Pharmacological profile and effects of mitotane in adrenocortical carcinoma.

Mitotane is the only adrenolytic drug approved by the Food and Drug Administration for treating adrenocortical carcinoma (ACC). This drug has cytotoxic effects on tumour tissues; it induces cell death and antisecretory effects on adrenal cells by inhibiting the synthesis of adrenocortical steroids, which are involved in the pathogenesis of ACC. However, high doses of mitotane are usually necessary to reach the therapeutic plasma concentration, which may result in several adverse effects. This suggests that important pharmacological processes, such as first pass metabolism, tissue accumulation and extensive time for drug elimination, are associated with mitotane administration. Few studies have reported the pharmacological aspects and therapeutic effects of mitotane. Therefore, the aim of this review was to summarize the chemistry, pharmacokinetics and pharmacodynamics, and therapeutic and toxic effects of mitotane. This review also discusses new perspectives of mitotane formulation that are currently under investigation. Understanding the pharmacological profile of mitotane can improve the monitoring and efficacy of this drug in ACC treatment and can provide useful information for the development of new drugs with specific action against ACC with fewer adverse effects.

Phytochemical analysis and biological activities of in vitro cultured Nidularium procerum, a bromeliad vulnerable to extinction.

This study reports the first phytochemical and biological characterization in treatment of adrenocortical carcinoma cells (H295R) of extracts from Nidularium procerum, an endemic bromeliad of Atlantic Forest vulnerable to extinction. Extracts of dry leaves obtained from in vitro-grown plants were recovered by different extraction methods, viz., hexanoic, ethanolic, and hot and cold aqueous. Chromatography-based metabolite profiling and chemical reaction methods revealed the presence of flavonoids, steroids, lipids, vitamins, among other antioxidant and antitumor biomolecules. Eicosanoic and tricosanoic acids, α-Tocopherol (vitamin E) and scutellarein were, for the first time, described in the Nidularium group. Ethanolic and aqueous extracts contained the highest phenolic content (107.3 mg of GAE.100 g-1) and 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) radical scavenging activity, respectively. The immunomodulatory and antitumoral activities of aqueous extracts were assessed using specific tests of murine macrophages modulation (RAW 264.7) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against adrenocortical carcinoma cell line, respectively. The aqueous extract improved cell adhesion and phagocytic activities and phagolysossomal formation of murine macrophages. This constitutes new data on the Bromeliaceae family, which should be better exploited to the production of new phytomedicines for pharmacological uses.

Anti-inflammatory, analgesic, and immunostimulatory effects of Luehea divaricata Mart. & Zucc. (Malvaceae) bark

Luehea divaricata (Malvaceae) is a plant widely used for treatment of various inflammatory and infectious conditions; however few reports discuss its biological properties. The aim of this study was to evaluate the anti-inflammatory and analgesic effects as well as the macrophage activity in mice treated with the hydroalcoholic crude extract of L. divaricata (CLD). Thin layer chromatography revealed presence of epicathequin, stigmasterol, lupeol and α,β-amyrin in the extract. To evaluate the anti-inflammatory and analgesic activities, animals were subjected to paw edema induced by carrageenan test, writhing, formalin and capsaicin tests. Immunomodulatory activity was evaluated by adhesion and phagocytic capacity, lysosomal volume, and reactive oxygen species (ROS) production by peritoneal macrophages, after daily treatment with CLD for 15 days. CLD promoted reduction in paw edema (36.8% and 50.2%; p<0.05 at doses of 100 and 300 mg/kg, respectively), inhibited writhing behavior at the higher dose (64.4%, p<0.05), reduced formalin reactivity (81.2% and 91.6% at doses of 100 and 300 mg/kg, respectively, p<0.05), and reduced capsaicin reactivity by 63.9% (300 mg/kg). CLD (200 mg• kg-1• day-1) increased phagocytosis capacity of macrophages (~3 fold, p<0.05), neutral red uptake (~50%, p<0.001), and ROS production (~90%, p<0.001). These data suggest that CLD possesses anti-inflammatory, analgesic and immunostimulatory properties.

Luehea divaricata (Malvaceae) é utilizada para o tratamento de várias condições patológicas, entretanto, há poucos relatos sobre sua bioatividade. O objetivo deste estudo foi avaliar o efeito anti-inflamatório e analgésico, bem como a atividade de macrófagos em camundongos tratados com extrato bruto hidroalcoólico (CLD) da planta. Cromatografia em camada delgada revelou a presença de epicatequina, estigmasterol, lupeol e α,β-amirina no material. Para avaliar a atividade anti-inflamatória e analgésica, animais foram submetidos a teste de edema de pata induzido por carragenana, teste de contorções, da formalina e da capsaicina. A atividade imunomodulatória foi avaliada pela capacidade de adesão e de fagocitose dos macrófagos, volume lisossômico e produção de espécies reativas de oxigênio (ROS), após tratamento diário com CLD por 15 dias. CLD promoveu redução do edema de pata (36,8% e 50,2%; 100 e 300 mg/kg, respectivamente; p<0,05), redução do número de contorções (64,4%; 300 mg/kg; p<0,05), redução da reatividade no teste da formalina (81,2% e 91,6%; 100 e 300 mg/kg, respectivamente; p<0,05), e no teste da capsaicina em 63,9% (300 mg/kg). CLD (200 mg• kg-1• day-1) aumentou capacidade de fagocitose dos macrófagos (~3 vezes, p<0,05), volume lisossômico (~50%, p<0,001) e produção de ROS (~90%, p<0,001). Estes dados sugerem que o CLD possui propriedades anti-inflamatórias, analgésicas e imunoestimulatórias.

Antitumor and anti-cachectic effects of shark liver oil and fish oil: comparison between independent or associative chronic supplementation in Walker 256 tumor-bearing rats.

BACKGROUND: Shark liver oil (SLOil) and fish oil (FOil), which are respectively rich in alkylglycerols (AKGs) and n-3 polyunsaturated fatty acids (PUFAs), are able to reduce the growth of some tumors and the burden of cachexia. It is known that FOil is able to reduce proliferation rate and increase apoptotic cells and lipid peroxidation of tumor cells efficiently. However, there are few reports revealing the influence of SLOil on these parameters. In the current study, effects of FOil chronic supplementation on tumor growth and cachexia were taken as reference to compare the results obtained with SLOil supplementation. Also, we evaluated if the association of SLOil and FOil was able to promote additive effects. METHODS: Weanling male Wistar rats were divided into 4 groups: fed regular chow (C), supplemented (1 g/kg body weight) with SLOil (CSLO), FOil (CFO) and both (CSLO + FO). After 8 weeks half of each group was inoculated with Walker 256 cells originating new groups (W, WSLO, WFO and WSLO + FO). Biochemical parameters of cachexia, tumor weight, hydroperoxide content, proliferation rate and percentage of apoptotic tumor cells were analysed. Fatty acids and AKG composition of tumor and oils were obtained by high performance liquid chromatography and gas chromatography - mass spectrometry, respectively. Statistical analysis was performed by unpaired t-test and one-way ANOVA followed by a post hoc Tukey test. RESULTS: Fourteen days after inoculation, SLOil was able to restore cachexia parameters to control levels, similarly to FOil. WSLO rats presented significantly lower tumor weight (40%), greater tumor cell apoptosis (~3-fold), decreased tumor cell proliferation (35%), and higher tumor content of lipid hydroperoxides (40%) than observed in W rats, but FOil showed more potent effects. Supplementation with SLOil + FOil did not promote additive effects. Additionally, chromatographic results suggested a potential incorporation competition between the n-3 fatty acids and the AKGs in the tumor cells' membranes. CONCLUSIONS: SLOil is another marine source of lipids with similar FOil anti-cachectic capacity. Furthermore, despite being less potent than FOil, SLOil presented significant in vivo antitumor effects. These results suggest that the chronic supplementation with SLOil may be adjuvant of the anti-cancer therapy.

Cordyceps sinensis biomass produced by submerged fermentation in high-fat diet feed rats normalizes the blood lipid and the low testosterone induced by diet.

This study investigated the effect of Cordyceps sinensis biomass supplementation obtained from submerged fermentation on blood lipid and low testosterone induced by high-fat diet (HFD). The experiments were carried out using a long-term intake of HFD and HFD plus Simvastatin or C. sinensis (4 months). Our results show that plasma cholesterol, triglycerides and LDL were decreased by Cordyceps sinensis biomass supplementation (CSBS). A long-term intake of HFD caused a significant liver damage which has been reverted by CSBS. CSBS normalized decreasing testosterone levels observed in high-fat diet feed rats. All these findings lead us to suggest that C. sinensis was able to decrease blood lipid concentration, increase hepatoprotective activity and normalize testosterone levels.

Neutrophil response of anaerobic jump trained diabetic rats.

This paper investigated the effect of jump training on blood biochemical parameters and neutrophil responses of diabetic rats. Male Wistar rats were divided into control, trained, diabetic and trained-diabetic groups. Diabetes was induced by i.v. injection of streptozotocin. Jump training consisted of six sets of ten jumps in water with overload of 50% of body mass with 1-min of resting, four times per week during 6 weeks. Plasma glucose, lactate, triacylglycerol and total cholesterol concentrations, differential leukocyte count, phagocytosis and anion superoxide production by neutrophils were evaluated. Diabetes caused hyperglycemia, hypertriacylglycerolemia, and body weight loss. Physical training reversed hypertriacylglycerolemia. Jump training increased phagocytosis and anion superoxide production by blood neutrophils from trained and trained-diabetic rats. Neutrophilia and lymphocytopenia occur in diabetic and trained-diabetic rats. Anaerobic jump training in diabetic rats reduced hypertriacylglycerolemia and increased neutrophil anion superoxide production. Phagocytosis was not altered in trained-diabetic rats.