Earl G. McNall

The treatment of systemic fungus infections with amphotericin B.

Since its introduction four years ago by Gold et al.,l amphotericin B t has received increasing clinical trial in the treatment of virtually all of the systemic mycoses that affect man. Much additional experience will be required before the ultimate value of amphotericin B can be determined, but accumulating clinical data suggest that to date it represents the most effective chemotherapeutic agent currently available for the treatment of these heretofor recalcitrant diseases. This paper deals with our clinical experience to date with amphotericin B in the treatment of systemic mycoses, particularly coccidioidomycosis. It is a member of a growing family of closely allied polyene antifungal agents, which includes amphotericin A, trichomycin, rimocidin, nystatin, candicidin, ascosin, pimaricin, and others. A tentative empirical formula, C~BH~~NOZ, has been assigned to it.2 In vitro, amphotericin B inhibits a wide variety of pathogenic and nonpathogenic fungi in concentrations ranging from 0.5 pg./ml. to 12.5 pg./ml.1p3 The growth of the majority of the organisms producing systemic mycoses is inhibited by amphotericin B in concentrations as low as 0.02 to 0.5 pg./ml.l These include Blastomyces dermatitidis, Blastomyces brasiliensis, Candida albicans, Cryptococcus neojormans, Histoplasma capsulatum, Coccidioides immitis, and the yeast phase of Sporotrichum schenkii. Initial toxicity studies indicated that calculated therapeutic levels of the drug could be obtained without serious sequelae in several species of animal^.^ These studies were followed by others designed to evaluate the effectiveness of amphotericin B on experimentally produced fungus infections in animals. Amphotericin B has favorably influenced the course of such infections due to C. albicans, C. neojormans, H. capsulatum, C. immitis, Rhizopus oryzae, Aspergillus fumigatus, and some Volutella ~pecies.~-ll Preliminary studies in man indicated that amphotericin B was in general poorly absorbed when given by mouth5 or intramuscularly. In addition, when the drug was given intramuscularly in therapeutic amounts, it proved too irritating for routine use.12 The currently available preparation of amphotericin B has been most usefully employed intravenously, although in certain instances it has been effective when given by other routes. The drug is highly insoluble in aqueous solutions, and the early intravenous preparations consisted of relatively coarse suspensions of the drug.13 The use of sodium desoxycholate as a solubilizing agent has improved the intravenous preparation considerably; however, true solutions

Assay of Properdin in Biological Fluids.

Summary 1. A sensitive, reproducible assay for properdin is described using spectro-photometric determinations of C3 content. 2. RP and R3 reagent sera for the properdin assay may be readily prepared from guinea pig serum. 3. RP and R3 from both human and guinea pig sources may be used interchangeably in the reported properdin assay. 4. Tnu-lin was found to be more satisfactory than zymosan as a properdin binding and C3 inactivating agent.

The Current Status of Silicone Injection Therapy

Clinical uses of silicones. Factors influencing persistence of the original size of the injected area.

THE EFFECTS OF NUCLEIC ACIDS ON HOMOGRAFT TOLERANCE

Although Fomon’ described the Egyptian barkers of 3500 B.C. as having a limited number of successful skin transplantation procedures, the Twentieth Century surgeon employing the most efficient methodology is still observing a consistent sloughing and demise of a high percentage of skin homotransplants. It should be stressed that we are not cognizant of the seemingly infinite mechanics of the homograft reaction. Which in the constellation of intricate antigens invokes this response, and which are the antibodies that contribute to it, also are facts unknown to modern researchers. Many investigator^^-^ have written extensive reviews on homotransplantation. These reviews not only inform the reader of advances made in the field, but also indicate the many links still missing in our understanding of homotransplantation immunity. The classic experiments performed by MedawaP clearly demonstrated that rejection of homografts is effected via the mechanism of an actively acquired immunity. Medawar postulated that this immunity response is developed by the host in order to reject genetically unrelated tissues, that the host’s acquisition of homograft sensitivity is an immunological reaction, and that the prolongation of homograft survival is a function of immunological tolerance. The genetic aspects of homotransplantation have been studied in ten~ive ly~-~ during the last twenty years, one of the first studies being of tumor transplantation.4J7 However, today’s interest has shifted largely to normal tissues. Snell18 proposed that the chromosomal locus relating to transplantation be called histocompatibility genes (H and h). Gorer and Amoslg referred to this locus as H-2,2O where, according to Bi1lingham:l some of the alleles, now considered to be less than 12, are determinants for the production of transplantation antigens. Hoecker (1956)22 presented a thorough discussion of the differences in the effects of H genes on transplantation. SchultzZ3 pointed out that the basis for the behavior of tissues on transplantation in the immunological and genetic phenomena seemed to be divided between two contradictory bodies of data. On the one hand, the rigorous “laws of transplantation” demand a common genetic constitution of host and implant if a graft is to take. Where successful transplantation is concerned, the antigenic constitution of tissue is related to specific genotype as directly as are the classic immunological blood groups. On the other hand, in contrast to this definite picture are the experiments in which tolerance is induced, histocompatibility barriers are

The treatment of systemic mycoses with orally administered pimaricin: preliminary report.

Pimaricin is a new crystalline antifungal antibiotic derived from Slreptomyces natalensis, originally isolated from a soil sample obtained near Pietermaritzburg, Natal, Union of South Africa. I ts chemical and physical properties have been characterized by Struyk et a1.l and by Dekker and Ark.* It is a tetraene antibiotic and is related to, but not identical with, rimocidin, antimycoin, nystatin, and chromin. These tetraenes are members of a larger group of antibiotics, the majority of which possess fungicidal activity and include such compounds as ampho tericin, trichomycin, ascosin, and candicidin. An empirical formula of C30-32H46-60N013 was assigned early to pimaricin.’ More recently, however, Patrick et ~ 1 . ~ have elucidated the structural formula of p i m a r i ~ i n ~ . ~ (see formula below), the first of the many polyene antifungal antibiotics to have its structure so determined:

Studies on mammalian homotransplants of skin: III. An attempt to induce tolerance across the placenta in rats with RNA and DNA☆

Abstract A review of the more pertinent aspects of work pertaining to the present study as performed by others and by us is outlined. Four experiments are presented which represent our preliminary efforts to induce tolerance across the placental membrane in rats. In the first experiment, RNA was used and the results were slightly encouraging in that 18 per cent of the graft took in the twenty-day old animals (age of grafting) which represents a significant increase over the control animals (8 to 9 per cent). In the second experiment with DNA as the injected material, the difference between the percentage take of the treated animals and the control animals was negligible. Experiments 3 and 4 involved the use of DNA and RNA tagged with C 14 , in an effort to determine the quantity which actually entered the fetus through the placenta. This phase of the work is encouraging in that significant quantities of C 14 were counted in the fetuses, thus indicating passage of these cellular components. In view of our previous findings that tolerance may be produced by injecting RNA intracardially into neonatal rats and our present findings that the injected substances (DNA and RNA) crossed the placenta, we are hopeful of more significant results in future experiments with increased and repeated injections of modified antigen.