CHNH2 CHNH2 @ @ @ COOH COOH COOH The transformation of cystein to cystin occurs in the air through oxygen, naturally with cooperation of constantly present traces of iron. This simplest form of sulphur-containing building stone is determining for the function of sulphur in the protein molecule, but, through further compounds, the complex gains some new properties. So cystin or cystein forms a dipeptid with glutaminic acid- CH (NH2) COOH = CH2 CH2 COOH namely the glutathion discovered by Hopkins in 1920. Probably this compound is present in most cells. The easy oxidation to cystin form and likewise the easy reduction to the cystein form also remains in this compound. In contrast to cystin, the cystein form of glutathion is soluble in the fluids of the body. This is a sign that the complex form is better adapted to the functional DOSE : Usually D 6 (trituration).
In group VI of the periodic system sulphur has such central position that we can designate the group according to it, particularly since the first element of the group, oxygen, provides no medicinal substance. The transition from the non- metallic sulphur to the metallic tellurium will come into evidence in the effect picture of this substance. Selenium and tellurium appear considerably less significant than sulphur and its compounds.
In the earth, sulphur, S, is the prevailing element of the chalkosphere. In this layer of the earth, which perhaps extends about 1200-2900 km: in depth, those metals are abundant which have a special affinity for sulphur. Here sulphur plays a role for the so-called metallogenous elements (earth builders) which has its group neighbor, oxygen, in the lithosphere for the petrogenous elements (stone builders). With the exception of the noble metals, all heavy metals occur in nature as sulphur compounds. In the earth crust the sulphur compounds of heavy metals are fairly strangers. However, we shall find the relation of sulphur to metallic foreign substance to be of some significance. Through volcanic eruptions sulphur comes from the great depths to the surface of the earth. The life- endangering forms of this volcanic source, hydrogen sulphide, H2S, and sulphur dioxide, SO2, reciprocal actions of which also lead to the deposition of free sulphur, are bound on the earth surface mostly as completely oxidized compounds, sulphates of alkalies, and particularly as earthy alkalies. In this form they are utilizable for the assimilative activity of of plants. The plants reduce sulphate and build organic sulphur compounds. In the reduction from sulphates, bacteria of the soil also participate. Other bacteria and certain algae (for example Beggiatoa) further oxidize H2S and deposit sulphur in their cells; they gain energy from this oxidation as other forms of the life from the oxidation of carbohydrates.
For the animal organism the building activity of plants is a necessary preliminary step for their sulphur metabolism; they convert plant protein compounds for their own function. More or less completely oxidized sulphur is excreted, or after death the animal organism undergoes decomposition into H2S. Then the circulation of sulphur can begin anew.
The chemical property of sulphur which occurs as an atom as the negative divalent (H2S) as well as the positive six valent (SO3=H2SO4 – H2O), remains decisive in the living organism. To lead the change between oxidation and reduction is the chief task of organically bound sulphur. So far the sulphur serves merely as an intermediator and its organic compound is not destroyed, so this function is a reversible catalysis. But the sulphur – containing building stone destroys itself in oxidative decomposition and indeed it seems to offer an especially good point of attack in the protein complex.
The diverse forms in which sulphur is able to appear according to its molecular structure, its modifications, gain considerable significance for the medicinal use of the pure substance. In homoeopathic uses these differences of modifications in general are exceeded through the extensive subdivision.
All proteins of cells and their higher split products (with the exception of peptones and protamines) contain sulphur. Even from this the great significance of sulphur for the organism can be measured. An important, perhaps the single, sulphur containing building stone is cystin. Cystin is dicystein, a product of the union of two cystein molecules with the liberation of H2. (Cystein is thio-amino-propionic acid). Between cystin and cystein we have a transformation relationship of the type:
CH2SH CH2 – S – S – CH2 @ @ @ 2CHNH2 = H2 + CHNH2 CHNH2 @ @ @ COOH COOH COOH
The transformation of cystein to cystin occurs in the air through oxygen, naturally with cooperation of constantly present traces of iron. This simplest form of sulphur-containing building stone is determining for the function of sulphur in the protein molecule, but, through further compounds, the complex gains some new properties. So cystin or cystein forms a dipeptid with glutaminic acid-
CH (NH2) COOH = CH2 CH2 COOH namely the glutathion discovered by Hopkins in 1920. Probably this compound is present in most cells. The easy oxidation to cystin form and likewise the easy reduction to the cystein form also remains in this compound. In contrast to cystin, the cystein form of glutathion is soluble in the fluids of the body. This is a sign that the complex form is better adapted to the functional requirements of the organism. Glutathion has its working optimum at a pH which it presents in the environment of the cells. The limitations of an element always to complicated organic compounds signifies obviously an orientation and a balance of the elementary properties to the reaction conditions in the living system with its very great liability in contrast to the test tube.
One has found further that, in many protein bodies, cells and tissues, the cystein form is present; in others, the cystin form (demonstration of SH group of cystein through a color reaction with sodium nitroprusside.) In particular it is worthy of note for this chief action that the sulphur-rich keratin in the upper layers of the skin contains the cystin form, while the lower layers contain the cystein form. Perhaps the capacity of absorption of ultraviolet rays by cystin is significant for skin function. In general the predominance of the cystein form, seems the active phase; and the exclusive presence of the cystin form, more the rest phase, because for example, the cartilage cells contain cystein the cartilage primary tissue, cystin.
The old conception of Heffter that the SH group of cystein functions as an oxygen carrier has recently received further support through the newer studies on glutathion. So the cystein form oxidized in the air to the cystin form also yields H2. The cystin form of glutathion is again able to take hydrogen on itself (for example the SH group of muscle protein) and thereby introduce an oxidation process of protein. So the action can consist at one time according to the substrate of an oxidation process; at another time, in the introduction of a reduction process, and indeed according to the manner of action of a ferment, which is active only under certain conditions.
The physiologic role of sulphur-containing protein compounds as the carrier serving for oxidation as well as reduction processes can be accomplished through the regular introduction of nutrient materials which contain sulphur in organic protein combination. How far these proteins are split in order to permit a resynthesis in the organism to cystein or the glutathion fraction of cell protein is not known as yet. It is not probable that the destruction proceeds as far as H2S. On the other side of protein metabolism, the sulphur fraction for a great part (about three-fourths of the total sulphur metabolism) seems completely oxidized and bound as sulphate ions of alkalies or earthy alkalies, or appears in the urine again as ether-sulphuric acid. The last compound of the sulphate ion with organic split products (phenols) also serves outside of excretion for the detoxication of these products. An intermediate step in the oxidative splitting of cystin is known as taurin, which is paired with cholic acid and, as taurocholic acid in the bile, plays a role in the digestion of fats. In the failure of cystin destruction cystinuria appears. The taurin is not excreted through the feces but is again utilized. About one-fourth of the total sulphur appears in the urine normally as organic bound, incompletely oxidized, so-called neutral sulphur. The sulphur excretion in the sweat is merely incidental in comparison to that of the urine. However, the dry excretion of sulphur through the skin and its appendages with their great content of sulphur is of significance. The traces of sulphur which are excreted in the saliva as the sulphocynate (KCNS) have a significance in the detoxification of CN. Whether the traces of sulphocyanate have a certain disinfectant action in mouth is doubtful.
A special content in sulphur is shown by keratin and probably also the pigment of the skin. Moreover, the chondroitin in the cartilage is united with sulphuric acid, and likewise the synovia apparently contain more sulphur than the other mucins. It is not improbable that with this marked presence of sulphur there is a connection between the special affinity of sulphur for the joint surfaces.
A quantitative insight into sulphur metabolism and its morbid alteration is difficult to obtain. The diversity of steps of splittings and the ways of discharge and the still very imperfect numerical conceptions of the single fractions in the blood and in the tissues have permitted only general conclusions up to the present time.
So the relation of neutral, imperfectly oxidized sulphur to the total sulphur in the urine gives a measure of the oxidation of sulphur compounds in the organism. And from the relation of the so-called, paired sulphuric acids to the total sulphur in the urine a point is gained for the measuring of the appearance of toxic intermediary metabolic products (phenol, indol, skatol, etc.) These intermediate products are detoxified by the sulphates and probably in the liver. Practically only the estimation of indican and the qualitative diazo-reaction is used for this purpose.
It may be assumed as very probable that the chief function in the splitting and in the oxidation of sulphur compounds occurs in the chemical center of the organism, the liver. To a remarkable action of sulphur in the liver, in the formation of glycogen, we shall return later.
The adrenals are especially rich in sulphur, particularly their yellow substance. Here the sulphur is said to be present almost exclusively as neutral sulphur. The adrenals are considered as the site of absorption and the regulation of sulphur metabolism.
That in all acute disease, in consequence to the increased destruction of protein, the amount of sulphur in the urine is increased is not surprising. Moreover remarkable it is that, in chronic diseases generally, the sulphur content of the urine is diminished. One might perhaps conclude from this that there is a depression of sulphur metabolism in many chronic diseases. And it exactly in chronic diseases that sulphur serves as a medicinal agent of the metabolism.
PHARMACOLOGIC SULPHUR ACTIONS BY H2S
What disturbances of sulphur metabolism are possible through elementary sulphur? Since it cannot simply be concerned with the introduction of more or less sulphur, so must it be the property elementary sulphur, so must it be the property of elementary sulphur which permits these disturbances. On the path of sulphur, exercising its effectiveness much is known, especially through the work of Heffter. In the intestine sulphur is reduced to H2S. This occurs principally through bacteria, particularly in the large intestine, as has been long known; but it can also occur through certain protein bodies of the intestinal mucous membrane and indeed the small intestine. The gastric mucous membrane does not contain this reducing protein substance. This reducing protein fragment is in all probability cystin. Between the H2S and the cystin develops an equilibrium of reversible reaction in which the hydrogen remains labile. The diffusion of H2S out of the intestine into the blood occurs easily. Thereby it must be reckoned that a part of the sulphur is dissolved in the presence of H2S, to polyhydrogen sulphides so that actually a reaction mixture of H2S, polysulphides and sulphur reaches the intestine. By the injection of finely divided sulphur into the blood stream or the musculature, the same thing happens in general, because everywhere the sulphur meets cystein and becomes H2S. In this case the disturbance of sulphur metabolism is a very stormy one. With large introductions of sulphur, the H2S, excretion through the lung and skin becomes very obvious.
In any case the pharmacologic action of sulphur is pressed to the side by hydrogen sulphide and the question is whether these is a chronic H2S poisoning from small doses. From the acutely fatal action of an air containing a strong content of H2S, not much can be withdrawn for our problem. It has great similarity with the action of another catalyser poison, HCN. Severe, but still not fatal, H2S poisoning proceeds with loss of consciousness and respiratory disturbances. The milder general symptoms of chronic H2S poisoning are headache, stupefaction and striking tendency to sleep. Such symptoms often accompany irregularity of intestinal evacuation, and it has been considered whether rightly or wrongly as due to actions of H2S from absorption from the intestine. The general actions of H2S can increase up to vertigo, states of excitation, intoxication and narcosis, and Lewin has suggested that the delirium of the priestess at Delphi can be traced to H2S vapors.
The action of larger amounts of sulphur after introduction into the intestinal canal has been known as a mild purgative effect.
Bokay had shown that the action of larger doses of sulphur consists in an increase of peristalsis through the formation of H2S in the intestine. Under the influence of the H2S developing from the sulphur the passage through the proximal colon is accelerated so that the thickening which otherwise occurs here cannot occur or incompletely occurs. The stimulating action on the intestine has also been proven on the surviving and isolated intestine of animals. Van Leersum found that H2S stimulates surviving guinea-pig intestine in Tyrode’s solution in a concentration of 1:4,000,000 = 4. Gordonoff and Hashimoto studied the action of H2S containing water on the isolated rabbit intestine according to the method of Magnus. They found in weak concentration, for example 1:500,000, 1:1 million but also 1:10 million, an increase of the tonus and the pendulum movements (to decide by the curves with the weakest concentration of 10 the strongest action). Larger concentrations (1:200) effect a paralysis which is reversible; that is, the transference to Ringer’s solution causes it to diminish. (The paralysing and stimulating action can here and there be observed from the same concentration which may be attributed to inexactitude of dose through varying solubility of hydrogen sulphide).
Moreover the studies which Gordonoff carried out with Umehara on the isolated frog heart do not speak for a different behavior of the heart of hydrogen sulphide. The reduction of the stroke height is observed under large doses (H2S water 1:10, Na2S 1:250 and 1:100); weak concentrations, however, apparently have not been tested.
The purgative action is perceived as the first crude regulatory measure against the penetration of massive H2S in the organism. Thereby it becomes clear that, in such doses generally, action on the intermediary metabolism in the intestine need not become evident. If however, the H2S formation in the intestine remains below the threshold of stimulation of peristalsis, then certainly a definite resorption of the (H2S-polysulphide, sulphur) mixture appears. But there are further regulatory trends available so that it need not amount to distinct disturbances in sulphur metabolism, because H2S is never completely absent from the intestinal canal. Still there is a chronic action of small doses of sulphur, likewise after oral administration. This experience of the homoeopathic school has been confirmed now through the many studies since those of H.Schulz. They could have been confirmed through the unprejudiced evaluation of experiences with sulphur water cures. In any case the presumption for a characteristic disturbance of physiologic equilibrium through small doses of sulphur has been a long continued study. And indeed they have been overlooked by pharmacologists until H.Schulz. We cannot say even today by what experimental arrangement the first regulatory trends are circumvented so that there appear distinct signs and symptoms of disturbance in the intermediary regulatory process. It is conceivable that the resistance of the periphery is gradually exhausted through the constant repetition of the attack with the very active, diffusible substance in the H2S form. It is probable that another site of resorption, perhaps the oral mucosa, must be involved in order to attain this result. A fine division of the sulphur is another indispensable presumption.
RESULTS OF TRIALS WITH CHRONIC USE OF SULPHUR
The physiologic function of organic cell sulphur to intermediate oxidations and reductions permits one to expect that the actions of sulphur introduced in a suitable form will become obvious in oxidative metabolism. The results of experimental investigation have confirmed this. The trial by Riesser, Simonson and Richter upon themselves with use of modern methods of investigation of metabolism have made possible for the first time a numerical conception of the effects. The subjective symptom picture in these four series of studies with a saturated alcoholic solution of sulphur (0.035 Percent, tinctura sulphuris or, according to another designation, the fourth decimal dilution of the homoeopathic pharmacopoeia) is naturally scanty in contrast to that known from homoeopathic provings. But it confirms an essential series of symptoms of earlier provers. Thereby it is especially worthy of remark that one investigator (O.R.) in a second study with two to three times as great dose reported that there were no alterations of sensation and likewise that the objectively observed alterations were slighter than he had observed in the first study. Accordingly, one may conjecture that the dose in all these investigations, in spite of the smallness, still moved, around the upper limits suitable for such a purpose. Otherwise the study corresponds in general with those common to homoeopathy with pre and post- observation with several weeks, duration of the introduction of the the drug.
With the Zuntz-Geppert method the measured value of the oxygen intake and carbon dioxide excretion gives naturally only a resultant of the total energy transformation. The most distinct result of the study was an increase of respiratory ventilation, at rest as well as with definite work during the sulphur ingestion period. The increase of ventilation was distinct only after about two weeks and was greater in the third and fourth weeks (that is under about 1-3 mg.) and in the fifth week even under greater doses of sulphur (about 5 mg.) it was less. In two people respiration was irregular, in the third the respiratory frequency increased to about double. At the same time as the ventilation increased, there was a slight tendency to increase of the basal metabolism, but this was distinct only with each increase in the dose of sulphur; if the daily dose remained the same then the basal metabolism fell, and moreover, it was lowered during the period of after-effect. Further, the capacity for restitution (that is, the duration of increase after an exactly, measured piece of bodily work, for which a numerical result was obtained), was determined at the height of the sulphur action. The capacity for restitution was depressed in all trials. Furthermore, from the estimation of the so called ventilation quotient (that is, the ratio of the ventilation volume in cc. to the transformed calories) in rest and work under sulphur action, an excitation and at the same time an increase in irritability of the respiratory center was disclosed. Since the absolute height of ventilation in work under sulphur influence was increased in comparison to normal and thereby was bound to an increased supply of oxygen, and though, nevertheless, the restitution was delayed, so must a depression of oxidation be assumed. The authors did not decide whether the excitation of the respiratory center and the increase of ventilation conditioned through this by sulphur depended on a direct action of H2S on the respiratory center, or whether the metabolic products entered the blood in consequence to oxygen depression and acted toxically on the respiratory center, or whether the metabolic products increased the H-ion concentration of the blood and thereby also the environment of the respiratory center. They held it as probable that it was composed of an increase in metabolic end product action and the direction action of H2S.
As it tends to happen in exact experimental investigations, there are also findings which prove the opposite. In the Berne Pharmacologic Institute, Siegfried has arranged similar metabolic studies on himself under the influence of sulphur. However, the size of the ventilation was not measured. Since he worked with another apparatus, a comparison of the results is also impossible. Siegfried summarizes his results of investigation as follows: The amount of excreted CO2 and of the oxygen taken in was not influenced in a distinct way with doses of 1-3 mg. of sulphur per day. With greater doses (4-6 mg. daily a distinct decrease occurred. The respiratory quotient sank. with doses of 1 mg. After the discontinuance of sulphur it rapidly rose again. The influence on general sensation and on the respiration was not observed. These later investigations, which apparently should contradict those of Simonson and Richter, cannot be compared with them without further discussion, and in any case do not signify a contradiction. First the introduction of sulphur lasted only fourteen days in Siegfried’s studies. That in this time no influence of the general sensation and the respiration was observed agrees in general with the report of Simonson and Richter: likewise, that in the first ten days no distinct influence on CO2 excretion and oxygen intake in accordance with the basal metabolism was observed. In Siegfried’s study, even after ten days with an increase of the dose to 4-6 mg. a decrease of CO2 excretion and oxygen intake appeared, and the basal metabolism fell. But this does not entirely contradict the reports of the previous workers who demonstrated with higher doses (indeed by them 5 mg. was the highest dose given) that here was a fall in the basal metabolism. Furthermore, Siegfried states that from the start the respiratory quotient, also the ratio CO2:O2 fell under the use of sulphur and remained low. On the contrary, the earlier workers had found in general no essential influence on the respiratory quotient. The deviations of Siegfried are without further discussion understandable from the concentration of larger doses of sulphur (he began also with 1 mg. that is about three times the dose of the earlier workers) to a shorter period of study (two weeks).