Quinine

Quinine (Chininum), the principal alkaloid contained in the bark of the cinchona tree (Cinchona succirubra, family Rubiaceae Cinchoneae). In the bark of Q., it is combined with quinic and cinchotannic acids (see Cinchona Bark). In pure form, Q. was first isolated from the bark in 1820 by Pelletier and Caventou. It has the formula C₂₀H₂₄N₂O₃, mol. wt. 378.26, anhydrous 324.20. Its structure in detail is not yet fully elucidated; at present it is assumed to be as follows: H H C C---------G------ C___________C_H C_HOC⁺/C_H H_H N-CH₃-CH_a-CH₂ n>/ \</ alcohol C N

vinyl group quinoline with methoxyloiponic residue From the structural formula it is seen that Q. is a derivative of quinoline and quinuclidine. It consists of methoxyquinoline and the so-called loiponic residue, connected between them by a carbinol group (CH₂OH), which gives the entire molecule of Q. the character of a secondary alcohol. Quinoline, or α/β-benzopyridine, is naphthalene, in the molecule of which one of the CH groups in the α-position is replaced by an N atom. In Q. the quinoline has also a side chain in the form of an oxymethyl group (CH₂OH). The loiponic residue consists of a quinuclidine ring with a side chain-vinyl group (CH=CH₂). The quinuclidine ring in turn represents a special condensation of piperidine nuclei: in the piperidine ring the γ-carbon atom is connected with nitrogen through an ethylene bridge (CH₂-CH₂), thanks to which the quinuclidine ring consists as if of 2 condensed piperidine rings, the nitrogen of which and 3 carbon atoms are common. Thus quinine is methoxy-quinoline-vinyl-quinuclidine-carbinol. At the same time Q. can be considered as the monomethyl ether of the alkaloid cupreine, found in the bark of plants of the same family. In the molecule of Q. there is an oxymethyl group (OCH₃), whereas in cupreine it is the OH group. Quinine is also considered as a para-methoxy derivative of the alkaloid cinchonine, which is also found in cinchona bark. In cinchonine instead of the OCH₃ group there is H. The structural formula of Q. is of great practical interest in view of the striving of modern synthetic chemistry to carry out the synthesis of Q. and to obtain compounds possessing a strong destructive action not only on the simplest organisms (especially on the plasmodia of malaria), but also on other microorganisms. If one takes into account that the world consumption of Q. amounts to 500,000 kg per year, then the practical significance of these works becomes easily understandable. At present the complete synthesis of compounds differing from Q. only by the absence of the vinyl group has already been carried out (Rabe). The study of their pharmacological action has shown that the replacement of the methyl group in Q. by other alkyl groups does not decrease their antimalarial action and may even enhance it. Removal of the alkyl group (absent in cupreine and cinchonine) significantly weakens the antimalarial activity and increases the convulsive action. It is believed that the methoxyquinoline is responsible for the antipyretic, disinfectant and analgesic action of Q., the vinyl-quinuclidine (or the so-called loiponic residue) is attributed to the selective action of Q. on certain types of unicellular organisms, while the carbinol group determines the intensity of the bitter taste of the alkaloid. Through the work of Morgenroth and his colleagues and successors, it has been established that one can sharply increase the bactericidal effect if by hydrogenation the vinyl group is converted to an ethyl group, and in the thus obtained methylhydrocupreine the methyl is replaced by other alcoholic radicals. This is seen e.g. when comparing the concentrations of these compounds which within 24 hours kill streptococci and staphylococci: methylcupreine (Q.)-1:1,000-1:4,000, methylhydrocupreine (hydroquinine)-1:4,000-1:6,000, ethylhydrocupreine (optoquin)-1:2,000-1:8,000, isoamylhydrocupreine (eucupine)-1:20,000-1:40,000, isobutylhydrocupreine (vucine)-1:40,000-1:80,000. Of these compounds, vucine, optoquin and eucupine have practical importance (see). The study of the action of various synthetic derivatives of quinoline on the extremely successful object proposed by Sergent (malaria-infected canaries) led to the synthesis of the drug plasmoquine (see) and the Soviet plasmoocide, an active agent against malaria. Q. as the free base is a white crystalline powder, which easily effloresces in air, of alkaline reaction, and very bitter taste. It is poorly soluble in cold water (1:1,670-1:1,960), somewhat better in boiling water (1:900), and easily soluble in alcohol (1:0.8), ether, chloroform, and carbon disulfide. Its solutions of alkaline reaction rotate the plane of polarization to the left. With dilute sulfuric acid it gives a bluish fluorescence, with chlorine water and excess ammonia it gives an emerald green coloring (talloquinine reaction). Q. is known as the anhydrous (incorrectly) 'anhydride' and hydrate, crystallizing with 3 molecules of water. With acids it forms well-crystallizing salts, and in this Q. behaves as a dibasic base, i.e. for the formation of a neutral salt 2 molecules of a monobasic acid are required; these salts react on litmus as acid and are very easily soluble in water; for the formation of a basic salt, however, only 1 molecule of a monobasic acid is required, and these salts are of weakly alkaline reaction (on litmus) and less soluble in water. The addition of hydrochloric or sulfuric acid therefore increases the solubility of the basic salts. As the free base Q. is almost never used. Action on living organisms. Q. is a general cell (protoplasmic) poison, and its depressing action extends to all cells of animal or vegetable origin. In many cases, however, it has been possible to establish that in very small doses or at the beginning of the action of large doses, the depressing action is preceded by a transient period of excitation, of increased activity, whereby small doses of Q. are attributed the so-called tonic action. Action on the simplest organisms (Protozoa). Particularly characteristic and easily attainable is the depressing action of Q. on the simplest organisms. As early as Binz (1867) in experiments on paramecia of hay infusion showed that at a concentration of Q. 1:20,000, after 5 minutes the movements slow down, after 2 hours they completely cease, and after several hours only detritus remains from the infusoria. In a number of cases the depressing action was noted even from a solution of 1:100,000. Binz, and after him many others, noted the same in regard to amebas and leukocytes. Even then he expressed the hypothesis of the etiotropic action of Q. against the hypothetical at that time causative agent of malaria. With the discovery of the plasmodia of malaria (Laveran, 1880) this was brilliantly confirmed. Laveran observed that the addition of Q. to blood in a dilution of 1:3,000 paralyzes the movements of the malaria parasites; at stronger concentrations they become granular and disintegrate. The concentration of Q. (1:5,000) obtained in human blood when therapeutic doses are injected into the vein is sufficient for the depressing action on the parasites; when Q. is administered per os it is considerably smaller (below 1:200,000). Therefore it is hardly possible to accept Binz's hypothesis of a direct bactericidal action of Q. in the blood (Giemsa, Schaumann). Later (1899-1901) it was found that even in very strong dilutions Q. causes contractions of the parasite, after which it leaves the erythrocyte. At that time a greater sensitivity to Q. of the causative agent of tertianae than of quartanae was noted. The mechanism of the parasitocidal action of Q. cannot yet be considered finally established. Mühlens believes that with Q. the young forms of the parasite cannot penetrate into the erythrocytes, which adsorb Q. (Morgenroth) and create conditions for a sharp negative chemotaxis. With repeated administration of Q. in humans a lesser effectiveness is observed, which is explained by the habituation of the malaria plasmodia. The mechanism of this phenomenon has not yet been clarified. Experimentally Neuschloss established that by gradually increasing the concentration of quinine one can cause habituation to it in infusoria. He believes that they acquire the ability to destroy Q. up to 80% of its amount. Action on the blood. In vitro solutions of Q. 1:20,000 cause symptoms of paralysis, and at a concentration of 1:10,000 even in a warm moist chamber complete paralysis of leukocytes sets in. Phagocytosis ceases already at a concentration of 1:100,000, and at weaker dilutions of Q. it is clearly increased. On the mesentery of the frog Binz showed that with local application of a solution of 1:3,000 the migration of leukocytes from the vessels into the tissues ceases, and granulation of their protoplasm is observed. Some explain with this fact the ability of Q. to limit the formation of pus. However, it should be borne in mind that in mammals to create such a strong concentration of Q. in the blood it would be necessary to give a dose which is lethal for the animal (Cushny). Therefore such an explanation of the action of Q. is hardly acceptable. In humans after large doses of Q. (equal to 1/20,000 of body weight) a decrease in the number of leukocytes to ³/₄ of the norm is noted. Leukopenia should probably be explained by the depressing action of Q. on the blood-forming organs; it is possible that in part there is also a direct destruction of leukocytes. Usually leukopenia is preceded by leukocytosis (mainly lymphocytosis), explained by the squeezing out of leukocytes into the bloodstream by the contractions of the spleen and lymph glands. After the period of leukopenia leukocytosis sets in again. From a dose of about 1 g per administration a slight increase in the opsonic index is noted. 34v* Occasionally with very large therapeutic doses in malaria patients damage to erythrocytes, hemolysis, has been observed. However, the hemolytic action of Q. in vitro can be observed only at a 7₂% concentration: such a strong solution of Q. in human blood can be obtained only from doses that stop the heart (Cushny). Action on bacteria.

The disinfecting power of Quinine is very weak, since bacteria are significantly less sensitive than protozoa. Their growth and reproduction cease only at a concentration of 0.2-0.8%, while spores of anthrax die only in a 1-2% solution of Quinine. Molds are even more resistant, and they develop freely even in these solutions of Quinine salts. The addition of blood serum or pus to a Quinine solution weakens its antiseptic action to a slight degree. For practical purposes, relatively strong solutions of Quinine salts are required: in case of wound infection with gas bacillus, a dressing with a 0.1% hydrochloric acid Quinine solution is recommended; for cystitis, irrigation with 0.05-0.5%; for conjunctivitis, 0.5%; for gonorrhea, up to 5%, but these solutions have a locally irritating effect, for which reason they are used very rarely. Comparative research by Müller (Fr. Müller) on the effect of antipyretics on various microorganisms (pneumo-, staphylo-, streptococci, diphtheria, anthrax, pus, and decay bacilli) showed that salicylic acid acts most strongly, then hydroquinine and Quinine, and significantly weaker is antipyrine. Enzymatic and catalytic processes. Quinine is credited with the ability to inactivate a number of enzymes, and the sensitivity of these enzymes to the action of Quinine varies greatly. In many cases, with small doses of Quinine, an intensification of enzymatic processes is observed. For oxidase, for example, intensification was noted with a 0.001-0.005% Quinine solution, while solutions stronger than 0.01% caused inhibition (Laqueur). For aldehydease, the inhibitory effect begins only with a 0.15-0.25% Quinine solution. The same can be said of splitting enzymes: catalase is even enhanced by a 1% Quinine solution (with brief exposure), while the liver glycogenolytic enzyme is already inhibited by a 0.12% Quinine solution (Pick), and the autolytic enzyme and invertase even by a 0.05% one. To judge the effect of Quinine on enzymatic processes in vivo (and not in vitro), one must take into account the dosage, the rate of its entry into the body and its excretion (see below). Binz (1875) observed at a concentration of 1:5,000 Quinine the cessation of Brownian molecular motion. More recent data (Ramsden) relate this to the ability of Quinine (like saponins and proteins) to concentrate on the surface of solutions to such an extent that a dense membrane is formed. The accumulation of Quinine often prevents the condensation of other substances on the surface and, consequently, certain catalytic phenomena (both organic and inorganic). Quinine has the ability to precipitate colloidal solutions (for example, proteins in serum), which is also linked to the aforementioned action. It is possible that the formation of a quinine membrane, with the resulting decrease in the permeability of cell membranes, can explain the decrease and cessation of movements (of protozoa, white blood cells, spermatozoa, etc.), the decrease in sensitivity of nerve endings, and the decrease in metabolism (see below). Local action. Quinine has a very intense and persistent bitter taste, which is still clear even in a dilution of 1:10,000. As a result of this, the secretion of saliva and, to some extent, gastric juice is reflexively increased. At the same time, the local irritating action of Quinine is also manifested, reaching varying degrees depending on the concentration of Quinine. The therapeutic effect on secretion is better achieved with galenic preparations from cinchona bark than with preparations of Quinine, but even in these cases, the effect from other bitter substances (see) is apparently better. When taking large doses of Quinine orally, a decrease in gastric secretion, stomach pains, nausea, vomiting, and diarrhea are noted; it is indicated that the absorption of salts and possibly food is slowed down. After subcutaneous injection of strong concentrations, the formation of extensive suppurations, phlegmons, has been described. In quinine factories, skin exanthemas and dermatitis were observed (the action of irritating vapors when boiling cinchona bark, the action of quinine dust when obtaining and processing the alkaloid), the same when washing the head with so-called quinine water. After taking large doses of Quinine, phenomena of kidney irritation, the appearance of protein and Hb in the urine are noted. Upon contact with sensitive nerves, Quinine and especially its derivatives cause local persistent (for several days) anesthesia, which is preceded by phenomena of irritation and pain (so-called anaesthesia dolorosa). However, this fact has no great practical significance, since the subcutaneous injection of a 1/4% Quinine solution already often causes considerable irritation, swelling, and fibrous induration, and solutions of about 1% lead to the formation of a scab. These phenomena are much less pronounced when using double salts of Quinine and especially compounds of Quinine with urea (see below). Of practical importance is the anesthetic action of derivatives of hydrocupreine (especially of equinquinine—see below). It should be noted that individual sensitivity to the local action of Quinine varies. Absorption of quinine and its fate in the body. When taken orally, Quinine salts are absorbed relatively slowly but completely. Even insoluble tannic acid Quinine is absorbed by 85-92%, but only somewhat more slowly than soluble salts (Flamini, Hartmann and Zila). A single large dose is absorbed relatively faster than the same amount in fractional doses. The acidity of gastric juice does not affect absorption. Absorption is hindered by phenomena of irritation of the gastrointestinal tract (vomiting, diarrhea, etc.), as well as by the change in Quinine in the latter. Bile precipitates glycocholates and taurocholates of Quinine from soluble salts. At first, basic, difficultly soluble salts are formed, which gradually pass back into soluble ones under the influence of excess bile, free carbonic acid, and carbonates of the intestine. Thus, for complete absorption of Quinine, at least several hours are required. Quinine is absorbed mainly by the small intestine and to some extent by the stomach. By mucous membranes, subcutaneous tissues, and muscles, Quinine salts (except non-irritating double salts) are poorly absorbed. Absorption of basic and neutral salts is hindered due to their irritating action and possible precipitation of Quinine in the alkaline juice of the tissues. To improve the solubility of Quinine salts and thus their better absorption, antipyrine, urethane, urea, caffeine, etc., are added. Absorbed Quinine is already found after a short time in much larger quantities in the brain, liver, lungs, spleen, kidneys, and adrenal glands than in the blood (Dyachkov, Hatcher, Baur, etc.). Therefore, it is believed that Quinine kills plasmodia not in the blood, but in the organs (Giemsa, Schaumann). From the blood plasma, it quickly disappears (90% already after 20 minutes), while on erythrocytes it accumulates and remains longer than in the plasma, being in a form from which it is even chemically difficult to free. 8 hours after intravenous administration of Quinine, it can no longer be detected in the blood (Hartmann and Zili). The larger part (60-70%, sometimes even up to 90%) of absorbed Quinine is destroyed in the body (mainly in the liver). With prolonged repeated administration, the body's ability to destroy Quinine does not increase, nor is habituation to it noted. With daily administration of Quinine per os, it is excreted by the urine up to 27%, after subcutaneous injections—up to 16%, after administration per rectum—up to 17.5%. When taking Quinine orally in doses of 1.0-2.0 pro die, its concentration in the urine reaches about 600 mg per liter, i.e., approximately 60 times more than in the blood (3-10 mg per 1 l). The products of transformation (destruction) of Quinine in the body are unknown; the opinion of Kerner (Körner) that Quinine is converted to dihydroxyquinine is disputed. Quinine is excreted mainly by the urine, in small amounts by the feces (even after parenteral administration), and only in negligible traces by saliva and tears. In women's milk, Quinine was not detected after its administration (Giemsa, Marza, etc.). Excretion by the urine begins already 20-30 minutes after taking Quinine orally (the appearance of a positive talloquinine reaction), then the amount of excreted Quinine gradually increases, reaching a maximum after 6 hours at a high level. The main part of a single dose is excreted after 24 hours, after which excretion sharply decreases but remains in traces for 3 days, and sometimes longer (for example, in severe nephritis, metabolic diseases, high fever, cardiac decompensation). Such prolonged excretion of Quinine is explained by its adsorption by tissues (brain, liver, heart, muscles, lungs, kidneys), since in the blood already after 3 hours (and according to some authors even sooner) only traces of Quinine remain (Hatcher). With prolonged repeated administration of large doses of Quinine, there is thus a danger of its cumulative toxic action on the body. The peculiarities of absorption, excretion, and the fate of Quinine in the body determine the short duration of its strong concentrations in the blood even with the administration of large doses. The most long-lasting (practically even for 24 hours) the same concentration is maintained with repeated oral administration of Quinine every 3-4 hours; depending on the dose, the concentration in the blood can reach 3-10 mg per 1 l. When administered intravenously with 0.8 g Quinine, a concentration of about 200 mg per 1 l is achieved, but it quickly (after 20-30 minutes) and sharply falls. Action on the body.

The organotropic action of Quinine is not manifested to the same degree on various organs and systems of the body. Basically, it can be assumed that only in very small doses can Quinine have a weak excitatory effect, which cannot be considered constant and prolonged. The most characteristic feature of Quinine is the depression of the function of all organs and systems, manifested to varying degrees and sequence. Although the parasitotropic action of Quinine is more pronounced than the organotropic one, the latter still always occurs in the therapeutic use of Quinine.

Cardiovascular system. In mammals and in humans, small doses of Quinine have an excitatory effect on the heart: the heart rate increases, and the contractions are somewhat strengthened. The origin of this action has not yet been clarified; it is believed that in addition to the direct excitatory effect, there is also excitation of the accelerating (sympathetic) nerves of the heart and an increase in the conductivity of impulses from the A-V node (Aschoff-Tawara node) to the ventricles. At the same time, an increase in blood pressure is observed, due mainly to the constriction of blood vessels due to the excitation of the smooth muscle of their walls. The excitatory effect of Quinine on the circulatory apparatus is not strongly expressed, it varies in different individuals, so it is often not possible to notice it. On the contrary, the depressing effect is very characteristic of Quinine and creates great dangers in its therapeutic use. This effect is manifested in relation to all functions of the heart: a negative ino-, chrono-, dromo-, batmo- and tonotropic effect occurs. Weakening of heart contractions occurs due to the direct depressing effect of Quinine on the cardiac muscle, and the slowing of the rhythm is also explained by a decrease in the excitability of the A-V node and the difficulty of conducting excitation through the bundle of His (Hering, 1917). Apparently, there is no significant effect on the vagus nerves, since atropine does not significantly change the effect of Quinine, although experiments with perfusion of the medulla oblongata of turtles with solutions of Quinine indicate excitation of the center of the vagus nerves (Bush, 1920). The excitability of the heart muscle itself also decreases. The negative batmotropic effect is particularly pronounced in the isomer of Quinine—quinidine.

After depressing doses of Quinine, dilation of blood vessels also occurs, explained by the direct relaxing effect of Quinine on the smooth muscle of the vessels, as well as (to a lesser extent) the depression of the vasomotor center. As a result, blood pressure falls, and the intensity of the fall is parallel to the concentration of Quinine in the blood. Therefore, the slow intravenous administration of Quinine in the treatment of malaria is practically important. It is interesting to note that in afebrile individuals, the cardiovascular effect of Quinine is less pronounced than in fever, where large doses of Quinine can easily cause collapse, which in turn contributes to a sharp drop in body temperature (see below).

Organs with smooth muscle. Special interest was aroused by the effect of Quinine on the uterus and spleen. The excitatory effect on the uterine muscle from relatively small doses of Quinine is noted in the late stages of pregnancy, while in a resting uterus, therapeutic doses of Quinine are insufficient to cause its contractions. The sensitivity of the uterus to Quinine at the beginning of pregnancy is very small, so even with toxic doses, an abortion does not always occur. However, when labor contractions are present, even after taking 0.5-1.0 g of Quinine (usually in fractions of 0.25-0.3 g each hour), uterine contractions noticeably strengthen after 10 minutes. This effect is longer-lasting but less strong than that of pituitrin. Sometimes, for the same purpose, simultaneous intravenous and intramuscular administration of Quinine is used, but without any advantages compared to oral administration. The effect of Quinine on the uterus is peripheral, as it is also observed in isolated organs (Kurdinovsky, Kehrer).

Quinine reduces the size of the spleen, especially pathologically enlarged, but it has not yet been established whether this is the result of contraction of its muscles or, as Valenti believes, vascular changes in the organ. Contractions of the spleen from Quinine were thought to be used for the purpose of squeezing plasmodia out of it into the blood (provocation of malaria), but in this respect, adrenaline and other means proved much more effective (see Malaria). The effect of Quinine on other organs with smooth muscle is weak and has no practical significance.

Skeletal muscle responds to Quinine with an initial increase in the absolute strength of the muscle (tonic effect), after which fatigue phenomena occur faster than without Quinine, and the restoration of working capacity is slowed down, so that the total amount of work of the muscle after Quinine is less than without it. With large doses of Quinine, the absolute strength and working capacity of the muscle decrease, and with very large doses, its rapid death and postmortem rigor mortis quickly occur. The effect of Quinine on the muscle is direct, as it is also observed after the depression of motor nerve endings by the introduction of curare.

Effect on metabolism. Even earlier studies showed that Quinine slows down and depresses the general life processes in cells of both anabolic and catabolic character (assimilation and dissimilation): the excretion of urea, uric acid, phosphoric and sulfuric acids decreases. The negative nitrogen and carbon balance in febrile (injected) dogs becomes positive even with an unchanged high body temperature. This is a decrease in metabolism, not a delay in the body of metabolic products, since after discontinuation of Quinine, no subsequent increase above normal in the excretion of metabolic products has ever been observed. All these data were obtained on healthy and febrile, fed and starving animals and humans and are an expression of the general cellular (protoplasmic) depressing effect of Quinine on all types of plant and animal cells. However, more recent data showed that the depressing effect of Quinine on metabolism can be detected only with relatively large doses. In a healthy person, for this, it is necessary to take about 1.5 g of hydrochloric Quinine orally. With smaller doses, even in febrile patients, where the effect of Quinine is more pronounced, the general metabolism (measured by the consumption of O₂ and the excretion of carbon dioxide) often remains unchanged, and in some cases, an increased excretion of nitrogenous protein breakdown products has been noted. Here, the side effect of Quinine on the central nervous system and the circulatory apparatus, especially in small doses, must be taken into account; some researchers come to the conclusion about a possible increase in metabolism at the same time. Therefore, it is hardly possible to attribute to Quinine the properties of a strengthening agent that improves the nutritional state of the body under normal conditions. In cases, however, where protein breakdown processes under the influence of pathological irritants (hyperthyroidism, infectious fevers, etc.) are excessively strong and lead to the rapid disappearance of body substances and loss of its strength, Quinine can have a protective effect by slowing down these processes. Meyer and Gottlieb therefore say that "Quinine slows down not only life, but also death." The cause of this kind of action of Quinine can be considered its effect on cellular enzymes, due to the weakening or complete cessation of the activity of which oxidative and synthetic processes, hydrolysis and breakdown in living and surviving organs are reduced. An increase in life processes, regeneration, or enhancement of growth, etc., has never been observed from Quinine.

Effect on temperature regulation. Therapeutic doses of Quinine have little or no effect on normal body temperature (a smoothing of the difference between morning and evening temperatures can be noted). In individual cases, as with other antipyretics (see Antipyrine), a slight increase in body temperature (so-called paradoxical effect of Quinine) has sometimes been noted. The same therapeutic doses in febrile individuals noticeably lower body temperature, although not as effectively as the antipyrine group. The cause of the antipyretic effect of Quinine in malaria is its destructive effect on the malarial plasmodia, not on the temperature regulation mechanism. In other febrile conditions, where such an etiotropic effect of Quinine has not been established, the decrease in temperature depends on the primary decrease in heat production with a secondary decrease in heat loss. The decrease in heat production, mainly of peripheral origin, is due to the decrease in nitrogen metabolism; it occurs almost to the same extent in experiments and after separation of the temperature-regulating center by transection of the cervical part of the spinal cord. The central effect of Quinine is weaker than that of the antipyrine group; it is manifested in labile temperature regulation, i.e., in fever, and consists in a calming (depressing) effect on the excited temperature-regulating center, which responds to concentrations of Quinine to which it does not respond under normal conditions. In the fall of body temperature, the main importance belongs to the reduced heat production. Heat loss also decreases, but to a lesser extent. In this respect, Quinine essentially differs in its action from the antipyrine group and salicylic acid. With the use of large doses of Quinine, the fall in body temperature also occurs due to the state of depression, muscle weakness, and collapse that it causes. These doses (not necessarily toxic) can therefore lower even normal body temperature.

Compared to aniline antipyretics, Quinine has several advantages: it conserves energy by lowering metabolism, its effect is more prolonged, and the risk of collapse is smaller. On the other hand, the use of Quinine is limited by possible poisoning and idiosyncrasy to it (see below). The effect is especially pronounced in cases where the temperature tends to fall. It is interesting to note that according to old Quinine observations by Zakharin, the effectiveness of Quinine is significantly higher in febrile conditions with respiratory tract involvement than in muscular phenomena, where salicylates take first place. Derivatives of hydrocupreine (optochin, eucupin, vucin and others) emphasize this difference, explained by their specific action on certain infectious agents (see below). Action on the central nervous system. At usual therapeutic doses, Quinine, except in cases of idiosyncrasy, has a weak effect on the central nervous system. Nevertheless, it can be noted that the activity of the cerebral cortex is depressed by a dose of 1.0 Quinine, as established by special tests (tests). Conversely, with very small doses, slight transient excitation of the cerebral cortex and especially of the medulla oblongata centers (respiratory, vagus nerves) was sometimes observed. The phenomena involving the sense organs are significantly more pronounced (see below). Idiosyncrasy to Quinine. This is often observed in healthy people even from very small doses of Quinine (e.g., after taking 0.2 of a Quinine salt or from several tablespoons of decoction of cinchona bark) with symptoms of acute poisoning (especially skin lesions), which pass after 2-3 days. Among the symptoms, the following should be noted: ringing in the ears, hearing loss, mental excitement, amblyopia, pruritus, urticaria, eczema, hemorrhages into the skin and intestines, hemoglobinuria, dyspnea, cardiac weakness. These phenomena can be avoided if 5 mg of Quinine (Negap) is given to the patient 1½ hours before the therapeutic dose. Apparently, we are dealing here with medicamentous anaphylaxis, which is also indicated by the fact that the introduction into the peritoneum of a guinea pig of serum from a person with idiosyncrasy to Quinine greatly increases the animal's sensitivity to Quinine. Sometimes the phenomenon of idiosyncrasy in humans disappears after changing the route of administration of Quinine (Montel and others). Some authors consider the so-called Schwarz-wasserfieber (see Hemoglobinuric fever) in malaria patients in severe cases with fatal outcome as a manifestation of idiosyncrasy. However, the pathogenesis of this symptom complex allows other interpretations. It should be emphasized that idiosyncrasy can suddenly occur in persons who previously tolerated Quinine well. The so-called paradoxical action of Quinine-increase in temperature, accompanied by chills-is also attributed to idiosyncrasy. Acute poisoning. Early symptoms: sensation of heaviness in the head, headache, ringing and noise in the ears, visual disturbances (seeing through a fog, double vision), decrease in tactile sensitivity, dizziness, hearing loss, often nausea, sometimes diarrhea, vomiting, drowsiness. These phenomena can be observed even after taking 1 g of Quinine; usually they pass quickly and without a trace. In pregnant women, Quinine can (but not always) cause an abortion. In more severe cases, the symptoms are as follows: photophobia, more or less prolonged deafness, severe visual disturbances (amblyopia and even complete blindness), marked drowsiness, difficulty in speech, confusion of thought, tremor, skin exanthems, decrease in blood pressure, respiratory disturbances, loss of consciousness, coma, sometimes convulsions, collapse due to general paralysis of the central nervous system and heart, death from respiratory arrest. Thus, the most pronounced phenomena in acute poisoning are observed in the sense organs (hearing, vision), the central nervous system, and the circulatory apparatus. The phenomena involving the organs of vision are mainly of a functional nature, but in severe cases, degeneration of ganglion cells of the retina has also been observed (see Amblyopia); in the inner ear, on autopsy, hyperemia and changes in the cells of the spiral ganglion were often noted. Many admit of a selective action of Quinine on the blood vessels of the eye and ear (ischemia of the retina, hyperemia of the vessels of the inner ear). From the side of the central nervous system, phenomena of excitation are sometimes observed, especially of the respiratory center. Convulsions are possibly due to impurities of other alkaloids of cinchona bark (cinchonine, cinchonidine), for which this action is characteristic. Fatal cases of Quinine poisoning are rare. They have been observed after taking 2.0 of hydrochloric Quinine internally, but for a fatal outcome, a dose of 8.0-12.0 is more often required, although survival has been observed after taking 30.0 of sulfuric Quinine internally. In any case, the lethal dose significantly exceeds the usual therapeutic dose. When Quinine is administered intravenously, fatal cases are more often observed, and here the main role is played not by the dose of Quinine, but by the speed of its entry into the blood, i.e., the strength of its concentration in the blood. With rapid administration, paralysis of the central nervous system and heart can almost immediately occur.-Help in poisoning consists in removing the poison from the stomach (emetic, stomach lavage) and intestines (repeated high enemas, oil laxatives), in maintaining the activity of the heart and respiration (subcutaneous caffeine, hot coffee internally, immersion in a warm bath with cold douches; see Poisoning). In case of damage to the organs of vision, complete rest is necessary, local bloodletting, injections of 0.5-1 cm³ of a 1:1,000 solution of nitric acid strychnine into the temporal region.-Chronic poisoning is observed with prolonged administration of small doses of Quinine to the body. The symptoms are as follows: chronic catarrh of the stomach, various skin lesions (see Dermatitis), constant ringing in the ears, hearing and vision loss. Long-term intake of small doses of Quinine does not contribute to hematuria. It is difficult to say anything definite about the doses causing chronic poisoning, as there are known cases of taking 0.36 of hydrochloric Quinine daily for 2½ years without any harmful consequences. Use of Quinine. The main use of Quinine is as an etiotropic agent in the treatment of malaria (see Malaria), while the derivatives of hydroquinine are used for corresponding bacterial infections (see below optochin, eucupin and vucin). In addition, preparations of Quinine are also used in other infectious diseases, such as influenza, typhoid fever, paratyphoid fever, Malta fever, whooping cough, catarrhal pneumonias, etc. The uterine-contracting action of Quinine is sometimes useful in cases of weakness of labor pains, although in these cases a more certain effect is achieved with pituitrin (see). As a tonic and appetite-increasing agent, Quinine is used in all kinds of conditions of weakness after acute and chronic diseases, blood loss, in conditions of anemia. The effectiveness of this type of therapy with Quinine is less than when using preparations of arsenic, iron, phosphorus. As an antipyretic and analgesic agent, Quinine is sometimes used instead of preparations of the antipyrine group (phenacetin, pyramidone, etc.); often Quinine is combined with these preparations. The combination achieves a summation of the effects of the ingredients, but not potentiation (i.e., an increase greater than the sum). For the purpose of lowering the basal metabolic rate, Quinine has been proposed for the therapy of Basedow's disease, all the more so since experimental data (on tadpoles) speak in favor of the antagonism between Quinine and thyroxine. The antiseptic properties of Quinine are used locally mainly in contraceptives to paralyze the movements of spermatozoa. Optochin, eucupin and vucin have significantly greater importance as antiseptics (see below).-Contraindications: 1) in all cases of idiosyncrasy, 2) in many forms of epilepsy, since Quinine can cause seizures, 3) after recent encephalitis, meningitis, otitis media, since severe phenomena of irritation of the affected organs may occur, 4) in severe organic defects of the heart with degeneration of the myocardium, 5) in nephritis, 6) in hemoglobinuric fever. Preparations of Quinine are numerous. The proposal of new Quinine compounds aims to eliminate some of its undesirable properties (bitter taste, toxic action on organs) or to increase its bactericidal action, etc. In accordance with the concept of the different significance of various chemical groups for the action of Quinine, there are attempts to synthesize derivatives of Quinine in which the parasitotropic action would be more pronounced, while the organotropic action, on the contrary, would be reduced. The study of the structure of Quinine has made it possible to synthesize other preparations with a similar character of action. For methods of using Quinine preparations in malaria-see Malaria. The usual salts of Quinine are extremely bitter white powders, without odor. In solutions, they are incompatible with alkalis, carbonates (soda) and other precipitants of alkaloids, with salicylates, benzoates and other salts of weak acids (precipitation of Quinine base or difficultly soluble salts). The average dosage for all salts of Quinine: as tonic-0.1, as antimalaric-up to 1.0 pro die.

The usual dose is 0.05-0.5. 1) Quinine hydrochloride, C20H24N2O2·HCl·2H2O (Formula VII), thin, white, silky, needle-shaped crystals that effloresce in warm, dry air. Extremely bitter taste. Contains about 82% quinine. Soluble in 30 parts cold water and in 1 part boiling water, in 3 parts 90% alcohol, in 10 parts glycerin. Solutions of neutral or very weakly alkaline reaction do not fluoresce, but after acidification with dilute sulfuric acid acquire an intense blue fluorescence. Solubility in water is significantly increased (up to 1:1), and irritating properties are diminished by the addition of urea (see below - Quinine carbamidate), urethane, caffeine, or antipyrine. Often adulterated and contains impurities of other alkaloids of cinchona bark. Used in powders, lozenges, pills, and solutions orally, per rectum, subcutaneously, intramuscularly, intravenously. Doses: orally 0.3-1.0. For children up to 3 years, as many centigrams as the child's months, or as many decigrams as the child's years. Solutions do not mold on standing. Stored in well-sealed containers in a place protected from sunlight. 2) Quinine bishydrochloride, s. bimuriaticum, quinine dihydrochloride, C20H24N2O2·2HCl·2H2O (Formula VIII), colorless crystals, very bitter taste, soluble in 0.7 parts water, easily soluble in alcohol and dilute hydrochloric acid. Aqueous solutions of strongly acid reaction, give blue fluorescence on strong dilution or after acidification with dilute sulfuric acid. Contains approx. 73% quinine. Irritates much less than the hydrochloride. Used subcutaneously, intramuscularly, intravenously, and per rectum. For dosage - see Malaria. Stored in well-sealed containers in a dark place. 3) Quinine sulfate, (C20H24N2O2)2·H2SO4·8H2O (Formula IX), white needle-shaped crystals with a silky luster, easily efflorescing in air. Soluble in 800 parts cold water and in 25 parts boiling water, in 90 parts cold and in 6 parts boiling alcohol, almost insoluble in ether and chloroform. Solutions of neutral reaction, extremely bitter taste, acquire a bright blue fluorescence when acidified with sulfuric acid. Contains over 72% quinine. Addition of acids (e.g., hydrochloric) significantly increases solubility in water (forms Quinine bisulfate, see below). Due to low solubility and slow absorption, it often irritates the stomach. Orally in lozenges 0.3-1.0 (see Malaria), usually in large amounts of liquid (e.g., in lemonade). Stored in well-sealed bottles in a place protected from sunlight. Solutions easily mold on standing. 4) Quinine bisulfate, quinine disulfate, C20H24N2O2·H2SO4·7H2O, white crystals, soluble in 10 parts cold water and in 23 parts alcohol. Solutions of acid reaction, intensely fluorescent. Contains 59% quinine. Locally irritates with subsequent anesthesia. Used subcutaneously (see Malaria), in 2% solution for operations on the tonsils and trachea, in the form of an ointment against eczema solare for absorbing strongly irritating ultraviolet rays. 5) Quinine hydrobromide, s. bromide, quinine hydrobromide, C20H24N2O2·HBr·H2O (Formula VII), thin white silky needles without odor, extremely bitter taste, efflorescing only in dry, warm air. Soluble in 45 parts cold water and in 1 part boiling water, in 0.9 parts alcohol and in 7 parts glycerin. Solutions of neutral or very weakly alkaline reaction, fluoresce only after strong acidification with sulfuric acid. Contains 77% quinine and 19% Br. Dosage and application same as with quinine hydrochloride, but especially in cases of functional neuroses, with cardialgias, vomiting of pregnancy in doses of 0.1-0.5 several times a day. Stored in well-sealed bottles in a dark place. 6) Quinine bishydrobromide, quinine dibromide, C20H24N2O2·2HBr·3H2O, white or yellowish-white crystals, soluble in water and alcohol. Contains 60% quinine. Orally 0.5-1.0 for the same conditions as the previous one. 7) Quinine tannate, C20H24N2O2·3C14H10O8·8H2O (?) (Formula VII), yellowish-white amorphous powder without odor, weakly bitter and astringent taste, difficult to dissolve in water (1:800) and alcohol. Contains 30-33% quinine (composition not always identical). Less irritating and more slowly absorbed than the hydrochloride. Prescribed in doses approximately twice as large as the hydrochloride. Stored in well-sealed containers. 8) Quinine acetylsalicylate, CH3CO-OC6H4-COOH-C20H24N2O2 (the English preparation is called Quaxaquin), white crystalline needles, very difficult to dissolve in water, easier (1:40) in alcohol. As an antipyretic 0.5 in powders or in emulsion (replaces the combination of quinine with aspirin). 9) Quinine salicylate, C20H24N2O2·C7H6O3, colorless crystals, soluble in 250 parts water and in 25 parts alcohol. Contains approx. 69% quinine. Orally in powders 0.5-1.0 up to 3.0 a day as an antipyretic. 10) Quinine citrate, quinine citrate (C20H24N2O2)2·C6H8O7·7H2O, white needle-shaped crystals, soluble in 900 parts cold or in 30 parts boiling water, in 45 parts cold and in 3 parts boiling alcohol, bitter taste. Used in doses 0.05-0.1 as a tonic. 11) Quinine hydriodide, quinine hydroiodide, C20H24N2O2·HI, yellow powder, very poorly soluble in cold water, easily soluble in boiling water and in alcohol. Used orally 0.1 or subcutaneously 0.2-0.5 in chronic malaria with scrofula. Replaces the combination of hydrochloride or sulfate quinine with iodine alkalis. 12) Quinine phosphate, quinine phosphate (C20H24N2O2)·H3PO4·8H2O, colorless shiny long crystals, soluble in 700 parts water. Orally 0.2-0.3 in chronic malaria. 13) Quinine glycerophosphate, quinine glycerophosphate (C20H24N2O2)2·C3H5(OH)2O·PO(OH)2·5H2O, white crystals, soluble in 300 parts cold or in 60 parts boiling water, in 40 parts cold alcohol. Orally as a tonic 0.1-0.2 and as an antineuralgic 0.3-0.6. 14) Quinine valerate, C20H24N2O2·C5H10O2·H2O, shiny white crystalline powder with a distinct odor of valeric acid, bitter taste, soluble in 100 parts cold water and in 5 parts alcohol. Orally in powders and pills 0.05-0.1 in intermittent neuralgias, especially in the presence of hysteria and with great irritation of the stomach. 15) Quinine arsenate - see Arsenic. 16) Quinine bishydrochloride (s. bimuriaticum) carbamidate, dihydrochloride (disulfate), urea quinine, Anacain, C20H24N2O2·HCl + CO(NH2)2·HCl·5H2O, colorless crystals or white granular powder, very easily (1:0.9) soluble in water, in alcohol (1:2.4); contains 60% quinine. Solutions of weakly acid reaction, bitter taste, weakly irritate with subsequent anesthesia. Used subcutaneously, less often intramuscularly in 1/2-1% solutions in a dose of 1.0 once a day. When administered intravenously, a 10% solution in 0.6% NaCl solution is used. Also proposed as an anesthetic for mucous membranes in 10-20% solutions. 17) Chinopyrin, quinopyrine, a supposed chemical compound of quinine with antipyrine; formed when e.g. 3.0 hydrochloride quinine and 2.0 antipyrine are mixed in water (up to 6%). The solution obtained by this recipe contains about 50% quinine and when administered subcutaneously (e.g. 1-1.5 g) does not cause irritation phenomena (pain, inflammation). 18) Basicin, basizin (German preparation), a mixture of hydrochloride quinine with caffeine. White crystalline powder, easily soluble in water (1:1), does not irritate locally. Used orally in mixtures 0.25-0.5 as an antipyretic, subcutaneously in 50% solution 1 g and externally in the form of rubbings of a mixture of basizin (5.0), chloroform (37.5), absolute alcohol (12.5) and fatty oil (50.0). 19) Quinine citrate, a mixture of quinine with iron citrate, containing about 9-10% quinine and 21% Fe. Shiny dark brown flakes, bitter taste, slowly but well soluble in water, very little in alcohol.

Orally 0.2-0.5 three times a day in powders and pills as a tonic and strengthening agent in anemias, chlorosis, and general malnutrition. 20) Amnesin, for amnesia, the double milk-acid salt of morphine and narcotine with anacaine (urea-H dichloride). Released in ampoules of 1 cm³ containing 0.01 morphine, 0.015 narcotine, and 0.2 urea-H dichloride. Recommended during childbirth in the form of subcutaneous injections to reduce pain and accelerate the delivery process. 21) Plasmochinum compositum, a preparation containing plasmochin and sulfuric acid X. (see Plasmochin). 22) Chineonalum, chineonal, the quinine salt of diethylbarbituric acid (veronal), white, poorly water-soluble crystals of bitter taste. Contains 64% X. and 36% veronal. Used in powders and tablets for neuralgia and sea sickness at 0.5-0.75 twice a day, for children with whooping cough at 0.05-0.2 (depending on age) 2-3 times a day. 23) Chinapheninum, chinaphenin, the carbonate X.-phenetidin, a white powder, tasteless and odorless, almost insoluble in water. Contains 66.5% X. Orally as an antipyretic at 1.0-2.0 in the evening or 0.75-1.0 twice a day, for children in milk, soup at 0.1-0.2 (for younger) and 0.3 (for older) three times a day for whooping cough. 24) Chinaphthol, chinaltol, or Chininum β-naphtholsulfonicum, betanaphtholmonosulfate of quinine, a yellow crystalline powder, poorly soluble in water. Contains 42% X. In the intestine it breaks down into its components and acts as an antiseptic and to some extent as an antipyretic. Used at 0.5 to 2.0-3.0 pro die in typhoid fever, dysentery, colitis. Esters of X. are insoluble in water and therefore tasteless. They pass through the stomach unchanged, are slowly saponified in the intestine, acting gradually and more weakly. Not always free from side effects. 25) Agisto-chin, aristochin, the carbonate diquininester, CO(OC₂₀H₂₄N₂O)₂, a white tasteless crystalline powder, insoluble in water, easily soluble in alcohol. Contains 96% X. Used in asthma (at 0.4), neuralgia (at 0.25-0.5), malaria (at 0.5) several times a day and in children with whooping cough - under one year old at 0.05-0.1, older ones at 0.3 three times a day. 26) Euchininum, s. Chininum aethylcarbonicum, eukhinin, or ethylcarbonic ester of X., C₂₀H₂₃N₂O-O-CO₂-C₂H₅ (Figure VII), a white light powder, almost insoluble in water, easily soluble in alcohol and diluted mineral acids, almost tasteless, does not irritate the digestive tract. Contains over 80% X. Orally in powders for malaria in children at 1.0, for whooping cough at 0.05-0.5 several times a day. When taking, it should not be taken with acidic drinks (lemonade), in which the bitter taste is easily felt; before taking, it is necessary to rinse the mouth thoroughly. Side effects are weaker than those of X. salts. 27) Insipin, insipine, the sulfate of glycolic acid ester of X., a white crystalline powder, tasteless, insoluble in cold water and alcohol, very easily soluble in hot water and alcohol. Contains 72.8% X. In action 1^g/₂-2 times weaker than hydrochloric acid X. Less toxic than eukhinin (Schmiedeberg). Especially recommended (Werner, 1912) for malaria in children at 0.2-0.5 several times a day. 28) Salochinin, salo-chinin, the complex ester of X. and salicylic acid, a white, tasteless, water-insoluble powder. Contains about 73% X. Orally for muscle pains, rheumatism, neuralgia at 1.0-2.0 three to four times a day. The salicylate salt of salochinin (Rheumatin) is somewhat soluble in water, used as salochinin. Often causes side effects from the stomach (heartburn, burning). 29) Quinisal, a compound of 1 molecule of X. with 2 molecules of diplosal, a white, flaky powder without odor, slightly bitter taste. Soluble in 100 parts of cold water, easily in alcohol and ether. Used for influenza, rheumatism at 0.25-0.5 g three times a day. 30) Quinetum, a mixture of all alkaloids from Cinchona succirubra; contains 50-70% cinchonidine. A gray powder, soluble in acidified water. Dose 0.06-0.5. 31) Totaquina contains all alkaloids of cinchona bark, not less than 70% crystallizable alkaloids, of which X. should be not less than 15%, amorphous alkaloids not more than 20%, mineral substances not more than 5%. Derivatives of hydrocupreine! Cupreine, C₁₉H₂₀N₂(OH)₂, is an alkaloid contained in the bark of China cuprea or Rameja pedunculata; chemically it is close to X. (see above). Hydrocupreine, C₁₉H₂₂N₂(OH)₂, does not occur in nature, can be prepared from cupreine by reduction with hydrogen; usually it is prepared from hydroquinine by removing the methyl group by boiling with HCl. Differs from cupreine by the presence of an ethyl group CH₂-CH₃ instead of a vinyl group CH:CH₂ (in the loipone residue). By replacing the methoxy group in the benzene nucleus of the quinoline residue (see the formula of X. above) with other alkylamines with 3-16 carbon atoms, a homologous series of hydrocupreine derivatives is obtained. Of these, it is necessary to indicate: 1) Ethyl hydrocupreine, s. Optochin, ethylhydrocupreine, or optochin, C₁₉H₂₃N₂O-O-C₂H₅. Its structural formula can be easily imagined if in the formula of X. instead of the vinyl group an ethyl group (CH₂-CH₃) is placed and instead of the methoxy group (CH₃-O) of the benzene nucleus an ethoxy group C₂H₅-O is placed. Basic optochin (Optochin basicum) is a white or slightly yellowish amorphous powder, without odor, very bitter taste, almost insoluble in water, soluble in fatty oils. Absorbed slowly. Used (rarely) for pneumonia orally at 0.1-0.2 per dose up to 1.2 in 24 hours (see Pneumonia, lobar pneumonia, clinic). Externally in the form of 1-2% ointment or in a solution in oil of almonds for the eye in ulcus serpens corneae. For external use, hydrochloric optochin (Optochin hydrochloricum) is more suitable, a white crystalline powder, very easily soluble in water (1 : 2) and alcohol (1 : 5), very bitter taste, without odor. Externally in the form of a 1-2% solution for instillation into the eye several times a day, gargles (solution 1 : 10,000 in a saturated aqueous solution of thymol), in pneumococcus carriers (Kolmer, Steinfeld). Morgenroth showed that optochin has an extremely strong bactericidal effect on pneumococci both in vitro (a solution of 1 : 1 million is sufficient) and in vivo (in pneumococcal sepsis in mice). Its action is 50 times stronger than X. and 20 times stronger than eucupin (see below). Thus, the specific action on pneumococci is due to the ethoxy group. In lobar pneumonia, many authors obtained good results with early administration of optochin. At the same time, severe complications in the form of visual disturbances, blindness, vomiting, ringing in the ears, hearing loss, heart weakness, and in some cases fatal outcome were often noted. In 1916, Morgenroth came to the conclusion that orally only poorly soluble preparations (O. basicum, O. tannicum, O. salicylicum) can be given (no more than 1.2 g per day), but not hydrochloric optochin. The intake should not be on an empty stomach, together with milk, which binds the HCl of gastric juice, converting the preparation into hydrochloride. Even under these conditions, internal use of optochin requires great caution. With external use, optochin proved to be an unsurpassed remedy for pneumococcal ulcus serpens corneae. Favorable results were also observed in other eye lesions (blepharitis, acute and chronic pneumococcal conjunctivitis, gonorrheal conjunctivitis, dacryocystitis, phlyctenae, etc.). However, complications in the form of superficial necrosis, corneal opacity, etc. were also noted. 2) Eucupinum basicum, basic eucupin, or isoamylhydrocupreine, C₁₉H₂₄N₂O-OC₅H₁₁, a white, water-insoluble and oil-soluble powder, almost tasteless. Externally as an anesthetic and disinfectant in 5-20% lanolin ointment, orally (rarely) at 0.25-0.5 per dose, no more than 3.0 per day or per rectum in suppositories (2%). Eucupinum bihydrochloricum, dihydrochloride eucupin, C₁₉H₂₄N₂O'OC₅H₁₁-2HCl-H₂O, colorless, delicate needle-shaped crystals, of a scraping bitter taste, easily soluble in water (1 : 15) and alcohol. Externally as an antiseptic on wounds (¹/₂%), for rinsing the mouth, pharynx and throat in meningococcal infection (70 cm³ of ¹/₂%), for smearing the pharynx in diphtheria (5% alcoholic solution several times a day), for local anesthesia of the nasopharynx (1-3%).

Equinol is an extremely powerful bactericidal agent against pyogenic infection (streptococci, staphylococci, etc.) and has found wide application in infected wounds, ulcers in bedsores, joint lesions, pleurisy, etc., where its local action was used. With resorptive action, good results were sometimes observed in influenza and pneumonia, etc. In addition, equinol has an anesthetic effect. Although the toxicity of equinol is less than that of optochin, complications are still noted with its use (damage to vision, symptoms of general poisoning). 3) Vutsin (see).

M. Nikolaev. Methods for determining quinine in urine. For qualitative detection, the urine is acidified with sulfuric acid and extracted with ether until the ether extract, upon evaporation, no longer gives a noticeable residue. After this, the urine is alkalized with ammonia and extracted again with ether. The ether extract is separated and evaporated to dryness. The residue is dissolved in dilute HCl, filtered, and the purification procedure is repeated once more. With the obtained hydrochloric acid solution, the talloquinine reaction is performed: a small amount of bromine water is added and then immediately a small excess of ammonia; the resulting emerald-green coloring is characteristic of quinine (Andre test). An excess of bromine makes the reaction less sensitive; the reaction is also inhibited by the presence of antipyrine, pyramidone, and caffeine. In addition to quinine, other oxyquinolines also give the talloquinine test. For quantitative determination of quinine, 100 cm³ of urine is alkalized with 10 cm³ of a 10% NaOH solution and extracted with ether in an extraction apparatus for 25-30 hours. From the ether extract, quinine is precipitated with anhydrous citric acid. The citric acid quinine (C₂₀H₂₄N₂O₂·C₆H₈O₇) is filtered, dried, and weighed. Multiplying the obtained weight by 0.627 gives the amount of quinine in percentage in the urine taken. The polarization test for quinine, based on the optical activity of quinine ([α]_D²⁰ = -158.7° in ether), is unreliable, since other optically active substances may be present in the urine.