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The Use of “Depropanex”—Deproteinated Pancreatic Tissue Extract—for the Relief of Renal and Ureteral Pain: Effect in the Passage of Renal and Ureteral Stones
THE USE OF "DEPROPANEX"-DEPROTEINATED PANCREATIC TISSUE EXTRACT-FOR THE RELIEF OF RENAL AND URETERAL PAIN: EFFECT IN THE PASSAGE OF RENAL AND URETERAL STONES THOMAS J. KIRWIN, OSWALD S. LOWSLEY
AND
JOSEPH H. MENNING
The management of urinary calculus is one of the oldest-if not the oldestproblem confronting the medical profession. "Cutting for stone" was the first major surgical intervention ever undertaken, and from the days of Hippocrates to our own times, physicians have sought for better and more expeditious methods of ridding the human urinary tract of those self-manufactured "foreign" bodies. The fact that the search is still in progress is the most eloquent testimony to the dissatisfaction generally felt with all the methods heretofore employed. Yet since the days of "cutting for stone" we have made not a little progress. Today it is only for an exceptionally large calculus, or one embedded in the ureteral wall that we are forced to resort to the knife. If a stone is not too firmly lodged in the ureter it can usually be "coaxed out" with instruments and judicious lubrication. The urologist who frequently resorts to open operation is probably too impatient or too lazy to use conservative methods of inducing passage by the natural route. Within the past decade much attention has been given to means of relaxing the ureteral musculature, either by local application, or intravenous or other introduction of drugs which have been demonstrated to be effective for this purpose. Atropine sulphate has been frequently employed, but there are many well founded objections to this drug, and an earnest search has been conducted to find something better. The real problem is to get rid of ureteral spasm. The calculus keeps the duct continually irritated, and any attempt to dislodge it is certain to bring about violent contraction of the musculature of the wall of the ureter, clamping it all the more firmly upon the impacted stone. In 1936 and again in 1940, Lazarus of the Urologic Service of Mount Sinai Hospital (New York), reported on the use of an insulin-free pancreatic extract as an aid in cystoscopic treatment of impacted ureteral calculi and spastic occlusion of the ureter. Similar investigations were made by Getzoff and his coworkers at the Louisiana State University School of Medicine in the early months of the year 1941. The subject was also studied by Carroll and Zingale of St. Louis University's School of Medicine, who published their results in March 1938. These reports stimulated the interest of urologists all over the country, for they appeared to offer a means not only of relaxing the ureteral muscles so that obstructions could be spontaneously evacuated, or easily removed through the cystoscope, but also of relieving the pain of ureteral colic and other conditions in the kidney and its duct which cause so much suffering among urological patients. The use of pancreatic tissue extract for the relief of pain through dilatation of 132
"DEPROPANEX" FOR RENAL AND URETERAL PAIN
133
the muscular tissue is not new, although its employment in urologic practice is of such recent date. For some years before Lazarus made his recommendation it had been regarded as a most useful vasodilator. By 1931 enough data on the subject had been accumulated to permit Giroux and Kisthinios to compile a book which they called Les extraits pancreatiques desinsulines en therapeutique. This volume contains nothing about the urologic uses of insulin-free pancreatic tissue extract, but to anyone who has struggled to overcome ureteral spasm, or sought for a means of relieving the sufferings of the patients under his care hecause of urinary tract disabilities, the information it contains will be highly suggestive. It was in 1929 that Frey and Kraut isolated from urine a substance possessing properties of vasodilatation. This so-called "Frey hormone" was believed to be of pancreatic origin, but when excreted remained inactive in the blood, and only exerted its influence when it had passed into the urine. The extract madefrom urine had properties seemingly identical with those of known pancreatic extract. About this same time, but independently, Gley and Kisthinios demonstrated that an extract of pancreatic tissue from which all insulin had been eliminated exercised the same vasodilating properties. The discovery came about as a by-product of the studies of Kisthinios, who had taken as a subject for his inaugural dissertation, the effect of insulin upon the parasympathetic system. Certain investigators had noted that insulin sometimes caused a marked fall in arterial pressure and that it occasionally offset the hypertensive action of adrenalin. It was the opinion of Kisthinios that the variations in these effects upon the vascular system were the results of differences in the purity of the commercial brands of insulin. In trying to obtain pure insulin he isolated the vasodilating principle, finding that "that which we call 'insulin' is in reality a pancreatic extract which includes a hypoglycemic substance. In addition it contains also substances other than insulin, which the methods of isolation heretofore employed have failed to produce." Thus he found that the vasodilating action of the pancreatic extract persisted when all insulin had been removed from it. Experiments made upon animals deprived of a pancreas showed the output of the "Frey hormone" to be reduced to one-fifth of the amount excreted before the pancreas was taken out. Other animal experiments demonstrated that when an otherwise lethal dose of adrenalin had been injected, prompt injection of suitable quantities of the pancreatic extract would neutralize the hypertensive effect of the adrenalin, and permit the rapid return to normal of the animal's arterial pressure. On the basis of these experiments, Giroux and Kisthinios used the extract in the treatment of angina pectoris, arterial hypertension and arteritis. They also employed it in certain cases of Raynaud's disease, and in one case of obstruction of the central retinal artery. Clinical reports are given in great detail, and the general conclusion reached was that though by no means a cure-all, insulin-free pancreatic tissue extract offered great promise as a vasodilator, and as an agent for the relief of pain due to vascular constriction. In the same year that this publication appeared, Wolffe and his co-workers in this country showed that some tissue extracts cause vasodilatation and counteract the physiological effects of epinephrine.
134
T. J. KIRWIN, O. S. LOWSLEY AND J. H. MENNING BLOOD SUPPLY OF THE URETER
In a recently published study of the ureteral blood supply, W. F. Harper of London found that all its sources of blood supply anastomose freely in a dense adventitial plexus from which the musculature and lamina ptopria of the duct are supplied. There was no difference in the two sexes, except that the vaginal arteries in the female do. not correspond exactly to the inferior vesical branches in the male, although they may be said in general, to be mutually representative. Though the relative position of the vagina and lower third of the ureter have been found by other observers to vary considerably in perfectly normal women, Harper declares that this variation has no effect upon the extent of the ureter's blood supply from the vaginal arteries. Especially noteworthy is the constant presence (in all specimens examined) of ureteric branches from the aorta which arise from the antero-lateral surfaces of this main artery, most commonly about midway between its bifurcation and the origin of the inferior mesenteric artery. These arteries contribute to the formation of an anastomosis upon the ureter with the testicular arteries in the male, or ovarian in the female, coming down from above as well as with twigs from the common iliac and superior vesical arteries from below. Harper found that these arteries play a part comparable to that enacted by the ureteric branches of the accessory renals, and that like the accessory arteries of the kidney, they are to be regarded as persistent portions of the lateral splanchnic arterial system. In both sexes, the lower segment of the ureter lies in an extraperitoneal area richly vascularized by the inferior vesical and middle rectal arteries. While the origins of these arteries vary insofar as their ureteric connections are concerned, they are, nonetheless, relatively constant in position and a high origin. The ureteric connections form a dense and complex outer plexus in the adventitial connective tissue coat of the ureter. The larger branches, Harper found, exhibited a tendency toward a generally upward direction, so that it was easier to demonstrate anastomoses by the injection of individual arteries from 'below upwards' rather than from 'above downwards'. From the plexus in the adventitial connective tissue coat the muscles in the ureteral walls get their blood supply directly and from it also, pass out those vessels which ramify on the outer aspect of the deepest epithelial layer. Contrary to the usual conception, however, there was found no special arterial plexus in the ureteric "sheath of Waldeyer" about the duct's lower end. SPASM OF THE URETER
In devising his hydrophoragraph, an instrument for measuring and recording ureteral function, Trattner observed that either the longitudinal or circular muscles may be involved, separately or simultaneously, in spasm. The whole length of the duct, or only its upper, middle or lower third, may be involved in spasm. If the longitudinal muscle alone is spastic, the flow of urine is diminished or retarded. In spasms of the circular coat, a single and very small segment, or many segments in different sections of the entire extent of the ureter
"DEPROPANEX" FOR RENAL AND URETERAL PAIN
135
may take part in the spastic contractions. He concluded, on the basis of these findings, that inhibition of secretion in the kidney might be due to muscular spasm in the pelvis or ureter, "without taking nerve influences into consideration as a primary causative factor." These observations of Trattner were published in July 1932. Just 10 years later, Gree:r;i. and Essex of the Mayo Foundation made use of his instrument and method to investigate the effects of the intravenous administration of certain drugs upon the activity of ureteral peristalsis. A number of different drugs were employed, but with several the results were too inconclusive to be of value. By using different methods they did demonstrate that epinephrine and mecholyl, when intravenously injected, produce an increase in ureteral tone and in the rate of ureteral contractions, the amplitude of which may be increased or decreased. These two drugs are supposed to stimulate the action of the sympathetic and parasympathetic nerves, and this investigation indicated that they actually bring about a similar response in the ureter. The possibility of influencing the ureteral muscles, both in the production of spasm and its relaxation when induced by other means, thus receives confirmation. In order to comprehend how tissue extracts may be useful in the management of urinary calculi, or reduce the pain of renal or ureteral spasm, a brief consideration of the innervation of the upper urinary tract will be necessary. Something more than a decade ago one of the present authors (T. J. K.) made an extended study of ureteral implantation, employing upwards of eighty dogs as experimental subjects. His own observations on the physiology of the ureter were compared with the reports of preceding investigators along these same lines and from those who had made a special study of the innervation of this duct he obtained much enlightening information. For example, along the entire course of the ureter, from the ureteropelvic junction to its meatus upon the vesical trigone, Satani found nerve fibers and ganglion cells. Very few of these fibers, however, are in the muscle layer. Most of the nerve tissue is in the outer fibrous coat, the mucosa and submucosa. Between the outer fibrous coat and the muscle layer, there is a well developed network of large nerves, the fibers lying parallel to the axis of the duct. Large ganglia could be made out only in the lowest section. Few, or in some instances, only one cell, were to be found in the middle, and these cells were of the smallest size. The main network, which supplies the ureter's innervation, lies between the submucosa and the layer of muscular tissue. We have seen that in the muscle itself nerve elements are very scanty. Most of the fibers seem to run obliquely, as if they penetrated the muscle layer to make connection between the two plexuses in the fibrous outer coat and the inner layer of mucous membrane. Nevertheless, Satani finished his description by stating that the entire duct is enfolded in two continuous networks of nerve fibers, including ganglia both inside and out. These conduct nerve impulses to the muscle tissue. In the quarter century which has elapsed since Satani made his investigations, his work has been considerably supplemented but in no way discredited. Whar-
136
T. J. KIRWIN, 0. S. LOWSLEY AND J. H. MENNING
ton in 1932 proved that the ureter receives a nerve supply which is independent of the innervation of the kidney and bladder. He found that these nerves go directly to the ureter from (1) the lowest renal ganglion at the upper end of the spermatic plexus; (2) the abdominal sympathetic (the aortic, hypogastric and pelvic plexuses). His work also confirmed observations previously made by Latarjet and others as to the constitution of the solar (coeliac) plexus, from which the renal and abdomin[l,l sympathetic plexuses are derived. Wharton did not, however, claim to have proved that the ureteral nerves convey sensations of pain. But because 6 out of 7 patients were relieved of pain when the nerves were cut, he feels there is a strong probability that they contain afferent or sensory fibers. The operative experience of the present writers likewise offers confirmation of this theory. The idea that pancreatic extract might be useful in relaxing ureteral spasm and other conditions related to urinary calculus was suggested by a consideration of Wharton's findings. It was considered possible that one of the important contributory causes of ureteral calculus impaction was a spasm of the ureteral musculature in that portion of the wall of the ureter surrounding the calculus. This spasm might be due to over-stimulation of both the intrinsic and extrinsic sympathetic nerve-fibers supplying the segment of the ureter harboring the stone, because of the irritation set up by its presence. It was further reasoned that sudden attacks of renal colic in cases of stricture of the ureter were usually caused by spasm secondarily induced by such irritation. Lazarus administered pancreatic extract intramuscularly in doses of 1.5 to 2 cc. and found that "so startling were the results obtained that its continuation was more than warranted". Further trial was made soon after by Carroll and Zingale who reported in 1938. They found that the injection of pancreatic tissue extract "exhibited superiority" in the following ways: (1) It definitely relaxes the ureter. (2) Relaxation occurs within 3 minutes following injection. (3) The effect is, in most instances, clinically permanent, although experimentally normal contractions return. (4) The action is local with no untoward general effects. Although the action is apparently on the smooth muscle, there is no blurring of vision, nor dryness of the throat, like that experienced after atropine. In contrast to morphine, the cerebral centers are not affected. These authors used pancreatic extract in renal colic due to stone, in stricture, kink and spasm of the ureter; in colic following cystoscopy; in the instrumental removal of stones from the lower third of the ureter; and in the passage of catheters and sounds which had previously been impossible to introduce for any distance. Carroll believes that the tissue extract may act by neutralizing epinephrine or a similar product present in the ureteral wall at the site of spasm, and not-as most investigators have reasoned-by depressing the parasympathetic nerves. He mentions specifically that the demonstration by one of us (T. J. K.) of nerve ganglia in the lower ureter "coincides with our concept". After extended observation of the results obtained by those whose work has just been reviewed, the present authors decided to make clinical trial in their own service of the insulin-free pancreatic tissue extract now obtainable under
"DEPROPANEX" FOR RENAL AND URETERAL PAIN
137
the trade name of Depropanex deproteinated pancreatic tissue extract1. This preparation is a saline solution of a chemically-derived, protein-free nitrogenous fraction obtained from an acid-alcohol treatment of beef pancreas. Physiological tests show it to be free from insulin, histamine and acetylcholine. It contains approximately 2.5 per cent solids, including 0.5 per cent non-protein nitrogen, 0.9 per cent sodium chloride, and 0.25 per cent phenol as preservative. It is adjusted to pH 6.5 to 6.8, and is assayed by comparing its effect upon the arterial blood pressure of anesthetized dogs with that of a standard preparation. The standard preparation is evaluated in depressor units and was adopted after it was shown that 1 cc produced, in a large series of dogs, an average lowering in arterial blood pressure equivalent to the rise in arterial blood pressure produced by 0.01 mg. of epinephrine. Each lot of Depropanex extract is adjusted to contain 10 depressor units per cubic centimeter. The physiological properties of each lot of Depropanex is also qualitatively observed by means of the heartblocking effect in mice. To test for the absence of histamine and acetycholine, its effect in lowering the arterial blood pressure in urethanized rabbits , and atropinized dogs is also observed. METHOD OF STUDY
Depropanex was used in two series of cases: The first study was undertaken to observe the effect of Depropanex upon renal and ureteral pain from various causes, such as the presence of calculi, or the introduction of contrast media for retrograde pyelography. We were likewise interested in testing the effectiveness of this drug in promoting the passage of renal or ureteral stones. The second study was concerned solely with patients who were cystoscoped for retrograde pyelography. Three cubic centimeters of Depropanex extract were given to each patient before and during the introduction of the cystoscope. Notation was then made of (1) the tentative diagnosis, confirmation of which was being sought through pyelography; (2) the degree of pain experienced by the patient throughout the examination; and (3) the time interval elapsing between the administration of Depropanex and the cessation of the pain (if any). Series 1. The first series included 20 cases of renal or ureteral calculi, in which the size of the stone or stones was not so great as to preclude the possibility of their being passed without assistance. Table 1 shows the location of the calculi (i.e., whether right, left, or bilateral); the amount of Depropanex given and the outcome (stone passed, pain relieved, no effect, etc.). It will be noted that 7 patients passed their stones several days after the drug was administered, but in none of these cases could we say with certainty that the medication was directly responsible for the stone's passage, even though the inference was very strong. Of the beneficial effects of the drug in lessening or abolishing pain, however, there can be no question. In 12 cases relief of pain was complete, so that no additional analgesia was necessary. Five patients, however, experienced no 1 We are indebted to the manufacturers, Sharp & Dohme, for a grant making this experiment possible.
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T. J. KIRWIN, O. S. LOWSLEY AND J. H. MENNING TABLE CASE
!.-Effects of "Depropanex" in urolithiasis
PATHOLOGY
DEPROPANEX GIVEN
A. S......... Ureteral stone
3 cc q. 20 minutes for 4 doses
G. L ......... Ureteral stone
3 cc q. 2 hours for 3 doses
S. D......... Lt. ureteral stone
3 cc q. 3 hours
M. D ........ Bilateral ureteral calculi
3 cc q. 3 hours for 4 ·doses
J.H ......... Rt. ureteral calculus, probably passed before admission F.N ......... Lt. ureteral stone
3 cc q. 2 hours for 3 doses (6 hours after colic) 3 cc q. 3 hours for 7 doses
G. S......... Rt. ureteral stone
3 cc q. 3 hours for 4 doses
A. V......... Rt. renal colic
4 cc during colic
S.P ......... Lt. ureteral colic and stone L.H ......... Rt. lumbar pain from stone in kidney N.B ........ Lt. ureteral calculus
5 cc q. 2 hours for 3 doses 3 cc q. 3 hours
N. C ........ Rt. ureteral stone
3 cc q. 4 hours for 3 doses
J. F ......... Rt. renal calculus and post-cystoscopic reaction J. R ......... Rt. renal calculus
3 cc q. 3 hours for 8 doses
W.W ........ Rt. ureteral calculi (small) S. F......... Rt. ureteral calculus R. W........ Lt. ureteral calculus
3 cc q. 3 hours for 4 doses
3 cc q. 3 hours for 3 doses
3 cc q. 3 hours for 10
doses 3 cc q. 3 hours for 6 doses 3 cc q. 3 hours for 4 doses
RESULT
Colic diminished; stone passed several days later Colic slightly relieved; no effect on position of stone No immediate effect on stone; three days later stone at ureteral orifice. Colic relieved Pain relieved. Rt. calculus passed two days later; It. unchanged Dull pain relieved
Pain relieved. No effect on stone; removed at operation No effect on stone or colic. Passed stone several days later Marked relief; unable to demonstrate stone No effect on colic or stone D~finite relief of pain; came to operation No pain but no effect on stone. Came to operation No effect on stone or pain; came to operation No effect on stone; some relief of post-cystoscopic reaction No effect on stone; no pain due to catheterization but had pain when "Depropanex" was not given No effect on stones; came to operation No effect on stone; came to operation No effect on stone; came to operation
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"DEPROPANEX" FOR RENAL AND URETERAL PAIN
TABLE I-Concluded CASE
PATHOLOGY
DEPROPANEX GIVEN
H. F......... Bilateral renal calculi, small calculi on rt.
3 cc q. 3 hours for 4 doses
H. T....... . Left ureteral calculi
3 cc q. 3 hours for 4 doses
L. B....... . . Rt. ureteral calculus
3 cc q. 3 hours for 4 doses
RESULT
No effect on stones; came to operation on left side; passed rt. stone several weeks later; pain relieved No effect on stones; came to operation; pain relieved No effect on stone; stone removed from ureteral orifice; pain relieved
relief from pain, so that administration of morphia was imperative. In three instances it was impossible to demonstrate whether slight relief from pain was, or was not due to the use of Depropanex. Two patients eventually passed their stones without instrumental aid but this occurred so long after the Depropanex therapy that there could have been no influence exerted by it. In 11 cases operation had to be performed. Thus, in no single instance can we say with certainty that Depropanex was actively responsible for passage of a stone. An attempt was made to differentiate between mild and severe pain, although it is realized that "pain" is relative, depending upon many factors, of which the skill of the cystoscopist is by no means least. Dull pain, enduring a relatively short time has been classed as mild. An accentuation of mild pain, of longer duration, was called moderate; while colicky pain, or frank post-cystoscopic reaction, was ranked as severe. The table records the type of pain associated with each case. Series 2. There were 33 patients in the second series, all of whom underwent cystoscopy for roentgenographic study. Three cubic centimeters of Depropanex were administered to each patient before the instrument was introduced. Of these, 22 (66.6 per cent) experienced no pain whatsoever; 4 (12.2 per cent) had mild pain; 2 (6 per cent) had moderate pain; and 5 (15.2 per cent) suffered severe pain. Table 2 shows the diagnosis under which examination was made; the type of pain experienced during examination; and the time relief of pain took place. Similar studies were carried out in a control group of 34 cases to whom Depropanex was not given prior to instrumentation. The results in these cases are summarized in table 3. It will be noted that 9 cases (26.4 per cent) had no pain; 8 (23.5 per cent) had mild pain; 11 (32.4 per cent) had moderate pain; and 6 (17.2 per cent) had severe pain. Elliott and Nuzum state that deproteinated pancreatic tissue extracts "do not contain histamine, choline, adenylic acid or adenosine in sufficient quantities to account for their physiologic action".
140
T. J. KIRWIN, 0. S. LOWSLEY AND J. H. MENNING
The usual dose of "Depropanex" is 2 to 4 cc given intramuscularly. There is, mild pain at the site of injection (probably due only to distention caused by the volume of fluid injected). But fortunately this pain lasts but a moment, and TABLE
2.-Retrograde studies in which 3 cc of Depropanex extract was given prior to instrumentation PAIN
CASE NO.
DIAGNOSIS
None Mild
12 13 14 15 16 17 18 19 20
21
22 23 24 25 26 27 28 29 30 31 32 33
TIME OCCm
-- -- -- --
-1 2 3 4 5 6 7 8 9 10 11
Mod- Severe erate
Ohr. pyelonephritis Bi. tuberculosis, renal Negative upper urinary tract Cystitis, spina bi:fida Normal upper urinary tract Normal upper urinary tract Right ureteral calculus Chronic pyelonephrosis Cystitis Normal upper urinary tract R. hydronephrosis; 1. chronic pyelonephritis No organic pathology Chronic right pyelonephritis Normal upper urinary tract Norma) upper urinary tract Pyelograms negative for bladder infection Normal upper urinary tract Negative pyelograms Normal upper urinary tract L. hydronephrosis and hydroureter Normal upper urinary tract No upper tract disease Chronic pyelonephritis, left R. hydronephrosis on basis of ureteropelvic obstruction Normal upper urinary tract No upper tract disease Normal upper urinary tract No upper tra
*
*
*
*
* * * * * * * * *
\
*
* * * * * *
*
*
After 2 hours After 2 hours
*
Immediately following
*
Moderate after 2 hours After 2 hours
*
* * * *
Immediately following Immediately following Within 2 hours
* *
After 2 hours
Within 2 hours Within 2 hours
* *
as it lessens, the renal colic is likewise relieved. In but 2 patients did we witness any reaction. They showed blanching of the face, and were dizzy and faint immediately upon injection, but the entire reaction passed in no more than one
141
"DEPROPANEX" FOR RENAL AND URETERAL PAIN
minute. As a rule, the relief afforded by Depropanex continues, and in but few instances has it been necessary to repeat the injection. Bransford Lewis has described a form of renal colic due to obstruction at the bladder neck, which brings about over-distention and pain in the kidney. Relief TABLE
3.-Retrograde studies without the administration of "Depropanex" PAIN
CASE NO.
TPdE OCCURRED
DIAGNOSIS
None
-- --
-1 2 3 4 5 6
7 8 9
10 11 12 13 14
15 16
17 18 19 20 21
22 23 24 25 26 27 28 29 30 31
32 33 34
Mild
Nephroptosis, right Chronic pyelonephritis N ephroptosis, right Pyelitis (B. coli), Bi. c cystitis Normal upper urinary tract Bi. hydronephrosis Normal upper urinary tract Normal upper urinary tract Normal upper urinary tract Tumor left kidney Normal upper urinary tract Normal -upper urinary tract Chronic pyelonephritis Normal upper tract Normal upper tract Left ureteral calculus Prostatic hypertrophy Normal upper urinary tract Solitary acquired right. Kidneychronic pyelonephritis Left ureteral calculus Negative upper urinary tract Tb. of left kidney Negative upper urinary tract Normal upper urinary tract Normal upper urinary tract Chronic pyelonephritis Normal upper urinary tract Left renal calculus Normal upper left urinary tract Left ureteral calculus Right renal calculi-urethral stricture urethritis No upper tract disease No upper tract disease Staghorn calculi-right
Moderate Severe -- --
*
* *
*
Within 2 hours After 2 hours Within 2 hours
*
After 2 hours
*
*
* *
* * *
*
Within 2 hours Immediately following Within 2 hours Immediately following Within 2 hours Within 2 hours Within 2 hours Within 2 hours Within 2 hours
*
* * * *
* *
* *
After 2 hours Immediately following Within 2 hours
*
Within 2 hours After 2 hours Within 2 hours
*
After 2 hours After 2 hours After 2 hours
*
* *
*
*
* * *
*
*
After 2 hours After 2 hours Within 2 hours a
from this type of pain can be obtained by catheterization of the bladder, not with either tissue extract or morphine. However, pain in renal ·colic is not always caused by overdistention. In many instances ischemia of the nerve endings causes a muscle spasm, and relaxation of this spasm will relieve the pain and
142
T. J. KIRWIN, 0. S. LOWSLEY AND J. H. MENNING
restore the normal ureteral muscular tone. brings about such relaxation.
Pancreatic tissue extract apparently
CONCLUSIONS
In a series of 53 cases, in which the patients suffered from a wide variety of urinary tract conditions causing obstruction, 'Depropanex' was administered, and the effect of this preparation was studied by comparison with a control series wherein the drug was not used. It appears to have been demonstrated that 'Depropanex' is an effective agent for the relief of renal and ureteral colic.
1 E. 63rd St., New York, N. Y. 111 E. 71st St., New York, N. Y. Station Hospital, Fort Knox, Ky.
AND
JOSEPH H. MENNING
The management of urinary calculus is one of the oldest-if not the oldestproblem confronting the medical profession. "Cutting for stone" was the first major surgical intervention ever undertaken, and from the days of Hippocrates to our own times, physicians have sought for better and more expeditious methods of ridding the human urinary tract of those self-manufactured "foreign" bodies. The fact that the search is still in progress is the most eloquent testimony to the dissatisfaction generally felt with all the methods heretofore employed. Yet since the days of "cutting for stone" we have made not a little progress. Today it is only for an exceptionally large calculus, or one embedded in the ureteral wall that we are forced to resort to the knife. If a stone is not too firmly lodged in the ureter it can usually be "coaxed out" with instruments and judicious lubrication. The urologist who frequently resorts to open operation is probably too impatient or too lazy to use conservative methods of inducing passage by the natural route. Within the past decade much attention has been given to means of relaxing the ureteral musculature, either by local application, or intravenous or other introduction of drugs which have been demonstrated to be effective for this purpose. Atropine sulphate has been frequently employed, but there are many well founded objections to this drug, and an earnest search has been conducted to find something better. The real problem is to get rid of ureteral spasm. The calculus keeps the duct continually irritated, and any attempt to dislodge it is certain to bring about violent contraction of the musculature of the wall of the ureter, clamping it all the more firmly upon the impacted stone. In 1936 and again in 1940, Lazarus of the Urologic Service of Mount Sinai Hospital (New York), reported on the use of an insulin-free pancreatic extract as an aid in cystoscopic treatment of impacted ureteral calculi and spastic occlusion of the ureter. Similar investigations were made by Getzoff and his coworkers at the Louisiana State University School of Medicine in the early months of the year 1941. The subject was also studied by Carroll and Zingale of St. Louis University's School of Medicine, who published their results in March 1938. These reports stimulated the interest of urologists all over the country, for they appeared to offer a means not only of relaxing the ureteral muscles so that obstructions could be spontaneously evacuated, or easily removed through the cystoscope, but also of relieving the pain of ureteral colic and other conditions in the kidney and its duct which cause so much suffering among urological patients. The use of pancreatic tissue extract for the relief of pain through dilatation of 132
"DEPROPANEX" FOR RENAL AND URETERAL PAIN
133
the muscular tissue is not new, although its employment in urologic practice is of such recent date. For some years before Lazarus made his recommendation it had been regarded as a most useful vasodilator. By 1931 enough data on the subject had been accumulated to permit Giroux and Kisthinios to compile a book which they called Les extraits pancreatiques desinsulines en therapeutique. This volume contains nothing about the urologic uses of insulin-free pancreatic tissue extract, but to anyone who has struggled to overcome ureteral spasm, or sought for a means of relieving the sufferings of the patients under his care hecause of urinary tract disabilities, the information it contains will be highly suggestive. It was in 1929 that Frey and Kraut isolated from urine a substance possessing properties of vasodilatation. This so-called "Frey hormone" was believed to be of pancreatic origin, but when excreted remained inactive in the blood, and only exerted its influence when it had passed into the urine. The extract madefrom urine had properties seemingly identical with those of known pancreatic extract. About this same time, but independently, Gley and Kisthinios demonstrated that an extract of pancreatic tissue from which all insulin had been eliminated exercised the same vasodilating properties. The discovery came about as a by-product of the studies of Kisthinios, who had taken as a subject for his inaugural dissertation, the effect of insulin upon the parasympathetic system. Certain investigators had noted that insulin sometimes caused a marked fall in arterial pressure and that it occasionally offset the hypertensive action of adrenalin. It was the opinion of Kisthinios that the variations in these effects upon the vascular system were the results of differences in the purity of the commercial brands of insulin. In trying to obtain pure insulin he isolated the vasodilating principle, finding that "that which we call 'insulin' is in reality a pancreatic extract which includes a hypoglycemic substance. In addition it contains also substances other than insulin, which the methods of isolation heretofore employed have failed to produce." Thus he found that the vasodilating action of the pancreatic extract persisted when all insulin had been removed from it. Experiments made upon animals deprived of a pancreas showed the output of the "Frey hormone" to be reduced to one-fifth of the amount excreted before the pancreas was taken out. Other animal experiments demonstrated that when an otherwise lethal dose of adrenalin had been injected, prompt injection of suitable quantities of the pancreatic extract would neutralize the hypertensive effect of the adrenalin, and permit the rapid return to normal of the animal's arterial pressure. On the basis of these experiments, Giroux and Kisthinios used the extract in the treatment of angina pectoris, arterial hypertension and arteritis. They also employed it in certain cases of Raynaud's disease, and in one case of obstruction of the central retinal artery. Clinical reports are given in great detail, and the general conclusion reached was that though by no means a cure-all, insulin-free pancreatic tissue extract offered great promise as a vasodilator, and as an agent for the relief of pain due to vascular constriction. In the same year that this publication appeared, Wolffe and his co-workers in this country showed that some tissue extracts cause vasodilatation and counteract the physiological effects of epinephrine.
134
T. J. KIRWIN, O. S. LOWSLEY AND J. H. MENNING BLOOD SUPPLY OF THE URETER
In a recently published study of the ureteral blood supply, W. F. Harper of London found that all its sources of blood supply anastomose freely in a dense adventitial plexus from which the musculature and lamina ptopria of the duct are supplied. There was no difference in the two sexes, except that the vaginal arteries in the female do. not correspond exactly to the inferior vesical branches in the male, although they may be said in general, to be mutually representative. Though the relative position of the vagina and lower third of the ureter have been found by other observers to vary considerably in perfectly normal women, Harper declares that this variation has no effect upon the extent of the ureter's blood supply from the vaginal arteries. Especially noteworthy is the constant presence (in all specimens examined) of ureteric branches from the aorta which arise from the antero-lateral surfaces of this main artery, most commonly about midway between its bifurcation and the origin of the inferior mesenteric artery. These arteries contribute to the formation of an anastomosis upon the ureter with the testicular arteries in the male, or ovarian in the female, coming down from above as well as with twigs from the common iliac and superior vesical arteries from below. Harper found that these arteries play a part comparable to that enacted by the ureteric branches of the accessory renals, and that like the accessory arteries of the kidney, they are to be regarded as persistent portions of the lateral splanchnic arterial system. In both sexes, the lower segment of the ureter lies in an extraperitoneal area richly vascularized by the inferior vesical and middle rectal arteries. While the origins of these arteries vary insofar as their ureteric connections are concerned, they are, nonetheless, relatively constant in position and a high origin. The ureteric connections form a dense and complex outer plexus in the adventitial connective tissue coat of the ureter. The larger branches, Harper found, exhibited a tendency toward a generally upward direction, so that it was easier to demonstrate anastomoses by the injection of individual arteries from 'below upwards' rather than from 'above downwards'. From the plexus in the adventitial connective tissue coat the muscles in the ureteral walls get their blood supply directly and from it also, pass out those vessels which ramify on the outer aspect of the deepest epithelial layer. Contrary to the usual conception, however, there was found no special arterial plexus in the ureteric "sheath of Waldeyer" about the duct's lower end. SPASM OF THE URETER
In devising his hydrophoragraph, an instrument for measuring and recording ureteral function, Trattner observed that either the longitudinal or circular muscles may be involved, separately or simultaneously, in spasm. The whole length of the duct, or only its upper, middle or lower third, may be involved in spasm. If the longitudinal muscle alone is spastic, the flow of urine is diminished or retarded. In spasms of the circular coat, a single and very small segment, or many segments in different sections of the entire extent of the ureter
"DEPROPANEX" FOR RENAL AND URETERAL PAIN
135
may take part in the spastic contractions. He concluded, on the basis of these findings, that inhibition of secretion in the kidney might be due to muscular spasm in the pelvis or ureter, "without taking nerve influences into consideration as a primary causative factor." These observations of Trattner were published in July 1932. Just 10 years later, Gree:r;i. and Essex of the Mayo Foundation made use of his instrument and method to investigate the effects of the intravenous administration of certain drugs upon the activity of ureteral peristalsis. A number of different drugs were employed, but with several the results were too inconclusive to be of value. By using different methods they did demonstrate that epinephrine and mecholyl, when intravenously injected, produce an increase in ureteral tone and in the rate of ureteral contractions, the amplitude of which may be increased or decreased. These two drugs are supposed to stimulate the action of the sympathetic and parasympathetic nerves, and this investigation indicated that they actually bring about a similar response in the ureter. The possibility of influencing the ureteral muscles, both in the production of spasm and its relaxation when induced by other means, thus receives confirmation. In order to comprehend how tissue extracts may be useful in the management of urinary calculi, or reduce the pain of renal or ureteral spasm, a brief consideration of the innervation of the upper urinary tract will be necessary. Something more than a decade ago one of the present authors (T. J. K.) made an extended study of ureteral implantation, employing upwards of eighty dogs as experimental subjects. His own observations on the physiology of the ureter were compared with the reports of preceding investigators along these same lines and from those who had made a special study of the innervation of this duct he obtained much enlightening information. For example, along the entire course of the ureter, from the ureteropelvic junction to its meatus upon the vesical trigone, Satani found nerve fibers and ganglion cells. Very few of these fibers, however, are in the muscle layer. Most of the nerve tissue is in the outer fibrous coat, the mucosa and submucosa. Between the outer fibrous coat and the muscle layer, there is a well developed network of large nerves, the fibers lying parallel to the axis of the duct. Large ganglia could be made out only in the lowest section. Few, or in some instances, only one cell, were to be found in the middle, and these cells were of the smallest size. The main network, which supplies the ureter's innervation, lies between the submucosa and the layer of muscular tissue. We have seen that in the muscle itself nerve elements are very scanty. Most of the fibers seem to run obliquely, as if they penetrated the muscle layer to make connection between the two plexuses in the fibrous outer coat and the inner layer of mucous membrane. Nevertheless, Satani finished his description by stating that the entire duct is enfolded in two continuous networks of nerve fibers, including ganglia both inside and out. These conduct nerve impulses to the muscle tissue. In the quarter century which has elapsed since Satani made his investigations, his work has been considerably supplemented but in no way discredited. Whar-
136
T. J. KIRWIN, 0. S. LOWSLEY AND J. H. MENNING
ton in 1932 proved that the ureter receives a nerve supply which is independent of the innervation of the kidney and bladder. He found that these nerves go directly to the ureter from (1) the lowest renal ganglion at the upper end of the spermatic plexus; (2) the abdominal sympathetic (the aortic, hypogastric and pelvic plexuses). His work also confirmed observations previously made by Latarjet and others as to the constitution of the solar (coeliac) plexus, from which the renal and abdomin[l,l sympathetic plexuses are derived. Wharton did not, however, claim to have proved that the ureteral nerves convey sensations of pain. But because 6 out of 7 patients were relieved of pain when the nerves were cut, he feels there is a strong probability that they contain afferent or sensory fibers. The operative experience of the present writers likewise offers confirmation of this theory. The idea that pancreatic extract might be useful in relaxing ureteral spasm and other conditions related to urinary calculus was suggested by a consideration of Wharton's findings. It was considered possible that one of the important contributory causes of ureteral calculus impaction was a spasm of the ureteral musculature in that portion of the wall of the ureter surrounding the calculus. This spasm might be due to over-stimulation of both the intrinsic and extrinsic sympathetic nerve-fibers supplying the segment of the ureter harboring the stone, because of the irritation set up by its presence. It was further reasoned that sudden attacks of renal colic in cases of stricture of the ureter were usually caused by spasm secondarily induced by such irritation. Lazarus administered pancreatic extract intramuscularly in doses of 1.5 to 2 cc. and found that "so startling were the results obtained that its continuation was more than warranted". Further trial was made soon after by Carroll and Zingale who reported in 1938. They found that the injection of pancreatic tissue extract "exhibited superiority" in the following ways: (1) It definitely relaxes the ureter. (2) Relaxation occurs within 3 minutes following injection. (3) The effect is, in most instances, clinically permanent, although experimentally normal contractions return. (4) The action is local with no untoward general effects. Although the action is apparently on the smooth muscle, there is no blurring of vision, nor dryness of the throat, like that experienced after atropine. In contrast to morphine, the cerebral centers are not affected. These authors used pancreatic extract in renal colic due to stone, in stricture, kink and spasm of the ureter; in colic following cystoscopy; in the instrumental removal of stones from the lower third of the ureter; and in the passage of catheters and sounds which had previously been impossible to introduce for any distance. Carroll believes that the tissue extract may act by neutralizing epinephrine or a similar product present in the ureteral wall at the site of spasm, and not-as most investigators have reasoned-by depressing the parasympathetic nerves. He mentions specifically that the demonstration by one of us (T. J. K.) of nerve ganglia in the lower ureter "coincides with our concept". After extended observation of the results obtained by those whose work has just been reviewed, the present authors decided to make clinical trial in their own service of the insulin-free pancreatic tissue extract now obtainable under
"DEPROPANEX" FOR RENAL AND URETERAL PAIN
137
the trade name of Depropanex deproteinated pancreatic tissue extract1. This preparation is a saline solution of a chemically-derived, protein-free nitrogenous fraction obtained from an acid-alcohol treatment of beef pancreas. Physiological tests show it to be free from insulin, histamine and acetylcholine. It contains approximately 2.5 per cent solids, including 0.5 per cent non-protein nitrogen, 0.9 per cent sodium chloride, and 0.25 per cent phenol as preservative. It is adjusted to pH 6.5 to 6.8, and is assayed by comparing its effect upon the arterial blood pressure of anesthetized dogs with that of a standard preparation. The standard preparation is evaluated in depressor units and was adopted after it was shown that 1 cc produced, in a large series of dogs, an average lowering in arterial blood pressure equivalent to the rise in arterial blood pressure produced by 0.01 mg. of epinephrine. Each lot of Depropanex extract is adjusted to contain 10 depressor units per cubic centimeter. The physiological properties of each lot of Depropanex is also qualitatively observed by means of the heartblocking effect in mice. To test for the absence of histamine and acetycholine, its effect in lowering the arterial blood pressure in urethanized rabbits , and atropinized dogs is also observed. METHOD OF STUDY
Depropanex was used in two series of cases: The first study was undertaken to observe the effect of Depropanex upon renal and ureteral pain from various causes, such as the presence of calculi, or the introduction of contrast media for retrograde pyelography. We were likewise interested in testing the effectiveness of this drug in promoting the passage of renal or ureteral stones. The second study was concerned solely with patients who were cystoscoped for retrograde pyelography. Three cubic centimeters of Depropanex extract were given to each patient before and during the introduction of the cystoscope. Notation was then made of (1) the tentative diagnosis, confirmation of which was being sought through pyelography; (2) the degree of pain experienced by the patient throughout the examination; and (3) the time interval elapsing between the administration of Depropanex and the cessation of the pain (if any). Series 1. The first series included 20 cases of renal or ureteral calculi, in which the size of the stone or stones was not so great as to preclude the possibility of their being passed without assistance. Table 1 shows the location of the calculi (i.e., whether right, left, or bilateral); the amount of Depropanex given and the outcome (stone passed, pain relieved, no effect, etc.). It will be noted that 7 patients passed their stones several days after the drug was administered, but in none of these cases could we say with certainty that the medication was directly responsible for the stone's passage, even though the inference was very strong. Of the beneficial effects of the drug in lessening or abolishing pain, however, there can be no question. In 12 cases relief of pain was complete, so that no additional analgesia was necessary. Five patients, however, experienced no 1 We are indebted to the manufacturers, Sharp & Dohme, for a grant making this experiment possible.
138
T. J. KIRWIN, O. S. LOWSLEY AND J. H. MENNING TABLE CASE
!.-Effects of "Depropanex" in urolithiasis
PATHOLOGY
DEPROPANEX GIVEN
A. S......... Ureteral stone
3 cc q. 20 minutes for 4 doses
G. L ......... Ureteral stone
3 cc q. 2 hours for 3 doses
S. D......... Lt. ureteral stone
3 cc q. 3 hours
M. D ........ Bilateral ureteral calculi
3 cc q. 3 hours for 4 ·doses
J.H ......... Rt. ureteral calculus, probably passed before admission F.N ......... Lt. ureteral stone
3 cc q. 2 hours for 3 doses (6 hours after colic) 3 cc q. 3 hours for 7 doses
G. S......... Rt. ureteral stone
3 cc q. 3 hours for 4 doses
A. V......... Rt. renal colic
4 cc during colic
S.P ......... Lt. ureteral colic and stone L.H ......... Rt. lumbar pain from stone in kidney N.B ........ Lt. ureteral calculus
5 cc q. 2 hours for 3 doses 3 cc q. 3 hours
N. C ........ Rt. ureteral stone
3 cc q. 4 hours for 3 doses
J. F ......... Rt. renal calculus and post-cystoscopic reaction J. R ......... Rt. renal calculus
3 cc q. 3 hours for 8 doses
W.W ........ Rt. ureteral calculi (small) S. F......... Rt. ureteral calculus R. W........ Lt. ureteral calculus
3 cc q. 3 hours for 4 doses
3 cc q. 3 hours for 3 doses
3 cc q. 3 hours for 10
doses 3 cc q. 3 hours for 6 doses 3 cc q. 3 hours for 4 doses
RESULT
Colic diminished; stone passed several days later Colic slightly relieved; no effect on position of stone No immediate effect on stone; three days later stone at ureteral orifice. Colic relieved Pain relieved. Rt. calculus passed two days later; It. unchanged Dull pain relieved
Pain relieved. No effect on stone; removed at operation No effect on stone or colic. Passed stone several days later Marked relief; unable to demonstrate stone No effect on colic or stone D~finite relief of pain; came to operation No pain but no effect on stone. Came to operation No effect on stone or pain; came to operation No effect on stone; some relief of post-cystoscopic reaction No effect on stone; no pain due to catheterization but had pain when "Depropanex" was not given No effect on stones; came to operation No effect on stone; came to operation No effect on stone; came to operation
139
"DEPROPANEX" FOR RENAL AND URETERAL PAIN
TABLE I-Concluded CASE
PATHOLOGY
DEPROPANEX GIVEN
H. F......... Bilateral renal calculi, small calculi on rt.
3 cc q. 3 hours for 4 doses
H. T....... . Left ureteral calculi
3 cc q. 3 hours for 4 doses
L. B....... . . Rt. ureteral calculus
3 cc q. 3 hours for 4 doses
RESULT
No effect on stones; came to operation on left side; passed rt. stone several weeks later; pain relieved No effect on stones; came to operation; pain relieved No effect on stone; stone removed from ureteral orifice; pain relieved
relief from pain, so that administration of morphia was imperative. In three instances it was impossible to demonstrate whether slight relief from pain was, or was not due to the use of Depropanex. Two patients eventually passed their stones without instrumental aid but this occurred so long after the Depropanex therapy that there could have been no influence exerted by it. In 11 cases operation had to be performed. Thus, in no single instance can we say with certainty that Depropanex was actively responsible for passage of a stone. An attempt was made to differentiate between mild and severe pain, although it is realized that "pain" is relative, depending upon many factors, of which the skill of the cystoscopist is by no means least. Dull pain, enduring a relatively short time has been classed as mild. An accentuation of mild pain, of longer duration, was called moderate; while colicky pain, or frank post-cystoscopic reaction, was ranked as severe. The table records the type of pain associated with each case. Series 2. There were 33 patients in the second series, all of whom underwent cystoscopy for roentgenographic study. Three cubic centimeters of Depropanex were administered to each patient before the instrument was introduced. Of these, 22 (66.6 per cent) experienced no pain whatsoever; 4 (12.2 per cent) had mild pain; 2 (6 per cent) had moderate pain; and 5 (15.2 per cent) suffered severe pain. Table 2 shows the diagnosis under which examination was made; the type of pain experienced during examination; and the time relief of pain took place. Similar studies were carried out in a control group of 34 cases to whom Depropanex was not given prior to instrumentation. The results in these cases are summarized in table 3. It will be noted that 9 cases (26.4 per cent) had no pain; 8 (23.5 per cent) had mild pain; 11 (32.4 per cent) had moderate pain; and 6 (17.2 per cent) had severe pain. Elliott and Nuzum state that deproteinated pancreatic tissue extracts "do not contain histamine, choline, adenylic acid or adenosine in sufficient quantities to account for their physiologic action".
140
T. J. KIRWIN, 0. S. LOWSLEY AND J. H. MENNING
The usual dose of "Depropanex" is 2 to 4 cc given intramuscularly. There is, mild pain at the site of injection (probably due only to distention caused by the volume of fluid injected). But fortunately this pain lasts but a moment, and TABLE
2.-Retrograde studies in which 3 cc of Depropanex extract was given prior to instrumentation PAIN
CASE NO.
DIAGNOSIS
None Mild
12 13 14 15 16 17 18 19 20
21
22 23 24 25 26 27 28 29 30 31 32 33
TIME OCCm
-- -- -- --
-1 2 3 4 5 6 7 8 9 10 11
Mod- Severe erate
Ohr. pyelonephritis Bi. tuberculosis, renal Negative upper urinary tract Cystitis, spina bi:fida Normal upper urinary tract Normal upper urinary tract Right ureteral calculus Chronic pyelonephrosis Cystitis Normal upper urinary tract R. hydronephrosis; 1. chronic pyelonephritis No organic pathology Chronic right pyelonephritis Normal upper urinary tract Norma) upper urinary tract Pyelograms negative for bladder infection Normal upper urinary tract Negative pyelograms Normal upper urinary tract L. hydronephrosis and hydroureter Normal upper urinary tract No upper tract disease Chronic pyelonephritis, left R. hydronephrosis on basis of ureteropelvic obstruction Normal upper urinary tract No upper tract disease Normal upper urinary tract No upper tra
*
*
*
*
* * * * * * * * *
\
*
* * * * * *
*
*
After 2 hours After 2 hours
*
Immediately following
*
Moderate after 2 hours After 2 hours
*
* * * *
Immediately following Immediately following Within 2 hours
* *
After 2 hours
Within 2 hours Within 2 hours
* *
as it lessens, the renal colic is likewise relieved. In but 2 patients did we witness any reaction. They showed blanching of the face, and were dizzy and faint immediately upon injection, but the entire reaction passed in no more than one
141
"DEPROPANEX" FOR RENAL AND URETERAL PAIN
minute. As a rule, the relief afforded by Depropanex continues, and in but few instances has it been necessary to repeat the injection. Bransford Lewis has described a form of renal colic due to obstruction at the bladder neck, which brings about over-distention and pain in the kidney. Relief TABLE
3.-Retrograde studies without the administration of "Depropanex" PAIN
CASE NO.
TPdE OCCURRED
DIAGNOSIS
None
-- --
-1 2 3 4 5 6
7 8 9
10 11 12 13 14
15 16
17 18 19 20 21
22 23 24 25 26 27 28 29 30 31
32 33 34
Mild
Nephroptosis, right Chronic pyelonephritis N ephroptosis, right Pyelitis (B. coli), Bi. c cystitis Normal upper urinary tract Bi. hydronephrosis Normal upper urinary tract Normal upper urinary tract Normal upper urinary tract Tumor left kidney Normal upper urinary tract Normal -upper urinary tract Chronic pyelonephritis Normal upper tract Normal upper tract Left ureteral calculus Prostatic hypertrophy Normal upper urinary tract Solitary acquired right. Kidneychronic pyelonephritis Left ureteral calculus Negative upper urinary tract Tb. of left kidney Negative upper urinary tract Normal upper urinary tract Normal upper urinary tract Chronic pyelonephritis Normal upper urinary tract Left renal calculus Normal upper left urinary tract Left ureteral calculus Right renal calculi-urethral stricture urethritis No upper tract disease No upper tract disease Staghorn calculi-right
Moderate Severe -- --
*
* *
*
Within 2 hours After 2 hours Within 2 hours
*
After 2 hours
*
*
* *
* * *
*
Within 2 hours Immediately following Within 2 hours Immediately following Within 2 hours Within 2 hours Within 2 hours Within 2 hours Within 2 hours
*
* * * *
* *
* *
After 2 hours Immediately following Within 2 hours
*
Within 2 hours After 2 hours Within 2 hours
*
After 2 hours After 2 hours After 2 hours
*
* *
*
*
* * *
*
*
After 2 hours After 2 hours Within 2 hours a
from this type of pain can be obtained by catheterization of the bladder, not with either tissue extract or morphine. However, pain in renal ·colic is not always caused by overdistention. In many instances ischemia of the nerve endings causes a muscle spasm, and relaxation of this spasm will relieve the pain and
142
T. J. KIRWIN, 0. S. LOWSLEY AND J. H. MENNING
restore the normal ureteral muscular tone. brings about such relaxation.
Pancreatic tissue extract apparently
CONCLUSIONS
In a series of 53 cases, in which the patients suffered from a wide variety of urinary tract conditions causing obstruction, 'Depropanex' was administered, and the effect of this preparation was studied by comparison with a control series wherein the drug was not used. It appears to have been demonstrated that 'Depropanex' is an effective agent for the relief of renal and ureteral colic.
1 E. 63rd St., New York, N. Y. 111 E. 71st St., New York, N. Y. Station Hospital, Fort Knox, Ky.