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Histaminase and Histamin Desensitization in Genito-Urinary Allergy
HISTAMINASE AND HISTAMIN DESENSITIZATION IN GENITO-URINARY ALLERGY H . McC. JOHNSON
Urology, perhaps more than any other specialty, is confronted with problems of expansion, both from the diagnostic and therapeutic consideration. Perhaps the biggest farce of all time is to be found in the neurogenic allocations, that so many of us are prone to consider in the diagnostic horizon as being the cause of many of our chronic urological ailments. This state of dissatisfaction has lead a goodly number of urologists into the field of allergy, which, in a small measure, seems to throw additional light upon the obscure etiological factors contributing to genito-urinary diseases. We are all familiar with focal infections such as found in pyorrhea! pockets, devitalized teeth, chronically infected tonsils, chronic gall bladder disease, chronic appendicitis, etc. More recently our attention has been drawn to the various infectious and toxic processes, associated with sluggish and inadequate bowel elimination, their relation to kidney excretion and effect upon the endocrine system, which now has a fairly well established role in the management of genital disturbances. With this scope of scientific activity in mind, we have been intensely interested in the production of putrefaction and its far reaching pharmacological effects upon the human organism. Histamin is one of these products, a toxic amino acid, derived from histidin by a process of putrefaction through the activity of carboxylase bacteria. The biochemical process involved is that of decarboxylation of histidin, which, to complete the chemical equation, gives rise to histamin and carbon dioxide. The same putrefactive processes occur in the decarboxylization of tyrosin with the production of tyramin, another of the toxic amino acids. Tyramin and histamin, strangely enough, are also found in disturbances of plant metabolism and are present in ergot, which is a parasitic fungus living on grains, particularly rye. Tyramin causes a contracture of smooth muscle, especially of the blood vessels and uterus, while histamin is a vasodilator, particularly of the capillary bed, causing an increased permeability of the capillaries and consequent tissue edema. The mother substances of these two toxic amino acids are of considerable importance in the structure of a 891
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protein molecule. Tyrosin, which then, is the parent of tyramin, is also the parent of adrenalin and enters into the protein structure of the medulla of the adrenal gland as well as controlling the sympathetic nervous system, blood pressure and also forms the basis of the phenomenon of pigment formation in the body. Histidin, from which the toxic histamin is derived, is one of the chief protein building substances. In the process of digestion, tyrosin and histidin are absorbed through the intestinal mucosa and carried to the liver through the system of the portal vein, where the liver, acting as a detoxifying agent,_secretes certain enzymes neutralizing the toxins (tyramin and histamin) allowing the amino acids themselves, such as tyrosin and histidin and others, to pass on to the tissue cells, where synthesis is brought about for purposes of growth and replacement of worn out tissues. Thus we see that a protein, having gone through the processes of digestion by the gastric and intestinal juices, augmented by pancreatic and liver digestants, enzymes, etc., is absorbed in the form of its amino acids. Due to putrefaction some of the histidin is further broken down by a process of decarboxylation into histamin, which is a toxic substance and is absorbed into the body as a toxin. It is up to the liver to detoxify this histamin, or we should better say, neutralize the histamin. In 1926 Best and his associates of the University of Toronto, found that histamin could be isolated from the liver, lungs, skin and other body tissues in pure form and when reinjected into another animal, would produce severe anaphylactic symptoms. Code, of the University College in London in 1937, found that when a patient suffered extreme trauma and shock, or came in contact with internal or external agents which might traumatize tissue, the amount of histamin in the blood was increased. Code concluded that injury to tissue caused the liberation from the tissue cells of an increased amount of histamin. This can easily be explained by reason of the fact that every protein molecule contains histidin, which, when altered chemically can give rise to varying amounts of histamin by a process of destruction. Barotsch, Dragstedt and others have shown that when an antigen comes in contact with a sensitized cell, substances resembling histamin are released in large quantities. The paramount question before the minds of most scientists is concerned with what may be the cause of a hypersensitization of tissue cells. It can be said with considerable certainty that a sensitized tissue cell is possessed with a lower state of vitality than a normal cell. It is
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susceptible to trauma and is a particularly vulnerable spot in the organism. It is further observed that the sensitivity of cells composing one tissue in the body is likewise accompanied by a hypersensitivity of other tissues in the same being. It has time and again been pointed out by many observers that the allergic patient is suffering from a constitutional deficiency, which makes him definitely below par in general health. There are a host of symptoms to be found common in sensitized persons, such as nervousness, readiness to fatigue, sensitivity to cold, susceptibility to infection in various organ systems, general irritability, eczemas, dermatoses, lowered threshold to pain, functional disturbances of the gastro-intestinal tract, accompanied by right sided colonic stasis and left sided spasticity, a hypertensive nervous system throughout, ocular disturbances manifested by muscular imbalances, errors of refraction and inflammatory lesions of the iris, ciliary bodies, conjunctivae and lids. The urological symptoms seen in this class of patients are associated with an irritable bladder, chronic infection of the kidneys, prostate, seminal vesicles and verumontanum, chronic nephritis of a toxic origin, sexual neuroses, and disturbances of libido. The symptoms of hay fever or asthma, up until the last few years, have been the only generally accepted symptoms referable to chronic allergy and are frequently associated with cases manifesting genito-urinary allergy. The association of all these symptoms has become so apparent, that it is imperative to investigate their presence by an adequate history that may give definite clues in obscure urological cases. The importance of this subject has brought about the necessity of a general physical examination, including routine blood count, blood Wassermann tests, glucose tolerance tests, stool examinations and basal metabolism tests, in addition to the urinalyses in practically all urological cases. To complete the picture properly, an x-ray study of the chest, gall-bladder, gastro-intestinal tract and teeth should be made, in addition to roentgenological study of the genitourinary tract. These observations must be made before any case can be designated as strictly an allergic subject, as obscure pathological conditions may be overlooked masking itself as an allergic symptom. There is no question but that the time has arrived for thorough and scientific work in the treatment of medical ailments and we must relegate to the past the former methods of treating a case upon symptoms alone. There has been one confusing issue, which at times has been overlooked and caused us all manner of embarrassment with regard to diag-
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nosis of allergic cystitis, both in men and women. This is the question of a chronic low grade trichomonas infection in the colon and vagina and directly affecting the female urethra. In men we find the trichomonas in his female partner to be the exciting cause of a great deal of chronic urethritis and prostatitis. If one is not careful to thoroughly examine the female for several times during the menstrual cycle, especially around the period, the trichomonas infection might be overlooked and an erroneous diagnosis made of allergic urinary trouble. It has been our experience that all patients with a vaginal infection of trichomonas do not necessarily have the organism present in the colon and when the infection is found in the colon there may be no vaginal symptoms. The trichomonads very seldom remain in the male urethra due to the acidity of urine, but repeated exposures to the trichomonas secretions furnish a persistent inflammatory reaction in the male. Investigations of focal infection should be made and when discovered should be treated perhaps with conservatism first. This attitude is assumed in contradistinction to the former technique of removing the foci with the initial treatment, except, however, teeth, which are devitalized or otherwise infected, and tonsils that are known to have been the seat of repeated infectious processes. The urologist is concerned ' with the treatment of chronic infectious processes in the kidney, prostate and seminal vesicles and bladder, where the removal of such foci in some cases cannot be done and in others should be contemplated only as a very last resort because of the magnitude and seriousness of the procedure involved. Since it is felt among many observers that an allergic state lowers the vitality and resistance of the tissues involved and in view of the fact that we now have antiseptics of a chemotherapeutic nature, sufficient to sterilize infected areas, it seems possible that by correcting the allergic state and thereby building up the resistance of tissues, the recurrence of infections should be brought under check and the chronicity of the process mitigated or relieved. Again returning to the question which concerns the reasons for a hypersensitivity of tissue cells and the consequent lowered resistance of tissue cells to infection, we are confronted with the problem of considering the nutrit,ional basis for this phenomenon. We have thought that the daily diet, that now comes to us preserved, dried, canned, frozen, pasteurized and aged with cold storage, was sufficient to maintain a state of normal resistance to disease. It is now apparent that such a diet is wholly inadequate in those vitamins that are unstable in
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the natural state, such as vitamin A, the flavin factors of vitamin B and the antipellagrinous factors of vitamin B which may include nicotinic acid, vitamin C and perhaps numerous other factors in the realm of vitamins and essential minerals that have as yet been undiscovered. There is no question that there are some essential factors in unrefined liver which are lost in the process of preparation in the liver concentrates. Time does not permit a detailed and argumentive discussion of the present day vitamin deficiencies of our people. It should be sufficient to say that the average diet is deficient in vitamins as well as essential minerals and chemical elements necessary to maintain a normal nutritional state in the absence of disease. This deficient state of nutrition is undoubtedly the basis for the sensitized tissue cells and it is further understood that unless this vitamin deficiency is supplemented either by the giving of rare or raw fresh meats, fruits, vegetables, such as raw or rare beef, liver or oysters, raw milk and eggs, fresh green vegetables or fruits, or by the administration of the recently isolated or synthetic vitamins in stable form, the susceptibility to allergy cannot be permanently brought under control. In the beginning of this discussion it was pointed out that histamine is liberated from the tissue cells whenever normal tissue is traumatized, and further, it is liberated in abnormally large amounts whenever sensitized tissue is traumatized. It was also stated that histamin is absorbed from the intestinal tract in abnormally large amounts whenever intestinal stasis and excessive putrefaction takes place within the bowel. Many physiologists believe that the manifestations of allergy are due to a failure of the body to metabolize or detoxify the excess of this substance. Histamin, on the other hand, serves a useful purpose in stimulating the gastric secretions, thereby aiding digestion in the stomach. In the small intestine, where the greater part of absorption takes place, it has been found that there is present an enzyme that detoxifies or neutralizes histamin, thereby preventing untoward effects from the intestinal absorption of histamin into the blood stream. Should histamin be absorbed through the intestinal mucosa, however, the second line of defense is found in the liver, where this same enzyme, now known as histaminase, neutralizes or detoxifies histamin. In 1915, Eustis reported that an extract prepared from liver when incubated with histamin, had the effect of neutralizing the histamin and rendered it non-toxic. He considers this substance derived from the liver to be an enzyme. In 1930 Best and McHenry recovered from the
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body tissues an enzyme they called histaminase because of its ability to detoxify histamin. Histaminase was found in the blood, liver, muscles, spleen and lungs, but more abundantly in the kidney and mucosa of the small intestines. Histaminase was absent in the gastric mucosa. These observations lead to a new approach in the treatment of protein sensitization. Histaminase also offers another source of usefulness by its inactivation of histamin in the treatment of gastric and duodenal ulcers, in that it serves to lower the acidity of the stomach by lessening the stimulus produced by histamin on the gastric mucosa, according to the work of Roth. Histaminase is now being produced commercially by the Winthrop Chemical Company and is found to be an active stable powder derived mainly from the intesinal mucosa, kidneys and liver. It is a fluffy, faintly yellowish white flakes and responds to chemical reactions common to albumins. It is soluble in water up to 10 per cent and has a total nitrogen value of 6 per cent, according to the manufacturer's assay. It is available for oral administration in enteric coated tablets containing 5 units each, and for parenteral administration in ampoules of 1 unit each. The substance seems to be non-toxic and doses of 100 units per kilogram body weight were administered to rats, mice without any ill effects in single doses. In repeated doses mice tolerated 100 units daily for 14 days, rats 20 units for 14 days, cats 10 units without any harmful effects. These were the largest doses tested. The scale of a unit was said to be that amount of histamin which contained the smallest amount of histaminase, causing no fall in blood pressure when injected into dogs, weighing between 6 and 12 kilograms. The injections were made on narcotized dogs, using veronal sodium. According to previously published data histaminase is indicated for trial in allergic conditions, such as asthma, hay fever, urticaria, serum sickness, sensitivity to insulin, cold allergy, acne, gastric and duodenal ulcer, toxicity of burns, and in radiation sickness. The human dose of histaminase is highly individualized as it must be used in the sense of substitution therapy. It is usually wise to start the patient with 5 units once, twice or 3 times a day and in the average case, 4 five-unit capsules a day will achieve the desired results. Some obstinate cases require 2 five-unit capsules 3 times a day. When the desired result has been obtained, the maintenance dose may be considered much less and frequently the dose may be tapered off. The manufacturer states that doses as high as 20 units 3 times a day have
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been well tolerated in some cases. As a prophylactic in serum sickness or in cases known to be sensitive to insulin, the drug should be administered several days prior to the administration of the offending medicinal treatment. At the same time the histaminase is being administered, active desensitizing therapy should be carried out by giving intradermal. injections of .05 cc. histamin acid phosphate 1: 5,000 every day for a period varying from 1 to 8 weeks, depending on the severity of the condition being treated. When allergic conditions have been relieved the injections may then be tapered off to every other day, twice a week, once a week and so on. As soon as the acute symptoms have subsided, histaminase may be discontinued and the patient maintained entirely on the desensitizing injections of histamin acid phosphate. Since it has been shown that these cases are all essentially deficient in vitamins, it is found that the simultaneous administration of vitamins is most important in obtaining lasting results in the desensitizing procedure. While the question is far from ultimate solution, it appears that the administration of vitamins should be continued over a period of years and the patient placed on a very high vitamin and mineral diet. As has been further pointed out the presence of colonic stagnation and excessive putrefaction is responsible for most intestinal allergy and another vital factor in the relief of these patients is to be found through the proper treatment of their stagnant and spastic colons. Strong purgatives, enemas, colonic irrigations are to be forcibly condemned, as well as the so-called bland diets of pureed, emulsified, overly-cooked foods previously adhered to in the treatment of spastic colons. With the use of any of the more co~mon bulk producing substances on the market that are derived from any of the mucilagenous gums or psyllium seed extracts, fortified if necessary with small amounts of cascara, and the prescribing of an adequate well balanced diet, high in vitamins and minerals, consisting of as much uncooked and fresh foods as possible, the great majority of patients will be relieved of symptoms of colitis, provided, of courses, they have no specific parasitic infectious enteritis. While such cases may be allergic to a number of foods, the allergy is quickly overcome with the use of histaminase and histamin desensitizing therapy, and patients so treated have been able to eat anything they desired without the fear of allergic reactions. This form of therapy has been of great advantage to the urologist because it furnishes a substitution for the abominable and unscientific alkaline treatment for gastric
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disorders, which plays havoc with the urinary tract by entering into the etiology of calculus disease and alkaline cystitis. It is to be noted here that the administration of too much alkali or too much acid (with special reference to hydrochloric acid, mandelic acid and ammonium nitrate) neutralizes the buffers of the blood, precipitates the insoluble oalcium phosphates, which have to be secreted by the kidneys as such, and furnishes the source of calculus disease of the kidneys, when such a kidney is the seat of a mild inflammatory change. I have treated some 37 cases exhibiting urological symptoms associated with allergy and in every instance the urological symptoms have definitely improved or have been entirely relieved by the histaminase and histamin desensitizing therapy. In addition, we have had gratifying results in the relief of associated allergic conditions in these same cases, such as asthma, hay fever, serum sickness, radiation sickness, sensitivity to insulin, migraine headaches, allergic dermatitis, allergic conjunctivitis, iritis and pansinusitis and in allergic hydroarthritis. Case 1. Mr. T. 0. M., age 65. Allergic symptoms : Cystitis; itching skin rash, chronic constipation. Diagnosis: Chronic cardiorenal vascular disease, general avitaminosis, chronic allergy. Therapy: All-vitamin therapy, especially C; histaminase, 20 units a day for 1 week, bulk producing laxatives. Results: Skin rash and cystitis relieved; no recurrence after 4 months. Case 2. Mrs. M. R. F., age 55. Allergic symptoms: Burning and frequency of urination; normal urine; herpes zoster, food allergy, indigestion, dryness of mucosal lining of nose with burning sensation. Diagnosis: General avitaminosis, multiple neuritis, chronic allergy. Therapy : All-vitamin therapy, especially B-1; histaminase, 20 units a day for 3 weeks; histamine desensitization for 3 weeks; ultra violet to herpes, 2000 units estrogenic substance twice a week. Results: Complete relief of allergic symptoms, and no recurrence at the end of 2 months. Patient required 2000 units of estrogenic substance once a week as a maintenance dose for control of menopausal symptoms. Case 3. Mrs. J. G., age 39. Allergic symptoms: Burning and aching in the bladder, soreness in the lower abdomen; urine normal, except for a trace of albumin; urticaria, nervous indigestion, food allergy, nausea, migraine headaches. Diagnosis: Estrogenic deficiency, general avitaminosis, chronic allergy, cystitis.
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Therapy: Histaminase, 20 units a day for 1 week, followed by histamine desensitization for 3 weeks; continued estrogenic therapy which she had been on for 2 years; also continuation of all-vitamin therapy which she had been on for 3 months previously. Results: Before taking histaminase developed urticaria, which histaminase did not relieve. Histaminase gave a reaction described as a choking sensation and a fullness in the throat, with increased nervousness. Histamine desensitization relieved urticaria, food allergy and bladder symptoms. No recurrence of allergic symptoms after four months. Case 4. Mr. L. H ., age 39. Allergic symptoms : Backache, burning on urination, loss of libido, nervousness, testicular pains; rhinitis, weakness, malaise, loss of voice, indigestion, intestinal flatus . Diagnosis : General avitaminosis, chronic food allergy. Therapy: Histaminase, 20 units a day for 2 weeks; all vitamin therapy, testosterone propionate, S mg. per week, which was started 6 months prior to allergic attacks. Histamine desensitization 3 times a week for 2 weeks and then once a week thereafter for 4 weeks and suprarenal concentrate, 4 gr. tid. for 1 month, relieved allergic symptoms. Results : Relieved of all allergic symptoms with histaminase; no recurrence in 5 months. Suprarenal and testosterone seemed to be necessary, together with vitamin therapy to prevent his chronic fatigue . Case 5. Mrs. L. B., age 67. Allergic symptoms: Frequency and burning on urination, soreness of the bladder; generalized eczema, estrogenic deficiency, gastrointestinal irritability. Diagnosis: General avitaminosis, chronic pollen allergy, estrogenic deficiency. Therapy : All-vitamin therapy, estrogenic therapy, histaminase, 20 units a day for 1 week when having an attack; histamine desensitization. Results : This case is unusual in that we have had the patient under observation off and on for 3 years. When allergic attacks occur, 2 or 3 histamine injections were all that were necessary to relieve the eczema, with the help of 20 units of histaminase daily for a few days. Bladder and skin symptoms always occur simultaneously. The attacks occur at intervals of 2 weeks to 2 months. We have been unable to get the patient to follow any definite desensitization course, due to the fact that she gets such spectacular relief from 1 or 2 doses that she does not feel the need of returning. Case 6. Mr. C. M . B., age 30. Allergic symptoms : Burning, frequency of urination, backache, reflex pains in lower abdomen and testicles, impotency; migraine headaches, gastrointestinal irritability, intestinal flatus, spastic colon.
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Diagnosis: General avitaminosis, chronic allergy, non-infectious verumontanitis. Therapy: All-vitamin therapy, histaminase 20 units a day for 1 month along with histamine desensitization injections daily. Urethral dilations and endoscopic applications of 10 per cent silver nitrate. Results : Completely relieved of food allergy, the gastrointestinal, genitourinary symptoms and the migraine headaches; 1 recurrent attack 2 months after therapy was started; relieved again with histamine and histaminase therapy for 2 weeks. Case 7. Mrs. C. M . B., age 23. Allergic symptoms : Soreness in the bladder and pelvis, frequency of urination, difficult urination at times; urticaria after eating chocolate, migraine headaches, chronic eczema of the scalp, malaise, extreme nervousness, chronic constipation. Diagnosis : General avitaminosis, mild hypothyroidism (BMR-16), hemoglobinemia (68 per cent), chronic non-infectious edema of the vesical neck. Therapy: All-vitamin therapy, thyroid and calcium, iron and copper ; histamine desensitization over a period of a month; urethral dilations and endoscopies. Results: Bladder symptoms, urticaria, migrain headaches all relieved in spite of the fact that she was eating regularly of foods to which she previously had allergic reactions. Case 8. Miss M . L. E. , age 32. Allergic symptoms : Burning, frequency of urination, backache, bearing down in lower abdomen, which comes concomitantly with general symptoms of allergy ; nervousness, malaise, fatigue, rhinitis, conjunctivitis, facial eczema, gastro-intestinal irritability. Diagnosis: General avitaminosis, pollen and food allergy. Therapy : All-vitamin therapy, neoprontosil oral, histamine desensitizations and 20 units histaminase a day when needed to control allergic symptoms; urethral dilations and endoscopic applications. Results: Bladder symptoms are always worse with symptoms of food and pollen allergy. The first course of histamine and histaminase kept her comfortable for 3 months. She had a recurrence and began again with the drugs and got immediate relief of all symptoms. Patient had been receiving local bladder treatments and urinary antiseptics off and on for 2 years with very poor results until it was observed that she was allergic. She can now eat anything without fear of bladder irritation. Case 9. Mrs. W. McD., age 34. Allergic symptoms : Burning, frequency of urination. Transient albuminuria, backache, legache, kidneys normal; migraine headache, fatigue , malaise, nervousness, chronic constipation, low blood pressure.
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Diagnosis: General avitaminosis, non-infectious urethritis. Therapy: All-vitamin therapy, urethral treatments, histamine desensitizations over a period of a month; histaminase, 20 units a day for 2 weeks, 10 units a day for 2 more weeks, parenteral administration of calcium gluconate, 15½ gr. Result: Until histamine and histaminase were begun, urinary symptoms were not much improved. Nor were the headaches or the gastro-intestinal irritability. Case 10. Mr. K. G. Allergic symptoms: Burning, frequency of urination, backache; asthma, severe form, chronic constipation. Diagnosis: Quiescent cholecystitis with cholelithiasis, congenital herniation of stomach through diaphragm and esophageal hiatus, multiple dental infection, (pyorrheal infection), general avitaminosis, non-infectious verumontanitis. Therapy: All-vitamin therapy, suprarenal concentrate, 6 gr. daily, following a course of histaminase, 20 units a day for 1 week; histamine desensitizations for a period of a month. Results: Patient was submitted to complete clinical and x-ray examinations of the gallbladder and intestinal tract. The gall bladder was quiescent. It was determined that herniation of the stomach had nothing to do with the asthma as the position of the patient did not influence the attacks. He had no dyspepsia or gastro-intestinal symptoms except constipation, which was relieved by bulk producing laxatives. Before extraction of the teeth, patient had complete relief of asthmatic and urinary symptoms with the suprarenal concentrate, histamine desensitization and all-vitamin therapy; no recurrence after 1 month. Following the course of histamine desensitization, patient had 1 infected tooth removed and refused to have the others out. Also refuses gall bladder surgery, although we are confident that the foci of infection mentioned are apparently the etiological factors in this case. It was mainly the histamine desensitizations that gave the patient relief, together with the all-vitamin therapy. He had no local treatment to the urinary tract. Urine was entirely normal. Case 11. Mrs. L.A., age 34. Allergic symptoms: Burning frequency of urination. Patient had previously had a trichomonas infection, which after much treatment, had apparently cleared up. Urine was normal, yet she continued to have bladder irritation, accompanied by backache, legache. Uterus had been removed S years previously. Marked urticaria, extreme nervousness, yearly attacks of hay fever, chronic eczema, gastrointestinal irritability. Diagnosis: Moderate hypothyroidism, general avitaminosis, chronic allergy, (eczema, urticaria, hay fever).
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Therapy: One urethral dilation to 35F caliber, a11-vftatn1n therapy, 1 gr. thyroid a day, bulk producing laxatives. Patient had been under observation for 2 years. Eczema did not improve, nor did the hay fever, urticaria, bladder or gastra-intestinal symptoms until histamine desensitization was carried out for a period of 3 weeks. With the first 2 injections the patient was symptom free. She has had no more hay fever for the first time in several years. Histaminase was given to this patient in 10 unit doses because of severity of urticaria, caused a severe reaction described as a choking sensation as if she had swallowed a bolus of food which was painfully passing down the esophagus. This patient had also had 3 injections of 1 cc. 1: 1,000 adrenalin solution in 24 hours to attempt to relieve the hives. We were never able to get her to take any more histaminase in smaller doses, especially since she got relief after 3 injections of histamine. An earlier injection of 15½ gr. calcium gluconate in the gluteal area relieved the spasm in the esophagus, which was thought to be the result of the histaminase. We had several other cases which suffered this type of reaction following histaminase. One could not tolerate any dose of histaminase without suffering spasm in the precordia and mediastinum. Two others were able to take histaminase in small doses. Case 12. Mr. J. L. P . Allergic symptoms: Edema of the vesical neck with retarded urinary stream, 5 ounces residuum, occurring comcomitantly with other allergic symptoms; during the acute spells there would be albumin in the urine, but no pus; an occasional pus cell in the prostatic secretions ; cystoscopically, there was no median bar, no prostatic enlargement or other obstructive phenomena; bladder mucosa appeared entirely normal between attacks; hydroarthritis of both knees, which would occur within 6 hours, always associated with constipation. Acute rheumatic changes in the joints, wrists, ankles, toes, fingers; iritis, involving one or both eyes. Diagnosis: Allergic cystitis, iritis, hydroarthritis and nephritis associated in attacks concomitant with constipation. Therapy and results : Histaminase, 20 units a day for a week failed to relieve the patient. Histamine desensitization, when given daily, relieved the cystitis, suppression of urine, the arthritis, provided it was accompanied by dehydrating influence of intravenous injections of mercupurine. Patient had recurrent attacks and histamine and histaminase therapy was given up. The case was carried through the worst attacks by injections of vitamin B-1, 5000 units every other day, together with calcium gluconate, 15½ gr., in the gluteal area, and prontylin, 20 gr. a day, over a period of 3 weeks. The constipation was controlled best with Breon's karabim with cascara, 2 teaspoonsful twice a day. This case was not tested for pollen or food allergy as we did not believe his attacks were produced by anything more than a protein putrefaction, resulting from his constipation. Complete x-ray examination of gall
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bladder, gastro-intestinal and genito-urinary tracts failed to reveal any pathological changes. Patient is still under observation but has been symptomfree for the last 4 weeks. This case illustrates one of the failures with histamine and histaminase therapy, but at the same time it serves to illustrate that protein putrefaction within the patient with a vitamin and mineral deficiency, is the basis of the allergic symptomatology, rather than specific foods or substances ingested. The patient has been on all-vitamin therapy in large doses, including large doses of vitamin D (Ertron, 50,000 units) to the point of saturation. Case 13. Mr. E. H. L., age 40. Allergic symptoms: He had been taking insulin for a 3 month period a year ago, for what appeared to be a transitory diabetes resulting from a syphilitic pancreatitis. His blood cholesterol was 266 mgm., blood sugar, 274 mgm. per 100 cc. of blood. After 3 months' treatment for his luetic condition and a restricted diet, he was able to maintain a normal blood sugar without insulin, the dose of insulin having been gradually decreased during his course of treatment. The patient quit his antiluetic treatment. Six months later double pneumonia developed. His blood sugar rose to 307 mgm. The patient was found to be allergic to insulin in all forms. Blood Wassermann was positive throughout. Diagnosis: Latent lues, syphilitic pancreatitis and diabetes. Therapy: Patient was given 20 grains of histaminase a day, which enabled him to tolerate his insulin. He was put on general vitamin therapy and and antiluetic treatment. He tolerates now 35 units of protamine zinc insulin. He is still under treatment.
These 13 cases a re presented as illustrative of a cross-section of our senes. The remaining 24 are practically identical with the types presented. Our only unsatisfactory result, (Case 13) was not considered an absolute failure because histamine desensitization offered sufficient benefit to warrant our repeating the treatment later in the course of our observation of the patient. With regard to reactions of histaminase, we obtained the choking and oppressive sensations in the chest and throat in 4 cases and found that migraine headaches in a fifth case were aggravated when as much as 10 units a day were administered. In 5 unit doses twice a day, these reactions were avoided in 3 of our 5 reactionaries; the other 2 were unable to tolerate any kind of dose . From our experience, it was evident that very small doses of histamine were more efficacious than the larger doses, and we made it a rule to give .025 cc. intradermally every day for some time, before in-
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creasing the dose to .05. One child received 3 histamine injections and was relieved of hay fever without further trouble and has remained symptom free for 2 months. Another child had histamine in 2 courses. A dose of .1 cc. was found to be too large and produced flushing of the face and nervous symptoms 20 minutes after injection. When this dose was reduced again to .025 cc., beneficial results were obtained without reaction. CONCLUSIONS
Certain urological symptoms do exist, that appear to be correlated with other conditions having an allergic basis, and that treatment of the allergy should be undertaken by the urologist when such conditions directly effect the relief of recurrent genito-urinary symptoms. Allergy is not a specific protein sensitization, but is a constitutional state of hypersensitivity or lowered resistance, produced by an avitaminosis, associated with a disturbed mineral metabolism. The local or general symptoms of allergy are provoked by an increased absorption, retention or failure of the body to properly detoxify the toxic amino acids, chief among which is histamine. The relief of the allergic state is not dependent on specific protein desensitization, but more logically should be brought about through the replacement of deficiencies ascertained in the individual case, not only by balancing the diet, but by medicinal mineral and vitamin therapy as well. Histaminase is the natural enzyme neutralizing histamine and is derived from the intestinal mucosa, and the liver, which are the natural detoxifying agents of the body, acting as a protective phenomenon against the absorption of the toxic products of putrefaction from the intestinal tract. Histamine desensitization is a more logical therapy for the relief of allergic symptoms than the older method of desensitizing against specific proteins, principally because it does not interfere with the normal balanced diet so essential in these cases, nor does it interfere with the economic and geographical environment of the patient. The histaminase used in these studies was supplied through the courtesy of the research department of the Winthrop Chemical Company.
Nix Professional Bldg., San Antonio, Texas
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REFERENCES BAROTSCH, R., FELDBERG, W., AND NAGEL, E.: Pfltiger's Arch. f. d . Ges. Physiol., 230: 129, 674, 1932. BERGER, HERBERT : Intermittent hydrathrosis with allergic basis. J. A. M.A., 112: 2402, 1939. BEST, C. H., DALE, H . H ., DUDLEY, H. W., AND THORP, W. V. : J. Physiol., 62: 397, 1926--27. BEST, C. H., AND McHENRY, E. A.: J. Physiol., 70: 349, 1930. BEST, C. H.: J. Physiol., 67: 256, 1939. BRAY, GEORGE W. : A case of physical allergy. A localized and generalized type of reaction cold. J. Allergy, 3: 367, 1932. CODE, C., AND MACDONALD, A. D.: Lancet, 2: 730, 1937. CODE, C. F ., AND ING, H . R. : J. Physiol., 90: 501, 1937. CODE, C. F.: J. Physiol., 90: 349, 1937. CODE, C. F.: J. Physiol., 89: 257, 1937. DRAGSTEDT, C. A., AND GEBAUER-FUELNEGG, E.: Am. J. Physiol. 102: 505, 1932. DRAGSTEDT, C. A. EYER, S. W., AND DEARELLANO, M . R .: Proc. Soc. for Exper. Biol. and Med. 38: 641, 1938. EusTIS, A. C. : Biochem. Bull. 4: 97, 1915. FOSHAY, LEE, AND HAGEBUSCH, 0 . C.: J. A. M.A., 112: 2398, 1939. HAWK, PHILIP B. : Practical Physiological Chemistry. 1921, P . Blakiston's Son and Co. lIJ:NTON, J. WILLIAM, MORTON, PAUL c., AND WEEKS, C.: Experimental and clinical studies of relationship of thyroid disease and pancreatic function. Ann. Surg., 99: 126, 1934. HORTON, B. T., MACLEAN, A. R., AND CRAIG, W. McK.: A new syndrome of vascular headache : Results of treatment with histamine and histaminase. Preliminary report. Proc. Staff. Meet. Mayo Clinic, 14: 257, 1939. HORTON, B. T., AND BROWN, G. B.: Cold allergy. Proc. Staff Meet., Mayo Clinic, 2: 276, 1937. MACLEOD, J. J. R.: Physiology and Biochemistry in Modern Medicine. 1919, C. V. Mosby Co. McHENRY AND GAVIN : Transcription Royal Soc. of Canada (Sect. 5, Biological Section) 26: 101-109, 1931. MORSE, WINTHROP : Applied Biochemistry. 1925, W. B . Saunders Co. ROTH, G. M., AND HORTON, B . T. : Proc. Staff Meet. Mayo Clinic, 12: 7, 1937. ROTH, G. M., AND RYNEARSON, E . H .: Use of histamine and histaminase in treatment of allergic reaction to insulin. Proc. Staff Meet. Mayo Clinic, 14: 353, 1939. WOLF, WILLIAM : Endocrinology in Modern Practice. 1937, W. B. Saunders Co.
Urology, perhaps more than any other specialty, is confronted with problems of expansion, both from the diagnostic and therapeutic consideration. Perhaps the biggest farce of all time is to be found in the neurogenic allocations, that so many of us are prone to consider in the diagnostic horizon as being the cause of many of our chronic urological ailments. This state of dissatisfaction has lead a goodly number of urologists into the field of allergy, which, in a small measure, seems to throw additional light upon the obscure etiological factors contributing to genito-urinary diseases. We are all familiar with focal infections such as found in pyorrhea! pockets, devitalized teeth, chronically infected tonsils, chronic gall bladder disease, chronic appendicitis, etc. More recently our attention has been drawn to the various infectious and toxic processes, associated with sluggish and inadequate bowel elimination, their relation to kidney excretion and effect upon the endocrine system, which now has a fairly well established role in the management of genital disturbances. With this scope of scientific activity in mind, we have been intensely interested in the production of putrefaction and its far reaching pharmacological effects upon the human organism. Histamin is one of these products, a toxic amino acid, derived from histidin by a process of putrefaction through the activity of carboxylase bacteria. The biochemical process involved is that of decarboxylation of histidin, which, to complete the chemical equation, gives rise to histamin and carbon dioxide. The same putrefactive processes occur in the decarboxylization of tyrosin with the production of tyramin, another of the toxic amino acids. Tyramin and histamin, strangely enough, are also found in disturbances of plant metabolism and are present in ergot, which is a parasitic fungus living on grains, particularly rye. Tyramin causes a contracture of smooth muscle, especially of the blood vessels and uterus, while histamin is a vasodilator, particularly of the capillary bed, causing an increased permeability of the capillaries and consequent tissue edema. The mother substances of these two toxic amino acids are of considerable importance in the structure of a 891
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protein molecule. Tyrosin, which then, is the parent of tyramin, is also the parent of adrenalin and enters into the protein structure of the medulla of the adrenal gland as well as controlling the sympathetic nervous system, blood pressure and also forms the basis of the phenomenon of pigment formation in the body. Histidin, from which the toxic histamin is derived, is one of the chief protein building substances. In the process of digestion, tyrosin and histidin are absorbed through the intestinal mucosa and carried to the liver through the system of the portal vein, where the liver, acting as a detoxifying agent,_secretes certain enzymes neutralizing the toxins (tyramin and histamin) allowing the amino acids themselves, such as tyrosin and histidin and others, to pass on to the tissue cells, where synthesis is brought about for purposes of growth and replacement of worn out tissues. Thus we see that a protein, having gone through the processes of digestion by the gastric and intestinal juices, augmented by pancreatic and liver digestants, enzymes, etc., is absorbed in the form of its amino acids. Due to putrefaction some of the histidin is further broken down by a process of decarboxylation into histamin, which is a toxic substance and is absorbed into the body as a toxin. It is up to the liver to detoxify this histamin, or we should better say, neutralize the histamin. In 1926 Best and his associates of the University of Toronto, found that histamin could be isolated from the liver, lungs, skin and other body tissues in pure form and when reinjected into another animal, would produce severe anaphylactic symptoms. Code, of the University College in London in 1937, found that when a patient suffered extreme trauma and shock, or came in contact with internal or external agents which might traumatize tissue, the amount of histamin in the blood was increased. Code concluded that injury to tissue caused the liberation from the tissue cells of an increased amount of histamin. This can easily be explained by reason of the fact that every protein molecule contains histidin, which, when altered chemically can give rise to varying amounts of histamin by a process of destruction. Barotsch, Dragstedt and others have shown that when an antigen comes in contact with a sensitized cell, substances resembling histamin are released in large quantities. The paramount question before the minds of most scientists is concerned with what may be the cause of a hypersensitization of tissue cells. It can be said with considerable certainty that a sensitized tissue cell is possessed with a lower state of vitality than a normal cell. It is
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susceptible to trauma and is a particularly vulnerable spot in the organism. It is further observed that the sensitivity of cells composing one tissue in the body is likewise accompanied by a hypersensitivity of other tissues in the same being. It has time and again been pointed out by many observers that the allergic patient is suffering from a constitutional deficiency, which makes him definitely below par in general health. There are a host of symptoms to be found common in sensitized persons, such as nervousness, readiness to fatigue, sensitivity to cold, susceptibility to infection in various organ systems, general irritability, eczemas, dermatoses, lowered threshold to pain, functional disturbances of the gastro-intestinal tract, accompanied by right sided colonic stasis and left sided spasticity, a hypertensive nervous system throughout, ocular disturbances manifested by muscular imbalances, errors of refraction and inflammatory lesions of the iris, ciliary bodies, conjunctivae and lids. The urological symptoms seen in this class of patients are associated with an irritable bladder, chronic infection of the kidneys, prostate, seminal vesicles and verumontanum, chronic nephritis of a toxic origin, sexual neuroses, and disturbances of libido. The symptoms of hay fever or asthma, up until the last few years, have been the only generally accepted symptoms referable to chronic allergy and are frequently associated with cases manifesting genito-urinary allergy. The association of all these symptoms has become so apparent, that it is imperative to investigate their presence by an adequate history that may give definite clues in obscure urological cases. The importance of this subject has brought about the necessity of a general physical examination, including routine blood count, blood Wassermann tests, glucose tolerance tests, stool examinations and basal metabolism tests, in addition to the urinalyses in practically all urological cases. To complete the picture properly, an x-ray study of the chest, gall-bladder, gastro-intestinal tract and teeth should be made, in addition to roentgenological study of the genitourinary tract. These observations must be made before any case can be designated as strictly an allergic subject, as obscure pathological conditions may be overlooked masking itself as an allergic symptom. There is no question but that the time has arrived for thorough and scientific work in the treatment of medical ailments and we must relegate to the past the former methods of treating a case upon symptoms alone. There has been one confusing issue, which at times has been overlooked and caused us all manner of embarrassment with regard to diag-
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nosis of allergic cystitis, both in men and women. This is the question of a chronic low grade trichomonas infection in the colon and vagina and directly affecting the female urethra. In men we find the trichomonas in his female partner to be the exciting cause of a great deal of chronic urethritis and prostatitis. If one is not careful to thoroughly examine the female for several times during the menstrual cycle, especially around the period, the trichomonas infection might be overlooked and an erroneous diagnosis made of allergic urinary trouble. It has been our experience that all patients with a vaginal infection of trichomonas do not necessarily have the organism present in the colon and when the infection is found in the colon there may be no vaginal symptoms. The trichomonads very seldom remain in the male urethra due to the acidity of urine, but repeated exposures to the trichomonas secretions furnish a persistent inflammatory reaction in the male. Investigations of focal infection should be made and when discovered should be treated perhaps with conservatism first. This attitude is assumed in contradistinction to the former technique of removing the foci with the initial treatment, except, however, teeth, which are devitalized or otherwise infected, and tonsils that are known to have been the seat of repeated infectious processes. The urologist is concerned ' with the treatment of chronic infectious processes in the kidney, prostate and seminal vesicles and bladder, where the removal of such foci in some cases cannot be done and in others should be contemplated only as a very last resort because of the magnitude and seriousness of the procedure involved. Since it is felt among many observers that an allergic state lowers the vitality and resistance of the tissues involved and in view of the fact that we now have antiseptics of a chemotherapeutic nature, sufficient to sterilize infected areas, it seems possible that by correcting the allergic state and thereby building up the resistance of tissues, the recurrence of infections should be brought under check and the chronicity of the process mitigated or relieved. Again returning to the question which concerns the reasons for a hypersensitivity of tissue cells and the consequent lowered resistance of tissue cells to infection, we are confronted with the problem of considering the nutrit,ional basis for this phenomenon. We have thought that the daily diet, that now comes to us preserved, dried, canned, frozen, pasteurized and aged with cold storage, was sufficient to maintain a state of normal resistance to disease. It is now apparent that such a diet is wholly inadequate in those vitamins that are unstable in
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the natural state, such as vitamin A, the flavin factors of vitamin B and the antipellagrinous factors of vitamin B which may include nicotinic acid, vitamin C and perhaps numerous other factors in the realm of vitamins and essential minerals that have as yet been undiscovered. There is no question that there are some essential factors in unrefined liver which are lost in the process of preparation in the liver concentrates. Time does not permit a detailed and argumentive discussion of the present day vitamin deficiencies of our people. It should be sufficient to say that the average diet is deficient in vitamins as well as essential minerals and chemical elements necessary to maintain a normal nutritional state in the absence of disease. This deficient state of nutrition is undoubtedly the basis for the sensitized tissue cells and it is further understood that unless this vitamin deficiency is supplemented either by the giving of rare or raw fresh meats, fruits, vegetables, such as raw or rare beef, liver or oysters, raw milk and eggs, fresh green vegetables or fruits, or by the administration of the recently isolated or synthetic vitamins in stable form, the susceptibility to allergy cannot be permanently brought under control. In the beginning of this discussion it was pointed out that histamine is liberated from the tissue cells whenever normal tissue is traumatized, and further, it is liberated in abnormally large amounts whenever sensitized tissue is traumatized. It was also stated that histamin is absorbed from the intestinal tract in abnormally large amounts whenever intestinal stasis and excessive putrefaction takes place within the bowel. Many physiologists believe that the manifestations of allergy are due to a failure of the body to metabolize or detoxify the excess of this substance. Histamin, on the other hand, serves a useful purpose in stimulating the gastric secretions, thereby aiding digestion in the stomach. In the small intestine, where the greater part of absorption takes place, it has been found that there is present an enzyme that detoxifies or neutralizes histamin, thereby preventing untoward effects from the intestinal absorption of histamin into the blood stream. Should histamin be absorbed through the intestinal mucosa, however, the second line of defense is found in the liver, where this same enzyme, now known as histaminase, neutralizes or detoxifies histamin. In 1915, Eustis reported that an extract prepared from liver when incubated with histamin, had the effect of neutralizing the histamin and rendered it non-toxic. He considers this substance derived from the liver to be an enzyme. In 1930 Best and McHenry recovered from the
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body tissues an enzyme they called histaminase because of its ability to detoxify histamin. Histaminase was found in the blood, liver, muscles, spleen and lungs, but more abundantly in the kidney and mucosa of the small intestines. Histaminase was absent in the gastric mucosa. These observations lead to a new approach in the treatment of protein sensitization. Histaminase also offers another source of usefulness by its inactivation of histamin in the treatment of gastric and duodenal ulcers, in that it serves to lower the acidity of the stomach by lessening the stimulus produced by histamin on the gastric mucosa, according to the work of Roth. Histaminase is now being produced commercially by the Winthrop Chemical Company and is found to be an active stable powder derived mainly from the intesinal mucosa, kidneys and liver. It is a fluffy, faintly yellowish white flakes and responds to chemical reactions common to albumins. It is soluble in water up to 10 per cent and has a total nitrogen value of 6 per cent, according to the manufacturer's assay. It is available for oral administration in enteric coated tablets containing 5 units each, and for parenteral administration in ampoules of 1 unit each. The substance seems to be non-toxic and doses of 100 units per kilogram body weight were administered to rats, mice without any ill effects in single doses. In repeated doses mice tolerated 100 units daily for 14 days, rats 20 units for 14 days, cats 10 units without any harmful effects. These were the largest doses tested. The scale of a unit was said to be that amount of histamin which contained the smallest amount of histaminase, causing no fall in blood pressure when injected into dogs, weighing between 6 and 12 kilograms. The injections were made on narcotized dogs, using veronal sodium. According to previously published data histaminase is indicated for trial in allergic conditions, such as asthma, hay fever, urticaria, serum sickness, sensitivity to insulin, cold allergy, acne, gastric and duodenal ulcer, toxicity of burns, and in radiation sickness. The human dose of histaminase is highly individualized as it must be used in the sense of substitution therapy. It is usually wise to start the patient with 5 units once, twice or 3 times a day and in the average case, 4 five-unit capsules a day will achieve the desired results. Some obstinate cases require 2 five-unit capsules 3 times a day. When the desired result has been obtained, the maintenance dose may be considered much less and frequently the dose may be tapered off. The manufacturer states that doses as high as 20 units 3 times a day have
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been well tolerated in some cases. As a prophylactic in serum sickness or in cases known to be sensitive to insulin, the drug should be administered several days prior to the administration of the offending medicinal treatment. At the same time the histaminase is being administered, active desensitizing therapy should be carried out by giving intradermal. injections of .05 cc. histamin acid phosphate 1: 5,000 every day for a period varying from 1 to 8 weeks, depending on the severity of the condition being treated. When allergic conditions have been relieved the injections may then be tapered off to every other day, twice a week, once a week and so on. As soon as the acute symptoms have subsided, histaminase may be discontinued and the patient maintained entirely on the desensitizing injections of histamin acid phosphate. Since it has been shown that these cases are all essentially deficient in vitamins, it is found that the simultaneous administration of vitamins is most important in obtaining lasting results in the desensitizing procedure. While the question is far from ultimate solution, it appears that the administration of vitamins should be continued over a period of years and the patient placed on a very high vitamin and mineral diet. As has been further pointed out the presence of colonic stagnation and excessive putrefaction is responsible for most intestinal allergy and another vital factor in the relief of these patients is to be found through the proper treatment of their stagnant and spastic colons. Strong purgatives, enemas, colonic irrigations are to be forcibly condemned, as well as the so-called bland diets of pureed, emulsified, overly-cooked foods previously adhered to in the treatment of spastic colons. With the use of any of the more co~mon bulk producing substances on the market that are derived from any of the mucilagenous gums or psyllium seed extracts, fortified if necessary with small amounts of cascara, and the prescribing of an adequate well balanced diet, high in vitamins and minerals, consisting of as much uncooked and fresh foods as possible, the great majority of patients will be relieved of symptoms of colitis, provided, of courses, they have no specific parasitic infectious enteritis. While such cases may be allergic to a number of foods, the allergy is quickly overcome with the use of histaminase and histamin desensitizing therapy, and patients so treated have been able to eat anything they desired without the fear of allergic reactions. This form of therapy has been of great advantage to the urologist because it furnishes a substitution for the abominable and unscientific alkaline treatment for gastric
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disorders, which plays havoc with the urinary tract by entering into the etiology of calculus disease and alkaline cystitis. It is to be noted here that the administration of too much alkali or too much acid (with special reference to hydrochloric acid, mandelic acid and ammonium nitrate) neutralizes the buffers of the blood, precipitates the insoluble oalcium phosphates, which have to be secreted by the kidneys as such, and furnishes the source of calculus disease of the kidneys, when such a kidney is the seat of a mild inflammatory change. I have treated some 37 cases exhibiting urological symptoms associated with allergy and in every instance the urological symptoms have definitely improved or have been entirely relieved by the histaminase and histamin desensitizing therapy. In addition, we have had gratifying results in the relief of associated allergic conditions in these same cases, such as asthma, hay fever, serum sickness, radiation sickness, sensitivity to insulin, migraine headaches, allergic dermatitis, allergic conjunctivitis, iritis and pansinusitis and in allergic hydroarthritis. Case 1. Mr. T. 0. M., age 65. Allergic symptoms : Cystitis; itching skin rash, chronic constipation. Diagnosis: Chronic cardiorenal vascular disease, general avitaminosis, chronic allergy. Therapy: All-vitamin therapy, especially C; histaminase, 20 units a day for 1 week, bulk producing laxatives. Results: Skin rash and cystitis relieved; no recurrence after 4 months. Case 2. Mrs. M. R. F., age 55. Allergic symptoms: Burning and frequency of urination; normal urine; herpes zoster, food allergy, indigestion, dryness of mucosal lining of nose with burning sensation. Diagnosis: General avitaminosis, multiple neuritis, chronic allergy. Therapy : All-vitamin therapy, especially B-1; histaminase, 20 units a day for 3 weeks; histamine desensitization for 3 weeks; ultra violet to herpes, 2000 units estrogenic substance twice a week. Results: Complete relief of allergic symptoms, and no recurrence at the end of 2 months. Patient required 2000 units of estrogenic substance once a week as a maintenance dose for control of menopausal symptoms. Case 3. Mrs. J. G., age 39. Allergic symptoms: Burning and aching in the bladder, soreness in the lower abdomen; urine normal, except for a trace of albumin; urticaria, nervous indigestion, food allergy, nausea, migraine headaches. Diagnosis: Estrogenic deficiency, general avitaminosis, chronic allergy, cystitis.
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Therapy: Histaminase, 20 units a day for 1 week, followed by histamine desensitization for 3 weeks; continued estrogenic therapy which she had been on for 2 years; also continuation of all-vitamin therapy which she had been on for 3 months previously. Results: Before taking histaminase developed urticaria, which histaminase did not relieve. Histaminase gave a reaction described as a choking sensation and a fullness in the throat, with increased nervousness. Histamine desensitization relieved urticaria, food allergy and bladder symptoms. No recurrence of allergic symptoms after four months. Case 4. Mr. L. H ., age 39. Allergic symptoms : Backache, burning on urination, loss of libido, nervousness, testicular pains; rhinitis, weakness, malaise, loss of voice, indigestion, intestinal flatus . Diagnosis : General avitaminosis, chronic food allergy. Therapy: Histaminase, 20 units a day for 2 weeks; all vitamin therapy, testosterone propionate, S mg. per week, which was started 6 months prior to allergic attacks. Histamine desensitization 3 times a week for 2 weeks and then once a week thereafter for 4 weeks and suprarenal concentrate, 4 gr. tid. for 1 month, relieved allergic symptoms. Results : Relieved of all allergic symptoms with histaminase; no recurrence in 5 months. Suprarenal and testosterone seemed to be necessary, together with vitamin therapy to prevent his chronic fatigue . Case 5. Mrs. L. B., age 67. Allergic symptoms: Frequency and burning on urination, soreness of the bladder; generalized eczema, estrogenic deficiency, gastrointestinal irritability. Diagnosis: General avitaminosis, chronic pollen allergy, estrogenic deficiency. Therapy : All-vitamin therapy, estrogenic therapy, histaminase, 20 units a day for 1 week when having an attack; histamine desensitization. Results : This case is unusual in that we have had the patient under observation off and on for 3 years. When allergic attacks occur, 2 or 3 histamine injections were all that were necessary to relieve the eczema, with the help of 20 units of histaminase daily for a few days. Bladder and skin symptoms always occur simultaneously. The attacks occur at intervals of 2 weeks to 2 months. We have been unable to get the patient to follow any definite desensitization course, due to the fact that she gets such spectacular relief from 1 or 2 doses that she does not feel the need of returning. Case 6. Mr. C. M . B., age 30. Allergic symptoms : Burning, frequency of urination, backache, reflex pains in lower abdomen and testicles, impotency; migraine headaches, gastrointestinal irritability, intestinal flatus, spastic colon.
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Diagnosis: General avitaminosis, chronic allergy, non-infectious verumontanitis. Therapy: All-vitamin therapy, histaminase 20 units a day for 1 month along with histamine desensitization injections daily. Urethral dilations and endoscopic applications of 10 per cent silver nitrate. Results : Completely relieved of food allergy, the gastrointestinal, genitourinary symptoms and the migraine headaches; 1 recurrent attack 2 months after therapy was started; relieved again with histamine and histaminase therapy for 2 weeks. Case 7. Mrs. C. M . B., age 23. Allergic symptoms : Soreness in the bladder and pelvis, frequency of urination, difficult urination at times; urticaria after eating chocolate, migraine headaches, chronic eczema of the scalp, malaise, extreme nervousness, chronic constipation. Diagnosis : General avitaminosis, mild hypothyroidism (BMR-16), hemoglobinemia (68 per cent), chronic non-infectious edema of the vesical neck. Therapy: All-vitamin therapy, thyroid and calcium, iron and copper ; histamine desensitization over a period of a month; urethral dilations and endoscopies. Results: Bladder symptoms, urticaria, migrain headaches all relieved in spite of the fact that she was eating regularly of foods to which she previously had allergic reactions. Case 8. Miss M . L. E. , age 32. Allergic symptoms : Burning, frequency of urination, backache, bearing down in lower abdomen, which comes concomitantly with general symptoms of allergy ; nervousness, malaise, fatigue, rhinitis, conjunctivitis, facial eczema, gastro-intestinal irritability. Diagnosis: General avitaminosis, pollen and food allergy. Therapy : All-vitamin therapy, neoprontosil oral, histamine desensitizations and 20 units histaminase a day when needed to control allergic symptoms; urethral dilations and endoscopic applications. Results: Bladder symptoms are always worse with symptoms of food and pollen allergy. The first course of histamine and histaminase kept her comfortable for 3 months. She had a recurrence and began again with the drugs and got immediate relief of all symptoms. Patient had been receiving local bladder treatments and urinary antiseptics off and on for 2 years with very poor results until it was observed that she was allergic. She can now eat anything without fear of bladder irritation. Case 9. Mrs. W. McD., age 34. Allergic symptoms : Burning, frequency of urination. Transient albuminuria, backache, legache, kidneys normal; migraine headache, fatigue , malaise, nervousness, chronic constipation, low blood pressure.
:DESENSlT!ZATION IN G];N1'.t0-tJRlNARY ALLERGY
901
Diagnosis: General avitaminosis, non-infectious urethritis. Therapy: All-vitamin therapy, urethral treatments, histamine desensitizations over a period of a month; histaminase, 20 units a day for 2 weeks, 10 units a day for 2 more weeks, parenteral administration of calcium gluconate, 15½ gr. Result: Until histamine and histaminase were begun, urinary symptoms were not much improved. Nor were the headaches or the gastro-intestinal irritability. Case 10. Mr. K. G. Allergic symptoms: Burning, frequency of urination, backache; asthma, severe form, chronic constipation. Diagnosis: Quiescent cholecystitis with cholelithiasis, congenital herniation of stomach through diaphragm and esophageal hiatus, multiple dental infection, (pyorrheal infection), general avitaminosis, non-infectious verumontanitis. Therapy: All-vitamin therapy, suprarenal concentrate, 6 gr. daily, following a course of histaminase, 20 units a day for 1 week; histamine desensitizations for a period of a month. Results: Patient was submitted to complete clinical and x-ray examinations of the gallbladder and intestinal tract. The gall bladder was quiescent. It was determined that herniation of the stomach had nothing to do with the asthma as the position of the patient did not influence the attacks. He had no dyspepsia or gastro-intestinal symptoms except constipation, which was relieved by bulk producing laxatives. Before extraction of the teeth, patient had complete relief of asthmatic and urinary symptoms with the suprarenal concentrate, histamine desensitization and all-vitamin therapy; no recurrence after 1 month. Following the course of histamine desensitization, patient had 1 infected tooth removed and refused to have the others out. Also refuses gall bladder surgery, although we are confident that the foci of infection mentioned are apparently the etiological factors in this case. It was mainly the histamine desensitizations that gave the patient relief, together with the all-vitamin therapy. He had no local treatment to the urinary tract. Urine was entirely normal. Case 11. Mrs. L.A., age 34. Allergic symptoms: Burning frequency of urination. Patient had previously had a trichomonas infection, which after much treatment, had apparently cleared up. Urine was normal, yet she continued to have bladder irritation, accompanied by backache, legache. Uterus had been removed S years previously. Marked urticaria, extreme nervousness, yearly attacks of hay fever, chronic eczema, gastrointestinal irritability. Diagnosis: Moderate hypothyroidism, general avitaminosis, chronic allergy, (eczema, urticaria, hay fever).
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Therapy: One urethral dilation to 35F caliber, a11-vftatn1n therapy, 1 gr. thyroid a day, bulk producing laxatives. Patient had been under observation for 2 years. Eczema did not improve, nor did the hay fever, urticaria, bladder or gastra-intestinal symptoms until histamine desensitization was carried out for a period of 3 weeks. With the first 2 injections the patient was symptom free. She has had no more hay fever for the first time in several years. Histaminase was given to this patient in 10 unit doses because of severity of urticaria, caused a severe reaction described as a choking sensation as if she had swallowed a bolus of food which was painfully passing down the esophagus. This patient had also had 3 injections of 1 cc. 1: 1,000 adrenalin solution in 24 hours to attempt to relieve the hives. We were never able to get her to take any more histaminase in smaller doses, especially since she got relief after 3 injections of histamine. An earlier injection of 15½ gr. calcium gluconate in the gluteal area relieved the spasm in the esophagus, which was thought to be the result of the histaminase. We had several other cases which suffered this type of reaction following histaminase. One could not tolerate any dose of histaminase without suffering spasm in the precordia and mediastinum. Two others were able to take histaminase in small doses. Case 12. Mr. J. L. P . Allergic symptoms: Edema of the vesical neck with retarded urinary stream, 5 ounces residuum, occurring comcomitantly with other allergic symptoms; during the acute spells there would be albumin in the urine, but no pus; an occasional pus cell in the prostatic secretions ; cystoscopically, there was no median bar, no prostatic enlargement or other obstructive phenomena; bladder mucosa appeared entirely normal between attacks; hydroarthritis of both knees, which would occur within 6 hours, always associated with constipation. Acute rheumatic changes in the joints, wrists, ankles, toes, fingers; iritis, involving one or both eyes. Diagnosis: Allergic cystitis, iritis, hydroarthritis and nephritis associated in attacks concomitant with constipation. Therapy and results : Histaminase, 20 units a day for a week failed to relieve the patient. Histamine desensitization, when given daily, relieved the cystitis, suppression of urine, the arthritis, provided it was accompanied by dehydrating influence of intravenous injections of mercupurine. Patient had recurrent attacks and histamine and histaminase therapy was given up. The case was carried through the worst attacks by injections of vitamin B-1, 5000 units every other day, together with calcium gluconate, 15½ gr., in the gluteal area, and prontylin, 20 gr. a day, over a period of 3 weeks. The constipation was controlled best with Breon's karabim with cascara, 2 teaspoonsful twice a day. This case was not tested for pollen or food allergy as we did not believe his attacks were produced by anything more than a protein putrefaction, resulting from his constipation. Complete x-ray examination of gall
bESENSITIZA".rION IN GENITO-URINARY ALLERGY
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bladder, gastro-intestinal and genito-urinary tracts failed to reveal any pathological changes. Patient is still under observation but has been symptomfree for the last 4 weeks. This case illustrates one of the failures with histamine and histaminase therapy, but at the same time it serves to illustrate that protein putrefaction within the patient with a vitamin and mineral deficiency, is the basis of the allergic symptomatology, rather than specific foods or substances ingested. The patient has been on all-vitamin therapy in large doses, including large doses of vitamin D (Ertron, 50,000 units) to the point of saturation. Case 13. Mr. E. H. L., age 40. Allergic symptoms: He had been taking insulin for a 3 month period a year ago, for what appeared to be a transitory diabetes resulting from a syphilitic pancreatitis. His blood cholesterol was 266 mgm., blood sugar, 274 mgm. per 100 cc. of blood. After 3 months' treatment for his luetic condition and a restricted diet, he was able to maintain a normal blood sugar without insulin, the dose of insulin having been gradually decreased during his course of treatment. The patient quit his antiluetic treatment. Six months later double pneumonia developed. His blood sugar rose to 307 mgm. The patient was found to be allergic to insulin in all forms. Blood Wassermann was positive throughout. Diagnosis: Latent lues, syphilitic pancreatitis and diabetes. Therapy: Patient was given 20 grains of histaminase a day, which enabled him to tolerate his insulin. He was put on general vitamin therapy and and antiluetic treatment. He tolerates now 35 units of protamine zinc insulin. He is still under treatment.
These 13 cases a re presented as illustrative of a cross-section of our senes. The remaining 24 are practically identical with the types presented. Our only unsatisfactory result, (Case 13) was not considered an absolute failure because histamine desensitization offered sufficient benefit to warrant our repeating the treatment later in the course of our observation of the patient. With regard to reactions of histaminase, we obtained the choking and oppressive sensations in the chest and throat in 4 cases and found that migraine headaches in a fifth case were aggravated when as much as 10 units a day were administered. In 5 unit doses twice a day, these reactions were avoided in 3 of our 5 reactionaries; the other 2 were unable to tolerate any kind of dose . From our experience, it was evident that very small doses of histamine were more efficacious than the larger doses, and we made it a rule to give .025 cc. intradermally every day for some time, before in-
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creasing the dose to .05. One child received 3 histamine injections and was relieved of hay fever without further trouble and has remained symptom free for 2 months. Another child had histamine in 2 courses. A dose of .1 cc. was found to be too large and produced flushing of the face and nervous symptoms 20 minutes after injection. When this dose was reduced again to .025 cc., beneficial results were obtained without reaction. CONCLUSIONS
Certain urological symptoms do exist, that appear to be correlated with other conditions having an allergic basis, and that treatment of the allergy should be undertaken by the urologist when such conditions directly effect the relief of recurrent genito-urinary symptoms. Allergy is not a specific protein sensitization, but is a constitutional state of hypersensitivity or lowered resistance, produced by an avitaminosis, associated with a disturbed mineral metabolism. The local or general symptoms of allergy are provoked by an increased absorption, retention or failure of the body to properly detoxify the toxic amino acids, chief among which is histamine. The relief of the allergic state is not dependent on specific protein desensitization, but more logically should be brought about through the replacement of deficiencies ascertained in the individual case, not only by balancing the diet, but by medicinal mineral and vitamin therapy as well. Histaminase is the natural enzyme neutralizing histamine and is derived from the intestinal mucosa, and the liver, which are the natural detoxifying agents of the body, acting as a protective phenomenon against the absorption of the toxic products of putrefaction from the intestinal tract. Histamine desensitization is a more logical therapy for the relief of allergic symptoms than the older method of desensitizing against specific proteins, principally because it does not interfere with the normal balanced diet so essential in these cases, nor does it interfere with the economic and geographical environment of the patient. The histaminase used in these studies was supplied through the courtesy of the research department of the Winthrop Chemical Company.
Nix Professional Bldg., San Antonio, Texas
DESENSITIZATION IN GENITO-URINARY ALLERGY
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REFERENCES BAROTSCH, R., FELDBERG, W., AND NAGEL, E.: Pfltiger's Arch. f. d . Ges. Physiol., 230: 129, 674, 1932. BERGER, HERBERT : Intermittent hydrathrosis with allergic basis. J. A. M.A., 112: 2402, 1939. BEST, C. H., DALE, H . H ., DUDLEY, H. W., AND THORP, W. V. : J. Physiol., 62: 397, 1926--27. BEST, C. H., AND McHENRY, E. A.: J. Physiol., 70: 349, 1930. BEST, C. H.: J. Physiol., 67: 256, 1939. BRAY, GEORGE W. : A case of physical allergy. A localized and generalized type of reaction cold. J. Allergy, 3: 367, 1932. CODE, C., AND MACDONALD, A. D.: Lancet, 2: 730, 1937. CODE, C. F ., AND ING, H . R. : J. Physiol., 90: 501, 1937. CODE, C. F.: J. Physiol., 90: 349, 1937. CODE, C. F.: J. Physiol., 89: 257, 1937. DRAGSTEDT, C. A., AND GEBAUER-FUELNEGG, E.: Am. J. Physiol. 102: 505, 1932. DRAGSTEDT, C. A. EYER, S. W., AND DEARELLANO, M . R .: Proc. Soc. for Exper. Biol. and Med. 38: 641, 1938. EusTIS, A. C. : Biochem. Bull. 4: 97, 1915. FOSHAY, LEE, AND HAGEBUSCH, 0 . C.: J. A. M.A., 112: 2398, 1939. HAWK, PHILIP B. : Practical Physiological Chemistry. 1921, P . Blakiston's Son and Co. lIJ:NTON, J. WILLIAM, MORTON, PAUL c., AND WEEKS, C.: Experimental and clinical studies of relationship of thyroid disease and pancreatic function. Ann. Surg., 99: 126, 1934. HORTON, B. T., MACLEAN, A. R., AND CRAIG, W. McK.: A new syndrome of vascular headache : Results of treatment with histamine and histaminase. Preliminary report. Proc. Staff. Meet. Mayo Clinic, 14: 257, 1939. HORTON, B. T., AND BROWN, G. B.: Cold allergy. Proc. Staff Meet., Mayo Clinic, 2: 276, 1937. MACLEOD, J. J. R.: Physiology and Biochemistry in Modern Medicine. 1919, C. V. Mosby Co. McHENRY AND GAVIN : Transcription Royal Soc. of Canada (Sect. 5, Biological Section) 26: 101-109, 1931. MORSE, WINTHROP : Applied Biochemistry. 1925, W. B . Saunders Co. ROTH, G. M., AND HORTON, B . T. : Proc. Staff Meet. Mayo Clinic, 12: 7, 1937. ROTH, G. M., AND RYNEARSON, E . H .: Use of histamine and histaminase in treatment of allergic reaction to insulin. Proc. Staff Meet. Mayo Clinic, 14: 353, 1939. WOLF, WILLIAM : Endocrinology in Modern Practice. 1937, W. B. Saunders Co.