João Xavier de Araújo-Júnior

The Antinociceptive and Anti-Inflammatory Activities of Caulerpin, a Bisindole Alkaloid Isolated from Seaweeds of the Genus Caulerpa

The antinociceptive and anti-inflammatory activity of caulerpin was investigated. This bisindole alkaloid was isolated from the lipoid extract of Caulerpa racemosa and its structure was identified by spectroscopic methods, including IR and NMR techniques. The pharmacological assays used were the writhing and the hot plate tests, the formalin-induced pain, the capsaicin-induced ear edema and the carrageenan-induced peritonitis. Caulerpin was given orally at a concentration of 100 μmol/kg. In the abdominal constriction test caulerpin showed reduction in the acetic acid-induced nociception at 0.0945 μmol (0.0103–1.0984) and for dypirone it was 0.0426 μmol (0.0092–0.1972). In the hot plate test in vivo the inhibition of nociception by caulerpin (100 μmol/kg, p.o.) was also favorable. This result suggests that this compound exhibits a central activity, without changing the motor activity (seen in the rotarod test). Caulerpin (100 μmol/kg, p.o.) reduced the formalin effects in both phases by 35.4% and 45.6%, respectively. The possible anti-inflammatory activity observed in the second phase in the formalin test of caulerpin (100 μmol/kg, p.o.) was confirmed on the capsaicin-induced ear edema model, where an inhibition of 55.8% was presented. Indeed, it was also observed in the carrageenan-induced peritonitis that caulerpin (100 μmol/kg, p.o.) exhibited anti-inflammatory activity, reducing significantly the number of recruit cells by 48.3%. Pharmacological studies are continuing in order to characterize the mechanism(s) responsible for the antinociceptive and anti-inflammatory actions and also to identify other active principles present in Caulerpa racemosa.

Antinociceptive and Anti-Inflammatory Activity from Algae of the Genus Caulerpa

Marine natural products have been the focus of discovery for new products of chemical and pharmacological interest. The aim of this study was to evaluate the antinociceptive activity of the methanolic (ME), acetate (AE), hexanic (HE) and chloroform (CE) extracts obtained from Caulerpa mexicana, and ME, CE and HE obtained from Caulerpa sertularioides. These marine algae are found all over the world, mainly in tropical regions. Models such as the writhing test, the hot plate test and formalin-induced nociception test were used to evaluate antinociceptive activity in laboratory mice. In the writhing test, all the extracts were administered orally at a concentration of 100 mg/kg, and induced high peripheral antinociceptive activity, with a reduction in the nociception induced by acetic acid above 65%. In the hot plate test, treatment with extracts from C. sertularioides (100 mg/kg, p.o.) did not significantly increase the latency of response, although the ME, AE and HE from C. mexicana showed activity in this model. This result suggests that these extracts exhibit antinociceptive activity. In the formalin test, it was observed that ME, AE and HE obtained from C. mexicana reduced the effects of formalin in both phases. On the other hand only CE from C. sertularioides induced significant inhibition of the nociceptive response in the first phase. To better assess the potential anti-inflammatory activity of the extracts, the carrageenan-induced peritonitis test was used to test Caulerpa spp. extracts on cell migration into the peritoneal cavity. In this assay, all extracts evaluated were able to significantly inhibit leukocyte migration into the peritoneal cavity in comparison with carrageenan. These data demonstrate that extracts from Caulerpa species elicit pronounced antinociceptive and anti-inflamatory activity against several nociception models. However, pharmacological and chemical studies are continuing in order to characterize the mechanism(s) responsible for the antinociceptive action and also to identify the active principles present in the Caulerpa species.

Flavonoids from Praxelis clematidea R.M. King and Robinson modulate bacterial drug resistance.

Chemical studies of Praxelis clematidea R.M. King & Robinson resulted in the isolation of six flavones: Apigenine, genkwanine, 7,4’-dimethylapigenin, trimethylapigenin, cirsimaritin and tetramethylscutellarein, which were tested for their toxicity against Staphylococcus aureus SA-1199B, a strain possessing the NorA efflux pump. Efflux pumps are integral proteins of the bacterial membrane and are recognized as one of the main causes of bacterial drug resistance, since they expel antibiotics from the cell. The inhibition of this transporter is one form of modulating bacterial resistance to antimicrobial drugs. The flavones tested did not show any significant antibacterial activity against the Staphylococcus aureus strain used, but were able to modulate bacterial drug resistance. This property might be related to the degree of lipophilicity of the flavones conferred by the methoxyl groups, since 4’,5,6,7 tetramethoxyflavone the most methoxylated compound, reduced the minimal inhibitory concentration of the drug 16-fold.

Mortalidade de larvas de Plutella xylostella tratadas com extratos etanólicos de Aspidosperma pyrifolium

The objective of this work was to assess the effects of Aspidosperma pyrifolium ethanol extracts on cabbage moth (Plutella xylostella) larvae. The ethanol extracts of the stem bark, fruits and roots of A. pyrifolium were obtained by classical phytochemical methods, and the resulting subfractions were tested on P. xylostella, using 4 and 5 mg L-1. The crude ethanol extract of the stem bark was more lethal. The alkaloid-rich aqueous subfraction derived from the stem bark extract caused 100% larval mortality at 4 mg L-1. Insecticidal activity was associated with the presence of the monoterpenoid indole alkaloids aspidofractinine, 15-demethoxypyrifoline, and N-formylaspidofractinine. These alkaloids presented excellent insecticidal properties against P. xylostella.

Tropane Alkaloids from Erythroxylum caatingaePlowman

Three tropane alkaloids, 1–3, were isolated from Erythroxylum caatingae, i.e., 6β‐benzoyloxy‐3α‐[(4‐hydroxy‐3,5‐dimethoxybenzoyl)oxy]tropane (1), a new tropane alkaloid, along with the known alkaloids 3α,6β‐dibenzoyloxytropane (2) and 6β‐benzoyloxy‐3α‐[(3,4,5‐trimethoxybenzoyl)oxy]tropane (catuabine B; 3). Their structures were determined by 2D‐ (1H and 13C) NMR. By LC/ESI‐MS/MS analysis of the fractions of alkaloids 1–3, it was possible to detect five more alkaloids, 4–8, two of these, 4 and 8, possibly being new natural products. X‐Ray crystallography of the chloride derivate of 1, i.e., 6β‐benzoyloxy‐3α‐(4‐hydroxy‐3,5‐dimethoxybenzoyloxy)tropane hydrochloride (1a) confirmed the structure of 1. Cytotoxicity was tested against the cell lines HEp‐2, NCI‐H292, and KB for the MeOH extract and alkaloid 3, and antitumor activity was tested against Sarcoma 180 only for the MeOH extract.

Efficacy and Safety of Medicinal Plants or Related Natural Products for Fibromyalgia: A Systematic Review

To assess the effects of medicinal plants (MPs) or related natural products (RNPs) on fibromyalgia (FM) patients, we evaluate the possible benefits and advantages of MP or RNP for the treatment of FM based on eight randomized placebo-controlled trials (RCTs) involving 475 patients. The methodological quality of all studies included was determined according to JADAD and “Risk of Bias” with the criteria in the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0. Evidence suggests significant benefits of MP or RNP in sleep disruption, pain, depression, joint stiffness, anxiety, physical function, and quality of life. Our results demonstrated that MP or RNP had significant effects on improving the symptoms of FM compared to conventional drug or placebo; longer tests are required to determine the duration of the treatment and characterize the long-term safety of using MP, thus suggesting effective alternative therapies in the treatment of pain with minimized side effects.

The Antinociceptive and Anti-Inflammatory Activities of Aspidosperma tomentosum (Apocynaceae)

We investigated the antinociceptive and anti-inflammatory activities of the crude ethanolic extract (CEE), its fractions, and the flavonoid isorhamnetin from Aspidosperma tomentosum using models of nociception and inflammation in mice. In the writhing test, the CEE and its fractions (except for soluble phase, CHCl3 100% and EtAcO 100%) at 100 mg/kg p.o. induced antinociceptive activity. Isorhamnetin (100 μmol/kg, p.o.) was also active. In the hot plate test, only the treatment with the fractions Hex : CHCl3 50%, CHCl3 100%, and CHCl3 : MeOH 5% (100 mg/kg, p.o.) increased the latency time, reversed by the opioid antagonist naloxone. Fractions that were active in the hot plate test did not show catalepsy condition. It was observed that CEE, all fractions, and isorhamnetin reduced the formalin effects in the neurogenic phase. In the inflammatory phase, only CEE, isorhamnetin, and CHCl3 100% and CHCl3 : MeOH 5% fractions were active. CEE and all fractions, except for CHCl3 : MeOH 10% fraction, isorhamnetin, and soluble fraction were able to produce an antioedematogenic activity in the ear capsaicin-induced edema test. In the thioglycolate-induced peritonitis, only EtAcO 100% fraction was not active. The results demonstrate that A. tomentosum has antinociceptive and anti-inflammatory activities in animal models.

Short-term stability studies of ampicillin and cephalexin in aqueous solution and human plasma: Application of least squares method in Arrhenius equation

A limited number of studies with application of the Arrhenius equation have been reported to drugs and biopharmaceuticals in biological fluids at frozen temperatures. This paper describes stability studies of ampicillin and cephalexin in aqueous solution and human plasma applying the Arrhenius law for determination of adequate temperature and time of storage of these drugs using appropriate statistical analysis. Stability studies of the beta-lactams in human plasma were conducted at temperatures of 20°C, 2°C, -20°C and also during four cycles of freeze-thawing. Chromatographic separation was achieved using a Shimpak C(18) column, acetonitrile as organic modifier and detection at 215nm. LC-UV-MS/MS was used to demonstrate the conversion of ampicillin into two diastereomeric forms of ampicilloic acid. Stability studies demonstrated degradation greater than 10% for ampicillin in human plasma at 20°C, 2°C and -20°C after 15h, 2.7days, 11days and for cephalexin at the same temperatures after 14h, 3.4days and 19days, respectively, and after the fourth cycle of freezing-thawing. The Arrhenius plot showed good prediction for the ideal temperature and time of storage for ampicillin (52days) and cephalexin (151days) at a temperature of -40°C, but statistical analysis (least squares method) must be applied to avoid incorrect extrapolations and estimated values out uncertainty limits.

SYNTHESIS OF NATURAL AMIDE ALKALOID PIPERDARDINE AND A NEW BIOACTIVE ANALOGUE

Piperdardine, (E,E)-1-[7-(1,3-benzodioxol-5-yl)-1-oxo-2,4-heptadienyl]-piperidine, isolated from the stem of Piper tuberculatum, was synthesized in 21% overall yield by an efficient pathway, in which safrole, an abundant Brazilian essential oil from Ocotea pretiosa, was used as starting material.

Use of 4-bromo pyridazine 3,6-dione for building 3-amino pyridazine libraries

An efficient method for preparation of 4,6 or 5,6 disubstituted 3-aminopyridazines was easily carried out starting from easily available 4-bromo-pyridazine-3,6-dione, and using combination of both amination and Pd(0) cross-coupling reactions under microwave irradiation.