Daily Intravenous Administration Research Articles

The initial uptake of copper by the liver in the dog.

The initial uptake of 64Cu and serum and tissue copper levels were examined in the dog. Plasma disappearance curves, multiple indicator dilution studies of initial hepatic uptake, and constant infusion experiments were carried out, at various doses, before and after preloading with cupric acetate. Over a range of plasma concentrations of direct-reacting copper extending to levels far above those encountered under physiological circumstances, little evidence of saturation of the initial hepatic uptake was evident. The countertransport of labeled copper was produced by administering unlabeled copper. The tissue levels of copper in the liver of the normal dog were, unexpectedly, found to be comparatively high, to average 82 μg/g wet weight. Attempts to produce manyfold increases in this copper content by daily intravenous copper administration failed because the doses of copper which would have been necessary to produce the increases, doses which would not have caused major toxic effects in the rat, were lethal for the dog. This low tolerance for copper loading presumably reflects the preexisting high copper concentration in the liver, the major organ which takes up exogenously administered copper. The degree of preloading which could be achieved produced no perceptible change in initial hepatic uptake. The copper levels in the liver are of the order of those found in some patients with Wilson's disease. Despite this, none of the other abnormalities which characterize this disease have been encountered in dogs.

Biochemical Lesion in Dilantin-Induced Erythroid Aplasia

Abstract Clinical and biochemical studies are reported in a patient who developed pure red cell aplasia after 2 years therapy with Dilantin but in whom aplasia could subsequently be induced with 4-5 Gm. of the drug. Recovery occurred regularly when the drug was discontinued. The administration of 1500 ml. of patient’s plasma obtained during the aplastic phase to a normal volunteer with Dilantin had no effect on the recipient’s reticulocyte count, number of nucleated red cells in his bone marrow, or Fe59 clearance. Attempts to demonstrate binding of gamma globulin to the patient’s nucleated red cells in the presence of Dilantin by immunofluorescence technic were unsuccessful. Dilantin, in a concentration of 20 µg./ml. in vitro, caused significant inhibition of the uptake of C14 formate, glycine, adenine, orotic acid, and uridine into DNA but not into RNA of patient’s bone marrow studied when fully recovered. There was no effect on the uptake of deoxyuridine or thymidine. The Dilantin effect was specific to the erythroid cells as shown by radioautographic studies and by the absence of inhibition when these cells were absent from the bone marrow. Vitamin B12 and folinic aci dgiven to the patient in large doses did not reverse the hematologic effects of Dilantin. The daily intravenous administration of all four deoxyribonucleosides, deoxyadenosine, deoxyguanosine, deoxycytidine and thymidine had a suggestive, but not clear-cut, effect. In an effort to examine a possible relationship of the pure red cell aplasia in this patient to riboflavin metabolism, the patient was started simultaneously on Dilantin and riboflavin. Dilantin was now without effect. However, the patient remains refractory to Dilantin a year after riboflavin was discontinued. It is concluded that Dilantin exerted its toxic effect in this patient by specifically inhibiting DNA synthesis in erythroid cells probably at the step of deoxyribotide formation. The role of riboflavin in the development of resistance to the toxic effect of Dilantin in this patient remains uncertain.

Studies of the effects of 4′4″-bis-(1,4,5,6-tetrahydro-2-pyrimidinyl)-terephthalanilide dihydrochloride on oxidative phosphorylation in mitochondria of rat kidney and liver

The effects of 4′,4″-bis(1,4,5,6-tetrahydro-2-pyrimidinyl)-terephthalanilide (NSC 57153) on oxidative phosphorylation in liver and kidney mitochondria of rat have been determined after daily intravenous administration of the drug for various periods up to 27 days, and after exposure to the drug in vitro. In all cases, phosphorylation and the oxidation of succinate were inhibited in proportion to drug concentration up to a limiting value. Inhibition of phosphorylation never exceeded about 60%, but it was always greater than the inhibition of oxidation. Although NSC 57153 caused equivalent inhibition of mitochondria from kidney and liver when added in vitro, the effects on liver mitochondria after exposure to drug in vivo were minimal because little drug was localized in the liver. It is estimated from the data that a higher drug concentration is required to produce an equivalent inhibition of oxidative phosphorylation after brief exposure to drug in vitro than after days of exposure to drug in vivo. Possible reasons for this findings are discussed.

Pleural and pericardial effusions associated with daily intravenous administration of acetylated tartaric acid esters

Experimental pleural and pericardial effusions have been produced in dogs by the intravenous administration of TEM. Thirteen dogs were infused daily with 0.5% TEM at a dose rate between 40 and 50 ml/kg. A fall in hemoglobin concentration occurred in 11 dogs, a pleural effusion in 6. BSP and BUN determinations remained within normal limits. The concentration of electrolytes in the effusion were slightly less than that of serum. Effusion protein concentrations were about half that of dog sera. The active principle of TEM or the mechanism responsible for the effusions are not known. TEM has been demonstrated as a component of the intravenous fat emulsion, SR emulsion, capable of producing the intravenous fat pigment.

The management of resistant fluid-retention states with intravenous L-arginine monohydrochloride in combination with mercurial diuretics

The daily intravenous administration of a large dose of l-arginine monohydrochloride is a safe and effective method of producing hyperchloremic acidosis and restoring responsiveness to mercurial diuretics in patients with refractory retention of fluid due to hepatic cirrhosis or congestive heart failure. Results obtained with 5 patients thus treated, and the advantages of this agent in certain clinical situations, are discussed.

Decrease in aerobic glycolysis of erythrocytes following the continuous administration of L-triiodothyronine.

The daily intravenous administration of L-triiodothyronine, L-T3 (125 μg-⁄ kg.), to rabbits produced biphasic effects on the aerobic glycolysis rate of erythrocytes, in vitro. An increase in the glycolysis rate was observed in 24 hours; the increase reached a peak in 4 days. Following this, the glycolysis rate fell off and at 21 days, when toxic effects occurred, it was only 62‰ of normal. The possibility that a decrease of RBC glycolysis rate might be used as a clinical laboratory test for thyrotoxicity must be considered.

Serum Lipids After Intravenous and Intragastric Fat Emulsion in Man

1. For the purpose of studying some mechanisms of lipid transport, the effect of fat emulsion on whole serum and subnatant serum lipids after single intragastric and intravenous administration and after daily intravenous infusion was studied in healthy young adults. 2. The level of whole serum neutral fat after intragastric administration of fat in the same subject did not result in as great an increase as was observed after intravenous administration. Following a single intravenous infusion of fat emulsion, subnatant serum neutral fat and free cholesterol reached a maximum eight hours after the start of the infusion. Increases were observed after intragastric administration of fat emulsion but not to the same degree as after intravenous infusions. During the first day, cholesterol and phospholipids decreased substatially in whole serum and subnatant after both intragastric and intravenous administration of fat emulsion, but returned to preinfusion levels on the second day of the experiment when no fat load was administered. 3. Daily intravenous administration of fat emulsion resulted in essentially similar patterns on the three days studied. Neutral fat and phospholipids peaked at the end of the infusion in the whole serum, and on successive days, the clearing rate of the infused fat emulsion decreased and the fasting level for neutral fat increased. Neutral fat in the subnatant serum reached its highest level four hours postinfusion along with an increase in cholesterol. The esterified cholesterol fraction dropped in serum from the beginning of the experiment and fell to its lowest point by the end of the third day, gradually returning to preinfusion levels by the sixth day. 4. The results of this study strongly suggest that the infused artificial chylomicrons are removed from the circulation essentially intact, reappearing, at least in part, as “soluble” lipoprotein. Serum cholesterol apparently becomes associated with the infused neutral fat thereby accounting for the immediate decrease in serum cholesterol. 5. The experiments described are discussed in the light of current knowledge in lipid transport.

METHITURAL, A NEW INTRAVENOUS ANESTHETIC

Investigations in the cat, dog and monkey showed methitural to possess twothirds the anesthetic potency of thiopental. Following equivalent anesthetic doses, recovery from anesthesia was significantly more rapid with methitural than with thiopental, and cumulative action with methitural considerably less than that observed with either thiopental or thiamylal. There was less respiratory depression and less cardiac acceleration with methitural than with thiopental anesthesia, but a greater incidence of reversible cardiac arrhythmias (ectopic beats and bigeminy) and abnormal vagal reflexes which were reduced or abolished by atropine premedication. Atropine, morphine, succinylcholine, d-tubocuranine and combinations thereof were found to be compatible with methitural in the dog. Atropine, as well as morphine, significantly increased the depth and duration of anesthesia and extended recovery of the righting reflex. No tolerance or cumulative action was noted in the dog following the daily intravenous administration of methitural (45 mgm./kgm.) or thiopental (25 mgm./kgm.) for thirty days. Microscopic examination of the tissues following chronic administration showed thiopental to be considerably more toxic to the liver than methitural.

癌浸出液の膵に及ぼす影響について

The cancer tissue extract was made from surgically removed stomach cancer. A pancreatic fistula was made on dog and the change of the content of the various ferments in the pancreatic juice was studied after daily intravenous administration of 10% cancer tissue extract 1 cc/kg.The following results were obtained;1) Diastase was markedly decreased. The decrease began on the 1st day of the experiment, and the lowest value occurred in 2nd or 3rd day. This lowest value was maintained as long as the injection of the cancer tissue extract were continued. However, when injection of cancer tissue extract was discontinued, diastase values were gradually increased.2) Trypsin also began to decrease on the 1st or 2nd day after injection of the cancer tissue extract. The lowest value occurred on the 2nd or 3rd day of the experiment. However, compared to diastase, this decrease was not marked.3) There was found no marked change regarding the content of lipase.4) In the control group, in which the extract of normal stomach tissue was used as injection material, there were found no change in the ferments of pancreatic juice.The nucleic acid in the pancreatic tissue was studied histochemically by the Pironin-Methylgreen stain using rabbits which were given the cancer tissue extract 1 cc/kg daily intravenously.The following results were obtained;1) The amount of RNA was decreased moderately after daily injection of the cancer tissue extract for 2 weeks and marked decrease was found after daily injection for 4 weeks.2) No significant changes were observed in DNA and KES.It is believed that the function of external pancreatic secretion is definitely inhibited by the injection of the cancer tissue extract.

Effects of digitoxin on exchangeable and tissue potassium contents.

Summary1. The daily intravenous administration of 0.1 mg of digitoxin per kg of body weight to normal rabbits resulted, within 7 days, in an increase in body weight and a reduction in the serum potassium concentration and the exchangeable potassium content. These changes in potassium metabolism were corrected within one week by discontinuing the glycoside. 2. The intravenous administration of a single large dose of digitoxin (0.2 mg per kg) to normal rabbits resulted within 24 hours in a decrease in the mean potassium content of all the tissues and organs. Statistically significant decreases in potassium content were noted in the abdominal and diaphragmatic muscles and in the subcutaneous connective tissue. The results suggest that one of the effects of the administration of digitoxin in these dosages is to deplete the body store of potassium.

DEPRESSION OF SERUM ALKALINE PHOSPHATASE ACTIVITY BY HUMAN SERUM ALBUMIN

The daily intravenous administration of 50 gm. of concentrated saltpoor human serum albumin’ produces a rise in serum albumin level and a decline in urinary calcium and phosphorus excretion (1). These latter changes have been interpreted as evidence for an albumin-induced stimulation of osteogenesis (2). The consistent finding of a concomitant depression of serum alkaline phosphatase activity was thus unexpected, inasmuch as we believe that, in the absence of liver disease, serum alkaline phosphatase is an index of osteoblastic activity. Fig. 1 illustrates the relation observed between serum alkaline phosphatase and serum albumin levels in eleven experiments on six patients. In general, as the serum albumin level rose, the serum alkaline phosphatase activity decreased 50 to 100 per cent. There was no concomitant constant change in serum globulin levels. The magnitude of depression of serum alkaline phosphatase activity was considerably greater than could be explained by expansion of plasma volume, as judged by decrease in blood hemoglobin concentration and hematocrit. The experiments in vitro which follow were designed to clarify the nature of this unexpected relation between human serum albumin and serum alkaline phosphatase activity.