.8 ó 2.5 Delayed rise, deat overnight
*31.1.38 1.8 a 3.0 Fall, rise and death
*31.1.38 1.7 a 3.0 Delayed fall and slight recovery
22.12.37 2.7 3 2.96 Slight gradual fall
23.12.37 2.5 g 3.2 Slight initial rise probably insignificant
27.1.38 3.4 t 3.0 Little change
** Rabbits were in poor condition. -83-
The comparison of all the results obtained with ergotoxine
.ethane sulphonate and ergotamine tartrate injected
intravenously in the rabbit shows that a rise of temperature
is obtained more consistently with lower doses of ergotoxine
than with ergotamine, but that at any given dose level there
may be a considerable scatter of results. The following
table, Table 16, gives the results obtained when the two
alkaloids were compared one on each of a pair of rabbits
under similar conditions on the same day. -84-
TABLE 16.
ERGOTAMINE TARTRATE AND ERGOTOXINE ETHANE SULPHONATE IN'1:R.tiVENO(1 ) .
Date Drug Wt. of Sex Dose Effect on rabbit mg. /kg. temperature of in kg. rabbit.
4.1.38 Ergotoxine E.S. 2.5 1.85 Rise
Ergotamine Tart. 2.7 a 1.85 Nil
5.1.38 Ergotoxine E. S. 2.5 $ 1.85 Delayed rise and death
Ergotamine Tart. 2.5 1.85 Short initial rise followed by steady fal
6.1.38 Ergotoxine E.S. 2.3 1.85 Gradual rise
Ergotamine Tart. 2.0 1.85 Slight gradua fall
6.1.38 Ergotoxine E.S. 3.7 -t- 1.85 Rise and early death
Ergotamine Tart. 3.3 1.85 Delayed rise and later, death -85-
These results confirm the facts shown in the two earlier tables (Tables 14 and 15). it was noted that in some of the rabbits where one would have expected hyperthermia there was none, but that polypnoea might be extreaely intense
(respiratory activity probably compensated the pyretic
effect of the drug) .
The comparison of ergotamine tartrate and er"otaminine was
not carried out very thoroughly but the experiment of 27.1.38
when 8.6 mg./kg. only produced a slight fall is sufficient evidence that ergotaminine is much less active than ergotamine
in raising the temperature of the rabbit. Table 17 summarises our findings. -86-
TABLE 17.
ERGOTAMINE TARTRATE AND ERGOTANININE ( INTRkV.ENOUS) .
Date Drug Wt. of Sex Dose Effect on rabbit mg. /kg. temperature in kf2. of rabbit
22.12.37 Ergotamine Tart. 2.7 2.96 blight gradual fall
Ergotaminine 2.7 2.96 Delayed slight fall and recovery
23.12.37 Ergotamine Tart. 2.5 3.2 Slight initial rise, probably insignificant
Ergotaminine 2.9 2.76 Slight initia rise, probably insignificant
27.1.38 Ergotamiine Tart. 3.4 3.0 Little change
Ergotarninine e-1 8.6 Slight fall -87-
Ergosinine is much less active in affecting the rectal temperature in the rabbit. In two cases 3.2 and 3.46 mg. per kilo of ergosine caused a fatal pyrexia whereas 3.2 and 2.4 mg ergosinine per kilo lowered the temperature, and further as
can be seen in the following table lower doses of ergosine
than those mentioned can cause fatal pyrexia. When ergotoxine
ethane sulphonate and ergosine were compared one against the
other for their pyretic effects it was found that ergosine was not far behind ergotoxine ethane sulphonate in its ability
to raise the rectal temperature of the rabbit. The
following table, Table 18, summarises our results. -88-
TABLE 18.
ERGOTOXINE ETHANE SULPkIONATE AND ERGOSIN:E ( INTRAVENOUS) .
Date Drug wit. of Sex Dose Effect on rabbit rngm. /kg. temperature in kgs. of rabbit
11.2.38 Ergotoxine Ethane Sulphonate 1.8 1.0 Rise: death
Ergosine 2.2 a 1.0 Rthse: death
11.2.38 Ergotoxine Ethane Sulphonate 2.5 6 1.0 Rise: dcath
Ergosine 2.6 3 1.0 Rise: death
14.2.38 Ergotoxine Ethane Sulphonate 3.1 0.5 Rise: death
Ergosine 2.4 a 0.5 Rise: death.
15.2.38 Ergotoxine Ethane Sulphonate 2.1 a 0.5 Rise: death
Ergosine 2.1 a 0.5 Rise
16.2.38 Ergotoxine Ethane Sulphonate 1.7 0.5 Slight. rise
Ergosine 1.9 a 0 5 Change: not significant
17.2.38 Ergotoxine Ethane Sulphonate 3.2 h 0'5 Marked rise
Ergosine 3.3 a 0.5 No change
1 8.2.38 Ergotoxine Ethane Sulphonate 3.0 3 0.5 Rise: death
Ergosine 3.6 a 0.5 Rise: death
24.2.38 Ergotoxine Ethane Sulphonate 2.1 fi 0.5 Rise: death Ergosine 1.6 a 0.5 No change -90-
The temperature raising effect of ergometrine has already
been described (17) but fig.10 may be useful in showing that even here considerable variation in effect may occur with closely similar doses.
Ergometrinine is inactive on the temperature control in the
rabbit as may be seen in the following table, Table 19. When
ere,omet_rine and ergometrinine were compared 20 mg. per kilo of ergometrine had no effect on the rectal temperature of the rabbit. -90 e.-
Figure 10
Fig. 10. The effect of the intravenous injection
er ometrine of I 2.95, II, 2.85, III, 3.0 mg. per kilo
respectively ori the rectal temperature of the rabbit.
Ordinate. Rectal Temperature 0C.
Abscissa. Time in hours.
+ Animal died under experiment. TABLE 19.
Date Drug Wt. of bex Dose Effect on rabbit mg. /kg. temperature in kg. of rabbit
10.11.3? rgometrine 2.8 a 2.85 Very gradual rise
Ergometrin- ine Nit. 2.8 S 2.85 Nil
11.11.37 Ergometrine 3.0 S 2.95 Rapid rise: death
Ergometrin- ine Nit. 3.0 2.85 Nil
25.1.38 Ergometrine 2.5 3.0 Temperature All
Ergometrin- ine Nit. 2.3 Q 10,0 Nil -92--
The few results with isolysergic acid and lysergic acid suggest that the isolysergic acid is only just more active in increasing the rectal temperature of the rabbit than is lysergic acid but neither acid appears to be very
active in this respect. Table 20 summarises our results. -93-
TABLE 20
ISOLYS+HGIC AND LYSERGIC ACIDS (INTRAVENOUS) .
Date Drug At. of Sex Dose Effect on rabbit kg. temperature in kg. of rabbit
17.11.37 I solyser;i c Acid 2.3 3.45 Initial ris then gradua fall
Lysergic Acid 2.3 3.55 Nil
24.11.3? Isolysergic Acid 2.9 4 2.75 Nil
Lysergic Acid 2.9 a 2.75 Nil
24.1.38 Isolysergic p Acid 3.4 7 5.0 Slight rise
Lysergic Aicd 3.8 3 5.0 Very slight rise -94-
Isoergine hydrochloride appears to be more active than ere- ne
hydrochloride in increasing the rectal temperature in the rabbi
but the pyretic action may be preceded by an initial drop in
tefflperature. In addition isoergine appears to be more toxic
than ergine, and also than the lysergic and isolysergic acids.
The results are summarised in Table 21 and Figure 11 shows
the actual results obtained on the 19.11. 37 when 0.72 mg
per kilo isoergine hydrochloride and 0.74 mg. per kilo of
ergine hydrochloride were injected intravenously. -95-
TABLE 21.
ISOE GINE AND ERGINE HYDROCHLORIDE ( INTRAVENOi7S ) .
Date Drug, W.t. of Sex Doee Effect on rabbit mg. k temperature in kpe of rabbit
18.11.37 Isoergine
HC1 3.0 1.0 Initial f_al , rapid rise, fall: deat
Ergine HCl 3.0 1.0 Slight rise
19.11.37 Isoergine HCl 2.8 h 0.72 Initial fall, rapid rise, fall toward' normal death
Ergine HC1 2.7 rj 0.74 Slight rise
23.11.3? Isoergine BC' 2.8 * O46 Slight initial fall with gradual recovery
Ergine HC1 2.8 0.36 Nil -6-
:Figure 11.
Figure 11. The effect of the intravenous injection of I,
0.72 .mg. per kilo isoergine, and II, 0.74 mg. per kilo of ergine on the rectal temperature of the rabbit.
Ordinate. Rectal Temperature oC.
Abscissa. Time in hours.
+ Animal died under experiment.