The Journal of
`Laboratory and Clinical
`Medicine
`
`VoL. VII
`
`ST. LOUIS, FEBRUARY, 1922
`
`No. 5
`
`ORIGINAL ARTICLES
`
`THE INTERNAL SECRETION OF THE PANCREAS*
`
`BY F. G. BANTING, M.B., AND C.H. BEST, B.A.
`
`THE hypothesis underlying this series of experiments was first formulated
`by one of us in November, 1920, t while reading an article dealing with
`the relation of the isles of Langerhans to diabetes. 1 From the passage in
`this article, which gives a resume of degenerative changes in the acini of
`the pancreas following ligation of the ducts, the idea presented itself that
`since the acinous, but not the islet tissue, degenerates after this operation,
`advantage might be taken of this fact to prepare an active extract of islet
`tissue. The subsidiary hypothesis was that trypsinogen or its derivatives was
`antagonistic to the internal secretion of the gland. The failures of other in(cid:173)
`vestigators in this much-worked field were thus accounted for.
`The feasibility of the hypothesis having been recognized by Professor
`J. J. R. Macleod, work was begun, under his direction, in May, 1921, in the
`Physiological Laboratory of the University of Toronto.
`•
`In this paper no attempt is made to give a complete review of the litera(cid:173)
`ture. A short resume, however, of some of the outstanding articles which
`tend to attribute to the isles of Langerhans the control of carbohydrate
`metabolism, is submitted.
`In 1889 Mering and Minkowski 2 found that total pancreatectomy in dogs
`resulted in severe and fatal diabetes. Following this, many different ob(cid:173)
`servers experimented with animals of various species and found in all types
`examined, a glycosuria and fatal cachexia after this operation. The fact
`was thus established that the pancreas was responsible for this form of
`diabetes.
`In 1884, Arnozan and Vaillard 3 had ligated the pancreatic ducts
`in rabbits and found that within twenty-four hours the ducts become dilated;
`the epithelial cells begin to desquamate; and that there are protoplasmic
`changes in the acinous cells. On the seventh day there is a beginning of
`
`*From the Physiological Department, University of Toronto, Canada.
`tF.G.Il., then Assistant in Physiology at Western University, London, Ontario.
`251
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`MPI EXHIBIT 1018 PAGE 1
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`THE JOURNAL OF LABORATORY AND CLINICAL MEDICINE
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`round-celled infiltration. On the fourteenth day the parenchyma was mostly
`replaced by fibrous tissue. Sscobolew 4 in 1902 noted in addition to the above,
`that there was a gradual atrophy and sclerosis of the pancreas with no
`glucosuria. However, in the later stages, from thirty to one hundred and
`twenty days after ligation of the ducts, he found involvement of the islets and
`accompanying glucosuria.
`Lewaschew 5 believed that the islets were modified acinous cells. La(cid:173)
`guesse, 6 an anatomist, first suggested that the islets might be the organ of
`pancreatic internal secretion. He showed that there were comparatively more
`islets in the fetus and the newborn than in the adult animal. Opie 7 and
`Sscobolew 8 independently furnished the first clinical foundation for the belief
`that the islets were involved in pancreatic diabetes.
`W. G. MacCallum, 9 in 1909, ligated the ducts draining the tail third of
`the pancreas. After seven months he excised the remaining two -thirds. This
`was followed by a mild glucosuria. Three weeks later he removed the de(cid:173)
`generated tail third. This second operation resulted in an extreme and fatal
`glucosuria. Kirkbridge, 10 in 1912, repeated and corroborated MacCallum's
`findings and, by the use of Lane 's 11 method of staining, proved that the
`atrophic tissue contained healthy islets.
`Kamimura 12 in 1917, working on rabbits, traced the degenerative changes
`in the parenchymatous tissue of the pancreas after ligation of the ducts, and
`found that the islets remained normal and that the animal did not develop
`glucosuria as long as the islets were left intact.
`The first attempt to utilize the pancreas in defects of carbohydrate metab(cid:173)
`olism was made by Minkowski. 13 This worker tried the effect of pancreatic
`feeding, with no beneficial results. Up to the present time only useless or
`even harmful effects have been obtained from repeated attempts to use
`this method.
`Knowlton and Starling, 14 in 1912, published experiments which show~d
`a marked decrease in the power of using sugar of a diabetic heart perfused
`outside the body, as compared with a normal heart under similar conditions.
`Macleod and Pearce, 15 using eviscerated animals were unable to confirm the
`above results. Patterson and Starling10 subsequently pointed out that a
`serious error was involved in the early experiments due to (1) excess glycogen
`present in diabetic hearts, and (2) to the irregular disappearance of glucose
`from the lungs.
`Murlin17 prepa~ed an alkaline extract of pancreatic tissue and after in(cid:173)
`jection of this solution, secured a reduction in sugar excreted in a diabetic
`animal. Kleiner 18 has pointed out that the reduction secured by Murlin might
`be due to the alkali per se. Kleiner himself has shown that "unfiltered-water
`extracts of fresh pancreas diluted with .90 per cent NaCl when administered
`slowly usually resulted in a marked decrease in blood sugar.'' There was
`no compensating increase in urine sugar, but rather a decrease, which Kleiner
`suggests may be partly due to a temporary toxic renal effect. Hemoglobin
`estimations made during the experiment showed that the reduction in blood
`sugar was not a dilution phenomenon. Paulesco 19 has recently demonstrated
`
`MPI EXHIBIT 1018 PAGE 2
`
`MPI EXHIBIT 1018 PAGE 2
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1018-0002
`
`

`

`INTERN AL SECRETIONS OF THE PANCREAS
`
`253
`
`the reducing effect of whole gland extract upon the amounts of sugar, urea
`and acetone bodies in the blood and urine of diabetic animals. He states
`that injections into peripheral veins produce no effect and his experiments
`show that second injections do not produce such marked effect as the first.
`From the work of the above-mentioned observers we may conclude: (1)
`that the secretion produced by the acinous cells of the pancreas are in no way
`connected with carbohydrate utilization; (2) that all injections of whole-gland
`extract have been futile as a therapeutic measure in defects of carbohydrate
`utilization; (3) that the islands of Langerhans are essential in the control
`of carbohydrate metabolism. According to Macleod there are two possible
`mechanisms by which the islets might accomplish this control:
`(1) the blood
`might be modified while passing through the islet tissue, i.e., the islands might
`be detoxicating stations and (2) the islets might produce an internal secretion.
`We submit the following experiments which we believe give convincing
`evidence that it is this latter mechanism which is in operation.
`In the t~n-week interval which we considered necessary for complete
`degeneration of the acinous tissue, we secured records of dogs depancreatized
`by the Hedon method. 20
`
`METHODS
`The first chart is a record of an animal depancreatized by the Hedon
`method. The details of this operation are given in Hedon 's article. 20 The
`remaining records are of animals (females) completely depancreatized at the
`initial operation. The procedure is as follows: under general anesthesia an
`upper right rectus incision is made through the abdominal wall. The duode(cid:173)
`num is delivered through the abdominal wound, and the pancreas traced to
`the tail portion. The mesentery beyond is cut between clamp and ligature.
`Vessels from spleen are then isolated, ligated and divided. Little dissection
`is then required until the duodenum is reached. The superior pancreatico(cid:173)
`duodenal vessels are located and great care is exercised to avoid damaging
`them. The pancreas is stripped from the duodenum by dry dissection. The
`vessels to the uncinate process are ligated and divided, and the process freed
`from its mesenteric attachments. The larger duct of the pancreas is then
`ligated close to its entry into the duodenum and the pancreas is removed.
`Special care must be exercised to preserve the splenic vessels. The superior
`pancreatico-duodenal vessels must be left intact. Failing this, duodenal ulcer
`is a frequent development. If this procedure is carried out the whole gland
`with the exception of the portion in contact with the duodenum is covered
`with mesentery. The abdominal wound is closed layer by layer with catgut.
`A collodion dressing is used. The urethral orifice is exposed by a midline
`incision of the perineum and the edges of the wound drawn together to
`facilitate healing.
`We have found that animals between eight and sixteen months old are
`the most suitable for this operation. At this age the pancreas is not so firmly
`fixed as it becomes later.
`vVe first ligated, under general anesthesia, the pancreatic ducts in a
`
`----
`
`MPI EXHIBIT 1018 PAGE 3
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`MPI EXHIBIT 1018 PAGE 3
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1018-0003
`
`

`

`254
`
`THE JOURNAL OF LABORATORY AND CLINICAL MEDICINE
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`(Blood sugar estimations on these animals were recorded
`number of dogs.
`from time to time. We have no record of a hyperglycemia).
`The extract was prepared as follows: The dog was given a lethal dose of
`chloroform. The degenerated pancreas was swiftly removed and sliced into
`a chilled mortar containing Ringer's solution. The mortar was placed in
`freezing mixture and the contents partially frozen. The half frozen gland
`was then completely macerated. The solution was filtered through paper
`and the filtrate, having been raised to body temperature, was injected intra(cid:173)
`venously.
`We have never found it necessary to cut down on a vein under general
`or local anesthetic. The skin surface above the vein is shaved and the needle
`inserted into the vein which is dilated by compression. The dogs make very
`little resistance to this procedure and after the first few punctures lie quietly
`during the operation. Sugar injections (100 c.c. of fluid) as well as the
`numerous administrations of extract were conducted by this method.
`We performed several experiments with the object of exhausting the
`zymogen granules of the pancreas. Prolonged secretin injections and vagus
`stimulation below the diaphragm were practiced. Fortune favored us in the
`first experiment. In subsequent attempts we were never able to exhaust the
`gland sufficiently to obtain an extract free from the disturbing effects of some
`constituent of pancreatic juice.
`The blood sugar estimations were made by the Myers-Bailey 21 modifica(cid:173)
`tion of the Lewis-Benedict method. The results of this method were corrob(cid:173)
`orated by the Schaffer-Hartman22 method at high and low percentages of blood
`sugar. The former method gave results which :were consistently slightly
`higher (.01 per cent) than those obtained by the Schaffer-Hartman method.
`We find the average normal blood sugar, from observations on thirty normal
`dogs, to be .090 per cent.
`Hemoglobin estimations were m_ade by the carbon-monoxide saturation_
`method, using the du Boscq colorimeter.
`
`RESULTS
`Chart 1 contains the record of a 6.5 kilogram dog ( 410). This experiment
`is not conclusive but is interesting to us at least, since we administered the
`first dose of extract of degenerated pancreas to this animal. On July 11, the
`pancreas, with the exception of the processus uncinatus, was removed. The
`processus was allowed to remain until July 18. In the interval between the
`operations there was no hyperglycemia or glucosuria. The curves on subse(cid:173)
`quent days show the effect produced by the removal of the pedicle. It will
`be noted that as the experiment ·progresses the percentage of blood sugar
`did not rise to the level usually attained in completely depancreatized animals,
`and also that there was a marked decrease in the daily amounts of nitrogen
`and sugar excreted and the volume of urine voided. The animal continued to
`lose weight and seemed to be entering the cachexial condition characteristic
`of depancreatized animals which had become infected.
`The chart for July 27 shows the effect produced on the percentage of
`
`MPI EXHIBIT 1018 PAGE 4
`
`MPI EXHIBIT 1018 PAGE 4
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1018-0004
`
`

`

`INTERNAL SECRETIONS OF THE PANCREAS
`
`255
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`blood sugar and on the sugar excretion by the oral administration of twenty(cid:173)
`five grams of dextrose in two hundred and fifty c.c. of water.
`At 10 A,M, July 30, the percentage of blood sugar was 0.20. Four c.c. of
`extract of degenerated pancreas were injected intravenously. At 11 A.M. the
`blood sugar had fallen to 0.12 per cent. The injections of extract are shown
`
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`
`MPI EXHIBIT 1018 PAGE 5
`
`MPI EXHIBIT 1018 PAGE 5
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1018-0005
`
`

`

`256
`
`THE JOURNAL OF LABORATORY AND CLINICAL MEDICINE
`
`in the chart. At 12 A.M. twenty grams of sugar in two hundred c.c. of water
`were given by stomach tube. The chart records the effect.
`The obvious criticism of this experiment is that the animal was moribnml
`when the effect of the extract was tried. The interesting features, which
`gave us great encouragement are (1) the extract caused a sudden fall in the
`blood sugar and (2) that in the presence of the extract the animal excreted
`.21 grams of a 20 gm. injection in a period of five hours following the injec(cid:173)
`tion, in contrast to an excretion of 15.88 grams of a 25 gm. injection in the
`same interval, when no extract was administered.
`Chart 2 is the record of dog 92, ,veight 11.9 kg. A complete pancreatec(cid:173)
`tomy was performed on this animal at three P.M. August 11. The first injec(cid:173)
`tion of extract was given six hours after the operation and subsequently an
`injection every four hours. This extract was freshly prepared from a ten Kg.
`dog whose pancreatic ducts had been ligated for ten weeks. One hundred
`and twenty-five c.c. of extract were prepared from the gland residue but this
`supply was exhausted by two P.M., August 13, after which other extracts
`were used. Blood samples were always taken before the injections of extract.
`On August 12, the blood sugar curve shows that neither five nor eight c.c. of this
`extract every four hours were sufficient to counterbalance the upward trend of the per(cid:173)
`centage of sugar of the blood. At 10 P. M. the dose was increased to twelve c.c. and a
`marked fall is noted. The chart at 10 A. M. August 14 records the ;reduction of the
`percentage of sugar in the blood below its. normal level, as a result of extract from
`(The exceptionally higher values for the volume of urine
`another degenerated gland.
`and the urinary nitrogen for August 15 and l(j may be due to the adulteration of the
`urine with vomit.) On August 15 at 10 A. M. the chart shows the effect produced by ten
`c.c. of the same gland extract made 0.1 per cent acid with HO!. This extract made
`0.1 per cent alkaline with NaOH causes a slight reduction (August 15, 8 P. M.) The
`effect may be du,e to the alkali.
`The extract administered at 10 A. M. August 16 was neutral and made from
`same degenerated gland.
`On August 16 and 17 effects of extracts from normal glands were tested. A nor(cid:173)
`mal pancreas from a ten kg. animal was divided into three equal parts. One third
`the second pmtion with 0.1 per cerit HCl and the
`was extracted with neutral saline,
`third with 0.1 per cent N aOH. On August 17 at four P. M. the neutral whole gland
`extract was administered. A marked fall in blood sugar resulted. The acid and alka(cid:173)
`line extracts were injected at 12 P. M. August 17, and 7 A. M. August 18. The last
`"\Ve
`their effects.
`two injections were perhaps not given a fair opportunity to develop
`do not take colorimeter readings by artificial light and therefore did not have an accu(cid:173)
`rate knowledge of the height of blood sugar at these times.
`The conclusion from this experiment is that freshly prepared neutral or acid ex(cid:173)
`tracts of the whole pancreas do have a reducing effect on blood sugar, thus confirming
`injections of whole gland extrads
`that repeated
`It may be stated here
`Kleiner.
`cause marked thrombosis of the veins where the injections are made and a noticeable
`It is obvious from the chart that the whole gland
`interference with kidney function.
`extract is much weaker than that from the degenerated gland.
`On August 20, we attempted to exhaust the pancreas of a nineteen kg. dog by con(cid:173)
`tinued injections of secretin and repeated stimulation of the vagus nerve below the
`juice and considered the gland
`diaphragm. We obtained eighty-five c.c. of pancreatic
`It was swiftly removed and immediately chilled. The marked effect of
`exhausted.
`injection of this material is shown on the chart at 7 P. M. August 20. On August 21
`we incubated ten c.c. of the extract and five c.c. of pancreatic juice for two hours at
`
`the
`
`MPI EXHIBIT 1018 PAGE 6
`
`MPI EXHIBIT 1018 PAGE 6
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1018-0006
`
`

`

`INTERNAL SECRETIONS OF THE PANCREAS
`
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`Chart 2.-(1) Degenerated pancreas, dog 394.
`(2) Degenerated pancreas, dog 390.
`(3) Degen(cid:173)
`erated pancreas, + .!% HCI.
`(4) Degenerated pancreas + 0.10% NaOH.
`(5) Degenerated pancreas,
`+ .!% HCI.
`(6) Whole gland extract, fresh, cold.
`(I) W,hole gland extract, + .!% HCI.
`(8) Whole
`gland extract+ ,!% NaOH.
`(9) Exhausted gland extract.
`(IO) 10 c.c. exhausted gland extract + 5 c.c.
`pancreatic juice incubated 2 hours.
`(11) 10 c.c. exhausted gland extract (-pancreatic juice) incubated
`2 hours.
`(12) Whole gland, cat. Dog died August 30.
`
`body temperature in alkaline solution. This solution was injected at 6 P. M. August
`21. The curve shows the very slight effect produced. As a control on the above, ten
`c.c. of extract and five c.c. of saline were incubated under similar conditions for two
`hours. The chart at 10 P. M. August 21 records the marked effect of the injection of
`this second solution. On August 22 at 6 P. M, eight c.c. of extract from the normal
`
`MPI EXHIBIT 1018 PAGE 7
`
`MPI EXHIBIT 1018 PAGE 7
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1018-0007
`
`

`

`258
`
`THE JOURNAL OF LABORATORY AND CLINICAL MEDICINE
`
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`pancreas of a cat were injected, We obtained a marked anaphylactic-like reaction.
`The curve shows the effect upon the blood sugar.
`No further injections were given to this animal after August 22. The dog died on
`August 30, nineteen days after the operation. The autopsy showed consolidation and
`necrosis of a large area in lower lobe of right lung, infection in right pleural sac. The
`operation wound was well healed. There was no sign of pancreatic tissue. The ab(cid:173)
`domen was not infected.
`
`MPI EXHIBIT 1018 PAGE 8
`
`MPI EXHIBIT 1018 PAGE 8
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1018-0008
`
`

`

`INTERNAL SECRETIONS OF THE PANCREAS
`
`259
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`Chart 3 is the record of dog 408. The weight of this animal was 9 kg.
`The details of the experiment will be given rather fully.
`The no1·mal blood sugar of dog 408 was .090 per eent. Eighteen hours after pan(cid:173)
`createctomy the percentage of sugar in the blood was .27. Twenty-two hours after
`
`MPI EXHIBIT 1018 PAGE 9
`
`MPI EXHIBIT 1018 PAGE 9
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1018-0009
`
`

`

`260
`
`THE JOURNAL OF LABORATORY AND CLINICAL MEDICINE
`
`the operation, 1 P, M. August 4, the blood sugar was .26 per cent. During the twenty(cid:173)
`two hours 3.10 grams of sugar were excreted. The volume of urine was 494 c.c. At
`one P. M, we administered five c.c. of extract of degenerated pancreas which had been
`prepared four days previously and kept in cold storage. At two P. M. the blood sugar
`.16 per cent. At three P. M. the percentage of sugar in the blood had fallen to
`was
`.J 5. From one to three P. M, .19 grams of sugar were excreted in a volume of twenty-
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`(3)
`(2) Exhausted gland extract neutralized.
`Chart 4.-(1) Exhausted gland extract 1 % HCI.
`(4) 20 c.c. exhausted gland extract and alkali + 10 c.c.
`Exhau~ted gland extract neutralized per rectum.
`(5) 20 c.c. exhausted gland extract incu(cid:173)
`pancreatic juice incubated 3 hours at 37°C. then neutralized.
`(6) Exhausted gland of cat, 0.2% HCl.
`bated 3 hours at 37° C., 0.1 % HCI.
`
`MPI EXHIBIT 1018 PAGE 10
`
`MPI EXHIBIT 1018 PAGE 10
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1018-0010
`
`

`

`INTERNAL SECl'tETI®NS (!)F THE l"ANQIREAS
`
`six c.c. of urine. Three and forty-three hundredths grams of urinary nitrogen were
`excreted in the twenty-four hours following the operation. The G. to N. ratio for this
`period was 1.4: 1. From 3 P. M.
`to 7 P. M.
`the percentage of sugar in the blood
`shows a gradual rise from .15 to .25 per cent. This latter level was maintained until
`9 P. AI. The chart shows a slight rise in sugar excretion following the rise of blood
`sugar. At 9 P. M. five c.c. of extract which had been exposed to room temperature
`for one hour was injected intravenously. The blood sugar was reduced to a value of
`.18 per cent. The chart shows a gradual ascent from this value to .27 per cent. At
`10 P. M. the percentage of sugar in the blood was .27. At this hour five c.c. of extract
`of liver, prepared in precisely the same manner as the pancreatic extract, were ad(cid:173)
`ministered intravenously. One hour later the blood sugar was .30 per cent. This level
`was maintained during the following three hours. It was unaffected by an injection of
`5 c.c. of extract of spleen. The chart shows the rise in volume of urine and amount
`of sugar excreted. At 2 P. M. (b. s .. 3 per cent), five c.c. of an extract of degenerated
`pancreas were injected. A sharp fall in the blood sugar resulted. At 3 P. M. and
`again at 4 P. M. a similar dose of extract was given. The chart records the lasting
`effect. The 2 P. M. level of .30 per cent was regained twelve hours after the first in(cid:173)
`jection, The hourly excretion of sugar ran approximately parallel with the percentage
`of sugar in the blood. Between 1 P, M. and 2 P, AI.
`.52 grams were excreted. Less
`than .02 grams we're excreted between 7 P. M, and 8 P, M, The highest glucose to nitro(cid:173)
`gen ratio observed in this experiment wa.s a 3:1 value for the 22-hour interval between
`2 P. AI. the 6th of August and noon the following day. At 12 noon August 6 the per(cid:173)
`centage sugar in the blood was .40 per cent.
`:B'ive c.c. of boiled extract of degenerated
`pancreas was injected intravenously at this stage and caused no reduction of blood
`sugar. At twelve midnight August 6 five c.c. of extract of degenerated pancreas which
`had been prepared 48 hrs. previously were administered. The blood sugar fell from
`.43 per cent at 12 P. M. to .37 per cent at 1 A. M. Five c.c. doses were given at 1, 2
`and 3 A. M, and a
`twenty-five c.c. dose at 4 A. M. The chart shows the reduction in
`blood sugar to a normal level and the beginning of an upward trend five hours after
`the last injection of extract. The animal died at 12 A. M. August 7.
`A brief description of the clinical condition of the animal at various stages of
`the experiment is necessary for
`the correct interpretation of the above results. The
`animal made a good postoperative recovery and was able to retain water and meat
`after the second day following the operation. On the morning of August 5 we noticed
`that the condition of the animal was much worne.
`It appeared excessively tired, did
`not eat, and vomited after drinking water and also after extract of spleen given intra(cid:173)
`venously. At 5 P. M. August 5
`the animal appeared considerably improved.
`It re(cid:173)
`tained water and ate meat. On August 6 at 10 P. M. the abdominal wound was moist
`with exudate, and the animal was not so active as on the preceding day. No marked
`variation from this condition "·as observed until 4 A. M. when 25 c.c. of extract were
`administered. After this injection the animal had a marked reaction and appeared
`to be dying. 1t was revived slightly by intravenous and intraperitoneal injections of
`warm saline. Considerable improvement was noted at 7 A. M., dog was able to stand.
`The improvement was short-lived. The dog died at 12 A. M, August 7.
`The post(cid:173)
`mo;rtem showed a widespread abdominal infection. There was no sign of pancreatic
`tissue.
`The entire degenerated pancreas from one 8 kg. dog and approximately one-hall'
`the degenerated gland from a G kg. dog was the substrate of the extract used in this
`experiment.
`
`Chart 4, Dog 9, gives additional evidence on several important points
`which have been referred to previously. At 6 P.M., September 8, we adminis(cid:173)
`tered ten c.c. of extract of degenerated pancreas per rectum. There was no
`reduction in blood sugar at 7 P.M. when we gave 12 c.c. of extract of ex(cid:173)
`hausted gland intravenously. The chart records the effect of this and sub-
`
`MPI EXHIBIT 1018 PAGE 11
`
`MPI EXHIBIT 1018 PAGE 11
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1018-0011
`
`

`

`262
`
`THE JOURNAL OF LABORATORY AND CLINICAL MEDICINE
`
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