Atovaquone suspension compared with aerosolized pentamidine for prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected subjects intolerant of trimethoprim or sulfonamides.
Atovaquone suspensions (750 mg and 1500 mg once a day) were compared with aerosolized pentamidine (300 mg once a month) for the prevention of Pneumocystis carinii pneumonia (PCP) in subjects with human immunodeficiency virus (HIV) infection who were intolerant to trimethoprim or sulfonamides (or both). Median time using the assigned therapy was 6.6 months, and the median follow-up was 11.3 months. Intent-to-treat analyses (n=549) showed no statistically significant differences among subjects with regard to the incidence of PCP (26%, 22%, and 17%, respectively) or mortality (20%, 13%, and 18%, respectively). The incidence of treatment-limiting adverse events with atovaquone was significantly higher (P<.01). There was, however, no significant difference in the time using therapy. Incidences of PCP and death were higher in subjects receiving 750 mg of atovaquone than in subjects receiving 1500 mg. Atovaquone suspension at 1500 mg once a day has an efficacy similar to that of aerosolized pentamidine for prevention of PCP in HIV-infected subjects and is a safe, effective alternative in those who are intolerant to trimethoprim or sulfonamides. (+info)
Exposure of health care workers to pentamidine isethionate.
Pentamidine isethionate is currently used for the prophylaxis and treatment of Pneumocystis carinii pneumonia. Its use has been associated with a number of symptoms in staff administering treatment, and there are some additional concerns about possible adverse health effects of long term exposure. The aim of this study was to quantify exposure of health care staff administering nebulized pentamidine to patients. Personal breathing zone and static air samples at the height of the patient's head were collected during the nebulization of pentamidine to nine sequential outpatients attending a haemophilia unit. These were analysed using a standard method allowing the exposure of staff to be estimated. The duration of treatment varied between 15 and 60 min. Personal breathing zone samples showed exposure to be between 2 and 100 micrograms/m3. Static samples showed the concentration of pentamidine in the room varied from 15 to 2,100 micrograms/m3. While these exposures were relatively low, they were higher than some other studies have reported, and may pose some risk of adverse effects to staff. Some simple measures could reduce staff exposure. (+info)
Adenosine transporters in bloodstream forms of Trypanosoma brucei brucei: substrate recognition motifs and affinity for trypanocidal drugs.
Adenosine influx by Trypanosoma brucei brucei P1 and P2 transporters was kinetically characterized. The P1 transporter displayed a higher affinity and capacity for adenosine (K(m) = 0.38 +/- 0.10 microM, V(max) = 2.8 +/- 0.4 pmol x 10(7) cells(-1) x s(-1)) than the P2 transporter (K(m) = 0.92 +/- 0.06 microM, V(max) = 1.12 +/- 0.08 4 pmol x 10(7) cells(-1) x s(-1)). To formulate a structure-activity relationship for the interaction of adenosine with the transporters, a series of analogs were evaluated as potential inhibitors of adenosine transport, and the K(i) values were converted to binding energy. The P1 transporter was found to be selective inhibited by purine nucleosides (K(i) approximately 1 microM for inosine and guanosine), but nucleobases and pyrimidines had little effect on P1-mediated transport. The P1 transporter appears to form hydrogen bonds with N3 and N7 of the purine ring as well as with the 3' and 5' hydroxyl groups of the ribose moiety, with apparent bond energies of 12.8 to 15.8 kJ/mol. The P2 transporter, in contrast, had high-affinity (K(i) = 0.2-4 microM) for 6-aminopurines, including adenine, 2'-deoxyadenosine, and tubercidin, but not for any oxopurines. The main interaction of adenosine with the P2 transporter is suggested to be via hydrogen bonds to N1 and the 6-amino group. Additional pi-pi interactions of the purine ring and electrostatic interactions with N9 may also be important. The predicted substrate recognition motif of P2, but not of P1, corresponds to parts of the melaminophenylarsenical and diamidine molecules, confirming the potent inhibition observed with these trypanocides for P2-mediated adenosine transport (K(i) = 0.4-2.4 microM). (+info)
Treatment of two patients with diffuse cutaneous leishmaniasis caused by Leishmania mexicana modifies the immunohistological profile but not the disease outcome.
Two patients with diffuse cutaneous leishmaniasis caused by Leishmania mexicana were treated with two leishmanicidal drugs (pentamidine and allopurinol) combined with recombinant interferon-gamma restoring Th-1 favouring conditions in the patients. Parasites decreased dramatically in the lesions and macrophages diminished concomitantly, while IL-12-producing Langerhans cells and interferon-gamma- producing NK and CD8 + lymphocytes increased in a reciprocal manner. The CD4+/CD8 + ratio in the peripheral blood normalized. During exogenous administration of interferon-gamma the parasites' capacity to inhibit the oxidative burst of the patients' monocytes was abolished. Even though Th-1-favouring conditions were restored, both patients relapsed two months after therapy was discontinued. We conclude that the tendency to develop a disease-promoting Th-2 response in DCL patients is unaffected by, and independent of, parasite numbers. Even though intensive treatment in DCL patients induced Th-1 disease restricting conditions, the disease-promoting immunomodulation of few persistent Leishmania sufficed to revert the immune response. (+info)
Effects of atovaquone and diospyrin-based drugs on the cellular ATP of Pneumocystis carinii f. sp. carinii.
Atovaquone (also called Mepron, or 566C80) is a napthoquinone used for the treatment of infections caused by pathogens such as Plasmodium spp. and Pneumocystis carinii. The mechanism of action against the malarial parasite is the inhibition of dihydroorotate dehydrogenase (DHOD), a consequence of blocking electron transport by the drug. As an analog of ubiquinone (coenzyme Q [CoQ]), atovaquone irreversibly binds to the mitochondrial cytochrome bc(1) complex; thus, electrons are not able to pass from dehydrogenase enzymes via CoQ to cytochrome c. Since DHOD is a critical enzyme in pyrimidine biosynthesis, and because the parasite cannot scavenge host pyrimidines, the drug is lethal to the organism. Oxygen consumption in P. carinii is inhibited by the drug; thus, electron transport has also been identified as the drug target in P. carinii. However, unlike Plasmodium DHOD, P. carinii DHOD is inhibited only at high atovaquone concentrations, suggesting that the organism may salvage host pyrimidines and that atovaquone exerts its primary effects on ATP biosynthesis. In the present study, the effect of atovaquone on ATP levels in P. carinii was measured directly from 1 to 6 h and then after 24, 48, and 72 h of exposure. The average 50% inhibitory concentration after 24 to 72 h of exposure was 1.5 microgram/ml (4.2 microM). The kinetics of ATP depletion were in contrast to those of another family of naphthoquinone compounds, diospyrin and two of its derivatives. Whereas atovaquone reduced ATP levels within 1 h of exposure, the diospyrins required at least 48 h. After 72 h, the diospyrins were able to decrease ATP levels of P. carinii at nanomolar concentrations. These data indicate that although naphthoquinones inhibit the electron transport chain, the molecular targets in a given organism are likely to be distinct among members of this class of compounds. (+info)
Pentamidine inhibition of group I intron splicing in Candida albicans correlates with growth inhibition.
We previously demonstrated that pentamidine, which has been clinically used against Pneumocystis carinii, inhibits in vitro a group I intron ribozyme from that organism. Another fungal pathogen, Candida albicans, also harbors a group I intron ribozyme (Ca.LSU) in the essential rRNA genes in almost half of the clinical isolates analyzed. To determine whether pentamidine inhibits Ca.LSU in vitro and in cells, phylogenetically closely related intron-containing (4-1) and intronless (62-1) strains were studied. Splicing in vitro of the Ca.LSU group I intron ribozyme was completely inhibited by pentamidine at 200 microM. On rich glucose medium, the intron-containing strain was more sensitive to growth inhibition by pentamidine than was the intronless strain, as measured by disk or broth microdilution assays. On rich glycerol medium, they were equally susceptible to pentamidine. At pentamidine levels selectively inhibiting the intron-containing strain (1 microM) in glucose liquid cultures, inhibition of splicing and rRNA maturation was detected by quantitative reverse transcription-PCR within 1 min with a 10- to 15-fold accumulation of precursor rRNA. No comparable effect was seen in the intronless strain. These results correlate the cellular splicing inhibition of Ca.LSU with the growth inhibition of strain 4-1 harboring Ca.LSU. Broth microdilution assays of 13 Candida strains showed that intron-containing strains were generally more susceptible to pentamidine than the intronless strains. Our data suggest that ribozymes found in pathogenic microorganisms but absent in mammals may be targets for antimicrobial therapy. (+info)
Treatment of Pneumocystis carinii pneumonitis with trimethoprim-sulfamethoxazole.
Pneumocystis carinii pneumonitis (PCP) is fatal in 90 to 100% of the cases if no treatment is given. Trimethoprim-sulfamethoxazole (TMP-SMX) was used at one of two dosage levels in the treatment of 20 children with PCP and cancer. Of 14 patients treated with 20 mg TMP--100 mg SMX/kgd, 12 recovered and 2 died. Treatment of the fatal cases and one of the patients who recovered was supplemented with pentamidine. When six patients were treated with 4 to 7 mg TMP--20 to 35 mg SMX/kgd, four recovered and two died. Both fatal cases and one of the patients who recovered were also treated with pentamidine. There was no significant adverse effects from TMP-SMX. (+info)
Presence of a Na(+)/H(+) exchanger in acidocalcisomes of Leishmania donovani and their alkalization by anti-leishmanial drugs.
Acidocalcisomes are acidic vacuoles present in trypanosomatids that contain most of the cellular calcium. The data presented here demonstrate that Leishmania donovani acidocalcisomes possess a Na(+)/H(+) exchanger. 3,5-Dibutyl-4-hydroxytoluene, in the concentration range of 0-20 microM, inhibited the Na(+)/H(+) exchanger, and strongly stimulated the activity of the vacuolar H(+)-ATPase responsible for vacuolar acidification. As occurs with Na(+), the cationic anti-leishmanial drugs pentamidine, WR-6026, and chloroquine promoted a fast and extensive alkalization of the L. donovani acidocalcisomes. (+info)