Robert A. Lehman

Further studies on the acute toxicity of mercurial diuretics.

Summary Mercuric chloride, Salyrgan-theophylline, Mercuzanthin, Mercuhydrin and N (γ-carboxymethylmercaptomercuri-β-methoxy) propyl camphoramic acid disodium salt (MT6) have been compared with respect to their ability to cause cardiac toxicity as manifested by changes in the electrocardiogram of the cat. The toxicity has been found to decrease in the order named. Compound MT6 causes no immediate changes in the electrocardiogram in doses up to 160 times the maximum tolerated dose of Mercuhydrin. This improvement appears to be due to the relatively greater stability of the mercaptide as compared with the theophylline complex.

Excretion of Mercury Following Administration of Mercurial Diuretics with and without Theophylline

It has recently been shown that the addition of theophylline to the mercurial diuretics Mercurin and Salyrgan practically prevents their local toxic action 1 2 and promotes their absorption after intramuscular injection. 3 Although Mercupurin (Mercurin with theophylline) has been found to have a somewhat greater diuretic efficiency than Salyrgan, 4 5 6 7 it remains to be proven unequivocally, however, that theophylline exerts any influence after the drug has reached the circulation. It was therefore decided to study the excretion of mercury by laboratory animals after the administration of these diuretics with and without theophylline. It is fully realized that results thus obtained cannot necessarily be referred to man. Nevertheless, it was felt that information concerning the pharmacology of drugs of this type could more readily be obtained by using animals whose food, salt and water ingestion could be kept perfectly constant. A total of 24 albino rabbits weighing between 2 and 3 kg were used in these experiments. All the animals had been raised on a diet of alfalfa hay and oats and had received a constant daily supply of water. On the day of the experiment each rabbit was tied to an animal board and 75 cc of water at body temperature administered by stomach tube. One hour later the animal was catheterized (French No. 10 catheter), the urine discarded and 0.10 cc of the drug to be studied was injected with a tuberculin syringe and 26 gauge needle either into the tibialis anterior muscle or one of the marginal veins of the ear. This was equivalent to 3.71 mg of mercury in the case of Salyrgan or Salyrgan with theophylline and 3.80 mg in the case of Mercurin or Mercupurin. The catheter was strapped in place with adhesive tape and all the urine excreted within the next 6 hours collected in 25 cc graduates. Since the rates of excretion vary considerably for the different drugs and methods of administration, it was necessary to space the collection of samples so that the time at which maximum excretion occurred could easily be determined.

Antagonism of Phospholine (Echothiophate) Iodide by Certain Quaternary Oximes

Summary Protopam (pralidoxime) Chloride (or Iodide) and TMB4 (1, 1′-trimethyl-ene-bis(4-formylpyridinium bromide) dioxime) when injected intraperitoneally in the mouse at 50% of LD50, raise the intraperitoneal lethal dose of anticholinesterase, Phospholine (echothiophate) Iodide, by factors of 50 and 280 respectively. When the same oximes are given orally 30 to 60 minutes before Phospholine the intraperitoneal LD50 is increased by factors of 23 and 450. Graphs relating log dose of oxime and log dosage ratio of Phospholine are linear over a considerable range. The therapeutic indices for arbitrary increase of 10 times in LD50 of Phospholine are 23 and 9 for Protopam and 114 and 120 for TMB4 by oral and intraperitoneal administration respectively. The possible nature of the antagonism is discussed.

Limiting Content of Theophylline Necessary to Prevent Local Toxic Action of Mercurial Diuretics

In a previous paper 1 it has been shown that theophylline greatly diminishes the toxicity of Mercurin∗ and Salyrgan at the site of intracutaneous injection. The beneficial action of theophylline in enhancing absorption after intramuscular injection has also been demonstrated 2 and it was found 3 that one mole equivalent (3.88% of theophylline monohydrate) produces the maximum effect. Since this and other data 3 are strongly suggestive of compound formation between theophylline and mercurial diuretics of general structure NaOCO-RII-HgOH it seemed advisable to determine the limiting amount of theophylline necessary to prevent local toxicity. The experimental procedure was the same as that described before 1 and consisted in the intradermal injection into the abdomen of the rabbit of 0.05 cc. of Mercurin and Salyrgan to which varying amounts of theophylline had been added. Each solution was prepared to contain 39 mg. of mercury per cc. (about 0.2 M) and its pH was accurately determined with the glass electrode. In the accompanying photograph, taken 24 hours after injection, the mole equivalents of theophylline and pH values for each of the 7 solutions are shown adjacent to the corresponding sites of injection. In all 5 rabbits were injected in this way for Mercurin and 3 for Salyrgan. The results for the 2 drugs are very much alike and were found to be so consistent that only one photograph is shown. It will be seen that the local toxicity decreases in proportion to the amount of theophylline present and in the case of the solutions containing 1, 1.25, and 1.5 mole equivalents, so little reaction was produced that it is difficult to locate exactly the sites of injection.

Action of vitamin A on the skin following intracutaneous injection.

Summary It has been found that a single intracutaneous injection of vit. A in the rabbit causes an increase in thickness of the epidermis (excluding corneum) which is due to an increase in both number and size of the cells in the germinative and granular layers. The corneum becomes thinner and denser. The occurrence of large, young appearing nuclei in the absence of an increase in mitotic rate indicates that the maturation process is slowed.

A Comparative Study of the Local Toxic Action of Mercurial Diuretics

Summary and Conclusions Three mercurial diuretics, Thiomerin, Mercuzanthin and Mer-cuhydrin have been compared with respect to the tissue reaction which they produce. Thiom-erin was tolerated by mice on subcutaneous injection without exhibiting gross pathology while Mercuzanthin and Mercuhydrin gave rise to necrosis of the skin under the same conditions. After intramuscular injection in rats all three drugs gave an early inflammatory response characterized by the appearance of a polymorphonuclear exudate. In the case of Thiomerin this exudate was entirely resorbed without evidence of residual damage. After injection of Mercuzanthin, or Mercuhydrin, however, the irreversible nature of the response was indicated by marked fibroblastic proliferation. These results would seem to furnish an adequate experimental basis for the clinical use of Thiomerin by subcutaneous injection. The authors wish to thank the Misses Florence Katine and Josephine Brosseau for able technical assistance.

Comparison of the Toxicity of Antiseptics for Embryonic Tissue and Bacteria

Summary A method has been described for quantitative comparison under identical physiological conditions of the toxicity of antiseptics for tissue and bacteria. The technic is simple and the results are reproducible. The toxicity indices were found to be as follows: iodine, 0.29; azochloramide, 0.64; phenol, 2.7; zephiran, 3.4; merthiolate, 3.9; saponated solution of cresol USP XII, 4.1.

Fate of the Lethal Effect of Sublethal Doses of Lanatoside C, Digoxin and Diǵoxiǵenin

Conclusions The lethal effect of lanatoside C dissipates rapidly

Further studies on relationship between activity and constitution in the cardiac glycoside series.

Summary The potency of a number of glycosides and related compounds for the embryonic chick heart has been reported and various implications suggested. As a means of studying the relationship of chemical constitution and physiologic action, the embryonic heart method appears to offer definite advantages over methods employing intravenous administration to intact animals.

Toxicity and Fate of the Lethal Effect of Theophyllinated Scillaridin in the Cat

Riseman and London 1 have recently described some of the properties of a substance which is obtained by condensing a disodium salt of a mixture of genins isolated from Squills (presumably scillaridin A and B) with 2 molecules of theophylline. They demonstrated by electrocardiographic studies that the substance so obtained differs in its action from either a mechanical mixture of theophylline with the genins, or from the original glycosides, thus giving physiological confirmation for a discrete compound. Since this appears to be the first report of an attempt to modify the action of a cardiac glycoside by chemical combination with a xanthine derivative, it seemed to be of considerable interest to determine the toxicity of the substance and the fate of the lethal effect of sublethal doses in the cat. The ratio of genins present in the compound has not been determined, but the empirical formula may be approximated as C24H28O3 (C7H7O2N4)2 2H2O. It should be pointed out however, that by the method of preparation used, structural rearrangement of the genin may well have taken place. The influence of structure on physiological action is discussed further by Lendle. 2 The preparation was assayed by the original Hatcher and Brody procedure using a 1:714 solution in normal saline and a rate of infusion such that the animals died within 30 to 90 minutes. The geometric mean lethal dose on the basis of 10 cats was found to be 21.4 mg per kg (or 28.2 micromoles per kg) and the standard deviation was 4.2. By comparison, the lethal doses 3 of Scillaridin A and of Scillarin A are respectively 0.150 and 1.72 mg per kg (0.217 and 4.73 micromoles per kg).