Artemether and lumefantrine dissolving microneedle patches with improved pharmacokinetic performance and antimalarial efficacy in mice infected with Plasmodium yoelii.

Malaria affects more than 200 million people annually around the world, killing a child every 2 min. Artemether (ART) and lumefantrine (LUM) are the gold standard choice to treat uncomplicated Plasmodium falciparum malaria; however, they are hydrophobic compounds with low oral bioavailability. Microneedle (MN) arrays consist of micron-sized needles on one side of a supporting base and have the ability to bypass the skin's stratum corneum barrier in a minimally invasive way, creating temporary channels through which drugs can diffuse, including those with poor water solubility. Herein, we report the development of dissolving MNs (DMNs) containing ART (MN-ART) and LUM (MN-LUM) as an alternative treatment regimen for malaria in low-resource settings. To incorporate the drugs into the MNs, nanosuspensions (NSs) for both molecules were developed separately to enhance drug solubility. The NSs were freeze-dried and the powder form was incorporated directly in an aqueous polymeric blend with poly-vinyl-pyrrolidone for MN-ART and a sodium hyaluronate hydrogel for MN-LUM. The in vivo bioavailability studies were performed using a MN reapplication scheme (1 × a day for 3 days), illustrating that an extended-release profile was achieved for both drugs when MNs were applied intradermally, and when compared to conventional oral treatment. The ART-LUM oral treatment was used as a positive control. For antimalarial activity, studies with animals infected with 106Plasmodium yoelii 17XNL (12 days) were also conducted using female C57BL/6JUnib mice, demonstrating a 99.5% reduction in parasitemia by day 12 post-infection. By abolishing the infection, MN-ART and MN-LUM may serve as a promising controlled intradermal delivery device for antimalarial drugs to be explored in endemic areas.

Efficient synthesis and antitumor evaluation of 4-aminomethyl-N-arylpyrazoles: Discovery of potent and selective agents for ovarian cancer.

A new one-pot two-step sequential methodology for synthesis of novel 3-carboxyethyl 4-[(tert-butylamino)methyl]-N-arylpyrazole derivatives is reported. One-pot transformation of ß-enamino diketones and arylhydrazines generated 4-iminium-N-arylpyrazole salt intermediates in situ, which were easily transformed into 4-[(tert-butylamino)methyl]-N-arylpyrazole derivatives by NaBH3CN. The products could be isolated in the free or hydrochloride salt forms. Also, it was possible to obtain the products in the zwitterionic form by ester group hydrolysis. Furthermore, all synthesised compounds were evaluated in vitro against a panel of eight human tumor cell lines. The 4-[(tert-butylamino)methyl]-N-arylpyrazole derivatives were much more powerful than the hydrochloride and zwitterionic forms. Moreover, the results suggest that the N-aryl group at the pyrazole ring is vital for modulating antiproliferative activity. The 3-carboxyethyl 4-[(tert-butylamino)methyl]-N-phenylpyrazoles 3a-g exhibited higher inhibitory activities against OVCAR-3, with GI50 values of 0.013-8.78 µM, and lower inhibitory activities against normal human cell lines. Molecular docking was performed to evaluate the probable binding mode of 3a into active site of CDK2.

Structural Characterization and Biological Evaluation of 18-Nor-ent-labdane Diterpenoids from Grazielia gaudichaudeana.

The phytochemical investigation of Grazielia gaudichaudeana aerial parts yielded 15 compounds, including diterpenes, triterpenes, sterols and flavonoids. With exception to ent-kaurenoic acid diterpenes, the compounds isolated are being described for the first time in this species. Some unusual 1 H-NMR chemical shifts of 18-nor-ent-labdane (7-9) led us carry out a conformational analysis by theoretical calculations in order to support the experimental data. Moreover, due to the limitation of studies focused on pharmacological potential of Grazielia gaudichaudeana, the present study was carried out to investigate the antioxidant, antiproliferative, antiviral, antileishmanial and antimicrobial activities from the extract, fractions and isolated compounds obtained from this species. Ethyl acetate fraction showed significant activity in the antiproliferative assay, with GI50 range of 3.9 to 27.2 µg mL-1 . Dichloromethane fraction, rich in diterpenoids, inhibited all human tumor cell lines tested, and the nor-labdane 7 showed potent cytotoxic activity against glioma and ovary cancer cell lines.

Morfologia do órgão vomeronasal da paca (Cuniculus paca Linnaeus, 1766) / Morphology of the paca vomeronasal organ (Cuniculus paca Linnaeus, 1766)

O órgão vomeronasal é um receptor químico capaz de detectar feromônios e por essa razão está envolvido nos comportamentos reprodutivos, sociais e de defesa. A reprodução de pacas tem se destacado na área de comercialização de carne e para fins conservacionistas e de pesquisa, como modelo experimental. Diante da necessidade do detalhamento da morfologia do sistema olfatório secundário, o sistema vomeronasal, foi descrita a anatomia macroscópica, anatomia microscópica e topografia do órgão vomeronasal (OVN) da paca (Cuniculus paca). Foram utilizadas cinco pacas adultas do Setor de Animais Silvestres da FCAV, UNESP, Jaboticabal-SP. Após a eutanásia dos animais, a solução fixadora de formaldeído 10% em tampão fosfato de sódio (PBS) foi perfundida sistemicamente (via aorta ascendente). Mediante dissecação, o OVN foi localizado e individualizado para a descrição topográfica e anatômica. Posteriormente, foi isolado e incluído em parafina plástica. Cortes de cinco micrômetros foram corados com Hematoxilina-Eosina. O OVN encontra-se no assoalho da cavidade nasal em ambos os lados da base do septo nasal e está relacionado com o osso vômer, processos palatinos dos ossos pré-maxilar e maxilar. Rostralmente, comunica-se com a cavidade oral estabelecendo relação com a papila incisiva. É um órgão par com superfície irregular, levemente elíptico em secção transversal, apresentando coloração amarronzada repleta de vasos sanguíneos. À microscopia de luz, notou-se presença da cartilagem vomeronasal. O órgão é revestido por um epitélio não sensorial e neurossensorial.(AU)

The vomeronasal organ is a chemical receptor capable of detecting pheromones and for this reason is involved in reproductive, social and defense behaviors. The breeding of pacas has been highlighted in commercialization of meat and for conservation and research purposes, as an experimental model. Regarding the necessity of detailing the morphology of the secondary olfactory system, the vomeronasal system, the macroscopic anatomy, microscopic anatomy and topography of the vomeronasal organ (OVN) was described. Five adult pacas, from the wild animal Sector at FCAV, Unesp, Jaboticabal, SP were used. After the euthanasia, it was perfused 10% formaldehyde solution by ascendent aorta. The OVN was dissected for topographic and anatomical descriptions. Then, it was included in plastic paraffin. Five micrometres sections were collected and stained with hematoxylin and eosin. The OVN is located on the floor of the nasal cavity in both sides of the base of nasal septum and it was related to the vomer, palatine process of the premaxilar and maxilar bones. In rostral aspect, it has a communication with the oral cavity and with the incisive papilla. It is a paired organ with irregular surface. In transversal section is slight elliptical with brownish colour similar to a sponge full of blood vessels. By light microscopy, it was observed the vomeronasal cartilage. The organ is covered with non-sensorial and neurossensorial epithelia.(AU)

Derivatives of furanditerpenes from Pterodon genus: Pharmacological studies disclose their potential as chronic pain relief in mice.

Pterodon genus fruits are commercially available at the Brazilian medicinal market used in folk medicine due to their anti-inflammatory, analgesic, and anti-rheumatic effects. Previous studies demonstrated that furanditerpenes possessing vouacapan skeleton, isolated from Pterodon genus, possess expressive antinociceptive activities, with promising moiety for the development of new analgesic products. The antinociceptive properties of compounds 6α,7ß-6α-hidroxivouacapan-7ß-17ß-lactone (HVL) and 6α-oxovouacapan-7ß-17ß-lactone (OVL), semi-synthetic analogues of furanditerpenes previously reported as analgesic agents were evaluated on animal experimental models (Spindola et al., 2010, 2011). The chemical-induced pain methods used in the present work, demonstrated for the first time that both compounds HVL and OVL have potential as important templates for the development of chronic pain control drugs. The main findings of this work were that both compounds were: effective in the writhing test; reduced paw edema in the carrageenan test; effective in the inflammatory phase of the formalin test corroborating their activity against inflammatory pain conditions; effective on reducing pain through the stimulation of vanilloid receptors sensible to capsaicin (an important pathway for chronic pain maintenance); reduced the pain stimulus caused by PGE2 injection (a pathway involved in chronic pain hypersensitivity); effective on decreasing mechanical allodynia in the CFA-model, demonstrating their potential use against chronic pain disorders.