Pentamidine aerosol in prophylaxis and treatment of murine Pneumocystis carinii pneumonia

Girard, Pierre‐Marie; Brun-Pascaud, Monique; Farinotti, Robert; Tamisier, L.; Kernbaum, S

doi:10.1128/aac.31.7.978

Cited by 45 publications

(11 citation statements)

References 13 publications

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“…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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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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confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…The following classes of drugs have shown anti-Pneumocystis activity in rats and/or mice: antifolate compounds, including inhibitors of dihydropteroate synthase (sulfonamides, sulfones, and sulfonylureas) alone or in combination with inhibitors of dihydrofolate reductase (DHFR) [5,6,14,92,[111][112][113][114][115][116][117][118]; sulfonamides combined with macrolides [119][120][121]; diamidines and related cationionic compounds [44,72,[122][123][124][125][126][127][128][129][130][131][132][133][134][135][136][137][138]; 8aminoquinolones alone or combined with clindamycin [139][140][141][142]; purine nucleoside analogues [117,143]; polyamine inhibitors [144][145][146][147][148]...…”

Section: Active Drugsmentioning

confidence: 99%

Preclinical Drug Discovery for New Anti-Pneumocystis Compounds

Cushion

Walzer²

2009

CMC

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Pneumocystis remains an important cause of fatal pneumonia (PCP) in HIV patients and other immunocompromised hosts. Preclinical drug discovery for agents active against PCP has been hindered in large part by the lack of a continuous in vitro growth system. Since approval in 1978, the combination of the folic acid synthesis inhibitor combination trimethoprim-sulfamethoxazole has been the primary agent for prophylaxis and therapy. Short term in vitro assays using cell monolayer-based and cell free systems in combination with in vivo studies in rodent models of infection have been the mainstay of candidate screening methods. These systems and their applications are reviewed here. Most strategies have focused on testing compounds already in clinical use, such as dapsone or atovaquone, for activity against Pneumocystis alone or in combination, and as parent compounds for chemical derivation, such as pentamidine and its analogues. Other successes from the bench include primaquine-clindamycin for moderate pneumonia and the family of Beta-glucan synthase inhibitors, which hold promise for clinical use against PCP. Despite the significant obstacles for drug discovery, progress in identifying novel agents has been made with current systems and the promise of future new targets is expected with the annotation of the Pneumocystis genome.

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“…As aerosolised pentamidine was reported to be efficient in both prophylaxis and the treatment of pneumocystosis in animal models : Girard et al 1987. clinical trials were designed to evaluate the effectiveness of aerosol therapy (Cork· cry et a1 : Kovacs & Masur 1988.…”

Section: Pentamidinementioning

confidence: 99%

The Effect of Respiratory Disorders on Clinical Pharmacokinetic Variables

Taburet

Tollier²,

Richard³

1990

Clinical Pharmacokinetics

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Respiratory disorders induce several pathophysiological changes involving gas exchange and acid-base balance, regional haemodynamics, and alterations of the alveolocapillary membrane. The consequences for the absorption, distribution and elimination of drugs are evaluated. Drug absorption after inhalation is not significantly impaired in patients. With drugs administered by this route, an average of 10% of the dose reaches the lungs. It is not completely clear whether changes in pulmonary endothelium in respiratory failure enhance lung absorption. The effects of changes in blood pH on plasma protein binding and volume of distribution are discussed, but relevant data are not available to explain the distribution changes observed in acutely ill patients. Lung diffusion of some antimicrobial agents is enhanced in patients with pulmonary infections. Decreased cardiac output and hepatic blood flow in patients under mechanical ventilation cause an increase in the plasma concentration of drugs with a high hepatic extraction ratio, such as lidocaine (lignocaine). On a theoretical basis, hypoxia should lead to decreased biotransformation of drugs with a low hepatic extraction ratio, but in vivo data with phenazone (antipyrine) or theophylline are conflicting. The effects of disease on the lung clearance of drugs are discussed but clinically relevant data are lacking. The pharmacokinetics of drugs in patients with asthma or chronic obstructive pulmonary disease are reviewed. Stable asthma and chronic obstructive pulmonary disease do not appear to affect the disposition of theophylline or beta 2-agonists such as salbutamol (albuterol) or terbutaline. Important variations in theophylline pharmacokinetics have been reported in critically ill patients, the causes of which are more likely to be linked to the poor condition of the patients than to a direct effect of hypoxia or hypercapnia. Little is known regarding the pharmacokinetics of cromoglycate, ipratropium, corticoids or antimicrobial agents in pulmonary disease. In patients under mechanical ventilation, the half-life of midazolam, a new benzodiazepine used as a sedative, has been found to be lengthened but the underlying mechanism is not well understood. Pulmonary absorption of pentamidine was found to be increased in patients under mechanical ventilation. Pharmacokinetic impairment does occur in patients with severe pulmonary disease but more work is needed to understand the exact mechanisms and to propose proper dosage regimens.

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Pentamidine aerosol in prophylaxis and treatment of murine Pneumocystis carinii pneumonia

Cited by 45 publications

References 13 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

Preclinical Drug Discovery for New Anti-Pneumocystis Compounds

The Effect of Respiratory Disorders on Clinical Pharmacokinetic Variables

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