In Vitro Studies of <i>Pneumocystis carinii</i>

Cushion, Melanie T.

doi:10.1111/j.1550-7408.1989.tb02691.x

Cited by 47 publications

(23 citation statements)

References 31 publications

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“…Several in vitro tests for evaluating compound activity against P. carinii have been described using axenic cultures or coculture with feeder cells (8,10,14). However, no universally accepted standard method is presently available for the in vitro evaluation of anti-P. carinii molecules (10). The anti-Pneumocystis activity of any given antimicrobial could be evaluated in terms of its intrinsic activity (in vitro) and serum time profile (in vivo) (12).…”

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confidence: 99%

“…The anti-Pneumocystis activity of any given antimicrobial could be evaluated in terms of its intrinsic activity (in vitro) and serum time profile (in vivo) (12). However, the results obtained with different in vitro assays (8,10) yield limited information on the intrinsic activity of anti-Pneumocystis compounds. Furthermore, comparisons between product activities and extrapolation to in vivo activity remain unreliable.…”

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In Vitro Pharmacodynamic Parameters of Sordarin Derivatives in Comparison with Those of Marketed Compounds against Pneumocystis carinii Isolated from Rats

Aviles¹,

Aliouat

Martı́nez³

et al. 2000

Antimicrob Agents Chemother

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Pneumocystis carinii pneumonia remains one of the most serious complications of immunosuppressed patients. In this study, the in vitro pharmacodynamic parameters of four sordarin derivatives (GM 191519, GM 237354, GM 193663, and GM 219771) have been evaluated by a new quantitative approach and compared with the commercially available drugs pentamidine, atovaquone, and trimethoprim-sulfamethoxazole (TMP-SMX). In vitro activities and in vivo therapeutic efficacies of sordarin derivatives against P. carinii were also evaluated. In vitro activity was determined by the broth microdilution technique, comparing the total number of microorganisms in treated and drug-free cultures by using Giemsa staining. The in vitro maximum effect (E max ), the drug concentrations to reach 50% of E max (EC 50 ), and the slope of the dose-response curve were then estimated by the Hill equation (

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In Vitro Pharmacodynamic Parameters of Sordarin Derivatives in Comparison with Those of Marketed Compounds against Pneumocystis carinii Isolated from Rats

Aviles¹,

Aliouat

Martı́nez³

et al. 2000

Antimicrob Agents Chemother

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“…While best known for this pathogenic activity, the following features of P. carinii suggest that it may be an obligate parasite of the immunocompetent rat. P. carinii organisms are difficult to find in the environment (Wakefield, 1994), do not grow well in culture (Cushion & Walzer, 1984a;Cushion, 1989;Cushion & Ebbets, 1990) and appear to be able to colonize immunocompetent rats, but are not able to proliferate in other host species, including mice, even when the host lacks immune function (Gigliotti et al, 1993;Sidman & Roths, 1994;Wakefield et al, 1998;Mazars & Dei-Cas, 1998; Demanche et al, 2001).…”

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Expression and complexity of the PRT1 multigene family of Pneumocystis carinii

et al. 2004

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Pneumocystis carinii has a multigene family, PRT1, that encodes proteins with homology to KEX2-like proteases. PRT1 genes cluster with MSG genes near the telomeres and, like MSG, PRT1 proteins seem to be surface-expressed. The clustering of PRT1 and MSG genes suggested that expression of the two multigene families might be coordinated. Studying gene expression in P. carinii has been hampered by the lack of a culture system, and by lack of clonality in P. carinii populations in naturally infected rats, the host of this fungus. Heterogeneity can be reduced, however, by low-dose intratracheal inoculation, which can produce P. carinii populations dominated by organisms derived from a single progenitor. To study PRT1 expression, nude rats were inoculated with approximately 10 P. carinii each. The clonality of the P. carinii populations from inoculated rats was assessed by analysis of the UCS locus, a site in the genome that is known to be very heterogeneous in naturally infected rats, but nearly homogeneous in rats infected by low-dose intratracheal inoculation. Each of the populations had the same MSG gene at the UCS locus in at least 80 % of the organisms. To investigate PRT1 gene expression, RNA was amplified using primers that amplify numerous PRT1 genes. Seventy-four cloned cDNAs were sequenced, including at least 12 clones from each population of P. carinii. Many differently expressed PRT1 sequences were identified in each population, and a total of 45 different sequences were detected. However, the same PRT1 sequence was present in 15 of 74 plasmids and was found in 3 of the 5 P. carinii populations, suggesting that some PRT1 genes may be either more commonly expressed or expressed at a higher level. These data show that many members of the PRT1 gene family can be expressed in populations of P. carinii derived from few progenitors and suggest that the regulation of this family is different from that governing expression of the MSG gene family.

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“…Others have reported increases in the number of trophozoites for as long as 10 days, accompanied by a 2-to 10-fold increase in cell number (5). Short-term cultures have also been used to demonstrate the antipneumocystis activities of trimetho- Artemisinin and its derivatives represent a promising new class of antiparasitic drugs which act as free-radical generators (10).…”

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Susceptibility of Pneumocystis carinii to artemisinin in vitro

Merali

Meshnick

1991

Antimicrob Agents Chemother

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The susceptibility of Pneumocystis carinii to artemisinin (qinghaosu) was determined in short-term primary culture. In untreated cultures, trophozoites increased an average of fivefold over 4 days. Inhibition of parasite growth in cultures treated with artemisinin at concentrations as low as 0.5 ,uM was seen. In contrast, artemisinin concentrations up to 100 ,uM had no effect on feeder layer cells. (2,4,9,11,15). In addition, artemisinin and artemether have recently been shown to be active against other parasitic organisms, including Toxoplasma gondii and Schistosoma mansoni (12, 13). We report here that artemisinin is also active against P. carinii in vitro.Growth, isolation, and cultivation of organisms. Male Sprague-Dawley rats (150 to 200 g; Taconic Farms, Germantown, N.Y.) were fed ad libitum and administered tetracycline in their drinking water (1 g/liter). Subcutaneous injections of cortisone acetate (25 mg) were given twice per week. After 4 to 6 weeks of injection, those rats which showed signs of sluggishness, rapid breathing, weight loss, and hair loss were utilized in this study.The rats were sacrificed and their lungs were then quickly removed and kept at 4°C. Impression smears were made from the lungs and stained with toluidine blue (7) (Fig. 1). The inhibitory effect of pentamidine was not seen on day 1 of culture (<26%) but was evident on days 2 and 3 of culture, when inhibitions by 63 and 79%, respectively, were seen. In contrast, the effect of 100 ,uM artemisinin was evident after 1 day (Fig. 2), with growth inhibited by 63, 76, and 78% on days 1, 2, and 3, respectively.Artemisinin at concentrations of 50 and 5 ,uM also completely inhibited the growth of P. carinii for 4 days, without affecting the feeder layer cells (Fig. 3). No effect at an artemisinin concentration of 0.1 ,uM was observed, although artemisinin at 0.5 ,uM had an intermediate effect.As controls, feeder layer cells were incubated for 4 days in the presence of 100, 50, 10, and 1 ,uM artemisinin but in the absence of parasites, under conditions identical to those used for parasite culture. No effect was observable by phase-contrast microscopy. Feeder layer cells from the 100 ,uM artemisinin control were also dislodged from the wells by trypsinization and found viable by trypan blue exclusion (>95%). Furthermore, 0.5% ethanol had no effect either on the feeder layer cells or on parasite growth over 4 days (data not shown).

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In Vitro Studies of Pneumocystis carinii

Cited by 47 publications

References 31 publications

In Vitro Pharmacodynamic Parameters of Sordarin Derivatives in Comparison with Those of Marketed Compounds against Pneumocystis carinii Isolated from Rats

In Vitro Pharmacodynamic Parameters of Sordarin Derivatives in Comparison with Those of Marketed Compounds against Pneumocystis carinii Isolated from Rats

Expression and complexity of the PRT1 multigene family of Pneumocystis carinii

Susceptibility of Pneumocystis carinii to artemisinin in vitro

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