Roy G. Herrmann

Effect of Taurine, Glycine and β-Sitosterols on Serum and Tissue Cholesterol in the Rat and Rabbit

Rats and rabbits were fed a hypercholesteremic diet until elevated serum cholesterol levels were observed in all animals. The animals were then divided into groups, one group remaining on the original diet and the others receiving the same hypercholesteremic diet fortified with either taurine, glycine, or β-sitosterols. In the rat, 4 per cent taurine in the diet significantly decreased the serum, liver, and aorta cholesterol concentration, but glycine was without significant effect. In the rabbit, 2 per cent β-sitosterol in the diet significantly reduced the serum, liver, and aorta cholesterol, while taurine or glycine produced no significant effect. Neither taurine, glycine, nor β-sitosterols produced any signs of toxicity.

Correlation of the in vivo anticoagulant, antithrombotic, and antimetastatic efficacy of warfarin in the rat

Fibrin formation has been hypothesized to be an element of the metastatic process in cancer, and pharmacological interference with such fibrin formation has been proposed as a means of antimetastatic therapy. We have tested this hypothesis through an in vivo study of warfarin in two independent rat disease models--a model of chemical-injury-induced arterial thrombosis, and a model of spontaneous metastasis. We found 0.50 mg/kg-day warfarin to be uniformly lethal after two weeks treatment. The chronic dose of 0.25 mg/kg-day was non-toxic and produced effective anticoagulation and marked antithrombotic and antimetastatic activity. The 0.125 mg/kg-day dose produced a reduction in factor IIc (50%) and factor VIIc (70%), and resulted in statistically significant antithrombotic and antimetastatic activity. The 0.0625 mg/kg-day dose failed to reduce the vitamin K-dependent clotting factors, and failed to produce any antithrombotic or antimetastatic effects. The substantial correlation (very similar dose-response effects) among the anticoagulant, antithrombotic and antimetastatic efficacies of warfarin in the rat suggests that anticoagulation provides the pharmacological mechanism underlying both the antithrombotic and the antimetastatic effects. The poor therapeutic index we observed in the rat may be the attribute which limits the efficacy of warfarin in the treatment of human cancer.

Effect of Adenosine Derivatives and Antihistaminics on Platelet Aggregation

Summary The inhibitory activity of ade-nosine derivatives on ADP induced platelet aggregation appears to be quite specific. Only one derivative, 5′-adamantoyl adenosine, retained the potency of adenosine. Isoadenosine was 1/100 as active as adenosine. Isoadenosine diphosphate did not induce platelet aggregation at a dose as high as 2.6 × 10- 4 M as compared to ADP which produces extensive aggregation at 4.2 × 10-7 M. All of the 6 antihistaminics tested inhibited ADP induced aggregation, but there was no correlation between antihistaminic and aggregation inhibitory potency. Both classes of compounds also inhibited collagen induced aggregation.

Determination of Serum and Tissue Cholesterol

Summary A simple and sensitive method for determination of serum and tissue total cholesterol is described.

Effect of Ionic Calcium and Magnesium on Human Platelet Aggregation

Summary The ionic calcium requirement for platelet aggregation is much lower than that required for fibrin formation. Maximal aggregation can still take place with the [Ca2+] well below 5 × 10−6 M. Chelation of Ca2+ with EGTA results in a decrease in aggregation at a higher [Ca2+] than when EDTA is employed. This seems to indicate that the [Ca2+]/[Mg2+] ratio may be of importance at low ionic concentrations. However, excess [Ca2+] and/or [Mg2+] above the normal levels inhibit aggregation. In fact, when both of these ions are added in excess of the normal levels their inhibitory effects are additive, indicating that the [Ca2+]/[Mg2+] ratio is of little consequence under these conditions. Platelet aggregation is not inhibited by the calcium complex of either EDTA or EGTA.

Effect of a New Anti-Inflammatory Drug, Fenoprofen, on Platelet Aggregation and Thrombus Formation

Summary Fenoprofen sodium (a new antiinflammatory drug), aspirin, and phenylbutazone were compared with respect to their inhibitory activity on platelet function. These compounds inhibit collagen-induced platelet aggregation both in vitro (human, rabbit, and guinea pig) and in vivo (rabbit and guinea pig). In an extracorporeal shunt experiment in the rabbit, both fenoprofen sodium and aspirin inhibited thrombus formation. Of the three compounds tested, fenoprofen sodium appears to be the most active inhibitor of platelet function.

Serum, bile and liver total cholesterol of laboratory animals, toads and frogs.

Summary 1. Serum, bile, and liver total cholesterol levels of 9 species of laboratory animals and 4 species of amphibians are reported. 2. Dogs, monkeys, hamsters, and mice have relatively higher serum total cholesterol concentration than cats, rats, rabbits, and guinea pigs. 3. Total cholesterol concentration in liver varies only slightly among these species. 4. Gall-bladder bile of monkeys contains large amounts of total cholesterol. Guinea pigs excrete very small amounts of total cholesterol in bile. 5. Serum and liver total cholesterol concentrations of the pigeon are very high. 6. Total cholesterol concentration in liver varies slightly among the 4 species of amphibians used. Frogs excrete significant amounts of cholesterol in bile. 7. Serum total cholesterol concentrations of both species of toads are higher than those of both species of frogs.

Intestinal absorption of cardiac steroids.

Summary 1. Six cardiotonic steroids—digitoxin, lanatoside E, acetyl strophanthidin, ouabain, bufalin and bovoside A—have been compared with reference to intestinal absorption in dogs with a chronic jejunal loop. 2. Because of the dominance of vomiting before electrocardiographic changes took place the median emetic dose was estimated after intravenous and intrajejunal injections in order to appraise the absorbability of each steroid from the intestine. 3. In the dog digitoxin and acetyl strophanthidin were more easily absorbed than lanatoside E and bufalin. Ouabain was least absorbed—less than 5%. Although bovoside easily crossed the intestinal membrane it produced persistent loss of appetite resulting in death.

An in Vivo Technique for Assessing the Formation of a Hemostatic Platelet Plug

Summary An in vivo method, using the mouse as the experimental animal, for assessing the formation of a hemostatic platelet plug has been presented. Six compounds were tested, and the results indicate the activity observed correlates with the known activity of these compounds both in man and the experimental animal. Furthermore, it was observed that in vitro activity does not necessarily parallel in vivo effectiveness.

Effect of Vitamin D, Sucrose, Corn Oil and Endocrines on Tissue Cholesterol in Rats

A diet containing 65 per cent sucrose with added cholesterol resulted in hypercholesteremia and increased tissue cholesterol deposition in rats. Ten per cent corn oil with added cholesterol in Purina laboratory chow had no apparent effect on the serum total cholesterol but increased cholesterol deposition in tissues. Ovariectomy was without significant effect. Thyroidectomy or hypophysectomy aggravated the hypercholesteremia and the increased tissue cholesterol deposition induced by the sucrose diet. The effect of hypophysectomy was not due to the loss of thyrotrophic hormone alone. Addition of vitamin D aggravated hypercholesteremia and increased liver cholesterol deposition in normal, thyroidectomized or hypophysectomized rats fed the sucrose diet. In ovariectomized rats, the tissue cholesterol deposition was also augmented. When corn oil diet was fed, the supplementary vitamin D increased the serum total cholesterol level of the thyroidectomized rat.