Ergot

ERGOT, Secale cornutum (Latin: Maternal rye, black rye), a persistent sclerotium of the fungus Claviceps purpurea Tulasne, family Hypocreaceae of the group Ascomycetes-Pyrenomycetes. Elongated, somewhat curved, rounded-trihedral hard bodies, narrowed at both ends or sometimes club-shaped; they reach up to 3 cm in length and up to 6 mm in thickness; externally colored brown-violet or black, often with an easily rubbed off whitish coating; inside, on a clean break, the ergot is yellowish-white in the center, with a narrow violet rim on the periphery. The tip of a whole ergot is provided with a grayish sphacelia cap (see figure), which usually falls off later. The taste of ergot is somewhat sweetish, fatty; the odor is weak, musty, unpleasant. The fungus Claviceps purpurea occurs on certain cereals and primarily on rye throughout almost all of Europe, in Asia, in North-western Africa, and in America¹. Maternal rye for medical use is recommended to be collected in dry weather from ripening rye ears, after which the collected ergots are carefully, at a temperature not exceeding 35°, well dried. Usually, ergot is not collected in fields directly from the ears, but on threshing floors after rye threshing during grain sorting. However, it is noted that ergot collected after threshing grain is inferior in its effect to that collected in the field from the ears. After drying the maternal ergots, they are kept whole in tightly closed jars, in a dry, cool, and dark place, thereby as much as possible protecting the constituent parts of ergot from changes that easily occur in the presence of moisture, air, and light. To protect the preparation from insects, pieces of cotton wool, slightly moistened with chloroform, are good to place from time to time in the jars with ergot.

In 1841, pharmacist Bonjean proposed for medical use the concentrated extract from ergot, prepared by him for the first time, which he named Ergotinum. Koberth isolated from ergot in 1884 three active principles—ergotinic acid, sphacelinic acid, and cornutin, but these were not chemically pure substances. Koberth characterizes cornutin as a convulsant poison. Jacoby (S. Jacoby) in 1897 pointed out that along with cornutin, ergot contains sphacelotoxin in the form of compounds of Chrysotoxin and Secalintoxin. Sphacelotoxin causes vascular spasm and gangrenous phenomena, observed by Koberth from sphacelinic acid. According to Jacoby, sphacelotoxin, secalintoxin, and chrysotoxin cause contractions of the pregnant uterus. Vahlen in 1905-06 isolated from ergot a new active principle—Clavin, which however Barger and Dale recognized as a mixture of lecithin and aspartic acid, and Kehrer clarified that Vahlen's clavin has no effect on the uterus. The pure substances isolated from ergot are now considered to be: ergotinin, C35H39OSN5, and ergotoxin, C33H41O5N5; ergotamine, C33H35O5N5, and ergotaminin, C33H36O5N5, and several biogenic amines of the fatty and aromatic series, such as: isoamylamine, p-oxyphenethylamine, or tyramine, imidazolylethylamine, or histamine, and some others; choline (see) and acetylcholine. Ergotinin was discovered by Tanret as early as 1875 in ergot and obtained in a crystalline state; at the same time Tanret found in ergot another alkaloid, very similar to crystalline ergotinin, but isolated only in an amorphous state and therefore named by the author amorphous ergotinin. Tanret attributed the toxic effect of ergot to the isolated crystalline ergotinin and amorphous ergotinin. Koberth decisively rejected any pharmacodynamic activity in crystalline ergotinin. The research of Kraft, Barger, and Carr confirmed Tanret's data, establishing that in Tanret's amorphous ergotinin a constituent part is a hydrated derivative of crystalline ergotinin—ergotoxin. Amorphous ergotinin was named by Kraft hydroergotinin. Ergotinin is soluble in 292 parts of alcohol at 18°, in 1,020 parts of ether, in 26 parts of acetone; melts at 229°; [α]D=338°; with acids gives salts, but non-crystalline, difficultly soluble in water. Ergotoxin—a light amorphous powder, almost insoluble in water, easily soluble in alcohol and ether, rotates the plane of polarization to the right, like ergotinin, but more weakly, melts at a temperature of about 162°; with acids forms crystalline salts, difficultly soluble in water. Both named alkaloids easily pass into each other. Ergotoxin has pharmacodynamic properties, ergotinin is inactive. In 1918, Stoll isolated from ergot the alkaloid ergotamine, a crystalline base, forming with acids salts difficultly soluble in water. Ergotamine content in ergot is 0.02-0.2%; in poor preparations of ergot it may not be present. Pure free ergotamine is extremely difficult to dissolve in water; the presence of CO2 in water increases the solubility of ergotamine; it dissolves very easily in alcohol and acetone, but quickly precipitates from the solution in the form of a crystalline mass; it dissolves easily in chloroform, with difficulty in ether and benzene; a 1% solution of ergotamine in absolute alcohol rotates the plane of polarization to the right by 41°, and a 0.6% solution in chloroform to the left by 155°. Ergotamine easily passes into its isomer—ergotaminin. The latter has not been found as a pre-existing constituent part of ergot, but is easily obtained by boiling a solution of ergotamine in methyl alcohol; ergotaminin dissolves in all solvents much more difficultly than ergotamine; a 0.6% solution of ergotaminin in chloroform rotates the plane of polarization to the right by 376-381°; begins to melt at 210°, and at 230° turns into a black-colored molten mass and decomposes. Ergotaminin is more stable to oxygen of the air than ergotamine. With acids, no stable salts can be obtained from ergotaminin. Ergotoxin in animals causes excitement, general restlessness, great mobility, and a number of other disorders of the central nervous system. In rabbits, from 0.002-0.004 of ergotoxin, introduced through a vein, restless tapping of the paws, ataxic movements, and loss of balance occurred; subsequently the animal became lethargic, lost its usual posture, lay stretched out, its head hung to the side, could not hold it—its head fell on the table; twitching, slight tremor appeared in the muscles, first in the muscles of the ears, eyeballs, and lower jaw, and then light clonic convulsions appeared in the limbs; salivation increased, and secretion of mucus in the bronchi increased. Breathing became frequent and difficult; body temperature rose by several degrees. Death occurred from cessation of breathing, while the heart stopped later. If rabbits were given ergotoxin in separate doses, paralysis and paralysis of the limbs and diarrhea developed in the animals. In cats, from ergotoxin, the same poisoning phenomena were observed, and in addition nausea, vomiting, and a sleepy condition. In pregnant cats, strong contractions of the uterus occurred, bleeding from it, and finally abortion occurred. In roosters, with subcutaneous introduction of ergotoxin, the comb and wattle first became pale, then cyanotic, in several cases mummified, and after several weeks fell off. Ataxia, a sleepy state (lethargy), loss of balance, dyspnea were also observed; lethal doses of ergotoxin cause deep depression, collapse, and finally death from cessation of breathing. If the ergotoxin preparation used for experiments was not completely pure, but contained other constituent parts of ergot, then gangrene phenomena did not always occur or developed much more weakly, because impurities could have an antagonistic effect on ergotoxin. Dale and Barger prove that ataxia, lethargy, and other symptoms from the central nervous system are caused by lesions of the midbrain and hindbrain, ending in paralysis of the respiratory center. Dale decides the question of the effect of ergotoxin on blood pressure differently. Blood pressure from ergotoxin, introduced through a vein in a cat, dog, and pig, quickly and significantly rises in these animals, remains elevated for a long time, and slowly returns to normal. In rabbits and monkeys, blood pressure from ergotoxin increases little, in goats even less, while in chickens, on the contrary, it becomes very high. Dale explains the increase in blood pressure by the effect of ergotoxin on the peripheral parts of the vessels, namely on the myoneural endings of the vasoconstrictor fibers of the sympathetic nerve, while the vasodilator fibers remain unaffected. From small doses of ergotoxin, the myoneural endings of the vasoconstrictor fibers of the sympathetic nerve are excited, from large doses they lose their excitability.

Therefore, adrenaline and nicotine, applied after large doses of ergotoxin, do not cause an increase in blood pressure, but, on the contrary, even cause a drop in it, dilating the vessels due to their influence through the normally functioning vasodilating fibers of the sympathetic nerve. Heart rate often increases at first from the action of ergotoxin, and then is replaced, which depends partly on irritation of the vagus nerve center when blood pressure rises, and partly on the direct action on the heart muscles. The effect of small doses of ergotoxin on the accelerator nerves in the heart and on the sympathetic nerve in the intestine (on the inhibitory fibers) is denied; also the endings of the vagus nerves in the heart and intestines are not affected in this case by ergotoxin. The increase in temperature is explained by increased heat production and impaired heat dissipation. The dilation of the pupil observed at the beginning of the action of ergotoxin depends on irritation of the endings of the sympathetic nerve in the iris, while the subsequent constriction of the pupil occurs from the direct action of ergotoxin on the muscles of the iris. In some animals, the hair rises from ergotoxin, which is explained by the effect of ergotoxin on the endings of the sympathetic nerves in the piloerector muscles. Ergotoxin injected intravenously causes a short-term contraction of the uterus, followed by a slowly developing relaxation: interrupted by numerous new contractions (Keshny). Ergotoxin in this case acts only on the motor nerve endings; on the inhibitory fibers, however, it has no effect. It acts much more strongly on the pregnant uterus than on the non-pregnant one. The reaction of the uterus in different animals to ergotoxin is not the same (Del). In rabbits, the pregnant uterus reacts more distinctly to ergotoxin than the non-pregnant one, while in cats and monkeys the non-pregnant uterus reacts better. The isolated uterus of a cat, fed by Lock's solution, hardly responds to ergotoxin, whereas the isolated uterus of a guinea pig contracts strongly. Ergotoxin, administered in large doses, weakens the motor reaction that usually occurs in the uterus when the hypogastric nerve is irritated or under the action of adrenaline; at the same time the inhibitory apparatus in the uterus remains unaffected. Irritation of the nerve trunk of the hypogastric nerve, containing both motor and inhibitory fibers for the uterus, therefore has only a depressing effect under these conditions (Keshny). Although ergotoxin causes contractions of the uterus, these nevertheless do not create the conditions necessary for the proper course of the act of childbirth (Keshny). Indeed, uterine bleeding often occurs from ergotoxin, and after a few days the fetus is born dead; therefore, one cannot place hopes on ergotoxin, resp. and on Ergot as a reliably acting abortifacient. Repeated administration of ergotoxin caused animals to develop increased tolerance to this poison (Barger, Del). As for ergotamine, it is pharmacologically completely identical to ergotoxin (Stoll). Rothlin's work on the effect of ergotamine on blood pressure, pulse, and vessels again confirms the similarity of the action of this substance with ergotoxin. Del's opinion on the influence and mechanism of action of ergotamine is shared by other researchers. Ergotamine, obtained in combination with tartaric acid, is well absorbed when introduced into the body per rectum; Langacker (Langacker), studying chronic poisoning with ergotamine, saw in neither rats nor muscle twitching nor convulsions. Ergotaminin in its action is similar to its isomer ergotamine, but in strength of action it is far inferior to it; this circumstance has great practical importance, because when obtaining galenic preparations from ergot, ergotamine easily turns into the weakly acting ergotaminin depending on an unsuccessfully chosen methodology. On the uterus of a guinea pig, ergotaminin acts, causing in it strong convulsive contractions. Isoamylamine excites the isolated uterus of a guinea pig, a rabbit, and a pregnant cat, whereas in a non-pregnant one it depresses. The indicated effectiveness of the preparation is very small. The mechanism of action of isoamylamine on the uterus is similar to the mechanism of action of adrenaline on it. The effect on blood pressure and vessels is the same as that of adrenaline, but in strength and expression it is far inferior to it. The action of tyramine and histamine (see): both of these substances act the same on the uterus, exciting contractions in it, but on the blood vessels differently-tyramine increases blood pressure, excitingly acting on the peripheral endings of the sympathetic nerve and thus strongly constricting the vessels, whereas from histamine, although arteries and veins constrict, blood pressure still falls, since the entire capillary network dilates. The recently named proteinogenic amines in Ergot are found in indeterminate quantities and according to some authors appear in preparations of Ergot as products of its processing. The presence in Ergot of choline and acetylcholine, causing dilation of capillaries and a drop in blood pressure, may be indifferent to the organism receiving ergot in one or another medicinal form. One should not forget that choline can under certain conditions turn into the highly poisonous neurine. Familiarization with the pharmacodynamic properties of the substances contained in Ergot allows to a certain extent to understand both the poisonous effect of Ergot and the nature of the action of Ergot preparations used for therapeutic purposes. Ergot can cause acute and chronic poisoning. Acute poisoning is observed in cases when Ergot is taken in large quantities (5.0-10.0), for example when attempting to cause an abortion; if during the first day of poisoning the symptoms of the disease begin to weaken, then the poisoned person recovers after a few days; if the condition of the patient worsens, then death occurs, on average, within the first day. Acute poisoning begins with dull pains in the abdomen, dryness in the throat, a feeling of strong thirst, salivation, nausea, vomiting, and diarrhea; the patient develops general weakness, shortness of breath, a sensation of crawling ants, chills, headache, insensitivity to painful irritations, weakening of vision, noise in the ears, clouding of consciousness, a comatose state; twitchings, individual contractions appear in the muscles, then painful tonic convulsions of the flexors of the limbs develop; convulsive seizures are sometimes replaced by relaxation. The pulse is somewhat accelerated at first, then slowed, uniform, but small; severe pain in the heart area. In pregnant women, uterine bleeding usually begins, and a miscarriage may occur, and the child will be born dead due to impaired nutrition and suffocation occurring under conditions of prolonged uterine contractions. The temperature remains normal. The comatose state is complicated by collapse, and death occurs from cessation of breathing. In some acute cases of Ergot poisoning, symptoms of only acute psychosis may develop, and convulsions may not occur. The disease manifests itself as motor excitement or a depressive state, amnesia, general confusion of thought, delirium. (Help in poisoning-see Poisoning.) The therapeutic use of Ergot most often aims to stop uterine bleeding, as well as from the lungs, stomach, and intestines. Postpartum bleeding easily responds to Ergot, because the strong muscular contractions of the uterus that occur lead to vigorous compression of the vessels, and bleeding stops, even if the vessels themselves were not constricted. In other cases of uterine bleeding- in menorrhagia and metrorrhagia-Ergot preparations are less effective and are often combined with other hemostatics. Cases of acute bleeding from the stomach, intestines, lungs, kidneys are often treated with Ergot preparations, expecting that Ergot, by causing vasoconstriction, will create conditions for easier formation of a thrombus at the site of vessel rupture. Many clinicians, however, doubt whether Ergot gives a positive result in such bleedings, because vasoconstriction usually leads to an increase in bleeding under the influence of the resulting rise in blood pressure. Only in the case of capillary bleeding does constriction of arterial vessels contribute to a decrease in the flow of blood to the site of rupture, and thus conditions are created for the quickest stop of bleeding. Ergot has the property of increasing the clotting of blood; this circumstance is an important reason for the success of using Ergot as a hemostatic. Ergot is widely used when it is necessary to strengthen weakened uterine contractions for the reverse involution of the uterus, after childbirth is completely finished or after an abortion has been performed. The above about the action of ergotoxin and ergotamine on the muscles of the pregnant uterus usually explains the brilliant effect of using Ergot for such an indication. The use of Ergot preparations in uterine myoma, to cause a reinvolutionary process in the newly developing muscle fibers, creating chronic anemia in the uterus by the medicinal substance, usually does not lead to the intended goal.

The use of Ergot in uterine fibroids should also be avoided because it must be administered for a very prolonged time in such a disease, which threatens the possibility of causing chronic poisoning. Ergot is not given to a woman in labor when delivery is not yet complete, when the child is still in the uterine cavity, or when the placenta has not been expelled, because from Ergot there occur prolonged tetanic contractions of the uterus, disrupting placental circulation and impairing the breathing of the unborn child; the contraction of the uterine muscles, acquiring from Ergot a very prolonged character, hinders the exit of the child or placenta from the uterine cavity; the tetanic contraction of the fundus and walls of the uterus that develops at this time with great force acts harmfully on the child and can sometimes lead to rupture of the uterus; if Ergot is given after the birth of the child but with the placenta not yet expelled, then the contraction of the uterine muscles causes retention of the placenta in the uterus and complications arising from this for the woman in labor. Therefore, the indication 'during the period of dilation of the cervix and expulsion of the fetus to strengthen contractions, Ergot should not be applied' is observed almost as a rule. However, some English clinicians approach the use of Ergot during childbirth somewhat differently, allowing its use in some cases, but only in very small doses, to enhance normal muscle contractions, but in no case to cause tetanic contractions of the uterus. In the absence of all possible obstacles to the passage of the child through the birth canal (narrow pelvis, abnormal fetal position, severe rigidity of the soft parts of the birth canal), perhaps one can agree to the use of Ergot in very small doses to increase the contractile capacity of the uterine muscles; in this case, one must know in detail the strength and character of the action of the Ergot preparation used, as well as its stability. Favorable results from the use of Ergot in veterinary practice to enhance uterine labor activity also provide material needed for further study of the question of using ergot in parturient women. Ergot is prescribed to women suffering from Basedow's disease during climacteric attacks, i.e., patients with signs of increased activity of the sympathetic system. The rationale for using Ergot in such cases is seen in the property of ergotoxin and ergotamine to reduce the activity of the sympathetic nerve if appropriate doses of these substances are used. Ergot is very often combined with pituitrin to stop postpartum hemorrhage; pituitrin, being absorbed faster than Ergot, begins to act on the uterus sooner, whereas the action of Ergot is much longer-lasting than that of pituitrin. For meno- and metrorrhagias, Ergot is given together with preparations of Hydrastis canadensis, because the synergistic action of Ergot and hydrastinine gives a better effect. Together with camphor, Ergot is prescribed for spermatorrhea developing on the basis of atony of the seminal vesicles and seminal duct. Preparations of Ergot 1. Pulvis Secalis cornuti (Ph. VII), a violet-gray powder, is prepared extemporaneously from whole uterine ergot collected in the current year. Storing Ergot in powder form in warehouses or pharmacies is not permitted, because in this form its active ingredients, which are generally unstable, change even more quickly; the fatty oil (up to 40%), proteins, and mucus in Ergot, if Ergot is stored in powder form, oxidize and spoil quickly, which further contributes to the deterioration of the active ingredients of Ergot. Ph. VII requires that Ergot be subjected annually to physiological testing for the content of active principles. The method of valuing Ergot indicated in Ph. VII, however, is unreliable. Ergot, even when stored according to all rules, quite quickly loses its strength of action. Kobert pointed out that the toxic properties of Ergot sharply decrease 5-8 months after its collection. Contrary to these generally accepted data are the studies of some authors (Rimskaya, Akimov), who claim that Ergot 10-25 years old was little inferior in toxicity to freshly collected. The German Ph. VI (ed. 1926) requires an alkaloid content in Ergot of not less than 0.05%, and the English Pharmacopoeia of 1932-not less than 0.1%. According to Ph. VII, uterine ergot is considered suitable if the extract prepared from it according to the instructions of Ph. VII has a valence of at least 12 (see above). The supplementary edition of Ph. VII (1934), eliminating the biological testing method for Ergot, replaced it with a chemical method in accordance with the German Ph. VI. To better preserve Ergot in powder form, a method of treating its powder with ether or petroleum ether to remove the fatty oil from the preparation was used; the spoilage of which, as indicated above, contributes to the more rapid change of the active principles of Ergot. But with such treatment, along with the oil, some active substances soluble in oil were removed from the Ergot powder; therefore, at present Pulvis Secalis cornuti exoleatus (defatted) is not prepared. According to Ph. VII, the highest single dose of freshly prepared Ergot powder is 1.0, daily 5.0. From coarsely powdered Ergot, an aqueous infusion is prepared. The preparation of a decoction, however, is irrational because during boiling some of the active substances of Ergot decompose. The unpleasant taste of the decoction and tincture of Ergot cause patients to refuse to take these dosage forms. 2. Extr. Secalis cornuti (Ph. VIII), a thick extract from Ergot, contains 15% water; the extract is reddish-brown in color, has a characteristic odor, and dissolves in water 1:1, forming clear solutions of acidic reaction. Its solutions should never be prepared in advance, as they provide an excellent nutrient medium for microorganisms. This extract is known under the name Ergotinum Bonjeani spissum. Mixed with milk sugar in equal parts, Bonjean's ergotin forms a dry, brown powder - Ergotinum Bonjeani siccum, prescribed in double the amount against Extr. Secalis cornuti, the highest single dose of which according to Ph. VII is 0.3, daily 1.0. 3. Extr. Secalis cornuti fluidum, a liquid extract of Ergot, reddish-brown, transparent, of acidic reaction, mixes with water in all proportions, forming clear solutions, but with an equal volume of alcohol it becomes strongly cloudy. The highest single dose is 1.0, daily 3.0 (Ph. VIII). The number of unofficial extracts prepared from Ergot is large; they are prepared according to various prescriptions and methods; most extracts received their name after the authors who proposed the corresponding extract: Ergotinum Bombelon, Ergotinum Fromme, Ergotinum Funck, Ergotinum Keller, s. Secacornin, Ergotinum Kohlmann, Ergotinum Merck, Ergotinum purum dialysatum Wernich, Ergotinum purum siccum Wiggers, Ergotinum Yvon, Secacornin Hofman la Roche; Extractum Secalis cornuti dialysatum Golaz, s. Secalan Golaz; Extractum Secalis cornuti dialysatum Burger, s. Secalysatum Burger, etc. The named ergotines are inconsistent in composition and action; they are not used in the USSR. In turn, instead of official pharmacopoeial preparations, our pharmaceutical industry prepares from Ergot the following two preparations: 4. Extr. Secalis cornuti 'Vokhimfarm' - a thick aqueous extract, easily soluble in water; highest single dose 0.3, daily 1.0; prescribed in powders, pills, and solutions; for subcutaneous administration, a 10% solution of this extract is dispensed in ampoules of 1 cm³ each. 5. Secalen 'Vokhimfarm' - a liquid extract of Ergot, purified as much as possible from ballast substances; used orally, subcutaneously, intravenously, and per rectum. Released in ampoules of 1 cm³. 6. Ergotaminum tartaricum (C₁₃H₃₅O₆N₅)₂·C₄H₆O₆, a crystalline powder, soluble in 500 parts water and 600 parts alcohol at 15°, released by the Basel firm Sandoz under the name Gynergen-Sandoz in tablets containing 0.001 of tartrate ergotamine each, or in solution in ampoules for subcutaneous administration of 0.5-2 cm³ of a 0.05:100 solution of the salt, can be administered per rectum. 7. Ergotoxinum, is offered by the London firm Burroughs, Wellcome in tablets under the name Ergotoxinum 'Tabloid'; each tablet contains 0.00065 of ergotoxin.

V. Pikolak,