Potential therapeutic applications of the genus Annona: Local and traditional uses and pharmacology.

ETHNO-PHARMACOLOGICAL RELEVANCE: Annona species (Annonaceae) have long been used as traditional herbal medicines by native peoples in tropical areas. In different countries they are used against a large variety of illnesses, such as parasitic and infectious diseases, cancer, diabetes, peptic ulcers, and mental disorders. AIM OF THE STUDY: This review aims to achieve a comprehensive understanding of the research conducted so far on the local and traditional uses, pharmacological activities, mechanism of actions of active compounds, toxicity, and possible interactions with other drugs of the Annona species. Through analysis of these findings, evidences supporting their applications in ethno-medicines are described. We discuss the possible research opportunities and stand out the weak points in our knowledge that deserves further investigation. MATERIAL AND METHODS: Information on ethno-medicinal uses and pharmacological activities of the Annona genus was collected. The main scientific biomedical literature databases (Cochrane, PubMed, Scopus, Lilacs, SeCiMed, Elsevier, SpringerLink, Google Scholar, SciFinder) were consulted. The search covered all the literature available until September 2017. National and regional databases of Herbal Medicine and Complementary and Alternative Medicine were also revised in order to explore further data. For a better understanding of the therapeutic importance of these species, we have classified the pharmacological activities within each group of disorders. The International Classification of Diseases (ICD), used from WHO Member States, was chosen as the reference classification. RESULTS: From among the 27 species revised, four species are highlighted for their important pharmacological activities in most of the groups of illnesses: A. muricata, A. squamosa, A. senegalensis, and A. cherimola. Many investigations have been performed with extracts from the leaves, bark, fruit and seeds and have shown a wide range of pharmacological activities, such as antiprotozoal, antitumoural, antidiabetic, hepato-protective, anti-inflammatory and anxiolytic activities. The chemistry on the annonaceous acetogenins (ACGs) has been extensively investigated due to their potent antitumoural activity. Many of the assays were carried out with the isolated acetogenins in different lines of tumour culture cells and were found effective at very low doses even in multidrug-resistant tumours, and hence constitute promising compounds in the treatment of different types of cancers. No studies were found with extracts rich in acetogenins in the clinical field. CONCLUSIONS: The experimental results from the pharmacological research enable the validation of their traditional uses in several of the groups of diseases in the countries of origin and reveal these plants to be a valuable source for therapeutic molecules. However, more toxicity assays and clinical trials would be necessary to establish optimal and safe doses of consumption on the application of these medicinal plants.

Pharmacological effects of mitraphylline from Uncaria tomentosa in primary human monocytes: Skew toward M2 macrophages.

ETHNOPHARMACOLOGICAL RELEVANCE: Uncaria tomentosa (Willdenow ex Roemer & Schultes) DC. (Rubiaceae) is a Peruvian thorny liana, commonly known as "cat׳s claw", and traditionally used in folk medicine to deal with several inflammatory diseases. Mitraphylline (MTP) is the most abundant pentacyclic oxindolic alkaloid (POA) from U. Tomentosa and has been reported to modify the inflammatory response. Herein, we have sought to identify the mechanisms underlying this modulatory effect of MTP on primary human monocytes and its ability to regulate differentiation processes on human primary monocyte and monocyte-derived macrophages. MATERIAL AND METHODS: In vitro studies with human primary monocytes and monocyte-derived macrophages were performed. Monocytes and M0 macrophages were exposed to MTP (25µM) and LPS (100ng/mL). M0 macrophages were polarized to M1 and M2 phenotypes in the absence or presence of MTP. The activation state of monocytes/macrophages was assessed by flow cytometry, gene expression and protein analysis of different specific markers. RESULTS: In human primary monocytes, the incubation of MTP for 24h reduced the number of classical (CD14(++)CD16(-)) and intermediate (CD14(++)CD16(+)) subsets when compared to untreated or LPS-treated cells. MTP also reduced the chemotactic capacity of human primary monocytes. In addition, MTP promoted the polarization of M0 macrophages toward an anti-inflammatory M2 phenotype, the abrogation of the release of pro-inflammatory cytokines such as TNFα, IL-6 or IL-1ß, as well as the restoration of markers for M2 macrophages in LPS-treated M1 macrophages. CONCLUSIONS: Our results suggest that MTP may be a key modulator for regulating the plasticity of monocytes/macrophages and the attenuation of the inflammatory response.

Uncaria tomentosa (Willd. ex. Roem. & Schult.) DC. and Eucalyptus globulus Labill. interactions when administered with diazepam.

The safety of natural drugs is defined by their side effects and toxicity as well as any interactions that may occur if taken together with other drugs. In particular, it is essential to identify synergies, antagonisms and other types of interference with other drugs so that the correct choice can be made from the range of phytomedicines available. The aim of this work was to investigate changes in the pharmacological effect of diazepam (2 mg/kg) on the CNS when administered together with a medicinal plant: Eucalyptus globulus Labill. (eucalyptus 6 mg/kg and 3.25 mg/kg) or Uncaria tomentosa (Willd. ex Roem. & Schult). DC. (cat's claw, 7.14 mg/kg and 3.54 mg/kg). Various different psychopharmacological effects were evaluated through assessing exploratory behavior, muscle relaxation and spontaneous motor activity. Both phytodrugs interacted with the benzodiazepine. Eucalyptus had an inhibitory effect at both doses and could be useful at the highest dose in cases where the desired effect of the depressant is moderate anxiolytic activity without marked muscle relaxation. Cat's claw, at both doses, enhanced the action of diazepam on spontaneous motor activity and, at the lowest dose, exploratory ability. These herbal drugs could be useful for their antiinflammatory activity in musculoskeletal pathologies treated with benzodiazepines.

Phytochemical analysis and anti-allergic study of Agave intermixta Trel. and Cissus sicyoides L.

Agave intermixta Trel. (Maguey) and Cissus sicyoides L. (Bejuco caro) are Caribbean plant species from the Dominican Republic used locally in traditional popular medicine that have shown an antiinflammatory effect in experimental animal models. A phytochemical analysis on these species allowed us the isolation and identification of the steroidal sapogenins hecogenin and diosgenin from Maguey and the hydroxystilbene resveratrol from Bejuco caro. The effects of these plant extracts and their isolated constituents on compound-48/80-induced histamine release from peritoneal mast cells were investigated. Significant inhibition was produced by 0.5 mg mL(-1) of a methanolic extract of Bejuco (41.1%) and by its constituent resveratrol (82.4%) at a dose of 250 microM. However, none of the steroidal sapogenins from A. intermixta showed a significant inhibitory effect on histamine release from mast cells. From these results, it can be deduced that the in-vitro anti-allergic activity towards the release of histamine from mast cells shown by the methanolic extract of C. sicyoides may be mediated by its constituent resveratrol and might contribute to the antiinflammatory activity shown by this species.

Anti-inflammatory activity of Agave intermixta Trel. and Cissus sicyoides L., species used in the Caribbean traditional medicine.

Agave intermixta Trel. and Cissus sicyoides L. are two tropical plants originating from the Dominican Republic. Aqueous extracts from these species are used in traditional medicine. In contrast, biological activity and toxicity of these plants are not yet evaluated systematically. The aim of the present work is to investigate a potential anti-inflammatory activity, and to elucidate the toxicity of the extracts. No lethal effects were produced after oral administration of the extracts. The values of the medium lethal doses after intraperitoneal administration were quite high for both species, although A. intermixta seems to be rather more toxic than C. sicyoides. The anti-inflammatory effects have been investigated in two experimental in vivo models. The carrageenan-induced rat paw oedema was chosen as a model for general inflammation, and the mice ear oedema test using tetradecanoylphorbol acetate as inflammatory agent as a model of topical inflammation. Dry extracts from decoctions of A. intermixta leaves and C. sicyoides stems were administered in doses of 300 and 500 mg/kg (p.o.) in the general model, and in doses of 3 and 5 mg/mouse ear for both plants in the topical model. In the general anti-inflammation assay, the oral administration of both extracts produced a significant anti-inflammatory effect, most pronounced for A. intermixta than for C. sicyoides. In the topical model, the administration of both extracts produced similar inhibitions of the oedema, with a reduction of approximately 50% in comparison with the control group. In homogenated tissue samples from the inflamed areas, a distinct decrease in the level of myeloperoxidase enzyme was noted.