The Chemotherapeutic Action of Phenanthridine Compounds

Brownlee, George G.; Goss, M. D.; Goodwin, L. G.; Woodbine, M.; Walls, L. P.

doi:10.1111/j.1476-5381.1950.tb01012.x

Cited by 18 publications

(15 citation statements)

References 14 publications

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“…Early drugs, phenidium and dimidium, were replaced by the compounds which had specific structural characteristics: ethidium, which had an ethyl group substituted for the methyl group on the quaternary nitrogen atom; prothidium, which had the pyrimidyl group of quinapyramine; and isometamidium, which had the aminobenzamidine moiety of diminazene. A variety of other agents have also been investigated (5,45). In this study, isometamidium was a moderately effective therapy for P. carinii pneumonia, but ethidium showed only slight activity.…”

Section: Resultsmentioning

confidence: 96%

Cationic antitrypanosomal and other antimicrobial agents in the therapy of experimental Pneumocystis carinii pneumonia

Walzer

Kim

Foy

et al. 1988

Antimicrob Agents Chemother

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Cationic compounds used in the treatment of veterinary African trypanosomiasis have structural properties similar to those of pentamidine, which has been used in the therapy of human trypanosomiasis and infection with Pneumocystis carinii. We have compared the activities of these drugs and other antimicrobial agents in an immunosuppressed rat model of P. carinii pneumonia. Diminazene, imidocarb, amicarbalide, quinapyramine, and isometamidium showed efficacy greater than or equal to that of pentamidine in the therapy of P. carinji infection, whereas ethidium and methylglyoxal bis(guanylhydrazone) were only slightly active against the organism. Diminazene and pentamidine also exhibited comparable efficacy in P. carinii prophylaxis. aLDifluoromethylornithine (DFMO), a polyamine inhibitor, was ineffective therapy when used alone and did not improve the effectiveness of pentamidine or diminazene. Quinine, quinidine, quinacrine, chlorpromazine, spiramycin, Pentostam, Astiban, dehydroemetine, ampicillin, gentamicin, chloramphenicol, and spectinomycin also showed little or no activity against the organism. Thus, in this model anti-P. carinii activity appears to be a common property of veterinary cationic trypanocidal compounds. This should be important in studying structure-activity relationships and in developing new drugs for the treatment of P. carinii infection in humans.Since the discovery of the acquired immunodeficiency syndrome (AIDS) in 1981 (13, 26), the incidence of Pneumocystis carinji pneumonia in this country has increased dramatically. P. carinii is the most frequent opportunistic pathogen in AIDS, occurring in over 60% of cases (10). The problems of treatment of P. carinii infection in AIDS (e.g., the high rate of relapse and adverse drug reactions) have emphasized the need to develop new forms of therapy (12,14,24,39).Drug development for P. carinii has generally been empiric because of a lack of knowledge about the metabolic pathways of the organism. An alternative approach would be to explore compounds which are related to drugs currently in use for the treatment of P. carinii infection. Pentamidine isethionate, one of the principal anti-P. carinii drugs, is a diamidine originally introduced for human clinical use over 40 years ago for the treatment of African trypanosotniasis (32). We wondered whether other old cationic quaternary ammonium compounds with structural properties similar to those of pentamidine, which have been used in the therapy of veterinary African trypanosomiasis, might have activity against P. carinii. Support for this hypothesis can be found in reports which have shown anti-P. carinji activity with hydroxystilbamidine, a diamidine, and with the structurally unrelated antitrypanosomal drugs a-difluromethylornithine (DFMO) and 9-deazinosine (4, 11, 28).Experimental systems for anti-P. carinii drug evaluation have mainly consisted of immunosuppressed animals. Rats administered corticosteroids for 6 to 8 weeks spontaneously develop P. carinii pneumonia with histologic features identic...

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Section: Resultsmentioning

confidence: 96%

Cationic antitrypanosomal and other antimicrobial agents in the therapy of experimental Pneumocystis carinii pneumonia

Walzer

Kim

Foy

et al. 1988

Antimicrob Agents Chemother

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“…It is this secondary uptake which results in a progressive decrease in the growth rate of organisms. The nature of these binding sites is not yet known, but there is some evidence to suggest that nucleic acid may be involved : the drugs can combine with, and are inactivated by, nucleic acid (Brownlee et al 1950; Seaman & Woodbine, 1953); cytochemical studies (Ormerod, 1951b) suggest that the chromophilic granules which appear in the cytoplasm of drug-treated organisms contain ribonucleic acid, protein and bound drug, and the present work indicates that there is a close relationship between the combination of drug with ' secondary binding sites ' and ribonucleic acid synthesis.…”

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The Mode of Action of Phenanthridines: The Effect of Ethidium Bromide on Cell Division and Nucleic Acid Synthesis

Newton

1957

Journal of General Microbiology

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SUMMARY : The action of 2 : 7-diamino-9-phenyl-10-ethyl phenanthridinium bromide (ethidium bromide) on the parasitic flagellate Strigomonas oncopelti has been studied. The drug is irreversibly active only against growing organisms. Addition of the drug to cultures of organisms in the logarithmic phase of growth did not result in an immediate inhibition of growth but in a progressive decrease in growth rate; at least a doubling in number of organisms always occurred before multiplication finally ceased. During the period of growth in the presence of drug the deoxyribonucleic acid content of the organisms fell to half its normal value whilst the ribonucleic acid remained approximately constant. Conditions have been determined which permit the synthesis of nucleic acids and proteins by washed suspensions of S. oncopelti and the effect of ethidium bromide on these processes has been studied. The drug rapidly inhibits DNA synthesis whereas RNA and protein synthesis continue for a period of 2-3 hr. after the addition of drug. A study has been made of the uptake of W-labelled ethidium bromide by organisms under conditions which will or which will not permit nucleic acid synthesis. The uptake of drug is of two types: (i) an initial rapid uptake which occurs in the absence of nucleic acid synthesis and which does not affect the subsequent growth of organisms ;(ii) an additional uptake by growing organisms which appears to follow the course of RNA synthesis and which results, eventually, in an inhibition of growth.Certain phenanthridinium compounds, originally synthesized by Morgan, Walls, Browning, Gulbranson & Robb (1938), possess trypanocidal properties (Browning, Morgan, Robb & Walls, 1938) and have been used with success against Trypanosoma congolense and T . vivax infections in cattle. Walls (1945) demonstrated that high trypanocidal activity in the phenanthridine series is a property of quaternary salts containing a primary amino group in the 7-and a phenyl group in the 9-position; the activity is much increased by the presence of a second amino group, thus 2 : 7-diamino-9-phenyl-lO-methyl phenanthridinium bromide (dimidium bromide) and the 10-ethyl analogue (ethidium bromide) are particularly effective (Watkins & Woolfe, 1952; Woolfe 1952). R = C,H, ethidium bromide

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“…With the advent of a stilbamidine-fast strain (Fulton and Grant, 1955) which is resistant to a very wide variety of trypanocides (Williamson and Rollo, 1959) and would therefore be expected to show metabolic changes most obviously, a preliminary examination was made of its response to a number of metabolic inhibitors (Williamson, 1953b). Some differences, of a fairly low order, from the normal response were detected in the groups of phosphorase and dehydrogenase inhibitors; the differential action of some of these compounds has now been studied further by examination of the individual enzymatic processes likely to be involved.As pathogenic African trypanosomes appear to rely on dehydrogenase rather than metalloporphyrin oxidase systems, and as some kinds of trypanocidal drug action are known to be affected by oxidation-reduction potential (von Jancs6 and von Jancs6, 1936;Brownlee, Goss, Goodwin, Woodbine and Walls, 1950), this factor has been examined in detail electrometrically and by the use of redox indicators. Marked differences occurred in the reaction of normal and resistant strains, but although oxidation-reduction potential was apparently related to trypanocidal activity it was not obviously connected with the development of resistance.…”

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DRUG RESISTANCE IN TRYPANOSOMES; EFFECTS OF METABOLIC INHIBITORS, pH AND OXIDATION‐REDUCTION POTENTIAL ON NORMAL AND RESISTANT TRYPANOSOMA RHODESIENSE

Williamson

1959

British Journal of Pharmacology and Chemotherapy

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A wide variety of metabolic inhibitors tested in vitro for trypanocidal activity on normal and drug-resistant strains of Trypanosoma rhodesiense showed no relation between acquired drug resistance and changes in specific enzymatic function. Oxidation-reduction potential is an important factor in trypanocidal action but is not obviously related to the development of resistance. The dependence on pH of the trypanocid I action of ionizing drugs against both normal and resistant trypanosomes supports the postulate that the development of resistance involves physical changes in cell structures associated with the uptake of drug.The development of acquired drug resistance in pathogenic trypanosomes is likely to involve at least two changes in the parasite, (i) a modification in the protein surface structure associated with drug uptake, and (ii) a change in metabolism whereby drug-sensitive enzyme reactions are modified, by-passed or eliminated; (i) and (ii) may obviously be related.Attempts to elucidate mechanism (i) by crossresistance analysis and selective interference experiments have been described (Williamson and Rollo, 1959;Williamson, 1959); the ionic basis of this behaviour has now been investigated by measuring the effect of pH on the trypanocidal action in vitro of representative anionic, cationic and feebly ionized drugs on normal and resistant parasites.Little evidence exists for mechanism (ii) although changes in dehydrogenase activity of a melarsen-resistant Trypanosoma rhodesiense have been described (Williamson, 1953a). With the advent of a stilbamidine-fast strain (Fulton and Grant, 1955) which is resistant to a very wide variety of trypanocides (Williamson and Rollo, 1959) and would therefore be expected to show metabolic changes most obviously, a preliminary examination was made of its response to a number of metabolic inhibitors (Williamson, 1953b). Some differences, of a fairly low order, from the normal response were detected in the groups of phosphorase and dehydrogenase inhibitors; the differential action of some of these compounds has now been studied further by examination of the individual enzymatic processes likely to be involved.As pathogenic African trypanosomes appear to rely on dehydrogenase rather than metalloporphyrin oxidase systems, and as some kinds of trypanocidal drug action are known to be affected by oxidation-reduction potential (von Jancs6 and von Jancs6, 1936;Brownlee, Goss, Goodwin, Woodbine and Walls, 1950), this factor has been examined in detail electrometrically and by the use of redox indicators. Marked differences occurred in the reaction of normal and resistant strains, but although oxidation-reduction potential was apparently related to trypanocidal activity it was not obviously connected with the development of resistance. METHODSTrypanosome Strains.-The strains of T. rhodesiense and the tests of trypanocidal activity in vivo were as described (Williamson and Rollo, 1959).Metabolic Inhibitor Experiments.-(i) Twenty-four different "specific" enzyme inhibitors we...

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The Chemotherapeutic Action of Phenanthridine Compounds

Cited by 18 publications

References 14 publications

Cationic antitrypanosomal and other antimicrobial agents in the therapy of experimental Pneumocystis carinii pneumonia

Cationic antitrypanosomal and other antimicrobial agents in the therapy of experimental Pneumocystis carinii pneumonia

The Mode of Action of Phenanthridines: The Effect of Ethidium Bromide on Cell Division and Nucleic Acid Synthesis

DRUG RESISTANCE IN TRYPANOSOMES; EFFECTS OF METABOLIC INHIBITORS, pH AND OXIDATION‐REDUCTION POTENTIAL ON NORMAL AND RESISTANT TRYPANOSOMA RHODESIENSE

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