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PostPosted: Fri Nov 08, 2019 5:21 pm 
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Antihemorrhagic Agents. Butanol

This section is from the book "Research In Physiopathology As Basis Of Guided Chemotherapy With Special Application To Cancer", by Emanuel Revici.

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In 1943, during research studies concerning the pharmacological activity of glycerol on abnormal foci, its hemorrhagiparous effect appeared as a serious handicap. Various hemostyptic substances were tested without sufficient effect. At this time, a new product, to which a hemostatic effect was attributed, appeared on the market. It was a very weak solution (around 1/10,000) of octanol in saline. We could find no therapeutic effect for it. However, we were studying butanol and other higher aliphatic alcohols with lipoidic properties, and we decided to test butanol for its antihemorrhagic activity, hoping that it might counteract the undesirable hemorrhagiparous effect of glycerol. It did and we have since added butanol to glycerol for this purpose.

We observed the remarkable hemostatic effect of butanol years later in a patient with severe hemorrhage, to whom doses of 10 cc. of a 6.5% solution were given intravenously. Hemorrhage stopped in a few minutes. Since then, we have successfully applied butanol clinically in hemorrhages of various origins.

As an antihemorrhagic agent, butanol is administered either parenterally as a 6.5% solution in saline, or orally as 6.5% solution in water. The route of administration—intravenous, intramuscular, subcutaneous or oral is chosen according to the severity of the hemorrhage. Doses of 5-20 cc. are given and repeated, if necessary, at intervals of a few minutes. Since butanol is not at all toxic in these large doses, we usually give them with good results in severe emergencies. The following cases illustrate the styptic effect.

R. E., a 64-year old man with an extensive ulcerated epidermoid carcinoma of the floor of the mouth and large bilateral cervical metastases, had received intensive radiotherapy. Occasionally, there was a small amount of bleeding from the oral lesion, but a sudden hemorrhage of about 500 cc. of blood during a half hour period occurred late at night while the patient was at home. Pressure, applied to the floor of the mouth, was of value but bleeding recurred immediately upon release. Oxidized gauze, adrenalin soaked gauze, vitamin K and vitamin C in large quantities were of no value. n Butanol solution in saline was finally obtained and 5 cc. injected intravenously. Bleeding ceased during the injection. A second equally severe hemorrhage occurred one week later and again could not be adequately controlled by pressure or oxidized gauze. 10 cc. of n butanol solution administered intramuscularly stopped the bleeding within 2-3 minutes. Three hours later, the floor of the mouth was carefully examined preliminary to right external carotid artery ligation, and the lesion was found to be free of bleeding. Despite the ligation, bleeding later recurred but was controlled each time by n butanol administered orally.

S. S., a 30-year old man, had an adenocarcinoma involving the right maxillary sinus with cervical metastases. During the period of observation, this patient experienced a profuse hemorrhage from nose and mouth. Blood flowed at the rate of approximately 5-6 cc. per minute, and pressure gave little or no relief. 5 cc. of n butanol in saline solution was injected intravenously and within two minutes, the profuse hemorrhage ceased and did not recur at that time. On several other occasions, bleeding was controlled following the administration of oral doses of 5-10 cc. of 6.5% n butanol solution in water.

A. M., a 36-year old man, had multiple pulmonary metastases from a primary malignant melanoma of the left foot. On several occasions, hemoptysis occurred and during three of these episodes bleeding was profuse. 5 cc. of n butanol in saline administered intramuscularly stopped two of these episodes rapidly, but in the third, an injection of 10 cc. intravenously was needed ten minutes after an initial intramuscular dose. Although the intramuscular injection was ineffective, the bleeding was halted within two minutes after intravenous administration.

Since then, these results have been consistently confirmed.

Additional progress was achieved with organic acids added to butanol in adequate amounts. Completely non toxic in the dosages used, they were observed to enhance the hemostatic effect of butanol. This hemostatic effect has been confirmed many times, particularly in Europe where, following our research, butanol has been widely used as a hemostyptic agent.

A hemostatic effect was also evident when butanol was used with the principal aim of controlling pain in postoperative cases. The hemostatic effect was especially important in cases where pathological bleeding usually represented a major complication, either because of the impossibility of obtaining hemostasis during operation or because the surgical wound could not be kept aseptic, as in tonsillectomy, prostatectomy and plastic surgery of the nose. In a study on the use of butanol for postoperative care in tonsillectomies, B. Welt has been able to show a preventive effect, and more important, a hemostatic one if hemorrhage occurs. (187) (Fig. 91) In prostatic surgery, the amount of bleeding was so reduced, that of a group of 40 cases, only one needed transfusion while in a similar number of controls, 8 had to have transfusions. (189)

Still more impressive results have been noted in pathological hemorrhages following plastic surgery, especially of the nose. In a significantly large number of cases, severe hemorrhages tend to occur around the 7th day after operation. We have discussed above the pathogenesis of these hemorrhages and the relationship to the allergic defense mechanism. Such hemorrhages have been difficult to control. The use of antibiotics has only partially reduced their frequency and gravity. S. Scher has obtained very good results with the administration of butanol in such cases, using an injection of 5 cc. of a 6.5% solution of butanol once before surgical intervention and four times daily for two days afterward, followed by oral administration of 15 cc. or one tablespoon four times a day for eight days. No hemorrhages occurred in more than two thousand cases treated. In a few patients who neglected to take the medication, and in whom a hemorrhage appeared, bleeding was rapidly controlled by butanol.

Experimental Research on the Hemostyptic Effect: In a series of studies we sought to find the mechanism by which butanol controls hemorrhage. In an investigation carried out in our laboratory, M. Bier and P. Teitel baum (194) showed that individual members of the homologous series of aliphatic alcohols decrease the degree of retraction of clots when added in vitro to blood. (Figs. 141 to 143) By varying the amounts added, this effect was observed to occur only at values above a critical concentration of the alcohol in blood. Bier could show that the critical value, which differs for members of the homologous series, is proportional to the lethal toxic dose in mice.

This non retraction of clots in vitro also can be recognized in cases treated with butanol through the gelatinous aspect of the clots at the moment when the hemorrhage stops. However, it is interesting to note that the amount of butanol injected, considered in terms of the amount of the circulating blood, results in concentrations considerably below the critical values needed to produce this effect in vitro. However, concentration of butanol at the site of the wound may explain this. It is also of interest that the same gelatinous character typifies the clots which remain attached to bleeding lesions in animals treated with butanol. In mice, when a portion of tail was cut and butanol was used, the abnormally long clot remained adherent to the wound, differing from that seen in controls.

n spite of changes in the clot, it seems that the effect upon the blood itself, and its coagulation in a wound, represents only one of the means through which butanol controls hemorrhage. The speed with which butanol acts, often within seconds after intravenous injection, is much greater than blood coagulation time. Consequently, changes in clot formation alone do not appear sufficient to explain the mechanism through which the rapid hemostasis occurs.

M. Bier and H. Lerner in our laboratory studied the influence exerted by butanol upon hemorrhage induced by the highly active proteolytic enzyme, ficine. (195) They were able to induce standardized hemorrhages by injecting ficine solutions under the skin of the abdomen of white mice. (Fig. 151a) (In other animals and with other sites of injection in mice, the individual variations were too great to make the resulting bleeding useful as material for testing the effect of agents upon hemorrhage.) With adequate doses of ficine, severe hemorrhages followed by skin ulcerations were induced. The bleeding, and even the ulcerations, were almost entirely prevented when butanol was administered. Figure 151b shows the results of this experiment, with the manifest differences, following ficine injections, between animals receiving butanol intraperitoneally and controls.

The antifibrinolytic activity of butanol (196) could explain its intervention in protracted bleeding, and especially in cases where the effect of butanol appears after hours or days. However, inhibition of fibrinolytic activity cannot be conceived to intervene in an action taking place in less than a few minutes.

In trying to explain butanol's antihemorrhagic effects, we also considered its pharmacological activities. We have noted the action of butanol upon the acid base balance of abnormal tissues, as shown by changes in the pH of the second day wound crust. In abnormal tissues, butanol reduces local pH but it does not do this to any great extent in normal tissues. This led us to investigate the difference in the influence of butanol upon pathological hemorrhages. The immediate bleeding induced by standard cutting of the tail in mice was not constant and, in general, was not markedly influenced by administration of butanol. But there was a marked effect upon hemorrhage induced by the displacement of the clots through mechanical maneuvers one to two hours after cutting of the tail. In controls, the bleeding lasted almost the same length of time as bleeding from fresh lesions, while in animals treated with butanol, it often stopped in a very short time.

These data, although interesting, did not seem to offer a completely satisfactory explanation of the mechanism by which butanol stops bleeding, especially in cases in which it acts within minutes or less. It appeared improbable that the formation of a clot alone would stop the hemorrhage under these conditions. An interesting observation led us to another hypothesis.

In several patients with wide ulcerations, we were able to examine the hemorrhaging vessel after bleeding had been stopped by butanol. Contrary to all expectations, we found that the artery, which usually was severed transversely, was not buried in a clot but remained almost isolated and somehow separated from it. It seemed that blood vessels themselves might have a role in hemostasis. The intervention of a spasm of the smooth muscles of the vessels was considered. This was indirectly confirmed when a patient with severe and prolonged bleeding from the bed of a prostate after ablation, was treated with butanol. An intravenous injection of 40 cc. of butanol was followed by such violent contraction of the bladder as to expel, with great force, the catheter together with clots and urine present in the bladder. At the same moment, bleeding, which had persisted for more than a week, stopped suddenly. We connected this sudden spasmodic contraction of the smooth muscles in the abnormal bladder with the injection of butanol and considered that butanol might produce a spasm of the muscular walls of abnormal blood vessels—abnormal because of the hemorrhagiparous condition itself. This would explain the rapidity of the hemostatic effect and the selective action upon small and medium arteries with important muscular walls. In fact, we saw that, while very severe arterial hemorrhages were completely stopped in less than one minute after an intravenous injection of butanol, the same effect was not obtained in oozing bleeding.

We tried to investigate further this spastic effect upon blood vessels as the mechanism in butanol hemostasis. Experiments with isolated aorta preparations of rabbits and rats showed that a spastic effect cannot be induced by butanol, even if the vessels previously have been harmed by manipulation. This can be explained by the fact that the aorta does not have muscular fibers. The same lack of spastic effect is seen in normal arteries of the hind legs of rats and frogs.

The administration of butanol to an animal after a small branch of the mesenteric artery was first crushed and, after some time, cut, produced a spastic effect which transformed the jet like hemorrhage into an oozing one, greatly reducing the blood loss. The hypothesis of vascular spastic contraction as the mechanism in butanol hemostasis has received further indirect confirmation through the study of the effect of butanol upon hemorrhage induced by single traumatic lesions in various organs. Differences were observed according to organs or tissues affected. While bleeding liver wounds are influenced only to a small degree by intravenous administration of butanol, hemorrhage from a kidney wound stopped rapidly. The fundamental difference between the liver portal circulation with minimum muscularity of the vessels, and that of the kidney, where highly developed artery muscular layers are seen, can explain the unequal response to butanol.

As we can see in these cases, the contraction of a pathological artery can insure rapid hemostasis and accords with the fact that the artery is not buried in a clot. This explains why, especially in clinical application, butanol is more active upon arterial hemorrhage and much less active upon capillary bleeding. This mechanism also would explain the same good effect upon hemorrhage from veins with important walls. Failure of butanol seen in three cases of hemorrhage from varices of the inferior esophageal veins can be explained by the almost complete lack of muscular layers in these varicose veins, which would bar a vasculo muscular contraction.

Parallel to these studies, other possible hemostatic mechanisms have been investigated. We tried to interpret the unusual fact that butanol stopped hemorrhage while agents such as nikethamide, thiamine, isamine blue, sterols and glycerol induced bleeding—yet all have positive polar groups in their molecules, represented by an amine or amide radical for most of them and by hydroxyls for glycerol and sterols. As we have mentioned before, all agents with such positive radicals induce a shift toward less alkaline values for the second day wound crust pH. Therefore, this could not be considered to be the factor that determines the antagonistic effects on bleeding. The aliphatic or cyclic character of the nonpolar group does not seem to be a factor since glycerol and butanol both have aliphatic chains.

However, correlation with another biological effect could be noted. All the substances with hemorrhagiparous effect, also produce a convulsive effect if administered in sufficiently high doses. The convulsive effect of Coramine and thiamine has been known for a long time and we used these substances any time we wanted to induce experimental convulsions. We also have seen that convulsions can be consistently induced in animals through the use of relatively large doses of glycerol or sterols. Convulsions in several human cases have followed the use of these agents. Doses as high as 20 cc. of a 5% solution of the insaponifiable fraction of placenta or of the 2% solution of cholesterol in oil, administered for therapeutic purposes have induced convulsions in patients, with a previous history of convulsive seizures. A convulsive effect in animals has been noted for all the agents mentioned above which also have hemorrhagiparous activity. We were able to induce convulsions in rats, even by injecting 20 cc. of a solution of 10% glucose subcutaneously once a day for a few days. In humans, we also saw convulsions appearing after glucose was administered intravenously in an amount of 100 gm. in a saline preparation to patients treated concomitantly with desoxycorticosterol, although the last substance has no convulsivant effect by itself.

On the other hand, the antihemorrhagic butanol produces a hypnotic effect if administered in high doses. The dose of butanol needed to prevent hemorrhage induced by ficine in mice, for example, was enough to provoke hypnotic activity comparable to that of barbiturates, chloroform and even ether. Very interesting is the fact that these agents also are able to prevent ficine induced hemorrhage if administered in doses sufficiently high to produce hypnotic or narcotic effects. The peculiar correlation between convulsive and hemorrhagiparous effect on the one hand, and hypnotic and hemostatic effect on the other, provides some further understanding of butanol hemostasis, but does not furnish the explanation for the mechanism through which this hemostasis takes place. The most plausible conclusion is that butanol intervenes through several mechanisms, some inducing immediate hemostasis through arterial contraction, while others have a later effect through changes in the blood clotting process, with lack of retraction of the clot and an influence upon fibrinolysis.

Contraction would explain why, with only few exceptions, it is the pathological arterial hemorrhage which responds most favorably to butanol. An immediate influence upon capillary or venous hemorrhage is less manifest and, in a very few cases, absent. The same is true for traumatic hemorrhages where, although there are some good immediate results, in general they are less rapid than for pathological arterial hemorrhage. Because of its immediate effect upon arterial bleeding, butanol became the agent of choice for those pathological hemorrhages which, through their arterial origin, could be fatal in a short time.

One of the big advantages of hemostasis induced by butanol over that obtained through other agents resides in the fact that there is no manifest increase in blood coagulability. Only in concentrations which never can be attained in vivo has butanol been seen to change the coagulability of blood. The inherent danger of thrombosis resulting from high blood coagulability limits the amount of the other agents to be administered. This danger does not exist for butanol and no such limitations are placed upon its use. The fact that normal prothrombin time is uninfluenced by butanol while high prothrombin time is reduced toward normal represents another advantage.

In further studies, we tried to enhance the hemostatic action of butanol without increasing blood coagulability. The addition of calcium salts was of no value but an enhancement was seen with potassium salts.

In a series of experiments, it was noted that, when a solution of butanol is kept for a long time in a stoppered bottle, its activity increases. For long standing preparations, 50% smaller doses were sufficient to protect mice against the action of ficine. The narcotic and toxic effects of these preparations also increased in the same proportion. This led us to add butyric aldehyde, the product of immediate oxidation of butanol, which increased butanol's coagulating effects only very slightly but enhanced its hemostatic effect considerably. The addition of hydrogen peroxide did much the same.
Blood Mixed With Butanol, Used Against Hemorrhages

S. Akad, working in our laboratory, showed that the coagulation time of blood is also increased if butanol, mixed previously with blood, is added. In the clinical application of this observation, we used the patient's own blood extemporaneously mixed with butanol. In a syringe containing, for instance, 10 cc. of the butanol solution, 2-5 cc. of the patient's blood is withdrawn. After mixing them, and without removing the needle from the vein, the contents of the syringe are injected intravenously. A similar mixture can be injected also intramuscularly or subcutaneously. The results have been very good. In some cases in which butanol alone was not able to stop a hemorrhage, the blood butanol mixture did. With this special technique, we have been able, in recent times, to bring most hemorrhages under control within a few minutes.

The fact that agents with positive polar groups, such as sterols, glycerol, coramine, thiamine and others, have hemorrhagiparous activity led us to try to influence hemorrhage with agents considered biologically antagonistic through their negative polar group.

Many years ago, experimenting with chlorine solutions in saline, we observed a manifest effect upon coagulation time. Intravenous injection of such solutions brought coagulation time to values as low as one minute. The addition of these solutions to butanol greatly increase its effect in vitro upon coagulation time but had less effect upon hemostasis in vivo. Similar but somewhat less manifest effects were obtained by adding hydrochloric acid to butanol solution. On the other hand, organic acids such as oxalic, malonic, citric, lactic maleic or citraconic showed a favorable effect. Without changing coagulability of the blood, these acids were seen to increase the hemostatic effect.
Fatty Acids

The same antagonism to sterols and glycerol led us to use fatty acids from cod liver oil. (197) While results in severe large arterial hemorrhages were not impressive, the effect upon oozing capillary, venous and small arterial hemorrhages was very good in a large proportion of cases. For example:

N. V., 57 years old, with multiple pulmonary metastatic lesions from a hypernephroma, had frequent hemoptysis. At times, the bleeding became more accentuated, the patient expectorating clots as well as uncoagulated fresh blood. Intramuscular administration of two doses of 10 cc. of a 6.5% solution of butanol at half hour intervals had little influence upon the bleeding. Intramuscular administration of 1 cc. of a solution of 10% of the mixture of fatty acids obtained from cod liver oil stopped the bleeding in less than 20 minutes, with the effect persisting for more than two months. A new episode of oozing bleeding was again immediately controlled by injection of the fatty acid preparation.

Other cases with hemoptoic sputum, prolonged bleeding from gastric or duodenal ulcers or from rectal or uterine tumors, all corresponding to oozing rather than to acute massive hemorrhage, have responded to administration of this fatty acid preparation. Almost uniformly, these oozing hemorrhages, which had not responded to butanol, were rapidly controlled. We now use butanol mixed with small amounts of hydrogen peroxide and organic acids mentioned above, to control severe arterial hemorrhages while for the oozing type, fatty acids from cod liver oil are used.

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PostPosted: Fri Nov 08, 2019 5:59 pm 
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N-butyl alcohol is a pre-race bleeding medication. The patented form of the medication, known as Clotol, contained 7 per-cent n-butyl alcohol, and is no longer produced commercially in Canada. Generic versions of the drug are produced by independent compounders and a small pharmaceutical company.

The main supplier to the industry has chosen to double the strength of the solution to 14% n-butyl alcohol.

Historically, in thoroughbred and quarter horse racing, private practitioners administered the medication prior to horses going over to the paddock. In standardbred racing, n-butyl alcohol was only administered by the official Ontario Racing Commission (ORC) veterinarian in the paddock on the day of a race.

As the administration of the substance in the SB paddock has been on the decline, the ORC will discontinue the practice of the Official Veterinarian giving n-butyl alcohol injections effective January 1, 2012. While n-butyl alcohol is a legal medication, the ORC advises horse people to be very cautious with its use. If they choose to use it with their horses, the medication should be administered under the direction of an ORC licensed veterinarian.

According to ORC Veterinarian Supervisor Dr. Bruce Duncan, as a general rule, extra care should be taken when using this product, practicing good intra venous technique. "Anyone administering this to a horse should be very cautious, especially with the 14% form. An ORC licensed veterinarian can advise you if the substance will have a therapeutic value to the horse, and if so, supervise the injection of the medication."

Those horse people who choose to continue the administration of the medication should do so with utmost care. There is a growing suspicion that some intra venous applications of the substance, particularly the double strength form, can cause damage to the jugular vein, including complete occlusion (or blocking) of the vein. This can put the health of the horse at risk.

The racing community is reminded that a basic aspect of good medication control is ensuring that you only use products that are properly manufactured and clearly labeled, and that are administered by a licensed veterinarian or under the direction of one.

Jacinth E. Chang ALLOY

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