4 H2O), its sodium salt, AuCl3. NaCl + 2 H2O) and aurum sulfurat. + gold sulphide (Au2S3) are proven, one has attempted to accelerate the slow metal actions and to link them to definite organs. Aurum muriaticum and aurum muriaticum natron are often preferred especially in arteriosclerotic and leutic affections. DOSE The salts and aurum colloidale are usually given in the lower potencies up to the D 6, aurum met. especially with the presence of the mental symptoms also in D 30. ZINC In the periodic system of elements zinc stands in a series related to cadmium and mercury. However the relationship to mercury is not very outspoken either chemically or pharmacologically. Even if one thinks that the working range of zinc is of a much slighter extent than that of mercury, nevertheless considerable similarity in the toxic manifestations is etested that no therapeutic recommendations can be based on them.
Concerning the additional group of the periodic system and the relation of the elements in it in respect to a general survey, the necessary things have already been said (see p. 113ff.). When we designate this class of elements with the term heavy metals, this signifies a characterization a potiori. Because transitions to the light metals of the type of aluminium exist in this group. On the other hand the heavy metals are not limited to the additional group but also appear in the related chief groups (for example, bismuth from whence there is an unclear transition over antimony and arsenic to the non-metals). A universal agreement on the conception of metal is scarcely possible so that it is not feasible to define the heavy metals sharply. The chemical criterion that the metal appear as a cation, the oxides and the metals should be base forming, proves unsuitable because undoubted metals form no bases and others form acids as well as bases. Difficult solubility is also insufficient as a criterion. The conduction capacity for an electro-magnetic stream is best adapted for characterization because it is associated with a special electron structure. But also this obtains only for the so- lid and fluid states of these materials; in the gaseous forms, the “metallic” state diminishes; also too crude for our purpose is the characterization by properties such as impermeability, sheen, etc. In solid state the metals are class I conductors. According to modern conceptions this signifies the presence of freely movable negative electrons within the interspaces of the atoms. These electrons are carriers of electrical conduction; conduction occurs in that the electrons transmit their movement pressure to one another in the same direction (toward the positive pole). Another physical characteristic of metallic elements is that they consist of free atoms which are positively charged (therefore in many typical metal compounds, the appearance of the metal as a cation). The heavy metals are further characterized by their high atomic weight and small atomic volumein contrast to the alkali-earthly alkali-and light metals. The heavy metal tendency increases in single chief groups with the atomic weight.
It should also be constantly held in mind that flowing transitions from all sides occur from the metallic state or the metallic or heavy metal tendency. But here we use the designation heavy metal for the type additional group.
Their physico-chemical mutual nature also conditions a series of common trends in the behavior to the organism. They are poorly soluble and therefore poorly absorbed from the unbroken mucous membrane, with the exception of mercury, which, under the usual conditions, is the only liquid metal. Only from mercury and from a few metal vapors (also removal from the metallic state) are there typical acute intoxications from the intact skin and mucous membranes. The heavy metals precipitate protein irreversibly but mercury albuminate again finds its best conditions for solubility in an excess of protein and salt. Moreover the defense of the uninjured organism fails easiest with lead, but here the persistent absorption of the smallest amounts first brings about a typical chronic metal poisoning. When the metals appear in their ionic forms, as salt solutions (or chromium for example as an acid) in reciprocal action with the organism, the dissociation of the compound, the reaction intensity of the liberated fraction (the acid) decides, whether and how far the local injury conditions the abnormal absorption and the acute poisonous action. These then are comparable to parenteral introduction. Likewise the valence of the metals (for example ferrous of ferric compounds) is important for absorbability.
In most cases the participation of the nervous system will be seen in an intoxication with a heavy metal. These affinities come predominantly to expression if the heavy metal is introduced into the organism in a finely divided form and over a long period, as in the provings on the healthy. Most heavy metals are therefore chronic nerve remedies, iron with its well demonstrated physiological function forming an important exception. The heavy metals appear particularly arranged for this affinity for the nervous system. They are outstanding conductors for electro-magnetic currents; their structure remains unaltered in this conduction (so far as the electron impulse is not altered by the excessive production of heat), therefore they are not destroyed by the conduction. The nervous system is a conducting and connecting system with insulating arrangements that certainly can be placed into activity be electromagnetic energy (light!) and this energy transmission, though perhaps of another type, is still comparable to the well-known electro-magnetic waves. One might advantageously represent in this way how the heavy metals as energy carriers find their receptors in the first line in the nervous system. And now finally must the phenomena be founded, indeed whether it is designated according to ordinal number as affinity, electromagnetically as resonance, in structure, whether it depends upon atom or electron groups, which has something in common in the type and ordinal number of the energy carrier and receiver, so that is may occur. The transference catalysis (comp. p. 115), which we have already discussed as an essential effect mechanism of colloidal heavy metals, is indeed nothing more than the continuation of equal processes up to the dimensions which are available for the experiments of today.
From this chief trend of heavy metals in the organism there are single deviatations in the single effect pictures of the materials of the group. In some the affinity for the nervous system appearance only in chronic poisoning, in chromium (as the chromi- c acid ion) the acid action is directed toward the peripheral parts. With iron there is the physiologically fixed position, as the transference catalysor in cell respiration and this gives the effect picture more a constitutional character than heavy metals have otherwise. So in spite of the narrow neighboring connections of the elements there is a great diversity of the effect pictures, a diversity not only in their symptomatic ramifications but also individually different in their origin and trend.
The element with an ordinal number 26 must be characterized by an extraordinary stability of its nucleus. Its abundance in the earth favors this. Although geologically it is peculiar to the interior of the earth as the chief constituent of the siderosphere and the chalkosphere, its appearance in the lithosphere is very significant, so that in its compounds it amounts to 4.2 Percent of the solid earth crust.
Even in the earth iron acts as an oxygen carrier, ferrous oxide, as it is liberated in the destruction of certain stones and is oxidized to ferric oxide. If now this comes in contact with decomposing organic substances then it oxidized to carbon compounds to carbon dioxide and from ferric oxide, ferrous oxide is again formed (Bunge). In experiments animal charcoal which adsorbs molecular oxygen, O2, cannot oxidize organic compounds without the presence of iron.
PHYSIOLOGIC ROLE OF IRON
The catalytic capacity of iron as transferer of active oxygen to the organic constituents of cells which are not able to react directly with molecular oxygen depends upon the easy change in the valence of iron. This ability to alter valence is indeed one characteristic of the elements of the additional group. In regular sequence the divalent (ferro) iron reacts with O2, changing into the trivalent (ferri) iron and this reacts with the organic substances with liberation of oxygen. Molecular oxygen, O2 is thereby activated to atoms carrying electricity. The catalytic action is limited only to define forms of iron, as they are present in protein compounds in the cells as respiratory ferments (according to Warburg). If this form of cell iron is altered by reaction with a poison as HCN (ferment poison, anticatalysator), then the catalytic capacity of the iron compound ceases.
The body iron belongs for the most part to the red blood cells and in them is bound to the hemoglobin. This role of easy absorption of oxygen to oxyhemoglobin and the yielding of it according to the partialpressure of the milieu is universally known. Iron is bound to the coloring material (hemin, that is the HCI ester of haematin) in the red blood corpuscles, and this is chemically closely related to the green coloring material of the higher plants chlorophyll. Now it is worthy of note that chlorophyll also needs iron for its formation. If iron is lacking in the nutrition of the green plants, then they become “chlorotic” that is, they show a deficiency in chlorophyll. However iron is not a constitution of chlorophyll. But an intermediate reaction with iron is obviously necessary in its formation. According to one conception 588 iron inactivates calcium in favor of magnesium which is known to be the essential constituent of chlorophyll. Accordingly one might also consider for hemoglobin that iron is not merely passive as a coloring substance but it actively necessary for its formation. The form of iron for this task can be variable.
For illustration of the amounts involved of iron metabolism, the report of Warburg may serve: the cell iron in the tissues of higher animals contributes a few tenths of a milligram per gram of cell substance (that is, about the D 4). The physiological iron requirement per day in adults is about 1-10 mg.
It was long held that absorption of iron which was present in the natural foods could not occur because at first it seemed as though a quantitatively complete excretion through the intestine followed. But since experience has shown clearly the effectiveness on blood formation, an attempt has been made to find a suitable explanation. Finally it was demonstrated that soon after the administration of iron chloride, it could be found microscopically in the intestinal mucosa and chemically in the lymph of the thoracic duct and the absorption from the intestine was demonstrated. The iron was absorbed in an ionized form. It is worthy of note that the capacity of absorption of the intestinal wall for iron is very rapidly paralyzed. 589 Lewin cites the old report that absorption occurs with a 1 Percent iron citrate solution introduced into the stomach, but in a 4 Percent it does not. There also exists an optimal concentration for absorption.
From the intestine the iron passes to the liver and is deposited in it, further in the spleen and bone marrow and is available for the body cells. To this is added the iron arising from the destruction of the erythrocytes, which again becomes useable iron. This reserve iron is stored chiefly by the reticulo-endothelial system. The excretion of the finally used iron occurs largely from the lower bowel, only a small part going through the kidney. Thus may there be the appearance after the marked use of iron as though the iron introduced was quantitatively (as one formely believed without absorption) excreted again through the intestine. The use of iron in metabolism is constant and in the state of hunger the excretion through the kidneys is largely independent of the introduction of iron. With increased blood destruction as in pernicious anemia, the excretion of iron in the urine is considerably increased.
Since excretion does not cease with deficient introduction, one might conjecture that the iron excreted is in another used state than that introduced, because otherwise there would be complete retention and reutilization of the iron by the organism. In fact the normal and pathologic iron metabolism is, perhaps, one of the best examples of how little the quantitative conception states about the actions and how outstanding the chemical and here the physical form is.
SIGNIFICANCE OF THE CHEMICAL AND PHYSICAL FORM
It has long been known that the inorganic iron salts are distinguished from the organic preparations in that they also posses the capacity for promoting the formation of hemoglobin in the growing animals by a iron rich diet. Moreover if sufficient the iron is offered a s a building material of hemoglobin through the organic compounds along have a stimulating influence of the new formation of hemoglobin. This activity is also associated with the iron form and the strongly ionized (divalent) ferro-compounds prove much more active than the (trivalent) ferri- compounds. Moreover it has also been proven in the test- tube that the iron of the healthy animal or a man dead from an acute disease accelerates certain chemical reactions catalytically, while the iron from the liver of a patient dead of pernicious anemia does not have this catalytic property. It is not known whether the activity here is joined to a definite chemical compound or to the physical structure of iron.
Starkenstein and Weden see the difference exclusively in the manner of chemical combination. Simple ferri-compounds which have been introduced into the organism from without are always inactive according to their report. They will be taken up by the spleen and indeed only by this in unaltered form, stored and then again excreted; on the other side reduced to the inactive ferrous iron in the liver, this is the hemoglobin building stone, but not available for the catalytic processes. Active ferro iron is also dissociated in the organism and it circulates long in the organisma nd is introduced from the blood into all organs outside of the spleen. It is oxidized to the ferri form in the blood, in which the iron is bound complexly in the anion. This differs however fundamentally from the directly introduced ferri-compound, in so far as they remain unaltered for a long time in the blood. The activity of this ferri iron, which enters the cell, consists of its biologic O2 yield, whereby it is reduced to the catalytically inactive ferro iron. This inactive divalent iron is deposited in the liver and can then (as it is concerted there into the ferri form) serve as a building stone. Ferro and ferri forms on introduction into the organism act in entirely different forms. If Starkenstein ascribed no pharmacologic actions to the simple ferri-compounds but only local toxic actions, because they precipitate proteins, then this holds only for large amounts introduced by injection. And also with the deposit of simple ferri-compounds in the spleen and its subsequent excretion is not ultimate proof of its medicinal inactivity, since all ferri iron need not take this way. Experience contradicts such an assertion.
But how important the physical sate of iron is for the therapeutic purpose is shown by Baudisch and Welo. They proceed from the well-known fact that where mineral springs appear on the surface they have very special effects and that the healing power of the fresh mineral water gradually diminishes and disappears. In many springs can this old folk experience be explained scientifically by the proof of radio-activity, and most strikingly in the iron containing waters. Only the iron water freshly appearing from the earth show catalytic properties. Chemical differences cannot be made responsible for this.
One knows chemical parallels; only freshly precipitated ferrous bicarbonate is able to activate the oxygen of the air so that oxidizable compounds present at the same time as oxidized. Brief existence without the presence of air makes ferrous bicarbonate inactive, although it takes up oxygen avidly on subsequent access of air, but is not activated. Such “active” properties of chemical substances in the statu nascendi are indeed known of many other substances. But this capacity is only very transient in preparations in the test tube. In the natural mineral springs the active or better activated state is more prolonged (some hours). And finally for the benzidine test on the blood the presence of H2O2 is well known, so that something
is contained in the blood (namely its iron compounds) which is colored by perioxidase action, that is, oxygen activation of H2O2 which colors benzine blue.
As Baudisch and Bass have shown, even light is able to accelerate the aging of mineral water and thereby it must be concerned with an involvement of the ferrous bicarbonate, while on the other hand potassium ferrocyanide solution is converted from its catalytically inactive state into an active form by radiation with sun light.
That also without alteration of the chemical composition. the physical form of an iron compound as iron oxide is decisive for the properties, one knows from magnetism. Baudisch and Welo proved with iron oxide, FeO3, that the artificially prepared magnetite, FeO Fe2O3, would oxide in an oxygen stream by heating. At 300o there develops a strongly magnetic red powder Fe2O2 which on heating to 550o goes over without external alteration into an almost non-magnetic Fe2)3. Through x-ray interference photography it is shown that the magnetic Fe2O3 has cubic structure while the more highly heated Fe2O3 has a rhomboid structure. Only the magnetic cubic Fe2O2 is active iron while the non-magnetic rhomboid iron is biologically in-active.
The arrangement of atoms in space is also decisive for the magnetic as well as the catalytic properties. Through the various arrangement of atoms the surface powers depending upon the free valences will be altered and only in the active form is a partial reaction with oxygen possible. The formation of such active surf- aces of a simple iron compound is compared by Baudisch and Welo with enzymatic or serologic processes. The activation of mineral compounds through sunlight is the simplest example of the format- ion of an inorganic vitamin. If now one adds to this effect of light on the arrangement of molecules and atoms still the physical photo-effect which also involves a reformation of the electron structure, then an entire world of structural alteration with whose appearance entirely new properties are bound is opened in chemistry even of the influence of radiant energy.
Bickel and his pupils have found that active iron as iron oxide preparations, so-called siderac, like the fresh Stahl spring, also has biologic actions on the red blood cells, growth and metabolism which are absent in inactive iron oxide and the older Stahl spring water. But the promotion of blood building can only be demonstrated in the previously disturbed equilibrium of anemic children. The lability in iron metabolism forms a pre-condition for such proof and this condition, the iron sensitivity of the side of the organism, has often been referred to by us. A transient increase in the hemoglobin formation has however been found by Adberhalden in the growing normal animal. However even during growth a definite although naturally slight lability may be presumed. The favorable action already demonstrated by Abderhalden on the growth of young animals by the introduction of inorganic iron salts can also be ascribed to active iron in a higher degree than to the inactive. Moreover an influence on the nitrogen balance of the growing animal 594 will also be found only from the active forms of iron.
TRANSFERENCE OF AND ACTIVATION OF OXYGEN
The physiologic role of iron in hemoglobin is not limited to the acceptance, transport and delivery of oxygen. Likewise the taking up of CO2 in the body capillaries and the release in the lung capillaries is facilitated by the iron containing hemoglobin, moreover hemoglobin participates in the buffering of the blood. Not only as an ampholte as all protein bodies-that is, in the property of being a weak acid and a weak base at the same time- does the buffer action exist, but also especially in that the oxyhemoglobin is relatively acid and reduced hemoglobin is relatively alkaline. The preponderance of reduced hemoglobin in the venous capillaries also signifies a tendency to alkalinity. By this the streaming in of CO2 into the blood will be facilitated without the acid-base equilibrium in the blood varying markedly. After yielding CO2 the alkalinity developing will be buffered by the formation of oxyhemoglobin.
The general function of iron in the respiratory ferment of the cells has become known through the work of Warburg. The respiratory ferment is an organic iron containing pigment staining very close to haemin. It has the task of oxidizing the hydrogen rich carbohydrate fraction remaining after fermentative splitting. Whether this occurs through the activation of hydrogen from the organic compound, as Wieland asserts, or through activation of O2 (to atomic oxygen), as Warburg believes, is immaterial for the effect. It is also assumed now that the activation of hydrogen as well as oxygen occurs. The cells, outside of the O2 activating respiratory ferment of Warburg, also contain hydrogen acceptore (as Kelin’s cytochrome), which with the help of suitable ferments (dehydrases) can activate the H of the organic compounds and react with the molecular O2.
Likewise the other catalysors belonging to the mechanism of cell oxidation are haemins: the peroxydase, the peroxide (as H2O2) activator, that is, liberate the atomic oxygen from it and the catalase, H2O2 being decomposed into H2O and O and thereby an excess of H2O2 made harmless.
The red blood cells in this respect contain no respiratory ferment, hemoglobin not being a respiratory ferment in the sense of an activation of O2 but only a carrier of it.