The Therapy of Experimental Psittacosis and Lymphogranuloma Venereum (Inguinale)

Abstract

In previous communications (Hurst, 1948;Hurst, Peters, and Melvin, 1950) we have recorded the therapeutic action of Nitroakridin 3582 and compared those of penicillin, chloramphenicol, aureomycin, and terramycin against psittacosis and lymphogranuloma venereum in mice or in developing chick-embryos. For the past eight years we have used these experimental infections (among others) in routine screening-tests of synthetic organic compounds for antiviral properties, and during this time have encountered a number of quite dissimilar chemical types each exhibiting some degree of activity against these particular infections. The most active compounds were quinoxaline-l: 4-dioxide and various substituted derivatives, the best of which closely approached aureomycin in therapeutic potency. Alergant (1953) has confirmed this action in human lymphogranuloma, though toxic side-reactions rule out the possibility that the compounds will be useful additions to the pharmacopoeia. The quinoxaline oxides also manifest anti-amoebic and antibacterial properties (Jones, Landquist, and Stewart, 1953; McIlwain, 1943;Francis, 1953). METHODSThe strains of virus used, the general method of working, and the method of computing 40% endpoints (not 40% mortalities) in titrations of virus are sufficiently described in our earlier publications. When this work first began aureomycin was unknown, and in the earlier experiments we had no suitable standard of therapeutic activity. When later aureomycin became available in strictly limited quantities, we used it as a standard of reference in all experiments, giving a single dose of 1 mg. to eggs or 2 mg. twice daily to mice. Although when the antibiotic was more freely available it appeared that these were perhaps not quite the optimal doses (see Hurst, Peters, and Melvin, 1950), for the sake of consistency we decided to retain them throughout this investigation. Our experience over more than a hundred experiments, however, strongly suggests that the earliest samples of aureomycin were less effective than those issued somewhat later, so that in fact we did not achieve perfect consistency over the years, though we believe that we have done so for the greater part of the time. The largest amounts administered of other compounds were usually the "maximal tolerated doses " defined as follows: (a) for the mouse, as that quantity which, given twice daily (once on Saturday and Sunday) over a period identical with that in the chemotherapeutic test, caused no deaths and allowed the animals to attain a final weight not less than 90% of that of the controls; (b) for the egg, as that quantity which killed no embryos within five days of a single injection into the yolk-sac on the seventh day of incubation. At this point it may be noted that on many occasions we found that the maximal tolerated dose did not necessarily give results as favourable as a rather smaller one. RESULTS

The Relation of the Psittacosis Group (Chlamydiae) to Bacteria and Viruses

“…The multiplication of members of the psittacosis group was inhibited by penicillin (60,124) and n-cycloserine (65,87) , anti biotics that inhibit the multiplication of bacteria by specifically interfering with the synthesis of the cell wall mucopeptide and are without effect on organisms lacking this structure (92) . Agents growing in the presence of penicillin and n-cycloserine formed large irregularly shaped and vacuolated bodies that were probably analogous to bacterial spheroplasts (60,83,87,116,124). n-Alanine competitively reversed the growth inhibition of n-cyclo :;erine in the psittacosis group (65,87), just as it does in bacteria.…”

Lymphogranuloma Inggguinale in the Male in Liverpool, England, 1947-1954

“…We have previously observed (Alergant, 1953) that some patients appear to derive more benefit when two different drugs are exhibited successively, than from any single drug. The demonstration by Hurst, Landquist, Melvin, Peters, Senior, Silk, and Stacey (1953) of the effectiveness of quinoxaline, 1: 4, dioxide and certain of its substituted derivatives against lymphogranuloma inguinale in mice, and of its effectiveness in developing chick embryos, led to a request for a trial of one of the most active of these compounds in human lymphogranuloma. The compound selected was 2 3 dimethyl quinoxaline, 1: 4 dioxide (7218).…”

Synthetic Amoebicides: Part Ii. The Anti‐amoebic Action of Quinoxaline‐1:4‐dioxide and Some Derivatives

“…In addition to its action against amoebiasis, quinoxaline-1 :4-dioxide (and certain related compounds) showed activity against certain of the larger viruses (Hurst et al, 1953) and certain Gramnegative bacteria (Francis, personal communication). The selection of representatives of the series for clinical trial against amoebiasis was thus governed not merely by the action of any particu'ar substance against this particular infection, but rather by the likely overall therapeutic value as judged from laboratory results with the three types of infection-protozoal, viral, and bacterial.…”