Albert A. Epstein

Concerning the causation of edema in chronic parenchymatous nephritis: Method for its alleviation☆

0 NE of the most striking clinical manifestations of chronic parenchymatous nephritis is the development of edema or anasarca. Its occurrence is intimately associated with a diminished elimination of salts and water, believed to he due to a reduced power of the kidneys to excrete these substances. Those who have had occasion to observe the condition know well the severe proportions which it may assume, the distress which it causes the patient, and the inadequacy of medicinal treatment or the usual dietetic restrictions. The present communication forms part of a larger study on nephritis begun a number of years ago. Its purpose is to put on record certain facts concerning the nature of the anasarca occurring in chronic parenchymatous nephritis which are of clinical importance and to suggest a new method of treatment which promises to be useful. The reason for selecting this particular phase of the subject is the conviction (gained in the study) that the edema, or anasarca, is one of the most important phenomena in the disease, and that by its alleviation and prevention great progress is made toward ultimate relief of the renal condition. Ever since Bright’s discovery of renal disease the opinion has prevailed that all the phenomena associated with it are attributable to the pathological changes and the disordered function of the kidneys. It is now conceded that the morbid manifestations of chronic parenchymatous nephritis differ from all other forms of renal disease. Its onset, progress, and duration, its tendency to subcutaneous and serous effusions, and the cardiovascular conditions and urinary findings-all differ from those observed in other varieties of renal disease. It is not the object, at present, to discuss the chemical and pathological features of chronic parenchymatous nephritis as a whole, but it is important to note (and the conclusion seems justifiable from the observations thus far made) that among the cases of parenchymatous nephritis there is a group with a constitutional disorder in which the renal and other manifestations are concomitant or secondary in point of development and importance. Much discussion has been indulged in concerning the origin of edema in nephritis, and many theories have been propounded concerning the mode of its production. Thus it was? believed that the edema was the result of a “hydremia” from the retention of water caused by the inability of the kidneys to excrete it. Cohnheim3 supposed that the edema was brought about by an increased permeability of the capillary vessels, induced by the malnutrition or poisoning incidental to the nephritis, which permitted fluid to filter through into the subcutaneous tissues and serous cavities. The hypothesis which has received the soundest clinical confirmation, and still retains man) adherents, is that of Widal” and his associates, which teaches that the kidneys in this disease have a deficient capacity to eliminate salt (sodium chlorid). The accumulation of salt in

The action of pepsin on insulin.

Summary 1. Pepsininactivatesinsulin but does not digest it. 2. Liberation or dissociation of insulin from pepsin takes place, even after prolonged contact, at a properly adjusted pH.

A study of phloridzin and its derivatives. Part I

The present work constitutes part of a study on the pharmacology of phloridzin and its derivatives. It is based on some earlier observations 1 concerning the influence of phloridzin on the formation of glycogen in the liver under certain experimental conditions. The results of the experiments referred to seemed to indicate that phloridzin possesses a two-fold action: namely, that of causing glycosuria, and that of stimulating the formation of glycogen in the liver. These experiments showed further that animals which had been rendered diabetic by pancreatectomy, and in which the glycosuria was interfered with by removal of the kidneys, the blood-sugar content was generally lower in those which had received phloridzin, than in those which had not received it. It therefore seemed reasonable to suppose that if a means could be found by which phloridzin could be deprived of its glycosuric action, its effect on the formation of glycogen and the reduction of the blood-sugar would be made manifest. Notwithstanding the importance of phloridzin in the study of certain problems of metabolism, little information is available concerning its derivatives. In view of the object of our investigation the work is comprised of two phases: first. an examination of the pharmacological effects of known derivatives of phloridzin and second, the preparation and study of new compounds of this substance. The purpose of the present cunlmunication is to state our problem and to record the new cotnyounds which have been prepared and identified. The following is a list of the substances: (1.) Tetrabenzoylphloridzin: This was obtained by the actin11 of benzoyl chloride on phloritlzin in pyritiin. The substance is white, and of a starchy character.

On the nature of the anti-tryptic action of serum and its biologic significance:

The power which serum possesses to inhibit tryptic digestion is a well known phenomenon, but the nature of the process is not well understood. This is evidenced by the fact that the anti-tryptic power of serum has been variously ascribed to the proteins, the lipoids, and the nitrogenous crystalloids of the serum, and more recently to the saponified unsaturated fatty acids present in it. The observations to be reported were made in the course of a study begun two years ago on the isolation of the different pancreatic ferments. For reasons which will be discussed at another time, the anti-tryptic action of serum was investigated. At first an inquiry was made into the particular substance in the serum which was endowed with the power to inhibit tryptic digestion. Our results were in conformity with those who found that the albumin fraction of the serum proteins was chiefly responsible for the phenomenon. It may be added that other substances contribute to the total inhibitory action of serum. The globulins, for example, possess the power to a limited degree, and only when present in concentration. While studying this phenomenon with whole serum, in great dilution, it was found that the degree of inhibitory action was proportionate to the quantity of albumin present. Under such conditions other substances apparently played no part in the reaction. The inhibitory action obtained from the fatty substances present in the serum is insignificant, when contrasted with the remarkable power which whole serum or its albumin fraction possesses. The next question investigated was the nature of the inhibitory action. You will recall that when the anti-tryptic action of serum was first observed it was thought to resemble the action of the specific anti-body of the immune system.

Observations on pancreatic rennet

Pawlow and Parastschuk, 1 Vernon 2 as well as Delezenne 3 have called attention to the presence of rennet in the pancreatic secretion of experimental animals. Wohlgemuth 4 claims to have found it in human pancreatic secretion, but not without some difficulty. Notwithstanding these observations some doubt seems to exist in the minds of a number of investigators in this field. Textbooks on physiology do not class rennet with the other pancreatic ferments. Fresh or well-preserved dried preparations of pancreatic extract ordinarily do not show any milk coagulating ferment. When solutions of such extracts are permitted to deteriorate the rennet function comes into evidence. While studying the pancreatic ferments I have found that the presence of rennet in extracts of this organ may be demonstrated constantly in a number of different ways. 1. Rennet may be liberated by heating a solution of the extract from 50 to 65°C. for a period of about 10-15 minutes; the most favorable temperature being 60°C. Flocculation usually occurs upon heating, but the ferment remains in solution. 2. The addition of suitable amounts of hydrochloric acids reveals the presence of rennet. 3. By treating solutions of pancreatic extract with colloidal iron and other precipitants such as uranium acetate, alcohol, sodium sulphate and others. Calcium chloride solution in concentration accomplishes the same result. 4. The addition of products of peptic digestion, such as those of gliadin or Wittes peptone, to solutions of pancreatic extract also liberate the rennet. 5. Serum of a rabbit immunized by intravenous injections of pancreatic extracts, when added to solutions of pancreatic extract, liberate the rennet. Whatever method of activation is used, in every instance, the rennet itself remains in solution, and some substance is precipitated, which before precipitation conceals the presence of the rennet.

The effect of pancreatic rennet on blood coagulation

At the last meeting of this society, one of us 1 presented certain observations on pancreatic rennet. Particular stress was laid on the state in which the rennet probably exists in pancreatic extract, and its intimate chemical association with trypsin. In speaking therefore of the pancreatic rennet we wish it understood that it is the rennet-trypsin unit and not the rennet alone that we are dealing with. Mention was also made of the absolute dependence of the milk coagulating function of rennet on the calcium ion. The theoretical considerations which have prompted the present investigation will be discussed fully at another time and place. Suffice it to say for the moment that rennet (as a class) appears to be widely distributed in nature, in the animal as well as in the vegetable kingdom. In the latter, its native function often seems to be that of a coagulant of the sap of the plant in which it exists, a process comparable, in some respects, to that of blood coagulation. Our first attempt to discover the effect of pancreatic rennet upon the coagulation of the blood consisted in the following simple experiment. A small quantity of the purified pancreatic rennet was added to a portion of blood freshly drawn from the cubital vein of an hemophilic individual, and the coagulation time noted. We found that whereas the blood in the control tube required I hour and 20 minutes for coagulation, the specimen to which the rennet was added clotted in 90 seconds. The result was so striking that we determined to make a careful investigation of the phenomenon. In a study of the effect of various tissue extracts on blood coagulation, Mills 2 found that a saline extract of pancreas has very slight coagulating power for blood.

The application of the Auer-Kleiner morphine test in human diabetes

Auer-Kleiner 1 have found that the administration of morphine of definite dosage to dogs, in which the pancreas had been injured experimentally, caused a very marked rise in the blood sugar, lasting several hours. The administration of opium and its derivatives in the treatment of diabetes mellitus has been a common practice for many years. Many noted observers ascribe beneficial results to this agent. Even today opiates are commonly used in diabetes, particularly in painful conditions, which often complicate this disease. The observations of Auer and Kleiner are therefore of interest and importance, not only from the standpoint that the administration of morphine to diabetic suspects might (in a very simple manner) give a clue as to the existence of the disease, but they would throw light also on two other phases; namely, (I) the relation of glycosuria to pancreatic disorders; (2) the effect of morphine on the course of the hyperglycemia in diabetes. In other words, if morphine is capable of superinducing a hyperglycemia in animals with pancreatic injury, the increase of a hyperglycemia after the use of morphine in a diabetic individual or its development in a diabetic suspect, would indicate, on the one hand, that a pancreatic disturbance is present; on the other, that the beneficial effects of morphine (as regards pain, etc.) are accompanied by undesirable developments. I have applied this test in a number of diabetics, both in the sugar-free and the glycosuric states, with the object of determining whether or not the results obtained in experimental animals occur in the human being. The dose of morphine used, given hypodermically, was 1/4 of a grain (0.015 g.). This dose is relatively small compared to that used by Auer and Kleiner, in their experiments on dogs; but it is the maximum dose that I felt justified in administering to patients.