Karl Meyer

Observations on the mechanism of action of penicillin

Summary Penicillin acts either as a bacteriostatic or bactericidal agent depending on the experimental conditions. The number of organisms decreases at a constant rate until 99% of the organisms have been destroyed. The rate of killing varies with different organisms. The action of penicillin on hemolytic streptococci is not accompanied by lysis of the organisms. No detectable amount of penicillin is destroyed or absorbed from solution by the organisms. It appears to be effective only when active multiplication takes place.

Mucoids and Glycoproteins

Publisher Summary This chapter focuses on mucoids and glycoproteins. Compared to the progress in the knowledge of chemistry, physiology, and pathology of the proteins proper, knowledge of the mucoids and glycoproteins has remained rather incomplete. Certain mucoids—for example ovomucoid, seromucoid, and gonadotropic hormones—are distinguished by great solubility in aqueous solutions. They are not readily precipitated by trichloroacetic, sulfosalicylic, picric, or flavianic acids. They are precipitated by alcohol or acetone without losing their solubility in aqueous media. No member of this group seems ever to have been crystallized. Most mucopolysaccharides and mucoids are characterized by a high solubility in water and a relative resistance towards denaturation by agents that denature proteins. The mucoids of the first group, those containing glucosamine and galactose in the ratio of 1:1, probably are widely distributed in animals and in microorganisms. The mucopolysaccharide group of some of these mucoids is responsible for blood group A activity and is related to the Forssman antigen. They occur in the gastric mucosa, in horse saliva, and in some ovarian cysts. It is unknown whether the mucoid of the oviduct of the frog—the glands that furnish the egg jelly—and that of salamander egg jelly (unpublished experiments) are related biologically to these substances. The distinction between mucoids and glycoproteins, based on a hexosamine content of the former of 4 percent or over, is arbitrary. In many instances a substance cannot be placed properly at the present time.

Activity of Penicillin in vitro

Summary The observations of Florey, et al. 3 on the antibacterial activity of penicillin against Gram positive organisms are confirmed and extended. Preparations have been obtained of such activity that 0.03 γ inhibits the growth of 2 to 4 million hemolytic streptococci. This represents an equivalent of 240-250 Oxford units per mg.

Inhibition of Vascularization of the Rabbit Cornea by Local Application of Cortisone.

Summary The subconjunctival injection of cortisone inhibits markedly the vascularization of the cornea caused by intracorneal injection of alkali.

PENICILLIN AS A CHEMOTHERAPEUTIC AGENT

Excerpt In 1929, while examining plates seeded with staphylococci, Fleming1observed that colonies failed to grow in the neighborhood of a colony of a contaminating mold. Following up this chance ob...

Hyaluronic Acid in Pleura Fluid Associated with Malignant Tumor Involving Pleura and Peritoneum

Conclusion Hyaluronic acid in high concentration has been isolated from the chest fluid of a patient with a malignant tumor, probably an endothelioma. The polysaccharide acid in the original fluid migrates in an electric field at pH 7.8 at essentially the same speed as the isolated pure polysaccharide acid, indicating the existence in the fluid of the free acid and not of a protein complex.

Relationship between “Spreading Factor” and Hyaluronidase.

Summary Evidence is presented to show that hyaluronidase and “spreading factor” exhibit certain attributes in common. However, there is also considerable evidence that “spreading factor” does not owe its activity solely to the presence of hyaluronidase. It would seem probable that the phenomenon of “spreading” is a complex one and that several factors may be involved in its production. Further work is required to explain the mechanism of “spreading” in terms of known chemical and physico-chemical reactions.

Experiments on Erythrocyte Sedimentation Rate

Summary Addition of desoxyribonucleic acid, gelatin, fibrinogen, and especially hyaluronic acid to normal human citrated blood causes a considerable increase in E.S.R. Hyaluronic acid acts only in its highly polymerized form, thus suggesting that molecular weight is an important factor in this reaction, as well as asymmetry of the molecule. Hyaluronidase specifically reverses the action of hyaluronate on E.S.R. Intravenous injection of hyaluron- ate in guinea pig and rabbit leads to increased E.S.R. Intravenous injection of hyaluronidase promptly causes the increased rate to become normal.

Hyaluronic acid-hyaluronidase and the rheumatic diseases.

‘The pathogeiicsis of the rheumatic diseases is obscure. Apparently, the disease process is localized in the connective tissue and particularly in the interfibrillar material, which is composed in part of one or both of the mucopolysaccharides-chondroitin sulfuric acid and hyaluronic acid. The only microorganisms known to produce hyaluronic acid are groups A and C hemolytic streptococci in the mucoid phase. Nonmucoid hemolytic streptococci may produce hyaluronidase, as do many other microorganisms, such as pneumococci, staphylococci, and some gas-producing anaerobes. I t appears significant that, following an outbreak of sore throat caused by type 4 streptococci (a hyaluronidase-producing strain) in a convalescent home for rheumatic children, Kuttner observed no recrudescence of rheumatic activity, while in previous years, sore throat due to other types of hemolytic streptococci led to a definite number of recurrences. In the light of Sallman and Birkeland’s work, this interpretation may have to be revised. Hyaluronic acid has been isolated from normal synovial fluids of animals and abnormal synovial fluids from man. Synovial fluid from the knees of normal human beings cannot be obtained in sufficient quantity for chemical isolation. The normal fluids, on dilution, acidification, and addition of normal horse serum, form a fibrous clot, whereas under the same conditions most pathologic fluids go into a state of colloidal turbidity. On addition of 0.01 unit of hyaluronidase, an amount insufficient to affect the viscosity or concentration of hyaluronic acid of the material under the experimental conditions, the fiber formation is prevented and the colloidal turbidity seen in pathologic fluids occurs. On dilution of a fluid containing hyaluronate, a straight line is evolved if the log of viscosity is plotted against dilution. In synovial fluid, the viscosity alone cannot be used as an index of polymerization of the hyaluronate, since dilution with extracellular water influences viscosity so markedly. If concentration of hyaluronate, determined turbidimetrically, and viscosity are known, however, using the straight-line relationship existing between log viscosity and concentration, a quotient can be derived which will give an approximation of the mean polymerization of the hyaluronate present in the fluid. A quantitative difference between normal and pathologic fluids was found. In fluids from normal joints, this quotient was always more than 10, while in fluids from patients who had rheumatoid arthritis or rheumatic fever the factor was as low as 1. The activity of the disease was roughly inversely propotional to this factor; the more active the disease, the lower the factor, and, as the activity diminished, the factor rose.

The Chemotherapeutic Effect of Esters of Penicillin.

Conclusions Although inactive in vitro, ethyl and n-butyl esters of penicillin have been shown to be highly effective chemotherapeutic agents in mice infected with large doses of virulent hemolytic streptococci. These esters are apparently hydrolyzed slowly with the liberation of active penicillin. They are effective when given by the subcutaneous or by the oral route of administration.