pafuramidine and Pneumonia--Pneumocystis

Pneumocystis jiroveci pneumonia remains one of the major worldwide contributors to the morbidity and mortality of those with HIV infection. The mainstay of therapy for treatment is trimethoprim-sulfamethoxazole (TMP-SMX); however TMP-SMX may be associated with significant side effects and intolerability. In addition, TMP-SMX has a moderate pill burden with three- to four-times daily dosing schedule. Patients unable to tolerate TMP-SMX are confronted with either parenteral therapy or other oral agents that may be less efficacious or are associated with potential serious adverse reactions. Pafuramidine (DB289) is an orally bioavailable prodrug of furamidine (DB75), an investigational diamidine that is less toxic than previous diamidines such as pentamidine. To date, human trials suggest that pafuramidine is well tolerated overall and has clinical activity against Pneumocystis pneumonia. In this article, we review the available data for the use of pafuramidine in Pneumocystis pneumonia.

Topics: Animals; Antifungal Agents; Benzamidines; Clinical Trials as Topic; HIV; HIV Infections; Humans; Pneumocystis carinii; Pneumonia, Pneumocystis

The synthesis and evaluation of 2,5-bis[4-(N-ethoxycarbonyl-N'-isopropyl)amidinophenyl]furan, 2,5-bis[4-(N-2,2,2-trichloroethoxycarbonyl-N'-isopropyl)amidinophenyl]furan and 2,5-bis[4-(N-cyclopentyl-N'-2,2,2-trichloroethoxycarbonyl)amidinophenyl]furan as prodrugs of bis-N-alkylamidines are reported. The results show that the bis-2,2,2-trichloroethyl carbamates function effectively in a rat model for Pneumocystis pneumonia.

Topics: Animals; Benzamidines; Carbamates; Cysts; Disease Models, Animal; Furans; Lung; Pneumocystis carinii; Pneumonia, Pneumocystis; Prodrugs; Rats

DB75 (2,5-bis(4-amidinophenyl)furan) is a promising antimicrobial agent against African trypanosomiasis and Pneumocystis carinii pneumonia. However, it suffers from poor oral activity in rodent models for both infections. In contrast, a novel prodrug of DB75, 2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime (DB289), has excellent oral activity. DB289 is currently undergoing clinical investigation as a candidate drug to treat primary stage African trypanosomiasis and Pneumocystis carinii pneumonia. In this study, metabolites of DB289 formed after incubation with freshly isolated rat hepatocytes were characterized using liquid chromatography/ion trap mass spectrometry. Administration of DB289 and octadeuterated DB289 in a 1 : 1 mixture greatly facilitated metabolite identification by providing isotope patterns with twin ions separated by 8 m/z units in the ratio 1 : 1, in the extracted ion chromatograms of molecular ions and in the product ion mass spectra of metabolites. Ten metabolites were identified. Series of O-demethylations and N-dehydroxylations led to the metabolic activation of DB289 to DB75 with the production of four intermediate phase I metabolites. Phase II glucuronidation and sulfation led to the formation of four glucuronide and one sulfate metabolites.

Topics: Administration, Oral; Animals; Benzamidines; Chromatography, High Pressure Liquid; Hepatocytes; Mass Spectrometry; Molecular Structure; Pneumonia, Pneumocystis; Prodrugs; Rats; Trypanosomiasis, African

Topics: Administration, Oral; AIDS-Related Opportunistic Infections; Antifungal Agents; Benzamidines; Clinical Trials as Topic; Drug Administration Schedule; Humans; Pilot Projects; Pneumonia, Pneumocystis