Protein Therapy

PROTEIN THERAPY, the parenteral administration of various protein substances into the organism for therapeutic purposes, i.e., not via the intestinal tract, but under the skin, intramuscularly, or intravenously. The experimental foundations for this therapeutic method were laid in the second half of the 19th century during the development of issues concerning non-specific immunity, but protein therapy gained citizenship in 1916, following the publication of the work by R. Schmidt. In 1887, Pavlovsky obtained immunity to anthrax in animals by preliminary administration of a culture of Bacillus prodigiosus into their abdominal cavity. In 1891, when Koch discovered tuberculin, Fr. Roemer showed that the same reactive phenomena observed in a tuberculous focus upon the injection of tuberculin can also be obtained upon the injection of other bacterial proteins. Furthermore, he showed that not only in the chronic tuberculous process, but also in other chronic infectious diseases, parenterally introduced proteins cause an exacerbation. In 1894, V. I. Isaev succeeded in protecting a guinea pig from a lethal dose of the cholera vibrio by introducing into the abdominal cavity or under the skin, 24 hours before infection, a culture of some non-pathogenic microbes, normal human serum, nucleic acid, or non-protein indifferent substances, even physiological NaCl solution or distilled water. In 1907, R. Deutschmann obtained a favorable effect in a number of infections (typhoid fever, lobar pneumonia, scarlet fever, influenza, erysipelas, angina, furunculosis) from the injection of horse serum into which yeast had been injected subcutaneously. Subsequently, a number of authors (Zlatogorov, Klein, Much, Frankel, and others) confirmed the possibility of obtaining immunity through preliminary parenteral introduction of both bacterial (vaccines, non-pathogenic microbes) and other proteins. Along with these experimental works, the existence of "non-specific" immunity was also confirmed by clinical observations. Thus, a favorable effect of the erysipelatous process on tuberculous lesions of the glands, and of malaria on the course of typhoid fever, etc., was noted. Furthermore, clinical observations showed that antidiphtheritic serum gives a good effect not only in diphtheria, but also in other infections, e.g., in erysipelas; on the other hand, in diphtheria, a good effect is also obtained from the injection of ordinary horse serum. After Bruck and Sommer obtained brilliant results upon the intravenous introduction of gonococcal vaccine in gonorrhea, and Ishikawa of typhoid vaccine in the treatment of typhoid fever, Kraus in 1914 showed that the same effect can be obtained from the use of non-specific vaccines (for example, B. coli vaccine in typhoid fever, etc.). After Lüdtke and others began to obtain equally good results in typhoid fever from the injection of a 2% solution of deuteroalbumose or peptone, Kraus, Weichardt, and R. Schmidt named this entire group of "non-specific therapy" by the general name "protein therapy." R. Schmidt proposed the parenteral introduction of milk (lactotherapy) as a therapeutic agent in both infectious and many other diseases, and after this, milk was for a time the most commonly used agent in protein therapy. It is impossible to list all protein preparations recommended for therapeutic purposes. The simplest and cheapest is cow's milk obtained from healthy animals, as freshly milked as possible, skimmed (to avoid fat embolism) by settling, centrifugation, or ether treatment, and sterilized by boiling on a fire or preferably in a water bath for 10 minutes. It should be injected intramuscularly (usually into the gluteal region), from 0.5 cm³ to 10 cm³, gradually increasing the doses at intervals of three to four days. In addition to natural cow's milk, industrial preparations prepared from it are used: aolan (see), ophthalmoszan (recently renamed "Abijon"), lactin, albuzol, Xifalmilch (skimmed milk with the addition of bacterial protein), hyperterman (whole milk with the addition of Bact. coli bovini vaccine); further, preparations from cow's milk casein—caseosan, actoprotin, yatrencasein (weak—2.5% casein and 2.5% yatren; strong—5% casein and 2.5% yatren). From serums, normal serum of the horse, bull, ram, as well as various blood serums of immunized animals (antidiphtheritic, anti-streptococcal, and others) are used. The dose is 5–30 cm³, preferably intramuscularly; to avoid the phenomena of serum sickness, the intervals between injections should be made no more than 3–4 days, or 1–2 hours before the injection, 0.5 cm³ of serum should be injected for desensitization purposes. Elfström and Grafström proposed (1893) treatment with the patient's own blood (see Autohemotherapy), and Gilbert—treatment with the patient's own blood serum (see Autoserotherapy). From bacterial preparations, various vaccines are used (typhoid, gonococcal, staphylococcal, cholera, etc.), tuberculin preparations, vaccineurin (autolysate from staphylococci and B. prodigiosus), omnadin (a mixture of various non-pathogenic microbes, bile lipoids, and neutral fats), and others. Then preparations from various proteins are used, for example, protin, novoprotan (crystalline plant protein), phlogetan (nucleoprotein degradation product), deuteroalbumose, the sodium salt of nucleic acid (nucleotherapy), peptone (5 cm³ of a 5% solution intramuscularly; Schur, Luria). Tissue extracts and human bodily excretion products were also proposed for parenteral introduction for therapeutic purposes. From the first group, mention should be made of the telatuten proposed by Heilner (from the vascular walls of young animals) for the treatment of arteriosclerosis, and sanarthrit (colloidal solution of animal embryonic cartilages) for the treatment of joint lesions; the second group includes the use of one's own pus (autopyotherapy by Mikai), sputum—for the treatment of pertussis (Kraus), tuberculosis (Belonovsky), bronchial asthma, and excrement—tylotherapy (Weinberg). M. Tushnov proposed degradation products of organs—histolysates—for parenteral introduction: testolysate, ovariolysate, luteolysate, thyreolysate, and others (salt solutions of products of enzymatic protein breakdown of the corresponding organs in the albumose stage). These preparations, according to Tushnov, possess specificity—they irritate the corresponding organ; depending on the dosage and the reactive state of the organ, this irritation can cause either an increase in functional activity or its suppression down to atrophy. Based on the same principle of organ specificity, Miyagawa proposes the parenteral introduction of organ emulsions, since experimental studies (by Japanese authors) have shown that the introduction of an emulsion of the renal cortex epithelium increases diuresis, the introduction of liver emulsion increases bile secretion, etc. Some non-protein substances, when introduced parenterally, cause the destruction of the body's cells, and the protein breakdown products formed in the process exert the same effect on the organism as that observed upon the parenteral introduction of protein preparations. On this is based the parenteral use in various infectious diseases of turpentine (20% in olive oil) according to Klingmüller, yatren, sulfur preparations (allergosan, sulfogel), colloidal metal solutions, hyper- and hypotonic solutions of salts and sugar. The mechanism of the therapeutic action in infectious diseases of some physical-therapeutic measures is partly of the same nature, such as: dry cups, blisters, mustard plasters, radiant energy, etc. The field of application of protein therapy is extremely vast—it covers all departments of medicine, and there is almost no disease in which this treatment method has not been tested. It proves most effective in cases of localized manifestations of infection, for example, in erysipelas, furunculosis, abscesses, phlegmons, pleurisy, mastitis, parametritis, salpingitis, adnexitis, subacute and chronic arthritis, pyelitis, pyorrhea, skin diseases (eczema, urticaria, etc.), epididymitis, and the like. In ophthalmological practice, protein therapy gives a good effect in scrofulous eye diseases, gonoblennorrhea, infectious iritis and iridocyclitis, keratitis, and a weaker effect in intraocular infections, purulent inflammation of the cornea and conjunctiva, and trachomatous pannus (autohemotherapy). With some success, protein therapy has been used in typhoid fever, paratyphoid, lobar and catarrhal pneumonia, sepsis, gonorrhea, etc. In view of the fact that protein therapy can cause a violent reaction in the organism, especially upon intravenous administration of protein preparations, caution is required in its application. Protein therapy is contraindicated in active pulmonary tuberculosis, cardiac compensation disorders, inflammatory kidney diseases, and pregnancy.

It should also be used with great caution in arteriosclerosis, hypertension, valvular heart disease, myocarditis, allergic diseases (angioneurotic edema, urticaria), epilepsy, and local tubercular processes (danger of activation and dissemination of the process). Protein therapy is not applicable in cases of complete exhaustion of the organism or cachexia. Parenteral administration of proteins produces general and local (focal) reactions. The strength of these reactions depends, on the one hand, on the nature of the protein preparation, the method of administration (subcutaneous, intramuscular, intravenous), the rate of administration, and especially the dose, and on the other hand, on the characteristics of the given organism and its ability to react to the introduced protein. The general reaction is expressed in an increase in temperature, changes in the blood, metabolism, and the functions of organs and tissues. The temperature reaction, of varying intensity, reaches a maximum after 6-10 hours, is generally transient, usually lasts no more than a day, is accompanied by malaise, and as soon as it passes, a good state of health ensues. Regarding the blood, after parenteral administration of protein, there is initially a slight leukopenia and subsequent neutrophilic leukocytosis with a leftward shift of the formula; the number of erythrocytes and blood platelets temporarily increases. Similar to coloring agents and bacteria, parenterally introduced proteins activate the cells of the reticulo-endothelial apparatus and enhance their resorptive activity. As a consequence of the irritation of the reticulo-endothelial system, histiocytes appear in the blood. In addition, a whole series of physicochemical and enzymatic changes are observed in blood serum. The amount of fibrinogen in it increases, it precipitates more easily, blood coagulability increases, surface tension decreases, blood viscosity increases, erythrocyte sedimentation is accelerated, a shift of the blood protein fraction toward globulins is observed, the refractometric index of the serum increases, its pH changes; the amount of enzymes—protease, lipase, catalase, amylase—in the blood serum increases, as well as complement and antibodies in sensitized animals. Along with this, a number of phenomena are observed indicating deep physicochemical changes in tissues; the oxidizing capacity of cells and tissues increases, the production of proteolytic enzymes by tissues is enhanced (leukoprotease - Petersen), the permeability of vascular walls increases, a redistribution of water occurs between the tissues and body fluids; initially, water mostly rushes from the tissues into the blood, and is then excreted through the kidneys. The secretion of saliva, gastric juice, bile, tears, sweat, and milk increases. General metabolism is enhanced, the excretion of nitrogen and phosphorus in the urine increases, and oxidative processes in tissues are heightened. As for mineral metabolism, after a short-term acidosis in the blood with a rapidly passing change in the content of sodium, chlorine, and bicarbonate ions, alkalosis ensues with more persistent changes in the content of potassium, calcium, and phosphorus ions. The activity of the cardiac, striated, and smooth musculature increases, the pulse quickens, blood pressure rises for several hours, but a decrease in it is also sometimes observed. The excitability of the autonomic nervous system first rises and then falls. Experimental studies by E. Müller and Petersen (E. Müller) have shown that during the parenteral administration of protein preparations, due to the influence of the latter on the autonomic nervous system, the motor function of the stomach is inhibited, its spastic contractions cease, which may explain, for example, the sometimes observed beneficial effect of protein therapy in gastric ulcer (Pribram). A change in the pharmacodynamic reaction of the autonomic nervous system is observed, e.g., the reaction to adrenaline (an increase in blood pressure does not occur). In some cases, especially with intravenous administration of large doses of protein preparations, phenomena of anaphylactic shock occur: a drop in temperature, a drop in blood pressure and cardiac activity. The focal reaction is expressed in the intensification of the inflammatory process in the diseased focus as a result of the influx of blood, lymph, leukocytes, and enzymes to it and an increase in exudation. Redness appears on the skin and in the joints (e.g., in rheumatism), and pain and swelling increase. The strength of such a focal reaction is of great practical importance. An excessively strong reaction acts deleteriously on the cellular elements of the focus and favors the generalization of infection, as well as its provocation (exacerbation and generalization of the tubercular process, provocation of malaria, relapsing fever, etc.), whereas a weaker reaction, which may not be accompanied by a temperature or general reaction, usually favors the regression of the inflammatory process and transition to recovery. In addition, parenterally introduced protein enhances the functions of all organs and, among other things, those that are already primed for the production of specific antibodies. Thus, it has been proved experimentally that if protein preparations are introduced into an organism in which immune bodies have begun to be produced thanks to vaccination, the number of the latter increases sharply. According to Zlatogorov, the therapy of infectious diseases carried out with the help of leukocytosis inducers (e.g., colloidal metal compounds), and according to Darier, the treatment of diphtheria with diphtheria antitoxic serum gives better results in combination with parenteral administration of milk. Zavodsky noted an enhancement of the effect of quinine in malaria with the simultaneous use of lactotherapy. In the same sense, protein therapy is used as an auxiliary agent in vaccine therapy. The mechanism of protein therapy was explained differently. At first, there were attempts to ascribe the favorable results exclusively to the febrile reaction occurring after protein injections. However, observations showed that the positive therapeutic effect of parenteral protein administration is not always accompanied by an increase in temperature. The attempt to ascribe a decisive role in the mechanism of protein therapy in infectious diseases to the enhanced production of complement, opsonins, and other antibodies also proved untenable. Studies by Lavrinovich, Tatarinov, and Khachikov showed that there is no parallelism between the favorable effect of nonspecific vaccination and the accumulation of antibodies in the blood. Rusznyak and Korányi (Rusznyak, Koranyi) see the essence of protein therapy's action in the desensitization of the organism against other proteins occurring under its influence; in their experiments, an anaphylactic temperature reaction did not occur in a sensitized guinea pig if a nonspecific protein was parenterally administered to it before the repeated injection of the specific protein. Solovtsova believes that during the parenteral administration of protein preparations, a series of specific reactions of the organism is excited, and some of them may prove curative against antigens that have nothing in common with the given nonspecific agent, but are close to it in some of their constituent parts. Wolff-Eisner, on the basis of his experimental studies, which showed that the parenteral administration of proteins does not enhance the resistance of the organism in relation to toxins (tetanus, diphtheria, ricin), but only to bacteria, explains the effect of this treatment method from the standpoint of the Pfeiffer phenomenon (Pfeiffer) by the enhancement of the formation of specific agents in inflamed foci that suppress the ability of bacteria to multiply. Weichardt's theory has gained the greatest citizenship, based not on some single phenomenon observed during the parenteral administration of protein, like the aforementioned theories, but proceeding from the general effect of proteins on the organism. According to this theory, parenterally introduced protein preparations, through the products of their cleavage in the organism or else, according to Freund, through the products of the breakdown of the organism's own cells caused by them, act on all its cells, but predominantly on pathologically altered, inflamed cells, which therefore possess increased irritability, and at a certain strength of irritation enhance their function—"activate" them, making them more resistant. Thus, protein therapy is one of the types of "irritation therapy" of Bier (Reiztherapie). During the parenteral administration of proteins, as we saw above, essential changes of a physicochemical character occur both in the cells and subsequently in the body fluids, as a result of which a "restructuring" (Umstimmung) of the entire organism occurs. As a consequence of this "restructuring," the reactive capacity of the organism changes in the sense of both a qualitative and quantitative change in sensitivity. Therefore, Kénigér, alongside the term "restructuring," introduces the term "modifying therapy." The "restructuring" of the organism under the influence of protein-therapeutic action can occur both in a favorable direction and in an unfavorable direction, depending on the type of preparation used, its dose, the method of application, and finally on the state of the given individual and his reactive capacity.

The appropriate dose has to be found empirically, starting with small doses and being guided primarily by the focal reaction, followed by the general reaction and the patient's subjective sensations. It is in this difficulty of the individual approach that the reason for the inconstancy of the effectiveness of protein therapy lies.