Still more than phosphorus itself is phosphoric acid used as a remedy in diabetes. And this will be comprehensible from the important role of phosphoric acid and at the same time from the physiologic action of weakened phosphorus on carbohydrate metabolism.
The significance of phosphoric acid in physiologic carbohydrate transformation in muscle function has been brought to light by the works of Embden and Meyerhof and American authors.
Muscle energy is obtained through anoxybiotic carbohydrate splitting. The mother substance, called lactacidogen, is a glucose monphosphate. In muscle contraction, very soon phosphoric acid is set free and this phosphoric acid seems, as Schmitz expressed it, to be the vehicle for conveying new quantities of carbohydrate to destruction. It can be assumed that in muscle work, lactacidogen is destroyed under the influence of lactic acid and phosphoric acid in the dissimilatory phase. Phosphoric acid unites with the hexes molecule again to form lactacidogen the assimilatory phase. Accordingly, the splitting of hexoses in the animal organism can occur only through the intermediate combination with phosphoric acid. The situation is, however, essentially more complicated. One knows now that other phosphoric acid, compounds, as creatinphosphoric, the so-called phosphagen, are present in muscle. This compound is also split on muscle irritation and is again elaborated during rest.
It is assumed that the undoubted favorable action of phosphoric acid on the capacity of performance of muscles, which has been proven in extensive investigations conducted on soldiers and workers by the increase in performance and the lessened fatigue, occurs through some type of connection with the discovered physiologic role of phosphoric acid. Perhaps the introduction of phosphoric acid serves as a vehicle for the activation of the already present but still not suitable phosphoric acid. The phosphates are just as important in the central nervous system as in the muscles as much for its function as for therapeutic influence. We shall return to this later. Phosphoric acid therapy in bodily and mental exhaustion has long been known to medical empiricism in the form of sodium phosphite-lemonade, indeed before the physiologic basis just discussed and before preparations like Recresal and Tonophosphan (an organic phosphite compound) we known. On the other side homeotherapy from the beginning through the consideration of the symptomatology, has drawn attention to this chief trend of phosphoric acid and its compounds.
PHOSPHITE AND PHOSPHATE ACTIONS
Experimental observations on muscular organs have brought great probability for the fact that the action of phosphorus does not differ in principle from its oxidation products (phosphites and phosphates) but that it is concerned more with a difference in intensity. K. Engel studied the inorganic phosphites in conjunction with the action of tonophosphans. With sodium phosphite (Na2 HPO3) he found a complete analogy but with the significant difference that sodium phosphite is not toxic. In a series of surviving organs of frogs and mammals (heart, intestine, bladder, uterus), it was seen that great dilutions (6-8 potency) acted stimulating on the movements, while larger doses (5-7th potency) damaged the function. The hypophosphites which constantly form when phosphorus comes into contact with water in the presence of oxygen, were shown to be even less effective.
In the same way as phosphites, though stronger, acted a highly diluted phosphorus solution (an alcoholic solution) of phosphorus 1:1000 was diluted with ringer or Locke solution. The solution contained essentially phosphorus and hypophosphoric acid. Engel states expressly that this solution is comparable to the blood after the absorption of phosphorus. Since only the highest dilutions were employed, so the acid character of these substances does not come into consideration for the action. The equality of functional increase through the smallest doses and the damaging of the same test object by larger doses suggest that the action of phosphorus solutions occurs through phosphites.
Contrary to the older reports of H. Schulz and J.Neumann phosphites proves themselves toxic upon the intact animal after subcutaneous injection (manifestations; paresis, flow of tears, diarrhea and polyuria, trembling and crying at every contact, death). While in acute intoxications nothing essential is found in the organs, guinea pigs treated for four weeks with phosphites show the following findings: “Lungs, isolated hemorrhages into the alveoli; kidney; marked congestion of the glomeruli, at times appearance of blood in the renal cortex; liver; moderate but unmistakable fatty degeneration of the liver cells and considerable hyperemia”. After these findings it is not comprehensible why Engel states in conclusion that in protracted intoxication with phosphites, one does not observe any striking organ degenerations which are characteristic for the acute, but primarily for the chronic poisoning of phosphorus. In this respect he himself stresses that the actions of phosphorus solutions on the entire animal are exactly the same, only more intensive and rapid in course, than with phosphites.
That phosphates also cause a functional improvement effect has been shown by Staub on insufficiently poisoned frog hearts. The secondary alkaline phosphate of sodium (Na2HPO4) acts more favorably than the primary acid (NaH2PO4). Addition of glucose improves the action further, though glucose alone is without influence. The functional increase of the heart, completely analogous with that of voluntary muscle, is perceived as the result of improved carbohydrate destruction in the heart muscle through the introduction of free phosphate ions. Staub does not consider that a calcium deprivation is the case of the functional increase of the mechanically or toxically insufficient heart, for the similarly calcium-depriving citrate does not cause the same actions.
It is worthy of remark that in the studies of Engel essentially larger doses (about 3-4th potency) of phosphates were necessary for the production of the functional increase than of phosphites. Correspondingly, that the poisonous doses of phosphates are still greater has been shown by the studies of Starkenstein. This study had given a complete parallelism of phosphoric acid (the ortho-pyro and metaphosphoric acid) or their alkaline salts with the other calcium-precipitating acids (oxalates, fluorides) in toxic action. Only the doses necessary vary, and likewise according to the method of administration. That it is concerned with a calcium precipitation in the intact animal and in single organs proceeds from the fact that the toxicity can be removed through calcium chloride injections or hindered by them. Also according to Staub, the depression of blood coagulation and the increase in temperature caused by the phosphates is common to all other calcium-precipitating salts and likewise conditioned through calcium deprivation. If one follows Staub in this regard so that the toxic action of phosphates depends upon an inactivation of calcium, then it is not said thereby that there are no other actions which are peculiar to the phosphate anion. Naturally, these will appear more in biologic actions, in actions approximating the physiologic.
Nothing stands in the way of the conception of a fundamental association in the type of actions from phosphorus over phosphites to phosphates; only the speed and severity of the effect and thereby the toxicity is connected to the step of oxidation.
The toxic actions of phosphates can be perceived as calcium-ion deficiency or potassium or vagus predominance on the striated and smooth muscle, and this without tracing the entire action of phosphate back to this de-ionization or synergism. The toxic action on the voluntary muscle and the heart, as with potassium, consists of a reduction of tonus, while the physiologic potassium as the phosphate is a pre-condition for muscle function; apparently it supplements in the the muscle as do calcium and phosphate in the bones. The toxic action of phosphate on the heart leads to slowing of the pulse and to stand-still in diastole, as does potassium. But with both, an improvement in the heart muscle can be obtained after mechanical or toxic damages. On smooth muscle, phosphates as well as potassium acts tonus-increasing. The poisonous action of phosphates expresses itself more distinctly than with potassium in the diarrhea. A significant increase in tonus and the pendal movements has been proven by Starkenstein on the isolated intestine. We shall discover this diarrhea again in the picture of phosphoric acid.
PHOSPHORUS AND PHOSPHATES IN METABOLISM
The influence on cellular metabolism by phosphorus, in particular on gas exchange, has been the subject of many investigations. The results are often contradictory. According to Lusk and Hirz, there seems at first to be an increase in metabolic conversion and gas exchange and then shortly before death a decrease in the action of phosphorus. It arose even more distinctly from the investigations of Nishura: phosphorus in small doses promoted cell respiration. 1/100 mg. of phosphorus injected subcutaneously into rats regularly produced a persistent increase of O2 use, whereby the weight slightly increased. The gas exchange was influenced for eight days after an injection. If the doses were increased, then a single injection of 1/10 mg. gave a persistent decrease of O2 use without a distinct influence on weight. Daily injections of 0.5 mg. for three days caused the O2 use to fall to 1/3 and the temperature to fall to 27 o C. Of particular importance is the fact that feeding thyroid substance reduces the consumption of O2 even with 1/1000 mg. of phosphorus, so that these animals seem at the same time sensitized to phosphorus effects by the administration of thyroid substance.
The gas exchange of phosphorus-poisoned animals was reduced about 20 per cent, the action beginning about twenty-four hours after the administration of phosphorus. Phosphates also promote cell respiration, and here too we have a parallelism between the action of phosphates and phosphorus. Surviving intestinal cells show an increase of respiratory effect even from the slight concentration of N/1000 primary and secondary natrium phosphate, while the optimum lies in a concentration of N/100-N/200, and with higher concentration consumption decreases. Likewise in other instances in organic life catalytic processes are favorably influenced through phosphorus salts. Bucher has already proven this for yeast fermentation and American investigators have shown that carbohydrate and fat formation increases in yeast cells under phosphates. Even for phosphorus a corresponding report is found in Hauser’s work in which a yeast- sugar mixture to which phosphorus was added showed initially a more rapid and stormily proceeding production of CO2 than under normal conditions.
CONNECTIONS TO ENDOCRINE GLANDS
Phosphorus has important connections to the thyroid and its function. In phosphorus-poisoned animals one found alterations in which the colloid was diminished or had disappeared, findings, which are also noted in Basedow goiters. On the cerebral ganglion cells the same histologic alterations were found as after thyroidectomy. The iodine and phosphorus rations stand inverse in the thyroid. The iodine content increases with the decrease in phosphorus and vice versa. Phosphates act weaker than elementary phosphorus. Alb. Kocher has recommended natr. phosphoricum in doses of 2-12 G. daily in Basedow. In pregnancy a fall in the iodine content to 1/30 normal is observed and the phosphorus triples. In a Basedow one has seen a similar fall of the iodine and the increase of phosphorus content to double. Under the use of thyroidin an excretion of phosphoric acid occurred and phosphorus content to double. Under the use
of thyroidin an excretion of phosphoric acid occurred and phosphorus treatment caused an enrichment of the thyroid in iodine. The sensitization for phosphorus action by the administration of thyroid preparations has already been mentioned. The reciprocal relation between iodine and phosphorus should not be conceived one-sidedly as an antagonism nor as a synergism.
On the adrenals Neubauer and Porges showed that, through phosphorus poisoning, the chromate discoloration of the medulla is removed and the formation of adrenalin depressed. They trace the lowering of blood pressure in phosphorus poisoning back to the adrenal damage instead of to the cardiac damage as is so frequently done. They also bring the disturbances of carbohydrate metabolism into connection with the functional failure of the adrenals since in extirpation of the adrenals the glycogen disappears and the blood sugar content falls. One has also prevented the disappearance of glycogen in phosphorus poisoning through the injection of adrenalin. Perhaps in analogy with the biphasic action in other organs with small doses of phosphorus there may be a stimulation of adrenal function and also in secretion of adrenalin. Vollmer described after the injection of adrenalin a biphasic action on the calcium and phosphorus content of the serum. The calcium content at first increases and then decreases and the phosphate content exactly the reverse: decreases and then increases.
The influences known up to the present of phosphorus on the endocrine system are not sufficient to indicate its constitutional peculiarity more than a general trend, chiefly in the direction of a Basedowoid sensitization. The influence on metabolism through phosphorus may be brought into good accord with this.
The toxic manifestations on the nervous system are often perceived as dependent upon the alterations in the vascular system. The great abundance of phosphatides (lecithin) in the central nervous system makes it probable from the start that the physiologic role of phosphorus likewise corresponds pathogenically and therapeutically. In old times phosphorus was considered particularly as an important agent in maladies of the motor and sensory nerves and also in homoeopathy (for example
in the monograph of Sorge this trend of action is always stressed).
From newer studies it has been shown that the phosphatide content of the brain is altered in progressive paralysis. It had been shown even earlier from the derivation of phosphoric acid in brain emulsions that phosphorus was important in the brain and today it is more than probable that disturbances in cholesterin-phosphatide metabolism lead to functional alterations of the brain. It can also be proven that in the retina of the frog, light stimuli discharge phosphoric acid. In peripheral nerves the nitrogen consumption on stimulation is markedly reduced through the addition of phosphatides. In the very lively metabolism of the central nervous system, phosphorus compounds must have even a greater significance. In mental diseases and experiences which are associated with general exhaustion occurs a marked destruction of the organic phosphorus compounds of the central nervous system and the excretion of phosphates is increased. Outside of the inorganic phosphates about 1 per cent of the total phosphate is excreted as organic compounds, and, when the oxidation processes are weaker in mental fatigue, the percentage of organic phosphates increases in the urine.
Naturally the organic alterations in the central nervous system are slight in acute and a chronic phosphorus poisoning. Only occasionally paralyses are observed (in contrast to arsenic), once under phosphorus therapy a paralyses of the auditory. The ordinary findings in the central nervous system are apparently a result of capillary bleeding and fatty deposits in the ganglion cells and also degeneration of the columns of Goll and Burdach. Findings of myelitis and pigment deposit are doubtful.
Probably the severe toxic actions are ended by some other occurrence before a destruction of the structure of the nervous system can occur. The severe psychic symptoms which are occasionally observed in phosphorus poisoning and other milder symptoms can be accepted as probable.
The previously mentioned mass investigations with phosphates make it very plausible that not only the muscle metabolism but also the nervous system participates similarly in an increase of performance. In larger series of investigations phosphoric acid produces mental invigoration and joy of work. With longer use the frame of mind of the psychically depressed is favorably influenced. In the clinical studies of Staub with di-sodium phosphate in cardiac patients, the patients in many instances reported themselves rapidly relieved, one patient as though he had been freed of something. Similar actions are observed with tonophosphan in the cyclothymic depression states. Likewise involuntary psychic results are observed. Many patients under the use of phosphates complain of much dreaming and disturbances of sleep, others of wandering pains in the extremities, restlessness and hypersensitivity to noise. It is to be observed that these symptoms appear first under large doses of phosphates. In the first few days of a phosphorus poisoning a euphoria is noted.
In any case the old clinical observation that impotency is favorably influenced by phosphorus and by phosphoric acid belongs to the picture of psychic excitation, and perhaps depending upon a similar action are cheese and egg yolks, these foods being particularly rich in phosphorus contents.
THEORY OF PHOSPHORUS ACTION
If now one glances over the facts known up to now, then the old question, in what form does phosphorus come into action, can no longer be answered either or, and particularly neither as pure phosphorus or in the form of an oxidation product (phosphites or phosphates). Much more we shall say: phosphorus can act damaging in the body-foreign, elementary forms as well as in phosphites and under certain conditions even in the physiologic form of phosphates.
After its resorption phosphorus goes through oxidation steps to phosphates. The reverse way to PH3, which one has assumed for toxic actions, can be designated today as practically excluded. Current pharmacology makes a sharp line of difference between pure phosphorus and phosphoric acid in respect to action on the organism. But we have seen that the middle position of phosphites offers a point of departure for this difference is not a fundamental one, but one of degree and action severity. Phosphorus can act in the type of phosphites or even by a more protracted course under small doses in a manner approximating phosphate action. (For example, the bone effects.) In the last case the phosphate action appears in the foreground in the ion synergism and antagonism, in particular in connection to calcium. In carbohydrate, lipoid and protein metabolism the phosphorus, as well as its oxidation steps, seem to be used as the physiologic phosphates.
The phosphite step still has a very acute toxic action; still in minimal doses the functional increase experimentally comes into appearance. A stepladder of actions leads from the promotion of cell respiration to its suppression with the end result of fatty degeneration. For the toxic action one must consider that the phosphites also press forward to further oxidation and to draw oxygen on themselves energetically, and thereby apparently anoxybiotic, fermentative destruction of cell nutrition material and eventually also protoplasm is effected. This is correct only when pure phosphorus in quite considerable amounts enters into reaction before an oxidation can be accomplished. It is very probable, because primarily the phosphorus-containing constituents, the phosphatides, are attacked and because in the attempt to reach physiologic paths, the lipoids with phosphorus affinities, the cells are more or less damaged, whereby the lipoids are increased or are transformed into another colloidal state.
That poisonous action occurs through combination to the phosphatides is also made very probable purely chemically. Willstatter and Sonnenfeld have shown, for example, that the olefines (unsaturated open carbon with a double C bond) appear in the phosphatides and unite with oxygen and phosphorus to phosphorates. Initially this reaction occurs very slowly, and this agrees with the pseudo-incubation stage of phosphorus poisoning.
We found in phosphoric acid the conception repeatedly lying near that the “action in” and “action out” go parallel or much more the pathologic actions stir up physiologic traces, but that the phosphorus compounds peculiar to single organ systems are still determining for the trend. Since we can further make plausible a natural graded effect connection between phosphorus, phosphites, and phosphates, so the stronger actions of phosphorus can be followed in the same paths.
DRUG PICTURE OF PHOSPHORUS
Provings on the healthy are found in: (1) Hartlaub and Trinks: “Reine Arzneimittell”, Bd. 1, 1828.
(2) Hahnemann: “Chron. Krankheiten” 2 Aufl Bd. 5, 1839.
(3) Sorge: “Der Phosphor ein grosses Heilmittel” Leipzig, 1862 (p. 115 older provings and p 123 personal provings on 15 people).
To phosphorus corresponds the slender, rapidly growing, delicate man usually of light complexion with delicate transparent skin, blue, often glistening eyes, delicate, silky blond or reddish hair. The development of the internal organs and of the connective tissue often does not keep pace with the rapid growth, so that an easily crumpling type appears. We have also the asthenic type before us, as it unfolds itself preferably at or after puberty. In the morbid increase of this type we see consumption, increased tissue destruction and hectic type of fever. To the asthenic body build corresponds the manner of psychic reaction. Psychically phosphorus belongs to the schizothymic group of Kretschmer and indeed with special stress upon the hyperesthesia. The phosphorus type is also sensitive and delicate psychically; also supersensitive toward sensory impressions, against light, noise, music, odors, perfumes and contact. Such people are also sensitive to personal influences. In general they are in need of support, they feel badly when they are alone and they welcome moving around and contact with healthy people. Dahlake’s view that the desire for massage and the improvement from it may be explained from this psychic situation is quite enlightening. The great sensitivity for improvement from it may be explained from this psychic situation is quite enlightening. The great sensitivity for impressions permits such people to proceed in an animated manner; indeed, it approaches ecstasy and clearsightedness which signifies the extremely fine sensitivity. To these corresponds the alert, animated facial expression; the psychic processes are found without difficulty in the gestures and mien. On the other side, from the intensity and the tempo of their experiences, these delicate people become easily fatigued, become tired and indifferent and ever demand rest. Memory fails; sleep improves. The conversion from the animated, indeed excited, and at times vehement, state to fatigued, indifferent, and anxious picture is sudden. Usually the phosphorus patient has many fears, fear of being alone and of homesickness, dismal forebodings and fantasies which make him anxious in the evening, at night, and particularly before and in storms. Thereby cardiac palpitation and trembling can appear. The excitation goes in morbid instances to delirium as in a dynamic fevers and drinkers; manic states and delusions such as appear in paralytics are cited. On the other side goes the depression from in-difference to the environment to a depression with disgust for life, apathy and stupor. Tension and relaxation alternate suddenly.