Brachytherapy for penile cancer: Efficacy and impact on sexual function

AbstractPurposePenis brachytherapy (PB) remains an alternative in the cancer treatment. The objective of this study was to assess the oncologic outcomes, sexual function, and the sexual behavior of men treated by PB for a cancer of the penis.Methods and MaterialsBetween 1992 and 2009, 47 patients with a cancer of the penis were treated by PB (192Ir), in the Toulouse, Montpellier, and Barcelona cancer centers. The investigation into their sexuality was obtained by means of questionnaire. A total of 21 French patients were approached, of whom 19 (mean age=73.2 years) agreed to answer the questionnaire (participation rate=90.5%).ResultsOncologic data: The specific survival and the disease-free survival at 5 years was 87.6% (95% confidence interval, 72.4–94.7%) and 84% (95% confidence interval, 57.6–94.7%), respectively. The rate of preservation of the penis was 66% (n=31). Sexual data: Among the 17 patients sexually active before brachytherapy, 10 patients remained sexually active after treatment (58.8%). Of the 18 patients who had erections before PB, 17 still had them after treatment (94.4%). Age was the main predictive factor.ConclusionThe PB seems to have a moderated impact on the sexual functions and the sexual behavior of the patients

Evidence for the Contribution of the Hemozoin Synthesis Pathway of the Murine Plasmodium yoelii to the Resistance to Artemisinin-Related Drugs

Plasmodium falciparum malaria is a major global health problem, causing approximately 780,000 deaths each year. In response to the spreading of P. falciparum drug resistance, WHO recommended in 2001 to use artemisinin derivatives in combination with a partner drug (called ACT) as first-line treatment for uncomplicated falciparum malaria, and most malaria-endemic countries have since changed their treatment policies accordingly. Currently, ACT are often the last treatments that can effectively and rapidly cure P. falciparum infections permitting to significantly decrease the mortality and the morbidity due to malaria. However, alarming signs of emerging resistance to artemisinin derivatives along the Thai-Cambodian border are of major concern. Through long-term in vivo pressures, we have been able to select a murine malaria model resistant to artemisinins. We demonstrated that the resistance of Plasmodium to artemisinin-based compounds depends on alterations of heme metabolism and on a loss of hemozoin formation linked to the down-expression of the recently identified Heme Detoxification Protein (HDP). These artemisinins resistant strains could be able to detoxify the free heme by an alternative catabolism pathway involving glutathione (GSH)-mediation. Finally, we confirmed that artemisinins act also like quinolines against Plasmodium via hemozoin production inhibition. The work proposed here described the mechanism of action of this class of molecules and the resistance to artemisinins of this model. These results should help both to reinforce the artemisinins activity and avoid emergence and spread of endoperoxides resistance by focusing in adequate drug partners design. Such considerations appear crucial in the current context of early artemisinin resistance in Asia

Recherche de nouveaux composés à activités antipaludiques à partir des différentes pharmacopées traditionnelles

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Implication of glutathione in the in vitro antiplasmodial mechanism of action of ellagic acid.

The search for new antimalarial chemotherapy has become increasingly urgent due to parasite resistance to current drugs. Ellagic acid (EA) is a polyphenol, recently found in various plant products, that has effective antimalarial activity in vitro and in vivo without toxicity. To further understand the antimalarial mechanism of action of EA in vitro, we evaluated the effects of EA, ascorbic acid and N-acetyl-L-cysteine (NAC), alone and/or in combination on the production of reactive oxygen species (ROS) during the trophozoite and schizonte stages of the erythrocytic cycle of P. falciparum. The parasitized erythrocytes were pre-labelled with DCFDA (dichlorofluorescein diacetate). We showed that NAC had no effect on ROS production, contrary to ascorbic acid and EA, which considerably reduced ROS production. Surprisingly, EA reduced the production of the ROS with concentrations (6.6×10(-9) - 6.6×10(-6) M) ten-fold lower than ascorbic acid (113×10(-6) M). Additionally, the in vitro drug sensitivity of EA with antioxidants showed that antiplasmodial activity is independent of the ROS production inside parasites, which was confirmed by the additive activity of EA and desferrioxamine. Finally, EA could act by reducing the glutathione content inside the Plasmodium parasite. This was consolidated by the decrease in the antiplasmodial efficacy of EA in the murine model Plasmodium yoelii- high GSH strain, known for its high glutathione content. Given its low toxicity and now known mechanism of action, EA appears as a promising antiplasmodial compound

In Vitro and In Vivo Properties of Ellagic Acid in Malaria Treatment▿

Malaria is one of the most significant causes of infectious disease in the world. The search for new antimalarial chemotherapies has become increasingly urgent due to the parasites’ resistance to current drugs. Ellagic acid is a polyphenol found in various plant products. In this study, antimalarial properties of ellagic acid were explored. The results obtained have shown high activity in vitro against all Plasmodium falciparum strains whatever their levels of chloroquine and mefloquine resistance (50% inhibitory concentrations ranging from 105 to 330 nM). Ellagic acid was also active in vivo against Plamodium vinckei petteri in suppressive, curative, and prophylactic murine tests, without any toxicity (50% effective dose by the intraperitoneal route inferior to 1 mg/kg/day). The study of the point of action of its antimalarial activity in the erythrocytic cycle of Plasmodium falciparum demonstrated that it occurred at the mature trophozoite and young schizont stages. Moreover, ellagic acid has been shown to potentiate the activity of current antimalarial drugs such as chloroquine, mefloquine, artesunate, and atovaquone. This study also proved the antioxidant activity of ellagic acid and, in contrast, the inhibitory effect of the antioxidant compound N-acetyl-l-cysteine on its antimalarial efficacy. The possible mechanisms of action of ellagic acid on P. falciparum are discussed in light of the results. Ellagic acid has in vivo activity against plasmodia, but modification of the compound could lead to improved pharmacological properties, principally for the oral route

Inhibition of ellagic acid antiplasmodial activity by antioxidants (ascorbic acid, N-acetyl-L- cysteine and glutathione ethyl-ester) on the FcM29 strain of <i>Plasmodium falciparum</i>.

<p>Ascorbic acid (113.55 µM) and N-acetyl-L-cysteine (857 µM) had no effect on <i>in vitro Plasmodium</i> growth. Ascorbic acid and NAC significantly decreased (p<0.05) the ellagic acid antiplasmodial efficacy since the IC₅₀ obtained were increased 2.4 fold and 1.5 fold respectively. Data are expressed as mean ±SEM for three independent experiments with triplicate sets in each assay.</p>**<p>p<0.05 indicates a significant difference compared with ellagic acid mean IC_50.</p

Effects of D,L-Buthionine- (S,R) sulphoximine (BSO) and desferrioxamine in combination with ellagic acid on the FcM29 strain.

<p>Values are the means of the FIC₅₀ (which is an interaction coefficient indicating whether the combined effect of the drugs is synergistic, additive, or antagonistic) and standard deviations for assays run in triplicate on different days.</p><p>The combination was considered to be synergistic if the FIC₅₀ was <1, additive if the FIC₅₀ was equal to 1 and antagonistic if the FIC₅₀ was >1.</p