Organotherapy (a2075)

ORGANOTHERAPEUTIC PREPARATIONS (organ preparations, opotherapy preparations, from the Greek opos meaning juice). In their raw (untreated) state, animal organs are now rarely used for therapeutic purposes, because many of them (especially endocrine glands) spoil extremely easily, have an unpleasant taste, and vary in activity, making correct dosing impossible; furthermore, ensuring their regular supply to patients is difficult. The pharmacopoeia requires that organ preparations be made from the organs of healthy and young animals. The drying of organs must be carried out either in a vacuum apparatus or in a stream of air or carbon dioxide, but at a temperature not exceeding 40°. The pharmacopoeia does not specify methods for manufacturing organ preparations. Commercially available organ preparations can be divided into the following groups: 1) powders made from organs and tissues, 2) dry extracts from them, 3) liquid extracts (aqueous, alcoholic, ethereal, glycerine, etc.) from organs or body "juices": blood (antithyroidin), milk, urine (prolan), etc., 4) products of artificial digestion of organs (optones and organopeptones according to Abderhalden), 5) emulsions from organs, 6) fluids obtained by passing Ringer's or Ringer-Locke's solution through the vessels of isolated organs (preparations according to Kravkov). In the vast majority of cases, organ preparations are marketed as so-called proprietary remedies, the manufacturing methods of which are kept secret by factories and plants. The French pharmacopoeia gives instructions regarding the method of manufacturing certain forms of organ preparations. Taken under aseptic conditions immediately after the slaughter of the animal and freed from extraneous tissues (fat, large blood vessels, etc.), perfectly fresh organs must be subjected as soon as possible to the following processing, prior to which they are placed in sterile water saturated with chloroform. Extracts from organs (not for injection). Organs minced to a pulp are macerated with a double quantity of sterile water saturated with chloroform for 24 hours with frequent agitation, then the mass is pressed through a sieve, slightly squeezed, and the first extract is collected; chloroform water (in an amount equal to the initial starting material) is poured onto the residue again, left to stand for 12 hours, then pressed through a sieve, the liquid is squeezed out, and it is mixed with the first extract. The extract obtained in this way is concentrated as quickly as possible to the consistency of a thick extract at a temperature not exceeding 40°, protecting it from dust from the air. This is best done in a vacuum or over sulfuric acid without heating. If significant amounts of fat are present, the latter is removed by drying the extract, mixing it with washed and calcined sand, and extracting it with ether or petroleum ether followed by their removal. Then the extract is dissolved in distilled water, the solution is filtered, and again concentrated to a thick extract. Organ powders. Organs are dried with several sheets of sterilized silk filter paper, then minced and ground into a pulp, which is placed in thin layers in flat sterile vessels, then dried either over sulfuric acid or in a vacuum at a temperature not exceeding 40° and turned into powder. If the organ contains fat that cannot be removed purely mechanically, the resulting powder must be extracted with ether or petroleum ether followed by their removal. Liquid extracts are prepared by extraction with water, physiological saline, alcohol, ether, or glycerin. They exist on the market in aqueous or glycerin solution for internal use and for subcutaneous injections. Optones, according to Abderhalden, are obtained by treating organs with digestive enzymes or splitting them with acids; this artificial digestion is carried out to such an extent that the resulting preparation no longer gives the biuret reaction. Organ fluids, according to Kravkov, are Ringer's or Ringer-Locke's solution that has passed through the vessels of an isolated organ placed in a thermostat at a temperature of 38°. Standing apart are preparations from the blood or milk of animals with removed thyroid glands (antithyroidin). The aspiration to obtain the active principles of organs in a chemically pure form has so far been realized only in relation to adrenaline and thyroxine; methods for their synthetic production are also known. All liquid organ preparations must be sterilized, which must be confirmed by bacteriological testing. The pharmacopoeia requires that the label of the preparation indicate (in addition to its name) the weight along with its ratio to the weight of the fresh organ, the time of manufacture, and, in the case of adding any sterilizing substance to the preparation, the name of the latter and its percentage relation to the mass of the preparation. Powdered preparations or tablets prepared from them must be stored in dark glass containers, tightly stoppered, in a dry room. Preparations in liquid form must be stored in hermetically sealed bottles or sealed ampoules of non-alkaline glass. Organ preparations obtained by various methods from different factories and plants are not identical in their chemical composition, even when extracted from the same organs; differences in chemical composition inevitably affect their pharmacological action. The reason for this is a whole range of conditions associated with the production of organ preparations. First of all, the raw organs themselves are not a homogeneous material. The content of constituent parts in them is influenced by the state of health and degree of fatness of the animals, diseases they have suffered, state of fatigue due to transport conditions to the slaughterhouse, species of animals, nature of their feed, presence or absence of sexual maturity, in females the period of the sexual cycle, season of the year, climate, conditions of the given locality, etc. As examples, one can point out that the thymus gland undergoes atrophy after the period of puberty; the thyroid gland in herbivores contains more active principles than in carnivores (according to some authors, the thyroid gland of a ram is the richest in them, and that of a pig is the poorest); due to the lack of feed during the war of 1914–18, German authors (Sehrt, Peiser) found on average only ⁸/₈ [sic] of the amount of adrenaline in the adrenal glands of rams that was obtained from them before the war; the iodine content in the thyroid gland was also significantly lower; due to periodic seasonal fluctuations in the activity of certain endocrine glands, the content of active principles in them can fluctuate sharply — for example, in summer the thyroid gland was found to contain 400–500% more thyroxine than in winter; in the ovarian follicles, the highest content of the sex hormone was found immediately before the onset of estrus; in Northern Germany, the thyroid glands of cattle are richer in iodine and more active against hypothyroidism than in Southern Germany (Trendelenburg); the same glands in the USSR are richer in iodine than in Western Europe, etc. In addition to those indicated, there are probably a whole series of conditions not yet studied, but having a significant impact on the content of constituent parts in the initial raw material for organ preparations. An organ excised from an animal is far from always processed immediately, and during this time significant post-mortem changes in its composition can occur; with regard to the adrenal glands, pancreas, posterior lobe of the pituitary gland, and some others, it has been proven with certainty that even over a comparatively short time under these conditions, the content of active principles in them significantly decreases due to rapidly ensuing autolysis under the influence of enzymes and other processes. The American pharmacopoeia, for example, requires that the processing of the posterior lobe of the pituitary gland to obtain an organ preparation from it begin no later than 30 minutes from the moment of slaughter of the animal, since the rapid destruction of active principles and the accumulation in the gland of a pharmacologically very active proteinogenic amine, histamine, formed from tissue histidine, has been proven. The very process of factory processing of organs is far from indifferent to the natural composition of organ preparations: some active principles (e.g., of the thyroid gland) apparently do not change significantly, while others (e.g., of the male sex organs), on the contrary, easily lose their specific properties. Among the agents affecting the active principles of organs during the preparation of organ preparations from them, the drying temperature, strong chemical agents (acids, alkalis, etc.) used to remove proteins and fats and for greater stability of the active principles in the finished organ preparation, chemical preservatives (chloretone, tricresol, etc.) added to organ preparations to prevent the development of bacteria in them, and so on, may be of importance. First of all, their impact can lead to a significant loss of active principles of the organ, which can be judged by the dosing of organ preparations, when a single dose often requires prescribing the contents of a whole organ or even several organs (Gley).

Furthermore, such a substantial change in the nature (denaturation) of the substances present in the organ can occur that the resulting organ preparation acquires types of action that physiologically cannot be attributed to the properties of the initial organ: this happens as a result of the formation during its processing of a number of active substances (choline salts, certain nucleoproteins, histamine and other proteinogenic amines, protein breakdown products of various characters, etc.), some of which may have been completely absent in the initial material or present in it in a negligible amount, or else represent intermediate products which did not even pass from the organ into the blood. Thus, a prepared organ preparation far from always corresponds in its action to the properties that physiology recognizes as the active principles of the corresponding organ. Some authors, such as Hoskins, believe that "if any 'hormone' requires for its 'liberation' such substances as sulfuric acid or caustic potash, it is hardly likely to exist in the normal gland." Be that as it may, in any case, when preparing organ preparations, one has to reckon with the indicated changes in the organs, especially since the majority of harmless protein substances can, in the process of processing organs, give rise to highly toxic material, as shown by Vaughan. To a greater or lesser extent, every organ preparation contains, along with specifically active principles (if any are present in it at all), non-specific substances as well, representing a complex of substances or a "heterogeneous mixture of many substances" (Hoskins). These substances may not be of significant importance (for example, when administering thyroidin per os), or they may significantly or even completely mask the specific action of the organ preparation (e.g., during parenteral administration of liquid thyroidin), or impart a high degree of toxicity to it (e.g., preparations from the pancreas in the pre-insulin era). The aforesaid cannot apply equally to every organ preparation, since a method unsuitable for obtaining an active preparation from one organ may prove quite satisfactory for another; for example, the method of protein removal used in processing extract from the posterior lobe of the hypophysis, when applied to an extract from the ovary, leads to the loss of the specific action by the latter (van den Velden). The following circumstances influencing the nature of the organ preparation coming into the hands of the physician or experimenter are those changes in the organ preparation that occur in it under various methods of storage: here, the surrounding air temperature, solar illumination, mechanical shaking during transportation, loss of sterility due to insufficient hermetic sealing (poorly ground stoppers), change in chemical reaction (when contained in glassware containing free alkali), change in the chemical composition of the organ preparation due to chemical processes not fully completed in it, etc., play a role. This can have a particularly sharp effect with respect to many liquid organ preparations, the activity of which is relatively short-lived due to this: thus, for the insulin of many factories, it is no more than 4-6 months after manufacture; the same apparently holds true for pituitrin, ovariin, and other preparations whose specific action can be biologically measured. A commercial solution of adrenaline (1:1,000), on the contrary, is relatively stable: according to studies by M. Tiffeneau, 15 months after manufacture it contains 92% biologically active adrenaline, after 3.5 years 51%, and after 4.75 years 34%. The stability of dry preparations is much higher: thus, regarding the thyroidin of the American Pharmacopoeia, Hunt showed that over the course of 12 years its activity did not decrease, judging by its physiological and clinical testing. Action on the organism. Specific (hormonal) and pharmacodynamic actions are distinguished. By the former is meant that kind of special action of an organ preparation on the organism which, according to modern physiological concepts, is inherent in hormones, i.e., special substances secreted into the blood by the corresponding organs; an example of this kind of action is the influence of thyroidin on metabolism, growth and metamorphosis, etc., the influence of insulin on carbohydrate metabolism, and so on. By pharmacodynamic action is understood generally the ability of a given organ preparation to exert one or another non-specific action on the organism or individual organs regardless of whether this takes place under physiological conditions, for example, the ability of adrenaline to stop (by relaxing the smooth musculature of the bronchi) attacks of certain forms of bronchial asthma, to excite contractions of the urinary bladder, etc. Hardly anyone would claim that these types of adrenaline action are specific for it as a hormone and not as a medicine. However, it is not always possible to strictly demarcate both types of action in connection with changing physiological concepts and methods of producing organ preparations. The presence in the chemical composition of certain organ preparations of identical substances due to the nature of the material from which they are obtained (animal tissues) and the methods of its processing (denaturation, formation of new substances, etc.) imparts to many organ preparations in certain respects an identical character of action. Thus, it is known that milk-secreting action is possessed by preparations from the posterior lobe of the hypophysis, corpora lutea, uterus in the stage of involution, mammary gland during the lactation period, thymus gland, pineal gland, as well as preparations from the hypophysis of fish and birds; contractions of the smooth musculature of the urinary bladder are caused by preparations from the thymus gland, thyroid gland, testicles, prostate gland, pancreas. It is completely improbable that milk secretion or the activity of the smooth musculature of the urinary bladder in the animal organism should be under such diverse physiological control. At the same time, progress in the methods of preparing organ preparations shows that as organ preparations are purified from non-specific (ballast) substances, they lose the types of action common to many organ preparations, while retaining or even acquiring specific activity. Thus, the previously characteristic ability of extracts from ovaries, the thyroid gland, and other organs to lower blood pressure when administered intravenously to animals, as shown by studies by Vincent and Sheen, is inherent in extracts from almost all organs (except the adrenal glands and the posterior lobe of the hypophysis) and, for modern preparations of insulin and ovariin, for example, may indicate only insufficient purification of hormones from ballast substances. Upon administration of preparations per os, the significance of the latter decreases sharply because they are digested or otherwise decomposed in the gastrointestinal tract. To the presence of these ballast substances is due the phenomenon of so-called tachyphylaxis, which consists in the fact that upon repeated intravenous administration of an organ preparation to an animal (e.g., extract from the posterior lobe of the hypophysis, adrenal glands, etc.), the characteristic action on blood pressure manifests itself to a lesser degree than upon the first administration, whereas a chemically pure product (e.g., adrenaline) under these conditions retains action of the same strength. Gley says that tachyphylaxis shows how imprudent it is to take as internal secretory (i.e., hormonal) an action against which the organism develops immunity in a few minutes. The presence of proteins in many liquid organ preparations upon their repeated parenteral application can lead to the development of a state of anaphylaxis, which was previously attributed to the influence of foreign proteins in the organ preparation, but at the present time, thanks to the works of Hoskins, it is known that the same thing is observed upon the administration to animals of extract from their own organs (e.g., from the pancreas, salivary gland) and is explained by the denaturation of tissue proteins in the process of obtaining the extract. Admixtures of non-specific substances to a large extent also determine the high toxicity of certain organ preparations, due to which they cannot be used in medicine at all (e.g., previous preparations of the pancreas, thymus, etc.) or can be introduced into the organism only through the gastrointestinal tract.

Action depending on the route of administration. For the majority of organ preparations, in which the presence of specifically active substances has been proven (e.g., preparations of adrenaline, insulin, pituitrin, female sex hormone, etc.), it can be taken as a rule that there is either an absence or a sharp (50–100-fold) attenuation of the specific action when administered per os in comparison with parenteral routes of administration. This is explained by the easy destructibility of the active principles in the digestive juices and in the liver (see Drugs). Certain organ preparations (e.g., thyroidin, parathyrin) retain their specific action even when introduced into the stomach. The subcutaneous route of administration is used for many organ preparations, but when evaluating the specific action in this case, one must reckon with the possibility of nonspecific parenteral therapy due to the presence of proteins, albumoses, lipoids, concentrated salt solutions, etc., in the organ preparations. Intravenous administration for the majority of organ preparations is inadmissible due to the toxic action of various chemical substances entering into their composition (see above), the effect on the physicochemical properties of the blood, the development of anaphylaxis, etc. Administered directly into the blood when there are vital indications requiring a very rapid and energetic action (e.g., insulin in diabetic coma) can be either solutions of chemically pure substances (e.g., adrenaline, thyroxine) or very well purified preparations; in this case, the observance of great caution is required. Organ preparations are used much less frequently intramuscularly, into the rectum, sublingually, and very rarely on the skin (rubbing in of extracts of the hypophysis, ovaries, and thymus in rickets). For local action on tissues (conjunctiva, nasal mucosa), almost exclusively adrenaline is used. The mechanism of action for the overwhelming majority of organ preparations is unknown, since their active principles have not been obtained in a chemically pure form, and the many active substances included in the composition of organ preparations greatly complicate the analysis of their specific action. For most organ preparations, their direct action on cells appears to be characteristic (e.g., preparations with the female sex hormone); less frequently, there is simultaneously an effect on the endings of autonomic nerves (e.g., thyroidin, pituitrin, insulin) or a selective action only on the endings of the sympathetic nervous system (adrenaline). Zondek and Ucko distinguish 2 phases of action (both active), the first being identical with the action of the corresponding hormone, and the second opposite to it and explained by the changes that the physicochemical structure of the cells underwent during the first phase. This view is disputed and is far from applicable to all organ preparations. Standardization of organ preparations. In view of the heterogeneity in composition and strength of action of organ preparations prepared even from identical organs, before releasing them for use on humans, it is necessary to preliminarily evaluate their activity both qualitatively and quantitatively. Chemical evaluation is applicable only to thyroidin according to its iodine content, which can serve to a certain extent as an indicator of the amount of the active principle. For other organ preparations, there are as yet no characteristic chemical reactions, and therefore where this has been worked out (preparations of adrenaline, pituitrin, sex hormones, parathyroid glands, anterior lobe of the hypophysis), determination of activity on animals or on isolated organs is used (see Standardization). In a number of cases (e.g., preparations from the thymus gland, pineal gland, liver, heart, etc.), there are also no recognized standardization methods as yet, and preparations of this sort go on sale only after determining their toxicity on animals, and sometimes even without this. To this day, such organ preparations whose action is generally doubtful are put on sale (e.g., oculin against eye diseases, reniin for kidney diseases, cerebrin for brain diseases, etc.). This situation is explained by the commercial interest of manufacturers and the crude empiricism of doctors uninformed in this field. In those cases where standardization is possible and developed, the quality of organ preparations improves from year to year, and their dosage becomes rational (by weight or in biological units of activity—see Standardization), whereas in other cases the dosage is purely empirical, taking into account the endurance of the gastrointestinal tract and the negative effect on patients of a large volume of a single dose. Examples of preparations whose dosage is based on their preliminary evaluation are adrenaline, thyroidin, pituitrin, preparations of the female sex hormone and the anterior lobe of the hypophysis. The State Pharmacopoeia of the USSR sets requirements for standardization with respect to adrenaline (effect on blood pressure in rabbits), pituitrin (effect on the uterus of a guinea pig) and thyroidin (chemical determination of iodine) and indicates higher doses for them. Application of organ preparations—see Organotherapy. Organ preparations existing on sale are manufactured from the thyroid gland (see Thyroidin, Thyroxine), parathyroid glands (see Parathyroidin), thymus gland, appendage of the brain (see Pituitrin, Prolay), pineal gland, brain, pancreas (see Insulin, Pancreatin), adrenals (see Adrenaline), sex glands, prostate gland, mammary glands, uterus, placenta, liver, heart, lungs, spleen, bone marrow, kidneys, bronchial glands, lymphatic and other glands, bile, blood, etc.