Lyotropic liquid crystal mesophases as transdermal delivery systems for lipophilic drugs: A comparative study.

The present work aimed to evaluate different Liquid Crystal Mesophases (LCM) as transdermal drug delivery systems (TDDS) for nifedipine (NFD), a lipophilic drug model. The formulations composed of water, Citrus sinensis essential oil (CSEO), PPG-5-CETETH-20, and Olive oil ester PEG-7 were obtained and characterized by polarized light microscopy (PLM), rheology, small-angle x-ray scattering (SAXS), Fourier transform infrared coupled with an attenuated total reflection accessory (FTIR-ATR) and in vitro assays: bioadhesion, drug release, skin permeation, and retention tests. As a result, changes in component proportions led to several transparent viscous systems with an anisotropic profile. PLM and SAXS proved the presence of lamellar (S1), hexagonal (S3), and lamellar + hexagonal (S2) LCM, and rheology showed a high viscoelasticity profile. LCMs were able to adhere to the skin, and S2 achieved higher adhesion strength. NFD (5 mg/mL) has not modified the organization of LCMs. Results also showed that S3 promoted higher permeation and retention and higher disorganization of stratum corneum lipids, which is the main permeation-enhancing mechanism. Thus, the formulations obtained can carry and improve drug delivery through the skin and are promising TDDS for lipophilic drug administration, such as NFD.

Phytochemical screening and cardiovascular effects of the ethanol extract of Erythroxylum passerinum mart.

Species of Erythroxylum genus are popularly used as anti-inflammatories and in the treatment of renal and respiratory disorders. Although it has been reported that species from the Erythroxylum genus induce cardiovascular effects, E. passerinum had not been studied specifically in this respect. However, previous phytochemical studies of E. passerinum demonstrated the presence of compounds which can have potential activity on the cardiovascular system. In this study, phytochemical screening of the ethanol extract of E. passerinum (EEEP) detected polyphenols, but not alkaloids. EEEP caused hypotension, bradycardia and vasorelaxation in rats. The vasorelaxation was attenuated by Nw-nitro-L-arginine methyl ester (L-NAME) or L-NAME + indomethacin (INDO), but not by INDO alone. Vasorelaxation was also significantly attenuated after endothelium removal or after incubation with high K+, 4-aminopyridine, glibenclamide or tetraethylammonium, but was not affected by pre-contraction with serotonin. Thus, EEEP induces hypotension and endothelium-dependent and independent vasorelaxation, which seems to involve the nitric oxide and K+-channels.

HPLC-DAD-UV analysis, anti-inflammatory and anti-neuropathic effects of methanolic extract of Sideritis bilgeriana (lamiaceae) by NF-κB, TNF-α, IL-1ß and IL-6 involvement.

Medicinal plants remain an invaluable source for therapeutics of diseases that affect humanity. Sideritis bilgeriana (Lamiaceae) is medicinal plant used in Turkey folk medicine to reduce inflammation and pain, but few studies scientific corroborates its medicinal use so creating a gap between popular use and scientific evidence. Thus, we aimed to evaluate the pharmacological effects of the methanolic extract of S. bilgeriana (MESB) in rodents nociception models and also performed its phytochemical analysis. Firstly, a screening was carried out that enabled the identification of the presence of phenolic compounds and flavonoids. In view of this, a chromatographic method by HPLC-DAD-UV was developed that made it possible to identify chlorogenic acid and its quantification in MESB. MESB-treated mice (MESB 50, 100 and 200 mg/kg, p.o.) reduced mechanical hyperalgesia and myeloperoxidase activity (p < 0.01), and also showed a reduced pain behavior in capsaicin test. In the carrageenan-induced pleurisy test, MESB (100 mg/kg p.o.) significantly reduced the leukocyte (polymorphonuclear) count in the pleural cavity and equally decreased the TNF-α and IL-1ß levels (p < 0.001). In the PSNL model, mechanical hyperalgesia was reduced on the first evaluation day and during the 7 days of evaluation compared to the vehicle group (p < 0.001). Thermal hyperalgesia was also reduced 1 h after treatment compared to the vehicle group (p < 0.001) and reversed the loss of force initially displayed by the animals, thus inferring an analgesic effect in the muscle strength test. Analysis of the marrow of these animals showed a decrease in the level of pro-inflammatory cytokine IL-6 (p < 0.001) and factor NF-κB, in relation to the control group (p < 0.05). Moreover, the MESB treatment produced no noticeable side effects, no disturb in motor performance and no signs of gastric or hepatic injury. Together, the results suggests that MESB could be useful to management of inflammation and neuropathic pain mainly by the management of pro-inflammatory mediators (NF-κB, TNF-α, IL-1ß and IL-6), so reinforcing its use in popular medicine and corroborating the need for further chemical and pharmacological studies for the species.

Dereplication and quantification of the ethanol extract of Miconia albicans (Melastomaceae) by HPLC-DAD-ESI-/MS/MS, and assessment of its anti-hyperalgesic and anti-inflammatory profiles in a mice arthritis-like model: Evidence for involvement of TNF-α, IL-1ß and IL-6.

ETHNOPHARMACOLOGICAL RELEVANCE: Miconia albicans (Sw) Triana (Melastomataceae), a medicinal plant widely used by practitioners of folk medicine in the northeast of Brazil, has been used to treat chronic inflammatory disorders, such as rheumatoid arthritis (RA) and other joint conditions. Oddly, there is little research on the species. AIM OF THE STUDY: We aimed to evaluate the anti-arthritic and anti-inflammatory profile of the ethanolic leaf extract of M. albicans (EEMA), as well as to perform dereplication and quantification by HPLC-DAD-ESI-/MS/MS. MATERIALS AND METHODS: The compounds present in the extracts were identified by HPLC-DAD-ESI-MS/MS. The possible anti-inflammatory effect of EEMA (50 and 100 mg/kg, p.o) was evaluated using the pleurisy model induced by carrageenan and its action on IL-1ß and TNF-α levels was also evaluated. The RA model was induced through the intra-articular injection of complete Freund's adjuvant (CFA). RESULTS: HPLC-DAD-ESI-MS/MS analysis identified 23 compounds, with glycoside flavonoids mainly derived from quercetin, and rutin being the main compounds. EEMA significantly reduced (p < 0.001) leukocyte migration in the pleurisy model and reduced TNF-α and IL-1ß levels in pleural lavage (p < 0.001). In the CFA animal model, EEMA significantly reduced the nociceptive and hyperalgesic behaviors demonstrated by the rearing test (p < 0.01 or p < 0.05) and decreased mechanical hyperalgesia (p < 0.001). EEMA produced a significant improvement in mobility in the open-field test (only at the higher dose, p < 0.05). EEMA significantly (p < 0.01) increased hindpaw grip strength. The diameter of CFA-induced ipsilateral knee edema was significantly reduced (p < 0.001) by EEMA, which was related to reduced levels of IL-6 and TNF-α in the joint knee (p < 0.01). No indication of hepatic injury after chronic treatment was found. CONCLUSION: Taken together, these results contribute to the chemical and pharmacological knowledge of M. albicans and demonstrated that this medicinal plant appears to be able to mitigate deleterious symptoms of RA, which supports its use in folk medicine.

Eplingiella fruticosa (Lamiaceae) essential oil complexed with ß-cyclodextrin improves its anti-hyperalgesic effect in a chronic widespread non-inflammatory muscle pain animal model.

Eplingiella fruticosa (Lamiaceae), formally known as Hyptis fruticosa, is an important aromatic medicinal herb used in folk medicine in northeastern Brazil. We aimed to evaluate the anti-hyperalgesic effect of essential oil obtained from E. fruticosa (HypEO) complexed with ßCD (HypEO-ßCD) in a chronic widespread non-inflammatory muscle pain animal model (a mice fibromyalgia-like model, FM). The HypEO was extracted by hydro distillation and its chemical composition was determined by GC-MS/FID. Moreover, Fos protein expression in the spinal cord was assessed by immunofluorescence. (E)-caryophyllene, bicyclogermacrene, 1,8-cineole, α-pinene, ß-pinene and 21 other compounds were identified in the HypEO. The treatment with HypEO-ßCD produced a longer-lasting anti-hyperalgesic effect compared to HypEO, without alterations in motor coordination or myorelaxant effects. Moreover, HypEO and HypEO-ßCD produced a significant anti-hyperalgesic effect over 7 consecutive treatment days. Immunofluorescence assay demonstrated a decrease in Fos protein expression in the spinal cord (p < 0.001). We demonstrated that the anti-hyperalgesic effect produced by HypEO was improved after complexation with ß-CD and this seems to be related to the central pain-inhibitory pathway, suggesting the possible use of E. fruticosa for chronic pain management.

Development of morin/hydroxypropyl-ß-cyclodextrin inclusion complex: Enhancement of bioavailability, antihyperalgesic and anti-inflammatory effects.

Morin is a flavonoid has been reported with several pharmacological effects such as, antioxidant, anti-inflammatory, anticancer, antidiabetic, etc. However, morin has low solubility in water, which decreases the bioavailability and limits its clinical application. In this way, to improve the pharmaceutical properties, morin was complexed in hydroxypropyl-ß-cyclodextrin (HP-ß-CD) and its oral bioavailability and anti-inflammatory effects were evaluated. Initially, a phase solubility study was performed, which showed that HP-ß-CD would be the better cyclodextrin for the formation of complexes with morin. The morin/HP-ß-CD inclusion complex (1:1) was prepared by freeze-drying method. The sample obtained was characterized by DSC, FTIR, PXRD, SEM and 1H NMR techniques, evidencing the formation of morin/HP-ß-CD inclusion complex. In addition, complexation efficiency (98.3%) and loading content (17.63%), determined by HPLC demonstrated that morin was efficiently complexed in HP-ß-CD. In vitro dissolution study confirmed that morin/HP-ß-CD inclusion complex increased the solubility and dissolution rate of morin. The oral bioavailability of the morin/HP-ß-CD complex and free morin were evaluated through a pharmacokinetic study in rat plasma. The oral bioavailability of morin complexed with HP-ß-CD was increased by 4.20 times compared with the free morin. Hyperalgesia induced by carrageenan and carrageenan-induced pleurisy were carried out in mice to evaluate the antihyperalgesic and anti-inflammatory activities of free morin and inclusion complex. Morin/HP-ß-CD inclusion complex showed antihyperalgesic effect in inflammatory pain model and anti-inflammatory effect decreasing leukocyte migration and TNF-α levels at a lower dose than free morin. Therefore, the morin/HP-ß-CD inclusion complex improved the solubility, dissolution rate, oral bioavailability, antihyperalgesic and anti-inflammatory effects of morin. In this way, the morin/HP-ß-CD inclusion complex exhibits potential for development of new pharmaceutical product for future clinical applications.

Computational Approaches in Multitarget Drug Discovery.

Current therapeutic strategies entail identifying and characterizing a single protein receptor whose inhibition is likely to result in the successful treatment of a disease of interest, and testing experimentally large libraries of small molecule compounds "in vitro" and "in vivo" to identify promising inhibitors in model systems and determine if the findings are extensible to humans. This highly complex process is largely based on tests, errors, risk, time, and intensive costs. The virtual computational study of compounds simulates situations predicting possible drug linkages with multiple protein target atomic structures, taking into account the dynamic protein inhibitor, and can help identify inhibitors efficiently, particularly for complex drug-resistant diseases. Some discussions will relate to the potential benefits of this approach, using HIV-1 and Plasmodium falciparum infections as examples. Some authors have proposed a virtual drug discovery that not only identifies efficient inhibitors but also helps to minimize side effects and toxicity, thus increasing the likelihood of successful therapies. This chapter discusses concepts and research of bioactive multitargets related to toxicology.

The ethanol extract of Leonurus sibiricus L. induces antioxidant, antinociceptive and topical anti-inflammatory effects.

ETHNOPHARMACOLOGICAL RELEVANCE: Leonurus sibiricus L. (Lamiaceae), popularly known as motherwort, or "erva-de-macaé" or "rubim" in Brazil, is a plant used for the treatment of inflammatory conditions, but few studies have evaluated this anti-inflammatory activity or other activities that may be relevant. AIM OF THE STUDY: This study was undertaken to investigate the antioxidant, antinociceptive and topical anti-inflammatory effects of the ethanol extract of L. sibiricus (EELs). MATERIALS AND METHODS: Chromatographic analysis, determination of total phenolic and flavonoid contents and in vitro antioxidant assays were performed, while the formalin test and ear inflammation induced by 12-0-tetradecanoylphorbol-13-acetate (TPA) were performed in mice. RESULTS: We observed that total phenolic and flavonoids content in EELs were respectively 60.1mg of gallic acid equivalent/g of extract and 15.4mg of catechin equivalent/g of extract. Chlorogenic, caffeic, p-coumaric and ferulic acids, as well as quercetin were identified in EELs. This extract also led to the consumption of the radicals 2,2-diphenyl-1-picrylhydrazyl, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) and nitric oxide, increased the ferric reducing/antioxidant power (FRAP) and inhibited the spontaneous or FeSO4-induced in vitro lipid peroxidation. In the formalin test, oral pretreatment with EELs (400mg/kg) reduced (p<0.001) the licking/biting time in the second phase, but not in the first phase. In the ear inflammation induced by TPA, the concomitant topical administration of EELs (0.3-3mg/ear) significantly reduced the edema, myeloperoxidase activity, levels of tumoral necrosis factor-α and interleukin-1ß and lipoperoxidation, as well as increased FRAP in ear tissue when compared to vehicle-treated ears. CONCLUSIONS: These results indicate that EELs has antioxidant, antinociceptive and topical anti-inflammatory activities, supporting the use of this plant in folk medicine.

Essential oil from fruit of Xylopia langsdorffiana: antitumour activity and toxicity.

CONTEXT: The genus Xylopia L. (Annonaceae) includes aromatic plants that have both nutritional and medicinal uses. Essential oils of Xylopia species have antitumour effects. However, the efficacy of the essential oil from the fruit of Xylopia langsdorffiana St. Hil & Tul. (EOX) has not been examined. OBJECTIVE: EOX was evaluated to determine its chemical composition, antitumour activity and toxicity. MATERIALS AND METHODS: EOX was obtained from fresh fruits of X. langsdorffiana subjected to hydrodistillation, and gas chromatography-mass spectrometry was used to characterize the chemical composition of EOX. The toxicity of EOX was evaluated using haemolysis, acute toxicity and micronucleus assays. The in vitro antitumour activity of EOX was investigated using the sulforhodamine B assay. The sarcoma 180 murine tumour model was used to evaluate the in vivo antitumour activity and toxicity of EOX (50 and 100 mg/kg) after 7 d of treatment. RESULTS: The major components of EOX were α-pinene (34.57%) and limonene (31.75%). The HC50 (concentration producing 50% haemolysis) was 293.6 µg/ml. EOX showed greater selectivity for the leukaemia cell line K562, with total growth inhibition (TGI) (concentration producing TGI) of 1.8 µg/ml, and for multidrug-resistant ovarian tumour cell line NCI/ADR-RES (TGI of 45.4 µg/ml). The LD50 was approximately 351.09 mg/kg. At doses of 50 and 100 mg/kg, EOX inhibited the in vivo growth of sarcoma 180 by 38.67 and 54.32%, respectively. EOX displayed minor hepatic alterations characteristic of acute hepatitis and induced no genotoxicity. CONCLUSION: EOX showed in vitro and in vivo antitumour activity and low toxicity, which warrants further pharmacological studies.

Structure­activity relationship of terpenes with anti-inflammatory profile ­ a systematic review.

Inflammation is a complex biological response that in spite of having available treatments, their side effects limit their usefulness. Because of this, natural products have been the subject of incessant studies, among which the class of terpenes stands out. They have been the source of study for the development of anti-inflammatory drugs, once their chemical diversity is well suited to provide skeleton for future anti-inflammatory drugs. This systematic review reports the studies present in the literature that evaluate the anti-inflammatory activity of terpenes suffering any change in their structures, assessing whether these changes also brought changes in their effects. The search terms anti-inflammatory agents, terpenes, and structure­activity relationship were used to retrieve English language articles in SCOPUS, PUBMED and EMBASE published between January 2002 and August 2013. Twenty-seven papers were found concerning the structural modification of terpenes with the evaluation of antiinflammatory activity. The data reviewed here suggest that modified terpenes are an interesting tool for the development of new anti-inflammatory drugs.

A systematic review for anti-inflammatory property of clusiaceae family: a preclinical approach.

Background. Clusiaceae family (sensu lato) is extensively used in ethnomedicine for treating a number of disease conditions which include cancer, inflammation, and infection. The aim of this review is to report the pharmacological potential of plants of Clusiaceae family with the anti-inflammatory activity in animal experiments. Methods. A systematic review about experiments investigating anti-inflammatory activity of Clusiaceae family was carried out by searching bibliographic databases such as Medline, Scopus and Embase. In this update, the search terms were "anti-inflammatory agents," "Clusiaceae," and "animals, laboratory." Results. A total of 255 publications with plants this family were identified. From the initial 255 studies, a total of 21 studies were selected for the final analysis. Studies with genera Allanblackia, Clusia, Garcinia or Rheedia, and Hypericum showed significant anti-inflammatory activity. The findings include a decrease of total leukocytes, a number of neutrophils, total protein concentration, granuloma formation, and paw or ear edema formation. Other interesting findings included decreased of the MPO activity, and inflammatory mediators such as NF- κ B and iNOS expression, PGE2 and Il-1 ß levels and a decrease in chronic inflammation. Conclusion. The data reported suggests the anti-inflammatory effect potential of Clusiaceae family in animal experiments.