Bases and foundations of the treatment of peritoneal carcinomatosis: Review article

Peritoneal carcinomatosis refers to a shedding or tumor that spreads to the peritoneal serosa and structures of the abdominal cavity. It is an entity with a poor prognosis. Several conditions can cause this, the most common being colon, rectum, ovary, stomach or appendix cancers, including peritoneal pseudomyxoma, among others. The abdominal cavity invasion is considered a clinical stage IV. For a long time life expectancy of this entity was very short. With the advent of meticulous techniques in cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) the prognosis of patients has changed. In some conditions, these procedures are standard treatments. CRS is a very important prognostic factor; leaving a less residual disease in the patient, the evolution will be better. The HIPEC starts immediately after the surgical event. The hyperthermia increases the cytotoxic effect of antineoplastic drugs. Numerous studies have appeared in medical literature wherein the clear improvement in survival of the affected population is demonstrated. It is essential that a multidisciplinary team participates in the decision for the best treatment option and the maximum clinical benefit of the patients

In Vivo Activity of the Benzothiazinones PBTZ169 and BTZ043 against Nocardia brasiliensis.

BACKGROUND:Mycetoma is a neglected, chronic, and deforming infectious disease caused by fungi and actinomycetes. In Mexico, N. brasiliensis is the predominant etiologic agent. Therapeutic alternatives are necessary because the current drug regimens have several disadvantages. Benzothiazinones (BTZ) are a new class of candidate drugs that inhibit decaprenyl-phosphoribose-epimerase (DprE1), an essential enzyme involved in the cell wall biosynthesis of Corynebacterineae. METHODOLOGY/PRINCIPAL FINDINGS:In this study, the in vitro activity of the next generation BTZ, PBTZ169, was tested against thirty Nocardia brasiliensis isolates. The MIC50 and MIC90 values for PBTZ169 were 0.0075 and 0.03 μg/mL, respectively. Because Nocardia is a potential intracellular bacterium, a THP-1 macrophage monolayer was infected with N. brasiliensis HUJEG-1 and then treated with PBTZ169, resulting in a decrease in the number of colony-forming units (CFUs) at a concentration of 0.25X the in vitro value. The in vivo activity was evaluated after infecting female BALB/c mice in the right hind food-pad. After 6 weeks, treatment was initiated with PBTZ169 and its activity was compared with the first generation compound, BTZ043. Both BTZ compounds were administered at 100 mg/kg twice daily by gavage, and sulfamethoxazole/trimethoprim (SXT), at 100 mg/kg sulfamethoxazole, was used as a positive control. After 22 weeks of therapy, only PBTZ169 and SXT displayed statistically significant activity. CONCLUSION:These results indicate that DprE1 inhibitors may be useful for treating infections of Nocardia and may therefore be active against other actinomycetoma agents. We must test combinations of these compounds with other antimicrobial agents, such as linezolid, tedizolid or SXT, that have good to excellent in vivo activity, as well as new DprE1 inhibitors that can achieve higher plasma levels

Intracellular activity of PBTZ169 against <i>Nocardia brasiliensis</i> HUJEG-1 after 8 h of replication inside THP-1 macrophages.

<p>The measurements were performed in triplicate. Each point represents the mean of the assays and error bars represent the standard deviations. There were significant differences at all concentrations for PBTZ169 (open diamonds) (<i>P</i>  =  0.021) (MIC = 0.0037 μg/mL). As a control, we used tedizolid (closed circles) (MIC = 8 μg/mL).</p

Alignment of <i>M</i>. <i>tuberculosis</i> DprE1 ortholog proteins in <i>Nocardia spp</i>. We observe that all species have orthologs with the susceptible genotype, a cysteine at position 368.

<p>This analysis included common <i>Nocardia</i> pathogens, such as <i>N</i>. <i>brasiliensis</i>, <i>N</i>. <i>cyryiacigeorgica</i>, <i>N</i>. <i>farcinica</i>, <i>N</i>. <i>transvalensis</i>, and <i>N</i>. <i>otitidiscaviarum</i>. We also included rarely pathogenic species, such as <i>N</i>. <i>tenerifensis</i>, <i>N</i>. <i>terpenica</i>, and <i>N</i>. <i>carnea</i>.</p

Effect of PBTZ169, BTZ043, and SXT on the development of mycetoma lesions in BALB/c mice infected with <i>N</i>. <i>brasiliensis</i> HUJEG-1.

<p>The Y axis is an arbitrary scale we developed to measure the degree of infection (14) and goes from the total absence of lesions (0.0 +) to the presence of abundant inflammation, abscesses and fistulae. Each dot represents the reading of one animal; all the groups were compared statistically against the saline control group by using the Variance test,. According to this analysis, significant differences were found for treatment with PBTZ169 (<i>P</i> = 0.017) but not BTZ043 (<i>P</i> = 0.667). The positive control group treated with SXT yielded a statistically significant value (<i>P</i> = 0.007).</p

Plasma levels observed in BALB/c mice after applying, by gavage, PBTZ169 (left) and trimethoprim-sulfomethoxazole (right), both at 100 mg/kg.

<p>Three mice were bled and sacrificed at each point. Bars represent the standard deviation.</p

Protein sequence alignment of <i>M</i>. <i>tuberculosis</i> H37Rv DprE1 (A) and two orthologs in the genome of <i>N</i>. <i>brasiliensis</i> HUJEG-1.

<p>In red, we show Cys387. B: <i>N</i>. <i>brasilie</i>nsis YP_006807368 has 97% query cover and 62% identity to MTB DprE1. C: <i>N</i>. <i>brasiliensis</i> YP_006805098, presents a 99% query cover and 74% identity to MTB DprE1.</p

Plasma levels of BTZ043 observed in BALB/c mice.

<p>Animals were given SXT at 100 mg/kg by gavage. Each point represent the mean of three mice with bars representing the standard deviation obtained.</p