Plantas medicinais e políticas públicas de saúde: novos olhares sobre antigas práticas / Medicinal plants and public health policies: new perspectives on old practices

Resumo As plantas medicinais são utilizadas nos cuidados a saúde desde a Antiguidade, mas apenas na década de 1970 a OMS se manifestou sobre sua importância para a saúde da população. Este artigo teve por objetivo identificar a sequência temporal e evolução dos marcos legais associados às políticas públicas de plantas medicinais, discutindo as implicações dessa evolução, bem como sua inserção no sistema de saúde, e apresentar essa evolução no Brasil. Foram identificados e analisados os conteúdos de Leis, Decretos, Resoluções, Políticas, Portarias e Instruções Normativas relacionadas ao tema. Apesar do longo histórico de uso da flora nacional, as primeiras legislações sobre seu emprego no campo da saúde são recentes. O Brasil, país com maior biodiversidade do planeta, aprovou, apenas em 2006, a Política Nacional de Práticas Integrativas e Complementares e a Política Nacional de Plantas Medicinais e Fitoterápicos. Necessita-se, entretanto, ampliar o investimento em pesquisas científicas para que haja segurança, qualidade e eficácia no seu uso.

Abstract Medicinal plants have been used in health care since Antiquity, but it was only in the 1970s that the WHO expressed its importance for the health of the population. This article aimed to identify the temporal sequence and evolution of legal frameworks associated with public policies on medicinal plants, discussing the implications of this evolution, as well as its insertion in the health system, and to present this evolution in Brazil. The contents of Laws, Decrees, Resolutions, Policies, Ordinances and Normative Instructions related to the topic were identified and analyzed. Despite the long history of using the national flora, the first legislation on its use in the health field is recent. Only in 2006, Brazil, the country with the greatest biodiversity on the planet, approved the National Policy on Integrative and Complementary Practices and the National Policy on Medicinal Plants and Phytotherapeutics. It is necessary, however, to increase investment in scientific research so that there is safety, quality and effectiveness in its use.

Brazilian panorama about the registration and use of herbal medicines / Panorama brasileño en cuanto al registro y el uso de las hierbas medicinales

It was evaluated the Brazilian panorama regarding the registration and use of phytotherapics. A descriptive study about herbal medicines was carried out using the Pubmed and Portal Capes databases, and online data from the National Health Surveillance Agency (ANVISA). Of the 114-plant species described in the list of Brazilian Common Denomination (CBD), 67 have at least one formulation registered by ANVISA, with emphasis on Ginkgo biloba L. Fifteen different pharmaceutical forms were observed, the most common being tablets. There are 22 different indications, laxative was the most cited. Publications in the field of herbal medicine have increased significantly in the last 2 decades.

Se evaluó el panorama brasileño sobre el registro y uso de fitoterápicos. Se realizó un estudio descriptivo de las hierbas medicinales utilizando las bases de datos Pubmed y Portal Capes, así como datos en línea de la Agencia Nacional de Vigilancia Sanitaria (ANVISA). De las 114 especies de plantas descritas en la lista de Denominación Común Brasileña (CBD), 67 tienen al menos una formulación registrada por ANVISA, con énfasis en Ginkgo biloba L. Se observaron 15 formas farmacéuticas diferentes, siendo las más comunes las tabletas. Hay 22 indicaciones diferentes, laxante fue el más citado. Las publicaciones en el campo de la medicina herbal han aumentado significativamente en las últimas 2 décadas.

Galactofuranose-rich polysaccharides from Trebouxia sp. induce inflammation and exacerbate lethality by sepsis in mice.

Trebouxia sp. is a genus of green algae that is a symbiotic partner of lichenized fungi. Previous studies conduced demonstrated that Trebouxia sp. is able to produce galactofuranose-rich polysaccharides (ß-d-galactofuranan, mannogalactofuranan), which were able to activate macrophages in vitro. The present study was proposed to investigate the effects of SK10 polysaccharides fraction from Trebouxia sp. on the model of polymicrobial sepsis induced by cecal ligation and puncture in mice in vivo. The subcutaneous administration of SK10 increased the late mortality rate by 20%, stimulated neutrophil accumulation in lungs (indirectly measured through myeloperoxidase activity) and also Interleukin-1ß, creatinine and glucose serum levels. Moreover this study demonstrates the in vivo proinflammatory effects of polymers of galactofuranose and that they can act as pathogen-associated molecular patterns being highly recognized by the immune system of mammals, even if they come from a non-pathogenic microorganism.

Galactofuranosyl glycosides: immunomodulatory effects on macrophages and in vivo enhancement of lethality on sepsis.

Galactofuranoside derivatives were synthesised by the classic Fischer glycosydation method, and their immune modulation properties were studied in vitro and in vivo. NMR spectroscopic and ESI-MS analyses confirmed the purity and authenticity of all derivatives. Their phagocyte capacities were tested in resident macrophages. Methyl ß-galactofuranoside (GFB-Me) and n-octyl ß-galactofuranoside (GFB-O) had an immune stimulant effect at 25µmolml(-1) with an enhancement of 35.12%±0.06 SD and 17.49%±0.11 SD, respectively, but Methyl α-galactofuranoside (GFA-Me) and n-octyl α-galactofuranoside (GFA-O) gave a low immune response. Methyl α-galactofuranoside 5,6-O-isopropylidene (GFA-IP) and Methyl ß-galactofuranoside 5,6-O-isopropylidene (GFB-IP) had negative values relative to the control group of minus 4.96%±0.10 SD and -40.72%±0.07 SD, respectively. Furthermore, GFB-Me and GFB-Me-IP were evaluated in vivo on the lethality induced by cecal ligation and puncture. Cytokine levels and iNOS expression were determined and correlated to mortality data. The results showed that the free HO-5 and HO-6 and the ß-configuration are essential for the induction of phagocytic activity by the galactofuranosyl units. The methyl ß-galactofuranosides also enhanced lethality during sepsis, increasing the levels of pro-inflammatory cytokines and iNOS expression.

Rhamnogalacturonan from Ilex paraguariensis: a potential adjuvant in sepsis treatment.

The present study evaluated the anti-inflammatory activity of a polysaccharide from maté, using a clinically relevant model of sepsis induced by cecal ligation and puncture (CLP). A polysaccharide from maté (SPI) was obtained from aqueous extraction followed by fractionation, being identified as a rhamnogalacturonan with a main chain of →4)-6-OMe-α-D-GalpA-(1→ groups, interrupted by α-L-Rhap units, substituted by a type I arabinogalactan. SPI was tested against induced-polymicrobial sepsis, at doses of 3, 7 and 10 mg/kg. Via oral administration, SPI prevented the late mortality of infected mice by a rate of 60% at 10 mg/kg, in comparison with untreated mice Dexamethasone, used as positive control, was slightly less effective, with an overall survival rate of 16.7% of mice at the end of the observation period. SPI also affected neutrophil influx, avoiding its accumulation in lungs, and significantly decreased tissue expression of iNOS and COX-2. In this context, maté is a potential nutraceutical, and its polysaccharide a promising adjuvant for sepsis treatment, being consumed as tea-like beverages with no related adverse effects.

Agaricus bisporus fucogalactan: structural characterization and pharmacological approaches.

The fucogalactan from Agaricus bisporus (EFP-Ab) obtained on aqueous extraction followed by purification had M(w) 37.1 × 10(4)g mol(-1) relative to a (1→6)-linked α-D-Galp main-chain partially methylated at HO-3, and partially substituted at O-2 by nonreducing end-units of α-L-Fucp or ß-d-Galp. EFP-Ab also inhibited significantly the neurogenic and inflammatory phases of formalin-induced licking, however, the antinociceptive effect was more pronounced against the inflammatory phase with ID(50) of 36.0 (25.8-50.3)mg kg(-1). In addition, EFP-Ab decreased the lethality induced by CLP. Its administration reduced the late mortality rate by 40%, prevented neutrophil accumulation in lungs and markedly decreased iNOS and COX-2 protein expression by ileum cells. These data show for the first time that EFP-Ab has significant anti-sepsis, antinociceptive and anti-inflammatory actions, which seems to be related to the decreased iNOS and COX-2 expression. Collectively, the present results demonstrate that EFP-Ab could constitute an attractive molecule of interest for the development of new drugs.

(1→2) and (1→6)-linked ß-D-galactofuranan of microalga Myrmecia biatorellae, symbiotic partner of Lobaria linita.

A structural study of the cell wall polysaccharides of Myrmecia biatorellae, the symbiotic algal partner of the lichenized fungus Lobaria linita was carried out. It produced a rhamnogalactofuranan, with a (1→6)-ß-D-galactofuranose in the main-chain, substituted at O-2 by single units of ß-D-Galf, α-L-Rhap or by side chains of 2-O-linked ß-D-Galf units. The structure of the polysaccharide was established by chemical and NMR spectroscopic analysis, and is new among natural polysaccharides. Moreover, in a preliminary study, this polysaccharide increased the lethality of mice submitted to polymicrobial sepsis induced by cecal ligation and puncture, probably due to the presence of galactofuranose, which have been shown to be highy immunogenic in mammals.

Natural product extract of Dicksonia sellowiana induces endothelium-dependent relaxations by a redox-sensitive Src- and Akt-dependent activation of eNOS in porcine coronary arteries.

BACKGROUND/AIMS: The consumption of polyphenol-rich food is associated with a decreased mortality from coronary diseases. This study examined whether a standardized hydroalcoholic extract of Dicksonia sellowiana (HEDS) triggered endothelium-dependent relaxations in porcine coronary artery rings and characterized the underlying mechanism. METHODS: The phosphorylation level of Src, Akt and eNOS was assessed by Western blot analysis, the formation of reactive oxygen species by dihydroethidine staining and the level of eNOS Ser1177 phosphorylation by immunohistochemical staining in sections of coronary arteries. RESULTS: HEDS-induced endothelium-dependent relaxations were strongly reduced by Nω-nitro-L-arginine, an eNOS inhibitor, and by its combination with charybdotoxin plus apamin, inhibitors of endothelium-derived hyperpolarizing factor-mediated responses. These relaxations were markedly reduced by MnTMPyP (a membrane-permeant mimetic of superoxide dismutase), polyethylene glycol catalase (PEG-catalase; a membrane-permeant analog of catalase), and by wortmannin (an inhibitor of PI3-kinase). HEDS-induced sustained phosphorylation of Akt and eNOS in endothelial cells was abolished by MnTMPyP, PEG-catalase and wortmannin. Oral administration of HEDS induced a significant decrease of mean arterial pressure in spontaneously hypertensive rats. CONCLUSION: These findings indicate that HEDS caused endothelium-dependent relaxations of coronary artery rings through the redox-sensitive activation of the endothelial PI3-kinase/Akt pathway leading to the subsequent activation of eNOS by phosphorylation. HEDS also has antihypertensive properties.

Analysis of Flavonoids from Eugenia uniflora Leaves and Its Protective Effect against Murine Sepsis.

Eugenia uniflora, referred to as Pitanga cherry shrub, is largely distributed in tropical and subtropical America. This plant is cultivated in many countries and it is suitable for the production of juice, frozen pulp, and tea. Besides, it can be used as treatment for inflammatory diseases. We reported that a flavonoid-rich fraction (HE-Bu) obtained from leaves decreased the lethality induced by cecal ligation and puncture (CLP), a clinically relevant model of sepsis. The oral administration of HE-Bu reduced the late mortality rate by 30%, prevented neutrophil accumulation in lungs, decreased TNF-α and IL-1ß serum levels, and markedly decreased iNOS and COX-2 protein expression by ileum cells. Chemical investigation showed myricetin and quercetin rhamnosides as the major components of this fraction. The results showed that HE-Bu protected mice from sepsis and indicated that this edible plant produces compounds that could be considered as potential adjuvants for sepsis treatment.

Standardized extract of Dicksonia sellowiana Presl. Hook (Dicksoniaceae) decreases oxidative damage in cultured endothelial cells and in rats.

AIMS: Aging and a variety of pathologies, including cancer, diabetes, cardiovascular and inflammatory diseases have been associated with reactive oxygen species (ROS), such as superoxide anion (O2·â»), hydroxyl radical (·OH) and hydrogen peroxide (H2O2) generation. Plant polyphenols bear radical scavenging/antioxidant activity. A phytomedicinal preparation obtained from aerial parts of Dicksonia sellowiana (Dicksoniaceae), a native plant from Central and South America, has been widely used in Brazil against asthma and presents beneficial effects in several other diseases, including cardiovascular disturbance. In this work, we investigated whether Dicksonia sellowiana, which is also known to contain high levels of polyphenols, presents antioxidant activity. METHODS: The antioxidant activity of the hydroalcoholic extract obtained from Dicksonia sellowiana leaves (HEDS) was investigated by in vitro and in vivo tests. RESULTS: HEDS (0.1-100 µg/mL) exhibited a strong scavenging activity against all reactive species tested (DPPH, O2·â»,·OH and H2O2; IC50=6.83±2.05, 11.6±5.4, 2.03±0.4, and 4.8±0.4 µg/mL, respectively). HEDS strongly protected endothelial cells against H2O2-induced oxidative stress by mechanisms other than increasing catalase activity. In addition, HEDS protected cell membrane from oxidative damage. HEDS, (20 and 40 mg/kg) inhibited lipid peroxidation in vivo (29.8% and 24.5%, respectively). CONCLUSIONS: According to our results, we can speculate that the traditional uses of Dicksonia sellowiana for cardiovascular diseases, asthma and skin diseases could be, at least in part, related to the potent antioxidant and endothelial protective activities of the plant.

A potent and nitric oxide-dependent hypotensive effect induced in rats by semi-purified fractions from Maytenus ilicifolia.

The aim of this study is to investigate whether extracts and semi-purified fractions obtained from Maytenus ilicifolia leaves have vascular effects in vivo.We tested the ethanolic supernatant of the infusion (ESI), and the ethanolic supernatant of the aqueous extract (ESAE) on the mean arterial pressure (MAP) and heart rate(HR) of anesthetized rats. Intravenous injection of ESAE caused a dose-dependent effect at 10, 20 and 30 mg/kg, reducing MAP by as much as 52.6 +/- 5.5 mmHg. Only the highest dose of ESAE (30 mg/kg) caused a significant reduction in HR during its hypotensive effect. The effect of ESAE was unchanged by atropine,propranolol, or bilateral vagotomy, but was significantly reduced (80%) in animals continuously infused with L-NAME. In addition, methylene blue and ODQ, as well as the potassium channel blockers tetraethylammonium,4-aminopyridine, and glibenclamide, impaired ESAE-induced hypotension. The ethyl acetate fraction(EAF) obtained from ESAE had a potency at least two times greater than ESAE in MAP, without causing any significant change in HR. The hypotension induced by EAF was circumvented by L-NAME, methylene blue andODQ, strongly reduced by tetraethylammonium and 4-aminopyridine (but not by glibenclamide), and abolished by association of these three potassium channel blockers. Chemical investigation revealed that flavonols, mainly catechin and epicatechin, as well as flavonol glycosides (mono- to triglycosides), and tannins, are the main components of this fraction. Our results demonstrate that preparations obtained from M. ilicifolia present a potent hypotensive effect in vivo, an event predominantly dependent on the nitricoxide/guanylate cyclase pathway.

Activation of muscarinic receptors by a hydroalcoholic extract of Dicksonia sellowiana Presl. HooK (Dicksoniaceae) induces vascular relaxation and hypotension in rats.

Dicksonia sellowiana (Presl.) Hook is a native plant from the Central and South Americas that contain high levels of polyphenols, antioxidant compounds involved in protection against inflammation, cancer and cardiovascular risk. A phytomedicinal preparation obtained from aerial parts of D. sellowiana is currently under clinical evaluation in Brazil against asthma, and has been associated with several other beneficial effects. This study demonstrates that a hydroalcoholic extract obtained from D. sellowiana leaves (HEDS) fully relax, in a concentration-dependent manner, rat aortic rings precontracted with phenylephrine. Moreover, administration of HEDS (10, 20 and 40 mg/kg, i.v.) in anaesthetized rats resulted in a strong but reversible hypotension. Aortic relaxation induced by HEDS was abolished by endothelium removal, by incubation of the nitric oxide synthase inhibitor L-NAME, or the soluble guanylate cyclase inhibitor ODQ. In addition, this effect was partially inhibited by indomethacin (a cyclooxygenase inhibitor) and KT 5730 (a PKA inhibitor). The potassium channels blockade by either tetraethylammonium or charybdotoxin also resulted in a potent inhibition of HEDS-induced aortic relaxation, whereas apamine only slightly reduced it. In addition HEDS-induced relaxation was unchanged by 4-amynopiridine and glibenclamide. The selective muscarinic receptor antagonist atropine counteracted both aortic relaxation and blood pressure reduction generated by HEDS. Experiments using HPLC revealed the presence of high amounts of phenolic compounds in this extract. Taken together, our results reveal that the D. sellowiana possess substances with both in vivo and in vitro activities and that the vascular effect of HEDS involves activation of muscarinic receptors, stimulation of the nitric oxide pathway and opening of calcium-activated potassium channels.

Morinda citrifolia Linn (Noni): in vivo and in vitro reproductive toxicology.

UNLABELLED: Morinda citrifolia Linn (syn. Noni) is a plant widely used as food and medicine worldwide but there are no toxicological tests about this plant focused on reproduction. AIM OF THE STUDY: To investigate possible endocrine activity and toxic effect on the reproductive system of Wistar rats by exposure of aqueous extract of the Morinda citrifolia. MATERIALS AND METHODS: Two experimental protocols in vivo were developed, (a) uterotrophic assay and (b) in utero and lactational assay, and one test in vitro to investigate the effect on the contractility of pregnant uteri isolated from rats (doses of the extract: 7.5, 75 and 750 mg/kg). RESULTS: The uterotrophic assay indicates presence of in vivo antiestrogenic activity of extract at doses of 7.5 and 750 mg/kg. The in utero and lactation exposure showed that the treatment with extract at the dose of 7.5mg/kg induced a reduction of 50% in parturition index and an increase of 74% in postimplantation losses index. The in vitro test showed that uteri from rats treated with 7.5mg/kg of the extract presented a 50% reduction on contraction induced by arachidonic acid. CONCLUSION: The exposure of aqueous extract of Morinda citrifolia in Wistar rats induced reproductive toxicity in nonlinear dose-response.

Vascular permeability and vasodilation induced by the Loxosceles intermedia venom in rats: involvement of mast cell degranulation, histamine and 5-HT receptors.

The mechanisms involved in both local and systemic effects of Loxosceles intermedia (brown spider) venom (LIV) are still poorly understood. We show using rats treated with Evans blue dye (50 mg/kg, i.v.) that small doses of the LIV (0.1, 0.3, 1 and 3 microg/site) dose-dependently increase the vascular permeability in rats, an effect unchanged by indomethacin (5mg/kg, i.p.), atropine (1mg/kg, i.p.), HOE-140 (2mg/kg, s.c.) or SR140333 (0.3mg/kg, i.p.), but fully avoided by promethazine (15 mg/kg, i.p.), methysergide (2mg/kg, i.p.) and compound 48/80 (3mg/kg/day for 3 days). Addition of cumulative concentrations of LIV (0.1-5 microg) in phenylephrine-contracted aortic rings resulted in a partial ( approximately 40%) and endothelium-dependent relaxation, inhibited by the nitric oxide synthase inhibitors L-NAME (10 microM) and L-NMMA (1mM), and the guanylate cyclase inhibitors methylene blue (100 microM) and ODQ (10 microM). LIV-induced relaxation was abolished by compound 48/80 (10 microM) and pyrilamine (a selective histamine H1 receptor antagonist; 100 microM), but not by atropine (1 microM) and indomethacin (10 microM). Our results disclose that LIV increases vascular permeability and induces vascular relaxation. These effects occur due to its ability to degranulate mast cells and release mediators such as histamine and serotonin.

Nitric oxide-dependent vasorelaxation induced by extractive solutions and fractions of Maytenus ilicifolia Mart ex Reissek (Celastraceae) leaves.

This study reveals that an ethanolic supernatant obtained from an aqueous extractive solution prepared from residues of methanolic extracts of ground leaves of Maytenus ilicifolia is able to cause a concentration- and endothelium-dependent relaxation in pre-contract rat aorta rings, with EC(50) of 199.7 (190-210) microg/ml. The non-selective nitric oxide synthase inhibitors l-NAME and l-NMMA abolished this effect, while superoxide dismutase and MnTBAP (a non-enzymatic superoxide dismutase mimetic) enhanced it. Further, relaxation induced by this ethanolic supernatant have been strongly inhibited by the guanylate cyclase inhibitors methylene blue and ODQ, as well as by the potassium channel blockers 4-aminopyridine and tetraethylammonium, but was unchanged by the cyclooxygenase inhibitor indomethacin and the membrane receptor antagonists atropine, HOE-140 and pirilamine. Partition of the ethanolic supernatant between H(2)O and EtOAc generated a fraction several times more potent, able to fully relax endothelium-intact aorta rings with an EC(50) of 4.3 (3.9-4.8) microg/ml. (13)C NMR spectrum of this fraction showed signals typical of catechin. This study reveals that the leaves of M. ilicifolia possess one or more potent substances able to relax endothelium-intact rat aorta rings, an event that appears to involve nitric oxide production, guanylate cyclase activation and potassium channel opening.

Effects of alkaloids of Himatanthus lancifolius (Muell. Arg.) Woodson, Apocynaceae, on smooth muscle responsiveness.

Himatanthus lancifolius, popularly known as "agoniada" in Brazil, is largely used in folk medicine against asthma, dysmenorrhea and as an emenagogue and abortive. This study reveals the effects of an alkaloid rich fraction (AlkF) obtained from the bark of Himatanthus lancifolius in vascular and non-vascular smooth muscle responsiveness. Incubation of AlkF (3-30 microg/ml) during 15 min generates a concentration-related and fully reversible reduction in maximal contractile responses evoked by acetylcholine and phenylephrine in rat jejune and aorta preparations, respectively. Exposition of endothelium-denuded pre-contracted rat aorta rings to AlkF results in a complete relaxation, with EC(50) of 22.2 (16.2-28.2 microg/ml). AlkF is also able to induce a concentration-related rightward shift of cumulative concentration curves for calcium in uterus and aorta rings maintained in depolarizing nutritive solution. Moreover, addition of AlkF in calcium-free solution also reduces, in a concentration-dependent manner, the ability of caffeine and phenylephrine to contract aorta rings. This study reveals that the bark of Himatanthus lancifolius possesses one or more indole alkaloids able to alter non-vascular and vascular smooth muscle responsiveness, an event that may involve the blocking of calcium entry or changes on intracellular calcium utilization or mobilization.