Limonene-carvacrol: A combination of monoterpenes with enhanced antileishmanial activity.

BACKGROUND: Leishmaniasis is a parasitosis with a wide incidence in developing countries. The drugs which are indicated for the treatment of this infection usually are able to promote high toxicity. PURPOSE: A combination of limonene and carvacrol, monoterpenes present in plants with antiparasitic activity may constitute an alternative for the treatment of these diseases. METHODS: In this study, the antileishmania activity against Leishmania major, cytotoxicity tests, assessment of synergism, parasite membrane damage tests as well as molecular docking and immunomodulatory activity of limonene-carvacrol (Lim-Car) combination were evaluated. RESULTS: The Lim-Car combination (5:0; 1:1; 1:4; 2:3; 3:2; 4:1 and 0:5) showed potential antileishmania activity, with mean inhibitory concentration (IC50) ranging from 5.8 to 19.0 µg.mL-1. They demonstrated mean cytotoxic concentration (CC50) ranging from 94.1 to 176.0 µg.mL-1, and did not show significant hemolytic effect. In the investigation of synergistic interaction, the 4:1 Lim-Car combination showed better fractional inhibitory concentration (FIC) index as well as better activity on amastigotes and IS. The samples caused considerable damage to the parasite membrane this monoterpene activity seems to be more related to Trypanothione Reductase (TryR) enzyme interaction, demonstrated in the molecular docking assay. In addition, the 4:1 Lim-Car combination stimulated macrophage activation, and showed at was the best association, with reduction of infection and infectivity of parasitized macrophages. CONCLUSION: The 4:1 Lim-Car combination appears to be a promising candidate as a monotherapeutic antileishmania agent.

Eugenia piauhiensis Vellaff. essential oil and γ-elemene its major constituent exhibit antileishmanial activity, promoting cell membrane damage and in vitro immunomodulation.

Leishmaniasis is considered as one of the most Neglected Tropical Diseases (NTDs) in the world, caused by protozoan parasites of the genus Leishmania. Treatment of leishmaniasis by chemotherapy remains a challenge because of limited efficacy, toxic side effects, and drug resistance. The search for new therapeutic agents from natural sources has been a constant for the treatment of diseases such as leishmaniasis. The objective of this study was to evaluate the biological activity of Eugenia piauhiensis Vellaff. essential oil (EpEO) and its major constituent γ-elemene on promastigote and amastigote forms of Leishmania (Leishmania) amazonensis, its cytotoxicity, and possible mechanisms of action. EpEO was more active (IC50 6.43 ± 0.18 µg/mL) against promastigotes than γ-elemene [9.82 ± 0.15 µg/mL (48.05 ± 0.73 µM)] and the reference drug miltefosine [IC50 17.25 ± 0.26 µg/mL (42.32 ± 0.64 µM)]. EpEO and γ-elemene exhibited low cytotoxicity against J774.A1 macrophages, with CC50 225.8 ± 3.57 µg/mL and 213.21 ± 3.3 µg/mL (1043 ± 16.15 µM), respectively. Additionally, EpEO and γ-elemene present direct activity against the parasite, decreasing plasma membrane integrity. EpEO and γ-elemene also proved to be even more active against intracellular amastigotes of the parasite [IC50 4.59 ± 0.07 µg/mL and 8.06 ± 0.12 µg/mL (39.44 ± 0.59 µM)], respectively), presenting indirect effects through macrophage activity modulation. Anti-amastigote activity was associated with increased TNF-α, IL-12, NO, and ROS levels. In conclusion, our results suggest EpEO and γ-elemene as promising candidates for new drug development against leishmaniasis.

Virtual Screening for the Development of New Effective Compounds Against Staphylococcus aureus.

Staphylococcus aureus is a notorious pathogenic bacterium causing a wide range of diseases from soft-tissue contamination, to more serious and deep-seated infections. This species is highlighted by its ability to express several kinds of virulence factors and to acquire genes related to drug resistance. Target this number of factors to design any drug is not an easy task. In this review, we discuss the importance of computational methods to impulse the development of new drugs against S. aureus. The application of docking methods to screen large libraries of natural or synthetic compounds and to provide insights into action mechanisms is demonstrated. Particularly, the studies that validated in silico results with biochemical and microbiological assays are highlighted. We also comment on the computer-aided design of new molecules using some known inhibitors. The confirmation of in silico results with biochemical and microbiological assays allowed the identification of lead molecules that could be used for drug design such as rhodomyrtone, quinuclidine, berberine (and their derivative compounds). The fast development of the computational methods is essential to improve our ability to discover new drugs, as well as to expand understanding about drug-target interactions.

Quantitative methods in electroencephalography to access therapeutic response.

Pharmacometrics or Quantitative Pharmacology aims to quantitatively analyze the interaction between drugs and patients whose tripod: pharmacokinetics, pharmacodynamics and disease monitoring to identify variability in drug response. Being the subject of central interest in the training of pharmacists, this work was out with a view to promoting this idea on methods to access the therapeutic response of drugs with central action. This paper discusses quantitative methods (Fast Fourier Transform, Magnitude Square Coherence, Conditional Entropy, Generalised Linear semi-canonical Correlation Analysis, Statistical Parametric Network and Mutual Information Function) used to evaluate the EEG signals obtained after administration regimen of drugs, the main findings and their clinical relevance, pointing it as a contribution to construction of different pharmaceutical practice. Peter Anderer et. al in 2000 showed the effect of 20mg of buspirone in 20 healthy subjects after 1, 2, 4, 6 and 8h after oral ingestion of the drug. The areas of increased power of the theta frequency occurred mainly in the temporo-occipital - parietal region. It has been shown by Sampaio et al., 2007 that the use of bromazepam, which allows the release of GABA (gamma amino butyric acid), an inhibitory neurotransmitter of the central nervous system could theoretically promote dissociation of cortical functional areas, a decrease of functional connectivity, a decrease of cognitive functions by means of smaller coherence (electrophysiological magnitude measured from the EEG by software) values. Ahmad Khodayari-Rostamabad et al. in 2015 talk that such a measure could be a useful clinical tool potentially to assess adverse effects of opioids and hence give rise to treatment guidelines. There was the relation between changes in pain intensity and brain sources (at maximum activity locations) during remifentanil infusion despite its potent analgesic effect. The statement of mathematical and computational aspects in the use of clinical data is frequent and elucidation of these aspects we use PhysioNet https://www.physionet.org/, Clinical Database online supported by the National Institutes of Health (National Institutes of Health of United States of America/NIH-USA) for the acquisition of EEG data and the Matlab program to do the simulations with the methods and thus create opportunities greater understanding.