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

Aviles, P.; Aliouat, El Moukhtar; Martı́nez, Antonio; Dei‐Cas, Eduardo; Herreros, Esperanza; Dujardin, L.; Gargallo-Viola, Domingo

doi:10.1128/aac.44.5.1284-1290.2000

Cited by 33 publications

(42 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1 and 2). It is noteworthy that current drug testing and therapeutic protocols against PCP are performed using P. carinii strains of rodent origin (4,7). For these reasons, the host specificity of P. carinii f. sp.…”

Section: Discussionmentioning

confidence: 99%

Phylogeny of Pneumocystis carinii from 18 Primate Species Confirms Host Specificity and Suggests Coevolution

Demanche

Berthelemy

Petit³

et al. 2001

J Clin Microbiol

Self Cite

114

104

View full text Add to dashboard Cite

Primates are regularly infected by fungal organisms identified as Pneumocystis carinii. They constitute a valuable population for the confirmation of P. carinii host specificity. In this study, the presence of P. carinii was assessed by direct examination and nested PCR at mitochondrial large subunit (mtLSU) rRNA and dihydropteroate synthetase (DHPS) genes in 98 lung tissue samples from captive or wild nonhuman primates. Fifty-nine air samples corresponding to the environment of different primate species in zoological parks were also examined. Cystic forms of P. carinii were detected in smears from 7 lung tissue samples corresponding to 5 New World primate species. Amplifications at the mtLSU rRNA gene were positive for 29 lung tissue samples representing 18 different primate species or subspecies and 2 air samples corresponding to the environment of two simian colonies. Amplifications at the DHPS gene were positive for 8 lung tissue samples representing 6 different primate species. Direct sequencing of nested PCR products demonstrated that a specific mtLSU rRNA and DHPS sequence could be attributed to each primate species or subspecies. No nonhuman primate harbored the human type of P. carinii (P. carinii f. sp. hominis). Genetic divergence in primate-derived P. carinii organisms varied in terms of the phylogenetic divergence existing among the corresponding host species, suggesting coevolution.

show abstract

Section: Discussionmentioning

confidence: 99%

Phylogeny of Pneumocystis carinii from 18 Primate Species Confirms Host Specificity and Suggests Coevolution

Demanche

Berthelemy

Petit³

et al. 2001

J Clin Microbiol

Self Cite

114

104

View full text Add to dashboard Cite

show abstract

“…Parasites were separated from the lung tissue as described previously (Aviles et al, 2000), with some modifications. Briefly, the lungs of infected animals were removed aseptically and cut into small pieces in sterile Dulbecco's modified Eagle's medium (DMEM).…”

Section: Methodsmentioning

confidence: 99%

Molecular typing of Pneumocystis jirovecii found in formalin-fixed paraffin-embedded lung tissue sections from sudden infant death victims

et al. 2004

View full text Add to dashboard Cite

Previous studies have provided histological evidence of an association between primary Pneumocystis infection and sudden infant death syndrome (SIDS). The aim of this work was to determine the species of clustered Pneumocystis organisms found in formalin-fixed paraffin-embedded (FFPE) lung tissue sections from Chilean sudden infant death (SID) victims. This approach needed first to optimize a DNA extraction method from such histological sections. For that purpose, the QIAamp DNA Isolation from Paraffin-Embedded Tissue method (Qiagen) was first tested on FFPE lung tissue sections of immunosuppressed Wistar rats inoculated with rat-derived Pneumocystis. Successful DNA extraction was assessed by the amplification of a 346 bp fragment of the mitochondrial large subunit rRNA gene of the Pneumocystis species using a previously described PCR assay. PCR products were analysed by direct sequencing and sequences corresponding to Pneumocystis carinii were found in all the samples. This method was then applied to FFPE lung tissue sections from Chilean SID victims. Pneumocystis jirovecii was successfully identified in the three tested samples. In conclusion, an efficient protocol for isolating PCR-ready DNA from FFPE lung tissue sections was developed. It established that the Pneumocystis species found in the lungs of Chilean SID victims was P. jirovecii.

show abstract

“…In recent years, several sordarin derivatives with a broad spectrum of activity and marked potencies in vivo, such as GM 193633, GM 211676, GM 222712, and GM 237354, have been synthesized (11). These derivatives have remarkable in vitro activity against key fungal pathogens, such as Candida species (including strains with decreased susceptibility to fluconazole), Cryptococcus neoformans, and Pneumocystis carinii (2,14), as well as potent fungicidal activity against important dimorphic endemic pathogens, such as Histoplasma capsulatum, Paracoccidioides brasiliensis, Blastomyces dermatitidis, and Coccidioides immitis (D. A. Stevens, Abstr. 37th Intersci.…”

mentioning

confidence: 99%

Antifungal Activities and Cytotoxicity Studies of Six New Azasordarins

Herreros

Almela

Lozano

et al. 2001

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

GW 471552, GW 471558, GW 479821, GW 515716, GW 570009, and GW 587270 are members of a new family of sordarin derivatives called azasordarins. The in vitro activities of these compounds were evaluated against clinical isolates of yeasts, including Candida albicans, Candida non-albicans, and Cryptococcus neoformans strains. Activities against Pneumocystis carinii, Aspergillus spp., less common molds, and dermatophytes were also investigated. Azasordarin derivatives displayed significant activities against the most clinically important Candida species, with the exception of C. krusei. Against C. albicans, including fluconazole-resistant strains, MICs at which 90% of the isolates tested are inhibited (MIC 90 s) were 0.002 g/ml with GW 479821, 0.015 g/ml with GW 515716 and GW 587270, and 0.06 g/ml with GW 471552, GW 471558, and GW 570009. The MIC 90 s of GW 471552, GW 471558, GW 479821, GW 515716, GW 570009, and GW 587270 were 0.12, 0.12, 0.03, 0.06, 0.12, and 0.06 g/ml, respectively, against C. tropicalis and 4, 0.25, 0.06, 0.25, 0.5, and 0.5 g/ml, respectively, against C. glabrata. In addition, some azasordarin derivatives (GW 479821, GW 515716, GW 570009, and GW 58720) were active against C. parapsilosis, with MIC 90 s of 2, 4, 4, and 1 g/ml, respectively. The compounds were extremely potent against P. carinii, showing 50% inhibitory concentrations of <0.001 g/ml. However Cryptococcus neoformans was resistant to all compounds tested (MIC > 16 g/ml). These azasordarin derivatives also showed significant activity against emerging fungal pathogens, which affect immunocompromised patients, such as Rhizopus arrhizus, Blastoschizomyces capitatus, and Geotrichum clavatum. Against these organisms, the MICs of GW 587270 ranged from 0.12 to 1 g/ml, those of GW 479821 and GW 515716 ranged from 0.12 to 2 g/ml, and those of GW 570009 ranged from 0.12 to 4 g/ml. Against Fusarium oxysporum, Scedosporium apiospermum, Absidia corymbifera, Cunninghamella bertholletiae, and dermatophytes, GW 587270 was the most active compound, with MICs ranging from 4 to 16 g/ml. Against Aspergillus spp., the MICs of the compounds tested were higher than 16 g/ml. The in vitro selectivity of azasordarins was investigated by cytotoxicity studies performed with five cell lines and primary hepatocytes. Concentrations of compound required to achieve 50% inhibition of the parameter considered (Tox 50 s) of GW 570009, GW 587270, GW 479281, and GW 515716 in the cell lines ranged from 60 to 96, 49 to 62, 24 to 36, and 16 to 38 g/ml, respectively. The cytotoxicity values of GW 471552 and GW 471558 were >100 g/ml for all cell lines tested. Tox 50 s on hepatocytes were in the following order: GW 471558 > GW 471552 > GW 570009 > GW 587270 > GW 515716 > GW 479821, with values ranging from higher than 100 g/ml to 23 g/ml. The cytotoxicity results obtained with fully metabolizing rat hepatocytes were in total agreement with those obtained with cell lines. In summary, the in vitro activities against important pathogenic fungi and the selectivity demonstrated in mam...

show abstract

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

Cited by 33 publications

References 19 publications

Phylogeny of Pneumocystis carinii from 18 Primate Species Confirms Host Specificity and Suggests Coevolution

Phylogeny of Pneumocystis carinii from 18 Primate Species Confirms Host Specificity and Suggests Coevolution

Molecular typing of Pneumocystis jirovecii found in formalin-fixed paraffin-embedded lung tissue sections from sudden infant death victims

Antifungal Activities and Cytotoxicity Studies of Six New Azasordarins

Contact Info

Product

Resources

About