Flavonoids from the aerial parts of <Emphasis Type="Italic">Houttuynia cordata</Emphasis> attenuate lung inflammation in mice

The aerial parts of Houttuynia cordata used for treating inflammation-related disorders contain flavonoids as major constituents. Since certain flavonoids possess anti-inflammatory activity, especially in the lung, the pharmacological activities of H. cordata and the flavonoid constituents were evaluated using in vitro and in vivo models of lung inflammation. The 70 % ethanol extract of the aerial parts of H. cordata inhibited the production of inflammatory biomarkers IL-6 and NO in lung epithelial cells (A549) and alveolar macrophages (MH-S), respectively. And the same plant material, administered orally (100 and 400 mg/kg), significantly inhibited lung inflammatory response in a mouse model of lipopolysaccharide (LPS)-induced acute lung injury. From the extract, major flavonoids including afzelin, hyperoside and quercitrin were successfully isolated and they also attenuated LPS-induced lung inflammation in mice by oral administration. In particular, quercitrin showed most potent activity at 100 mg/kg. These results demonstrate for the first time that H. cordata and three flavonoid constituents have a therapeutic potential for treating lung inflammatory disorders.     

Antiproliferative and toxicological properties of methanolic extract obtained from <Emphasis Type="Italic">Solanum capsicoides</Emphasis> All. seeds and carpesterol

Natural products are considered important sources of potential chemotherapeutic agents. Here, we evaluated the antiproliferative activity and the toxicological effects of the methanolic extract and a pure compound obtained from Solanum capsicoides seeds. The phytochemical profile was analyzed by chromatographic and spectroscopy methods. The acute toxicity was assessed in mice orally treated with the extract (2000 mg/kg), in vitro hemolytic activity and micronucleus test. The mutagenicity, developmental toxicity, and lethal dose (LD50) of carpesterol were estimated by the Toxicity Estimation Software Tool (TEST) software. A sulforhodamine B assay was employed to evaluate the antiproliferative activity. The toxicological assays did not observe signs of toxicity, either during the behavioral observations or in the autopsies, as well as no mutagenicity and hemolytic activity. The carpesterol did not present mutagenic effect and hemolytic activity but presents developmental toxicology and LD50 of 410 mg/kg in toxicity estimations by the TEST software. The S. capsicoides extract exhibited antiproliferative activity mainly in leukemia (K562) cell lineage. However, carpesterol presented antiproliferative activity in glioma (U251), breast (MCF-7), kidney (786-0), ovary (OVCAR-03), and K562 cell lineages. The data obtained show that S. capsicoides extract presents antiproliferative and does not present toxicological effects. In addition, it was shown for the first time the antiproliferative and toxicological parameters of carpesterol.     

Analgesic and anti-inflammatory effect of aqueous extract of the stem bark of <Emphasis Type="Italic">Allanblackia gabonensis</Emphasis> (Guttiferae)

Allanblackia gabonensis (Guttiferae) is a plant used in the African traditional medicine as remedies against pain, rheumatism, inflammations. In the present work, the analgesic effect of aqueous extract has been evaluated using acetic acid, formalin, hot-plate test, tail immersion and paw-pressure test. The anti-inflammatory effect of this extract was also investigated on carrageenan, histamine or serotonin induced by paw oedema. Aqueous extract of stem bark of A. gabonensis administrated p.o. showed significant activity against paw oedema induced by carrageenan, with a maximum percentage of inhibition reaching the 74.01% at the preventive test at a dose of 200 mg/kg. A. gabonensis exhibited a significant reduction of paw oedema induced by both histamine and serotonin with a maximal inhibition of 56.94% (200 mg/kg) and 40.83% (100 mg/kg), respectively. It showed significant protective effects against chemical stimuli (acetic acid and formalin) in the mouse. Administered orally at the doses of 100–400 mg/kg, exhibited protective effect of at least 69.78% on the pain induced by acetic acid and also reduced first (67.18% at 200 mg/kg) and second (83.87% at 400 mg/kg) phase of pain-induced par formalin. It also produced a significant increase of the threshold of sensitivity to pressure and hot plate-induced pain in the rats. These results suggest a peripheral and central analgesic activities as well as an anti-inflammatory effect of the stem bark of A. gabonensis.     

Anti-diabetic Effect of <Emphasis Type="Italic">Boerhavia diffusa</Emphasis> L. Root Extract via Free Radical Scavenging and Antioxidant Mechanism

Objective

The present study was proposed to assess the in vitro free radical-scavenging activity of B. diffusa methanolic extract (BDME) and its modulatory effect against streptozotocin (STZ) induced diabetes in male Wistar rats.

Methods

Experimental diabetes was induced in Wistar albino rats by administering single dose of STZ 40 mg/kg. One week later rats with blood glucose level >200 mg/dL were segregated as diabetes in three groups each containing 6 rats in number.

Results

Total phenolic content in B. diffusa methanol extract (BDME) was found to be 87 mg of gallic acid equivalents/g extract and total flavonoid content found to be 54.1 mg of quercetin equivalents/g extract. Its extract also exhibited DPPH (IC₅₀, 163.1±6.7 μg/mL), nitric oxide (295 μg/mL) and H₂O₂ (159±5.25 μg/mL) radical scavenging activity. Pre-treatment with BDME (100 and 200 mg/kg b.w.) in streptozotocin-induced diabetic rats resulted in significant improvement in blood glucose, blood plasma enzymes SGOT, SGPT and ALP, weight loss, total protein, serum insulin and liver glycogen levels. Furthermore, it restores the activity of antioxidant enzymes viz. SOD, CAT and GPx.

Conclusion

Thus, the result suggests that BDME employed significant anti-diabetic effect in Wistar rats which is associated with its free radical scavenging and antioxidant activity.

     

<Emphasis Type="Italic">Apium graveolens</Emphasis> extract influences mood and cognition in healthy mice

Apium graveolens is a food flavoring which possesses various health promoting effects. This study investigates the effect of a sub-acute administration of A. graveolens on cognition and anti-depression behaviors via antioxidant and related neurotransmitter systems in mice brains. Cognition and depression was assessed by various models of behavior. The antioxidant system of glutathione peroxidase (GPx), % inhibition of superoxide anion (O₂ ^?), and lipid peroxidation were studied. In addition, neurochemical parameters including acetylcholinesterase (AChE) and monoamine oxidase-type A (MAO-A) were also evaluated. Nine groups of male mice were fed for 30 days with different substances—a control, vehicle, A. graveolens extract (65–500 mg/kg), and reference drugs (donepezil and fluoxetine). The results indicated that the effect of the intake of A. graveolens extract (125–500 mg/kg) was similar to the reference drugs, as it improved both spatial and non-spatial memories. Moreover, there was a decrease in immobility time in both the forced swimming and tail suspension tests. In addition, the A. graveolens extract reduced lipid peroxidation of the brain and increased GPx activity and the % inhibition of O₂ ^?, whereas the activities of AChE and MAO-A were decreased. Thus, our data have shown that the consumption of A. graveolens extract improved cognitive function and anti-depression activities as well as modulating the endogenous antioxidant and neurotransmitter systems in the brain, resulting in increased neuronal density. This result indicated an important role for A. graveolens extract in preventing age-associated decline in cognitive function associated with depression.     

Effects of methanolic extract from leaves of <Emphasis Type="Italic">Rubus imperialis</Emphasis> in DSS-induced colitis in mice

This study investigated the effects of Rubus imperialis, a berry known as “amora-branca”, in colitis dextran sulfate sodium (DSS)-induced in mice. Animals were treated orally with vehicle (water), 5-aminosalicylic acid (100 mg/kg) or methanolic extract from leaves of R. imperialis (MERI, 100 mg/kg), once a day during seven days. The disease activity index (DAI) was observed daily. Colons were collected for histological, histochemical and biochemical analysis. The administration of MERI exacerbated colitis, as indicated by DAI heightened weight loss and increased histological colonic injury. MERI also decreased the colon mucin levels and increased colonic TNF content. The colonic levels of reduced glutathione and the superoxide dismutase activity in colitic group treated with MERI were decreased. Despite the worsening of colitis, MERI not altered the intestinal transit, body weight, colon length or organs weight in normal mice. Tormentic acid (TA) and 2β,3β,19α-trihydroxyursolic acid (THA), compounds isolated from MERI, reduced the L929 cells viability. Thus, MERI may have aggravated the DSS-induced colitis through intense intestinal mucus barrier impairment, which would lead to inflammatory responses, TA and THA contribute to the intestinal damage verified suggesting caution about the use of R. imperialis preparations, particularly in inflammatory bowel diseases.     

Effect of Gastric Fluid Volume on the <Emphasis Type="Italic">In Vitro</Emphasis> Dissolution and <Emphasis Type="Italic">In Vivo</Emphasis> Absorption of BCS Class II Drugs: a Case Study with Nifedipine

Nifedipine is a BCS Class II drug used for treatment of hypertension and preterm labor. Large inter-patient variability in nifedipine absorption results in variable exposure among different patients. We conducted in vitro dissolution studies to compare nifedipine dissolution from immediate release (IR) capsules with different volumes of dissolution media. Results from dissolution studies were used to design a crossover study in healthy volunteers to evaluate the effect of coadministered water volume with nifedipine 10 mg IR capsules on nifedipine pharmacokinetics, especially absorption (C _max, t _max, and AUC_0-6). Dissolution studies demonstrated that larger gastric fluid volumes result in enhanced nifedipine dissolution from 10 mg IR cosolvent capsules (73 vs. 17% in 200 and 100 mL simulated gastric fluid, respectively, at 30 min). The pharmacokinetic crossover study in healthy volunteers (N?=?6) did not show a significant effect of the water volume administered with the capsule (50 vs. 250 mL) on C _max, t _max, or AUC_0-6 of orally administered nifedipine IR capsules (10 mg). However, administration of large water volumes resulted in lower variability in nifedipine C _max (47 vs. 70% for 250 and 50 mL, respectively). Administration of large water volumes with nifedipine 10 mg IR cosolvent capsules may reduce inter-individual variability in plasma exposure. Evaluation of similar effects in other BCS Class II drugs is recommended.     

Pharmacological evaluation of the efficacy of <Emphasis Type="Italic">Dysoxylum binectariferum</Emphasis> stem bark and its active constituent rohitukine in regulation of dyslipidemia in rats

The antidyslipidemic effect of the ethanolic extract of Dysoxylum binectariferum stem bark and its major active constituent rohitukine was evaluated in a high fat diet (HFD)-fed dyslipidemic rat model. Chronic feeding of ethanolic extract (200 mg/kg) in HFD-fed rats showed significant lipid lowering activity. The bioassay guided fractionation of ethanolic extract resulted in the identification of known alkaloid rohitukine as major active constituent. Rohitukine (50 mg/kg) significantly decreased the plasma levels of total cholesterol (24 %), phospholipids (25 %), triglycerides (27 %), very low density lipoprotein (27 %) and low density lipoprotein (32 %) accompanied with an increase in high density lipoprotein (21 %). The present study demonstrated that ethanolic extract of Dysoxylum binectariferum stem bark and its major constituent rohitukine both have antidyslipidemic as well as antioxidant potentials. The antidyslipidemic activity of rohitukine can be correlated to its effect on enzymes involved in lipid metabolism.     

Inhibition of <Emphasis Type="Italic">Klebsiella pneumoniae</Emphasis> growth by selected Australian plants: natural approaches for the prevention and management of ankylosing spondylitis

A wide variety of herbal remedies are used in traditional Australian medicine to treat inflammatory disorders, including autoimmune inflammatory diseases. One hundred and six extracts from 40 native Australian plant species traditionally used for the treatment of inflammation and/or to inhibit bacterial growth were investigated for their ability to inhibit the growth of a microbial trigger for ankylosing spondylitis (K. pneumoniae). Eighty-six of the extracts (81.1%) inhibited the growth of K. pneumoniae. The D. leichardtii, Eucalyptus spp., K. flavescens, Leptospermum spp., M. quinquenervia, Petalostigma spp., P. angustifolium, S. spinescens, S. australe, S. forte and Tasmannia spp. extracts were effective K. pneumoniae growth inhibitors, with MIC values generally <1000 µg/mL. The T. lanceolata peppercorn extracts were the most potent growth inhibitors, with MIC values as low as 16 µg/mL. These extracts were examined by non-biased GC–MS headspace analysis and comparison with a compound database. A notable feature was the high relative abundance of the sesquiterpenoids polygodial, guaiol and caryophyllene oxide, and the monoterpenoids linalool, cineole and α-terpineol in the T. lanceolata peppercorn methanolic and aqueous extracts. The extracts with the most potent K. pneumoniae inhibitory activity (including the T. lanceolata peppercorn extracts) were nontoxic in the Artemia nauplii bioassay. The lack of toxicity and the growth inhibitory activity of these extracts against K. pneumoniae indicate their potential for both preventing the onset of ankylosing spondylitis and minimising its symptoms once the disease is established.     

Induction of apoptosis and cell cycle arrest by <Emphasis Type="Italic">Negombata magnifica</Emphasis> sponge in hepatocellular carcinoma

Marine sponges have been considered as a gold mine, with respect to the diversity of their secondary metabolites. Many sponge extracts and isolated compounds are potential anticancer agents. In the present study, the antiproliferative activity of Negombata magnifica was investigated as petroleum ether extract (PE), total methanolic extract (ME) and two sub-fractions II and III, isolated pure compounds (palmitic acid and pregnanediol), sponge mesohyl and primmorphs ethyl acetate extract. Palmitic acid was used as a positive control. Cell viability was assessed via MTT assay, and apoptosis was investigated in terms of DNA fragmentation and BCl2 gene expression. Cell cycle analysis was performed via flow cytometry. GLC analysis of PE revealed that it contains 84.46 % hydrocarbons and 15.54 % sterols, whereas the fatty acids contain 38.62 % saturated and 61.38 % unsaturated fatty acids. Results revealed that except for pregnanediol and fraction II, all treatments exhibited cytotoxic activity. Primmorphs ethyl acetate extract and fraction III arrested cells in G0–G1, while fraction II arrested cell cycle in G2/M. PE extract arrested cells in G0–G1 and G2/M. Mesohyl, PE and fraction III could be apoptotic agents as indicated by DNA fragmentation independent on BCL2 expression, while ME and pregnanediol could exhibited pro-apoptotic effect through decreasing BCL2 expression although no DNA ladder was observed.     

Effect of Cd<Superscript>+2</Superscript> on phosphate solubilizing abilities and hydrogen peroxide production of soil-borne micromycetes isolated from <Emphasis Type="Italic">Phragmites australis</Emphasis>-rhizosphere

The aims of this work were to evaluate the phosphate-solubilization and hydrogen peroxide (H₂O₂) production by the soil-borne micromycetes, Aspergillus japonicus, Penicillium italicum and Penicillium dipodomyicola, isolated from Phragmites australis rhizosphere and to study the effect of several concentrations of Cadmium (Cd²⁺) on both variables. Our results showed that P. italicum achieved a higher P-solubilization and H₂O₂ production than A. japonicus and P. dipodomyicola, as only P. italicum showed a positive correlation (R² = 0.71) between P-solubilization and H₂O₂ production. In dose–response assays, P. italicum was also more tolerant to Cd²⁺ (0.31 mM) in comparison to A. japonicus (0.26 mM). Analysis of the 2⁴ factorial experimental design showed that P-solubilization by P. italicum was negatively affected by increases in Cd²⁺ (p = 0.04) and yeast extract (p = 0.02) in the culture medium. The production of H₂O₂ was positively affected only by glucose (p = 0.002). Fungal biomass production was reduced significantly (p = 0.0009) by Cd²⁺ and increased (p = 0.0003) by high glucose concentration in the culture medium. The tolerance and correlation between P-solubilization and H₂O₂ production in the presence of Cd²⁺ was strain and species dependent. The effects of Cd²⁺, glucose, ammonium sulfate and yeast extract on those variables were evaluated through a two-level factorial design. P. italicum is promising for P-solubilization in soils contaminated with Cd²⁺ and may be an alternative for manufacture of biofertilizers to replace chemical fertilizers.     

Bioactivity evaluations of betulin identified from the bark of <Emphasis Type="Italic">Betula platyphylla</Emphasis> var. <Emphasis Type="Italic">japonica</Emphasis> for cancer therapy

Identification of bioactive natural products with anticancer activity as well as alleviating effects on chemotherapy-induced side effects has significant implications for cancer treatment. Betula platyphylla var. japonica, commonly known as Asian white birch, has been used in Chinese traditional medicine for a variety of purposes. In this study, the medicinal properties of betulin from B. platyphylla var. japonica useful for cancer management were investigated. LC/MS analysis revealed that betulin is a main chemical component of the EtOH extract of B. platyphylla var. japonica bark, and betulin was isolated from EtOH extract using an LC/MS-guided isolation method. Its structure was identified with ¹H and ¹³C NMR spectroscopic data and LC/MS analysis and then compared to the previously reported spectroscopic and physical data. We first verified the cytotoxicity of betulin against three human lung adenocarcinoma cell lines, A549, H1264, and Calu-6, with IC₅₀ values ranging from 18.7 to 39.6 μM. Regarding alleviation of side effects associated with anticancer chemotherapy, betulin ameliorated cisplatin-induced renal cell damage to 80% of the control value from the concentration of 5 μM. In addition, betulin showed anti-gastritis activity against ethanol-induced gastric damage in rats and notably reduced the gastric damage index compared to control in a concentration-dependent manner. These findings provide the first experimental evidence for potential use of B. platyphylla var. japonica as a functional food for cancer treatment that simultaneously alleviates the side effects of chemotherapy.     

Anti-inflammatory,antioxidant and anti-acetylcholinesterase activities of <Emphasis Type="Italic">Bouvardia ternifolia</Emphasis>: potential implications in Alzheimer’s disease

Bouvardia ternifolia has been used medicinally to treat inflammation. In the present study, we investigate the anti-Alzheimer’s potential effect of the hydroalcoholic extract of B. ternifolia through evaluation of anti-inflammatory and antioxidant activities, quantification of the percentage inhibition of acetylcholinesterase activity, protection effect against β-amyloid fibrillar-induce neurotoxicity, and the identification of the main constituents. Our results show that B. ternifolia extract and ethyl acetate fraction induced anti-inflammatory effects by reducing inflammation by >70 %, while antioxidant test revealed significant IC₅₀ values for flavonoid content fraction (30.67 ± 2.09 μg/ml) and ethyl acetate fraction (42.66 ± 0.93 μg/ml). The maximum inhibition of acetylcholinesterase was exhibited by scopoletin content fraction (38.43 ± 3.94 %), while ethyl acetate fraction exerted neuroprotective effect against β-amyloid peptide (83.97 ± 5.03 %). Phytochemical analysis, showed the presence of 3-O-quercetin glucopyranoside (415 mg/g), rutin (229.9 mg/g), ursolic and oleanolic acid (54 and 20.8 mg/g respectively), 3-O-quercetin rhamnopyranoside (12.8 mg/g), chlorogenic acid (9.5 mg/g), and scopoletin (1.38 mg/g). Our findings support the use of B. ternifolia since the extract induced significant neuroprotection against β-amyloid peptide, anti-inflammatory, antioxidant and anti-acetylcholinesterase effects that could be attributed to its contents of polyphenols, coumarins, and triterpenes, and encourage further studies for development of this extract as therapeutic agent in treatment of Alzheimer’s disease.     

Gender-Dependent Pharmacokinetics of Veratramine in Rats: <Emphasis Type="Italic">In Vivo</Emphasis> and <Emphasis Type="Italic">In Vitro</Emphasis> Evidence

Veratramine, a major alkaloid from Veratrum nigrum L., has distinct anti-tumor and anti-hypertension effects. Our previous study indicated that veratramine had severe toxicity toward male rats. In order to elucidate the underling mechanism, in vivo pharmacokinetic experiments and in vitro mechanistic studies have been conducted. Veratramine was administrated to male and female rats intravenously via the jugular vein at a dose of 50 μg/kg or orally via gavage at 20 mg/kg. As a result, significant pharmacokinetic differences were observed between male and female rats after oral administration with much lower concentrations of veratramine and 7-hydroxyl-veratramine and higher concentrations of veratramine-3-O-sulfate found in the plasma and urine of female rats. The absolute bioavailability of veratramine was 0.9% in female rats and 22.5% in male rats. Further experiments of veratramine on Caco-2 cell monolayer model and in vitro incubation with GI content or rat intestinal subcellular fractions demonstrated that its efficient passive diffusion mediated absorption with minimal intestinal metabolism, suggesting no gender-related difference during its absorption process. When veratramine was incubated with male or female rat liver microsomes/cytosols, significant male-predominant formation of 7-hydroxyl-veratramine and female-predominant formation of veratramine-3-O-sulfate were observed. In conclusion, the significant gender-dependent hepatic metabolism of veratramine could be the major contributor to its gender-dependent pharmacokinetics.     

Evaluation of the inhibitory effects of eckol and dieckol isolated from edible brown alga <Emphasis Type="Italic">Eisenia bicyclis</Emphasis> on human monoamine oxidases A and B

Eckol and dieckol are important phlorotannins found in edible brown algae including Eisenia bicyclis, Ecklonia stolonifera, and others. Inhibition of monoamine oxidase (MAO) play an important role in the early management of Parkinson’s disease (PD). The aim of this study was to determine the effectiveness of eckol and dieckol isolated from the methanolic extract of E. bicyclis against PD by the inhibition of human MAO-A and MAO-B (hMAO-A and hMAO-B). A sensitive enzyme-based chemiluminescent assay and kinetics methods were used to investigate enzyme inhibition and mode of inhibition. A molecular docking simulation was performed to clarify the binding characteristics of eckol and dieckol to hMAO-A and hMAO-B. The results suggested that methanolic extract of E. bicyclis and its isolated phlorotannins, eckol and dieckol, have potent inhibitory activity against hMAO-A and hMAO-B. The enzyme-based kinetics results demonstrated eckol mixed and non-competitive inhibition of hMAO-A and hMAO-B, respectively, while dieckol non-competitively inhibited both hMAOs. Molecular docking simulation predicted that eckol and dieckol exhibit higher binding affinity towards hMAO-A and hMAO-B through hydrogen bonding and hydrophobic interactions. These findings implicate eckol and dieckol as inhibitors of hMAOs that might be of potential value in the management of PD.     

Suppression of P2X7/NF-κB pathways by Schisandrin B contributes to attenuation of lipopolysaccharide-induced inflammatory responses in acute lung injury

The aim of the present study was to assess the effects and mechanisms of Schisandrin B (SchB) on lipopolysaccharide (LPS)-induced acute lung injury (ALI). ALI was induced in mice by intratracheal instillation of LPS (1 mg/kg), and SchB (25, 50, and 75 mg/kg) was injected 1 h before LPS challenge by gavage. After 12 h, bronchoalveolar lavage fluid (BALF) samples and lung tissues were collected. Histological studies demonstrated that SchB attenuated LPS-induced interstitial edema, hemorrhage, and infiltration of neutrophils in the lung tissue. SchB pretreatment at doses of 25, 50, and 75 mg/kg was shown to reduce LPS-induced lung wet-to-dry weight ratio and lung myeloperoxidase activity. In addition, pretreatment with SchB lowered the number of inflammatory cells and pro-inflammatory cytokines including tumor necrosis factor-α, interleukin-1β, and interleukin-6 in BALF. The mRNA and protein expression levels of nuclear factor kappa B (NF-κB) signaling-related molecules activated by P2X7 were investigated to determine the molecular mechanism of SchB. The findings presented here suggest that the protective mechanism of SchB may be attributed partly to the decreased production of pro-inflammatory cytokines through the inhibition of P2X7/NF-κB activation.     

Lipid-based Formulations for Danazol Containing a Digestible Surfactant,Labrafil M2125CS: <Emphasis Type="BoldItalic">In Vivo</Emphasis> Bioavailability and Dynamic <Emphasis Type="BoldItalic">In Vitro</Emphasis> Lipolysis

Purpose

To evaluate the use of Labrafil® M2125CS as a lipid vehicle for danazol. Further, the possibility of predicting the in vivo behavior with a dynamic in vitro lipolysis model was evaluated.

Methods

Danazol (28 mg/kg) was administered orally to rats in four formulations: an aqueous suspension, two suspensions in Labrafil® M2125CS (1 and 2 ml/kg) and a solution in Labrafil® M2125CS (4 ml/kg).

Results

The obtained absolute bioavailabilities of danazol were 1.5?±?0.8%; 7.1?±?0.6%; 13.6?±?1.4% and 13.3?±?3.4% for the aqueous suspension, 1, 2 and 4 ml Labrafil® M2125CS per kg respectively. Thus administration of danazol with Labrafil® M2125CS resulted in up to a ninefold increase in the bioavailability, and the bioavailability was dependent on the Labrafil® M2125CS dose. In vitro lipolysis of the formulations was able to predict the rank order of the bioavailability from the formulations, but not the absorption profile of the in vivo study.

Conclusions

The bioavailability of danazol increased when Labrafil® M2125CS was used as a vehicle, both when danazol was suspended and solubilized in the vehicle. The dynamic in vitro lipolysis model could be used to rank the bioavailabilities of the in vivo data.

     

Synthesis of coumarin-based 1,3,4-oxadiazol-2ylthio-<Emphasis Type="Italic">N</Emphasis>-phenyl/benzothiazolyl acetamides as antimicrobial and antituberculosis agents

In an attempt to find new agents to fight against microbial infections, a series of coumarin-based 1,3,4-oxadiazol-2ylthio-N-phenyl/benzothiazolyl acetamides was synthesized starting from coumarin-3-carboxylic acid ethyl ester obtained through Knoevenagel and Pinner reaction. In vitro antimicrobial activity against several bacteria (S. aureus, B. cereus, E. coli, P. aeruginosa, K. pneumoniae, S. typhi, P. vulgaris, S. flexneri), fungi (A. niger, A. fumigatus, A. clavatus, C. albicans) and antimycobacterial activity against Mycobacterium tuberculosis H37Rv strain was assessed. This study shows to what extent the presence of various electron withdrawing/donating substituents on the phenyl or benzothiazole ring affects the activity profiles of the newer molecules. The relationship between activity profiles (MICs, 3.12–25 μg/mL) and the lipophilic character (LogP) of the prepared products is also discussed and the MIC values of the active conjugates seem to correlate to some extent with the lipophilicity profiles. Two (5e and 6c) of the final analogues displayed promising antimycobacterial activity at 12.5 μg/mL of MIC, half fold potent to the standard drug pyrazinamide (6.25 μg/mL). Compounds were characterized by IR, ¹H NMR, ¹³C NMR spectroscopy and elemental analysis.     

Treating <Emphasis Type="Italic">Staphylococcus aureus</Emphasis> infections in an intensive care unit at a University Hospital in Brazil

Background Optimizing antimicrobial therapy is important for treating patients who are critically ill with Staphylococcus aureus infection, and susceptibility tests are necessary. Objective The aim of the present study was to evaluate antibacterial therapy after susceptibility testing of S. aureus infections. Setting The setting was an intensive care unit at a University Hospital in Brazil. Methods An observational and retrospective study was conducted over 6 years. The antimicrobials that were used for S. aureus infection treatment were calculated as the defined daily dose per 1000 patient-days (DDD₁₀₀₀). Antimicrobial susceptibility data were obtained by reviewing bacteriological tests. Patient profiles and treatment were determined by analyzing patient charts. Results Methicillin-resistant S. aureus (MRSA) was prevalent in this study (76.13 %). Patients who were infected with MRSA had total antimicrobial consumption that was three-times higher (9567.2 DDD₁₀₀₀) than patients who were infected with methicillin-susceptible S. aureus (MSSA; 3101.1 DDD₁₀₀₀). The average length of stay in the intensive care unit was 19 days (interquartile range 17 days) for MSSA and 20 days (interquartile range 20 days) for MRSA. Mortality in patients who were infected with MSSA was higher (52.17 %) than in patients who were infected with MRSA (33.80 %), and de-escalation was not identified in 73.90 % of MSSA patients.     

Design,synthesis, and evaluation of the anticonvulsant and antidepressant activities of pyrido[2,3-<Emphasis Type="Italic">d</Emphasis>]pyrimidine derivatives

A series of pyrido[2,3-d]pyrimidine derivatives (4a–4n, 5a–5n, 6, and 7) were designed and synthesized as potential anticonvulsants and antidepressants. Their pharmacological activities were evaluated by maximal electroshock test, forced swimming test, and tail suspension test in mice. Pharmacological analyses showed that compounds 4-benzyl-6,8-dimethylpyrido[3,2-e]tetrazolo[1,5-a]pyrimidin-5(4H)-one (4a) and 4-(3-fluorobenzyl)-6,8-dimethylpyrido[3,2-e]tetrazolo[1,5-a]pyrimidin-5(4H)-one (4e) exhibited the greatest anticonvulsant activity (PI 12.02 and 12.25, respectively, 30 min after intraperitoneal injection), and were more efficient than the reference drug, carbamazepine. In addition, 4-(4-fluorobenzyl)-6,8-dimethylpyrido[3,2-e]tetrazolo[1,5-a]pyrimidin-5(4H)-one (4f) and 6-(4-fluorobenzyl)-2,4-dimethylpyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrimidin-5(6H)-one (5f) possessed potent antidepressant properties that lead to significant reduction in the duration of the immobility time than did the control (P < 0.001), which possessed activities similar to those of fluoxetine. 4f showed obvious antidepressant activity at doses of 10 mg/kg.