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

Walzer, Peter D.; Kim, C K; Foy, J; Linke, Michael J.; Cushion, Melanie T.

doi:10.1128/aac.32.6.896

Cited by 48 publications

(43 citation statements)

References 42 publications

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“…The Merrell-Dow, Cincinnati, Ohio, were administered alone and in combination with other agents, but they showed little anti-P. carinii activity; DFMO was tolerated poorly by the rats (40). Similar data were obtained with arsenical derivatives synthesized by Ernst Friedheim, Rockefeller University, and with antimonials.…”

supporting

confidence: 63%

“…The diamidines and related cationic compounds constituted the other major group of highly active anti-P. carinji drugs (40). In contrast to the sulfonamides, these agents demonstrated a hierarchy of anti-P. carinii activity.…”

mentioning

confidence: 99%

“…Most drug testing has been performed in an immunosuppressed rat model of pneumocystosis, which accurately predicts activity against human P. carinii. Compounds which have exhibited anti-P. carinii activity in the rat model include antifolate drugs (alone or in combination) such as dihydrofolate reductase (DHFR) inhibitors, sulfonamides, sulfones, and sulfonylureas (7, 9, 12, 14, 16-20, 23, 24, 27, 35, 39, 42, 43); sulfonamides in combination with other drugs (e.g., macrolides) (13); diamidines and related cationic compounds (8,11,21,34,40); 8-aminoquinolones, alone or in combination with other agents (1, 28); purine nucleosides (la, 32, 36); polyamine inhibitors (3, 4); nitrofurans (38); 3-glucan inhibitors (26, 29, 30); hydroxynaphthoquinones (14); fluoroquinolones (2); iron chelators (4); and immunological agents (antibodies, cytokines) (10,31).Although the rat model has been very valuable, evaluation of anti-P. carinii drugs is time-consuming, expensive, and labor intensive; only a few compounds can be tested in a given experiment. Treatment studies have been performed by different experimental protocols and methods of evaluating drug efficacy; this lack of standardization has prevented the results of one investigator from being compared directly with those of another.…”

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confidence: 99%

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confidence: 99%

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Treatment of experimental pneumocystosis: review of 7 years of experience and development of a new system for classifying antimicrobial drugs

Walzer

Foy

Steele

et al. 1992

Antimicrob Agents Chemother

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Over a 7-year period, we analyzed 261 dose regimens of antimicrobial drugs in the treatment and prevention of Pneumocystis carinii pneumonia in an immunosuppressed rat model. These compounds ranged from drugs in clinical use to newly synthesized agents. Drug efficacy was expressed as the magnitude of the reduction in median P. carinii cyst or nucleus counts on a scale ranging from inactive (<5-fold) to very markedly active (.1,000-fold). The classification system was reproducible and allowed drugs studied at different times to be compared with each other. The system demonstrated a hierarchy of anti-P. carinii activity not only among classes of compounds but also among individual members of a drug class. Sulfonamides, sulfones, and diamidines were the most active agents; some purine nucleosides and nitrofurans also showed promising activity; and most antiparasitic, antifungal, antibacterial, and antiviral drugs were inactive. We conclude that this classification system represents a simple, quantitative method of comparing the activities of antimicrobial drugs against P. carinii. Information gained from this system should be helpful in developing new anti-P. carinii compounds and establishing standard procedures for their evaluation.Over the past decade, there has been a major rise in the number of cases of Pneumocystis carinii pneumonia associated with AIDS. The well-publicized limitations of currently available anti-P. carinii drugs in AIDS patients have emphasized the need for new therapeutic approaches (37). Most drug testing has been performed in an immunosuppressed rat model of pneumocystosis, which accurately predicts activity against human P. carinii. Compounds which have exhibited anti-P. carinii activity in the rat model include antifolate drugs (alone or in combination) such as dihydrofolate reductase (DHFR) inhibitors, sulfonamides, sulfones, and sulfonylureas (7, 9, 12, 14, 16-20, 23, 24, 27, 35, 39, 42, 43); sulfonamides in combination with other drugs (e.g., macrolides) (13); diamidines and related cationic compounds (8,11,21,34,40); 8-aminoquinolones, alone or in combination with other agents (1, 28); purine nucleosides (la, 32, 36); polyamine inhibitors (3, 4); nitrofurans (38); 3-glucan inhibitors (26, 29, 30); hydroxynaphthoquinones (14); fluoroquinolones (2); iron chelators (4); and immunological agents (antibodies, cytokines) (10,31).Although the rat model has been very valuable, evaluation of anti-P. carinii drugs is time-consuming, expensive, and labor intensive; only a few compounds can be tested in a given experiment. Treatment studies have been performed by different experimental protocols and methods of evaluating drug efficacy; this lack of standardization has prevented the results of one investigator from being compared directly with those of another. Little attention has also been devoted to quantitating the reduction in organism burden which can be achieved with different doses of anti-P. carinii drugs. In addition, there have been few published sources of information of the compound...

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supporting

confidence: 63%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Treatment of experimental pneumocystosis: review of 7 years of experience and development of a new system for classifying antimicrobial drugs

Walzer

Foy

Steele

et al. 1992

Antimicrob Agents Chemother

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“…10,13,14 Pentamidine was used as positive control and saline as negative control. Table 1 shows the results of these studies.…”

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confidence: 99%

Pentamidine congeners 1: Synthesis of Cis- and Trans-butamidine analogues as anti-Pneumocystis carinii pneumonia agents.

Donkor

Jones

Tidwell

1993

Bioorganic & Medicinal Chemistry Letters

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Butamidine analogues possessing unsaturation in the ether bridge between the bisamidinophenyl or bisimidazolinophenyl functionalities have been synthesized as semirigid congeners of pentamidine. These compounds demonstrated good anti-P. carinii pueumonia activity in a rat model of the disease.The incidence of Pneumocystis carinii pneumonia (PCP) has increased dramatically in the United States with the advent of acquired immunodeficiency syndrome (AIDS). Over 70% of AIDS patients develop PCP1. This opportunistic infection is the common cause of mortality of AIDS patients. The first line of therapy of PCP is either trimethoprimsulfamethoxazole or pentamidine isethionate. These drugs precipitate serious adverse effects2 , 3 hence there is the need for new less toxic agents for treating PCP (eg. atovaquone, a hydroxy-1,4-naphthoquinone with limited side effects has recently been approved for treatment of mild to moderate PCP in AIDS patients).At the molecular level pentamidine is known to interact with a number of macromolecules however the exact mechanism by which the drug achieves its anti-PCP activity is yet to be established. [4][5][6][7][8] This set-back coupled with the fact that the metabolic activity of P. carinii is poorly understood have limited anti-P. carinii drug discovery to an empirical approach. 9 Structure-activity relationship studies demonstrated that ether bridge contracted homologues of pentamidine (1), such as butamidine (2), and propamidine (3) are as active as pentamidine in treating experimental PCP in a rat model of the disease. 10 Pentamidine and its analogues such as butamidine are flexible molecules hence they can assume a variety of interconvertible conformations. The significance of reducing conformational flexibility of these compounds on biological activity is unknown. We have The following scoring criteria were used to evaluate the compounds for toxicity in vivo: A score of 0 was assigned if no local, clinical, or histologic toxicity was observed; 1+, if all aminals survived with no observable distress, but some local toxicity; 2+, if most animals survived with severe distress and marked local toxicity as well as some clinical toxicity and histopathology; 3+, if an acute toxic effect occurred after a single dose and/or a sharp decrease in animals' health following multiple doses and resulted in loss of less than 50% of the animals; 4+, if more than 50% of the animals died at the test dose.Synthesis of 4 11 commenced with a Williamson ether synthesis between 4-cyanophenol and cis -1,4-dichloro-2-butene to give dicyano 10. Subjection of 10 to Pinner reaction 12 followed by refluxing the resulting imidate 11 in methanolic ammonia gave bisamidino derivative 4. Treatment of imidate 11 with a five fold excess of ethylenediamine in absolute methanol at reflux gave bisimidazolino derivative 6. Trans isomers 5 and 7 were synthesized following the above procedures but using trans -1,4-dichloro-2-butene in place of the cis isomer.Compounds 4-7 were evaluated for anti-PCP activity as we...

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Synthesis of pentamidine labelled with tritium and carbon‐14

Hesk

Jones

Lockley³

et al. 1990

Labelled Comp Radiopharmac

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SUMMARYTritium labelled pentamidine has specific activity of 90 mci mmol-9 using a one-step exchange reaction between the unlabelled drug and tritiated water. The labelling utilised a homogeneous rhodium trichloride catalyst and yielded pentamidine regiospecifically labelled in the positions ortho to the amidine groups. Carbon-14 labelled pentamidine was prepared via a seven-step procedure in which the isotope was introduced via a nu eophilic substitution of 4-bromophenol with copper(1) ["Clcyanide.een prepared with a

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

Cited by 48 publications

References 42 publications

Treatment of experimental pneumocystosis: review of 7 years of experience and development of a new system for classifying antimicrobial drugs

Treatment of experimental pneumocystosis: review of 7 years of experience and development of a new system for classifying antimicrobial drugs

Pentamidine congeners 1: Synthesis of Cis- and Trans-butamidine analogues as anti-Pneumocystis carinii pneumonia agents.

Synthesis of pentamidine labelled with tritium and carbon‐14

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