Validation of a UV-spectrophotometric analytical method for determination of LPSF/AC04 from inclusion complex and liposomes

The aim of this study was to develop and validate a UV spectrophotometric method for determination of LPSF/AC04 from inclusion complex and encapsulated into liposomes. The validation parameters were determined according to the International Conference on Harmonisation (ICH) and National Health Surveillance Agency (ANVISA) guidelines. LPSF/AC04 was determined at 250 nm in methanol by a UV spectrophotometric method, exhibiting linearity in the range from 0.3 to 2 µg.mL−1 (Absorbance=0.18068 x [LPSF/AC04 µg.mL-1] + 0.00348), (r2=0.9995). The limits of detection and quantification were 0.047µg.mL−1 and 0.143µg.mL−1, respectively. The method was accurate, precise, reproducible and robust since all the samples analyzed had coefficient of variation of less than 5% and no statistically significant difference between theoretical and practical concentrations was detected. Thus, a rapid, simple, low cost and sensitive spectrophotometric method was developed and validated for determining the content of inclusion complex and liposomes containing LPSF/AC04.

O objetivo deste estudo foi desenvolver e validar um método espectrofotométrico para determinação do LPSF/AC04 em complexo de inclusão e encapsulado em lipossomas. Os parâmetros de validação foram determinados de acordo com o International Conference on Harmonisation (ICH) e Agência Nacional de Vigilância Sanitária (ANVISA). OLPSF/AC04 foi determinado a 250 nm em metanol pelo método espectrofotométrico UV, que apresenta linearidade na faixa de 0,3 a 2 µg/mL (Absorbância = 0,18068 x [LPSF/AC04 µg/mL] + 0,00348), (r2 = 0,9995). Os limites de detecção e quantificação foi 0,047 µg/mL e 0,143 µg/mL, respectivamente. O método foi exato, preciso, reprodutível e robusto e todas as amostras analisadas apresentaram coeficiente de variação menor que 5% e não houve diferença estatisticamente significante entre a concentração teórica e a prática. Assim, um método espectrofotométrico rápido, simples, sensível e de baixo custo foi desenvolvido e validado para determinar o conteúdo do LPSF/AC04 em complexos de inclusão e encapsulados em lipossomas.

Hydroxychloroquine decreases Th17-related cytokines in systemic lupus erythematosus and rheumatoid arthritis patients.

OBJECTIVES: Hydroxychloroquine is an antimalarial agent that has been used in systemic lupus erythematosus and rheumatoid arthritis treatment for many years. Recently, novel mechanisms of action have been proposed, thereby broadening the therapeutic perspective of this medication. The purpose of this study was to evaluate the immunomodulatory activity of hydroxychloroquine in T helper 17 (Th17) cytokines in healthy individuals and patients. METHODS: Eighteen female patients with systemic lupus erythematosus (mean age 39.0±12.9 years) and 13 female patients with rheumatoid arthritis (mean age 51.5±7.7 years) were recruited from Universidade Federal de Pernambuco-Brazil. The patients were included after fulfilling four classification criteria for systemic lupus erythematosus or rheumatoid arthritis from the American College of Rheumatology. After being stimulated with phorbol 12-myristate 13-acetate and ionomycin in the absence or presence of different concentrations of hydroxychloroquine, the interleukin 6, 17 and 22 levels were quantified with an enzyme-linked immunosorbent assay in culture supernatants of peripheral blood mononuclear cells from healthy individuals and patients. RESULTS: We demonstrated that in peripheral blood mononuclear cells from healthy volunteers and in systemic lupus erythematosus and rheumatoid arthritis patients, there was a significant reduction in the IL-6, IL-17 and IL-22 supernatant levels after adding hydroxychloroquine. CONCLUSIONS Our in vitro results demonstrated that hydroxychloroquine inhibits IL-6, IL-17 and IL-22 production and contributes to a better understanding of the mechanism of action of this medication.

Hydroxychloroquine decreases Th17-related cytokines in systemic lupus erythematosus and rheumatoid arthritis patients

OBJECTIVES: Hydroxychloroquine is an antimalarial agent that has been used in systemic lupus erythematosus and rheumatoid arthritis treatment for many years. Recently, novel mechanisms of action have been proposed, thereby broadening the therapeutic perspective of this medication. The purpose of this study was to evaluate the immunomodulatory activity of hydroxychloroquine in T helper 17 (Th17) cytokines in healthy individuals and patients. METHODS: Eighteen female patients with systemic lupus erythematosus (mean age 39.0±12.9 years) and 13 female patients with rheumatoid arthritis (mean age 51.5±7.7 years) were recruited from Universidade Federal de Pernambuco-Brazil. The patients were included after fulfilling four classification criteria for systemic lupus erythematosus or rheumatoid arthritis from the American College of Rheumatology. After being stimulated with phorbol 12-myristate 13-acetate and ionomycin in the absence or presence of different concentrations of hydroxychloroquine, the interleukin 6, 17 and 22 levels were quantified with an enzyme-linked immunosorbent assay in culture supernatants of peripheral blood mononuclear cells from healthy individuals and patients. RESULTS: We demonstrated that in peripheral blood mononuclear cells from healthy volunteers and in systemic lupus erythematosus and rheumatoid arthritis patients, there was a significant reduction in the IL-6, IL-17 and IL-22 supernatant levels after adding hydroxychloroquine. CONCLUSIONS Our in vitro results demonstrated that hydroxychloroquine inhibits IL-6, IL-17 and IL-22 production and contributes to a better understanding of the mechanism of action of this medication. .

Decreased serum interleukin 27 in Brazilian systemic lupus erythematosus patients.

The immunological role of interleukin 27 has been reported in various inflammatory diseases, but its importance in systemic lupus erythematosus pathogenesis is not completely established. The aim of this study was to evaluate serum levels of IL-27 in SLE patients and its correlation with clinical manifestations and disease activity. IL-27 levels were assessed in 70 SLE patients and 30 healthy controls by ELISA. Clinical and laboratory parameters were recorded. Statistic analyzes were performed by Graph Prism 3.02 software. The IL-27 serum levels were significantly decreased in SLE patients compared with controls (mean 899.92 and 1,531.22 pg/ml, P=0.0005). There was a correlation between IL-27 levels and C3 levels (P=0.004). Nevertheless, there was no association of serum IL-27 levels with disease activity evaluated by SLEDAI score (P=0.9605). No significant difference was found regarding IL-27 levels between SLE patients with and without nephritis, haematuria, proteinuria and positive anti-dsDNA. Correlation analysis between serum IL-27 levels and SLEDAI, SLICC, proteinuria levels, C4 and CH50 levels also showed no association. These data demonstrated decreased serum levels of IL-27 in SLE patients but further studies are needed to clarify the precise role of this cytokine and its potential use as therapeutic target.

Cratylia mollis 1, 4 lectin: a new biotechnological tool in IL-6, IL-17A, IL-22, and IL-23 induction and generation of immunological memory.

Cratylia mollis lectin has already established cytokine induction in Th1 and Th2 pathways. Thereby, this study aimed to evaluate Cramoll 1, 4 in IL-6, IL-17A, IL-22, and IL-23 induction as well as analyze immunologic memory mechanism by reinducing lymphocyte stimulation. Initially we performed a screening in cultured splenocytes where Cramoll 1, 4 stimulated IL-6 production 5x more than ConA (P < 0.05). The same behavior was observed with IL-22 where the increase was greater than 4x. Nevertheless, IL-17A induction was similar for both lectins. In PBMCs, the same splenocytes course was observed for IL-6 and IL-17A. Concerning the stimulation of IL-22 and IL-23 Cramoll 1, 4 was more efficient than ConA in cytokines stimulation mainly in IL-23 (P < 0.01). Analyzing reinduced lymphocyte stimulation, IL-17A production was higher (P < 0.001) when the first stimulus was realized with Cramoll 1, 4 at 1 µ g/mL and the second at 5 µ g/mL. IL-22 shows significant differences (P < 0.01) at the same condition. Nevertheless, IL-23 revels the best response when the first stimuli was realized with Cramoll1, 4 at 100 ng/mL and the second with 5 µ g/mL. We conclude that the Cramoll 1, 4 is able to induce IL-6, IL-17A, IL-22, and IL-23 cytokines in vitro better than Concavalin A, besides immunologic memory generation, being a potential biotechnological tool in Th17 pathway studies.

The evolution of drugs on schistosoma treatment: looking to the past to improve the future.

Schistosomiasis is a devastating worldwide widespread tropical disease that currently affects more than 230 million people, making it an issue of great socioeconomic and public health importance. Unfortunatelly there is a single drug for the treatment of all forms of schistosomiasis, praziquantel, which was introduced in therapy in 1980. The article goes by antimony compounds, emetine, hydantoin, nitrofurans, lucanthone, hycanthone, oxamniquine derivatives and organophosphates until it finally gets to praziquantel derivatives. The intent of this review is to provide a panorama of drugs that were and are being used in human chemotherapy looking to the past to improve rational design drugs in the future. Not only clinical used compounds will be shown but also synthesized and tested compounds in vitro and in vivo in animal models which haven't yet to be used in humans. Prospects for drug discovery and vaccines to be used in the treatment and prevention of schistosomiasis, clinical trials, concerns about the resistance/decreased effectiveness of the treatment, and patent database will also be discussed. At the end of the review the reader will notice that much has been done but much still needs to be done yet.

Effect of new thiazolidine derivatives LPSF/GQ-02 and LPSF/GQ-16 on atherosclerotic lesions in LDL receptor-deficient mice (LDLR(-/-)).

BACKGROUND: Atherosclerotic cardiovascular disease is a chronic inflammatory condition. Thiazolidinediones (TZDs) are used to enhance sensitivity to insulin and have demonstrated a protective effect over a variety of cardiovascular markers and risk factors. Controversially, the TZDs are associated with the development of heart failure. Thus, lines of research have invested in the search for new molecules in order to obtain more selective and less harmful treatment alternatives for the pathogenesis of atherosclerosis and its risk factors. METHODS: Animals were fed a diet rich in fat for 10 weeks. In the last 2 weeks, animals received either pioglitazone, LPSF/GQ-02, or LPSF/GQ-16 daily through gavage. At the end of the treatment, blood was collected for biochemical analysis and the aortas were dissected for subsequent analyses. RESULTS: No changes in the blood lipid profile were found following the use of the drugs in comparison to the control. However, the new thiazolidine derivatives were more efficient in improving insulin resistance in comparison to pioglitazone and the control group. Morphometric analyses revealed that neither pioglitazone nor LPSF/GQ16 led to satisfactory effects over atherosclerosis. However, LPSF/GQ-02 led to a reduction in area of the atherosclerotic lesions. Ultrastructural analyses revealed extensive degeneration of the endothelium and an increase in apoptotic cells in the subendothelial space following the use of pioglitazone and LPSF/GQ-16. However, LPSF/GQ-02 caused minimal cell alterations in the aortic endothelium. Regarding markers, endothelial nitric oxide synthase (eNOS) and matrix metalloproteinase 9 (MMP-9), LPSF/GQ-16, and pioglitazone exerted similar effects, increasing the expression of MMP-9, and had no effect on the expression of eNOS compared with the control group. On the other hand, LPSF/GQ-02 was effective in reducing the expression of MMP-9 and increased eNOS significantly. CONCLUSIONS: The results suggest that the new thiazolidine derivative LPSF/GQ-02 is a promising candidate for the treatment of atherosclerosis.

New imidazolidine derivatives as anti-Trypanosoma cruzi agents: structure-activity relationships.

Imidazolidine derivatives are key components for the development of bioactive compounds for the treatment of many diseases, especially Chagas. In fact, others studies showed that the imidazolidine-2,4-dione has stood out by presenting a wide spectrum of pharmacological activities including anticonvulsants, antiarrhythmic, and antiparasitic. In the present study, we investigated the morphological alterations induced by imidazolidine derivates LPSF/NN-52 and LPSF/NN-100 on trypomastigotes forms of Trypanosoma cruzi through ultrastructural analysis by electron microscopy. Many concentrations were used to measure the antiparasitic propriety promoted by imidazolidine derivatives, and our study indicates that parasites treated with 13 µg mL(-1) of the imidazolidine derivates for 24 h revealed severe damage to the parasite's mitochondrial complex. Beyond that, also observed in treated parasites were the following: myelin bodies, enlargement of cytoplasm vacuole, fragmentation of endoplasmic reticulum, and some treated samples clearly showed signs of necrosis. To confirm the ultrastructural results, some assays were performed for knowledge cellular death induction promoted by imidazolidine derivates against immune spleen cells. The induction of the necrotic process through derivatives LPSF/NN-52 and LPSF/NN-100 showed similar results in relation to nifurtimox and benznidazole. In the last assays, it was demonstrated that NN-100 was efficient against epimastigotes and trypomastigotes forms and these results reinforce the mechanisms of action of both new imidazolidine derivatives against T. cruzi.

Study of the activity of 3-benzyl-5-(4-chloro-arylazo)-4-thioxo-imidazolidin-2-one against Schistosomiasis mansoni in mice.

Previous studies conducted with the imidazolidinic derivative 3-benzyl-5-(4-chloro-arylazo)-4-thioxo-imidazolidin-2-one (LPSF-PT05) show outstanding activity against adult Schistosoma mansoni worms in vitro. In the first phase of this study, S. mansoni-infected mice were treated, orally, with 100 mg/Kg of the LPSF-PT05 in three formulations: Tween 80 and saline solution, oil/water (70 : 30) emulsion, and solid dispersion with polyethylene glycol (PEG). In the second phase, three other doses of the LPSF-PT05 in PEG were tested: 3, 10, 30 mg/kg. These treatment regimens significantly reduced the number of recovered worms due to increases in the solubility of the compound in this formulation; the greatest reduction (70.5%) was observed at the dose of 100 mg/kg. There was no changes in the pattern of mature egg compared to immature eggs; however there was a significant increase in the number of dead eggs. Histopathological analysis of liver tissue showed changes in morphological aspects of the hepatic parenchyma with decrease exudative-productive hepatic granuloma stages, although we found no significant differences in IFN-γ, IL-4, IL-10, or NO production in response to the specific antigen SEA. The results show the derivative LPSF-PT05 to be a potential candidate in the etiological treatment of schistosomiasis with a possible dampening effect of the granulomatous process.

Synthesis and cytotoxic activity of new acridine-thiazolidine derivatives.

Although their exact role in controlling tumour growth and apoptosis in humans remains undefined, acridine and thiazolidine compounds have been shown to act as tumour suppressors in most cancers. Based on this finding, a series of novel hybrid 5-acridin-9-ylmethylene-3-benzyl-thiazolidine-2,4-diones were synthesised via N-alkylation and Michael reaction. The cell viability was analysed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and DNA interaction assays were performed using electrochemical techniques.

Increased serum interleukin 22 in patients with rheumatoid arthritis and correlation with disease activity.

OBJECTIVE: To analyze the role of interleukin 22 (IL-22) in rheumatoid arthritis (RA). METHODS: IL-22 serum levels were measured in 83 patients with established RA under treatment with disease-modifying antirheumatic drugs and in 30 healthy controls matched for age and sex. Patients were assessed for clinical and laboratory variables. Correlations of IL-22 serum levels with disease activity measures [Clinical Disease Activity Index (CDAI) and Disease Activity Score for 28 joints (DAS28)], serological markers, bone erosions, and demographic factors were assessed. Peripheral blood mononuclear cells (PBMC) from 30 patients with RA and 14 controls were purified and stimulated in vitro with phorbol myristate acetate (PMA)/ionomycin. IL-22 production by PBMC and in serum was investigated by ELISA. RESULTS: IL-22 levels were increased in patients with RA compared with controls (mean 432.37 pg/ml and 67.45 pg/ml, respectively; p < 0.001). Levels of IL-22 correlated with DAS28 and CDAI measures. Rheumatoid factor (RF) positivity was correlated with higher levels of IL-22 in patients with RA (mean 575.08 pg/ml; p = 0.001). The presence of bone erosions was associated with high IL-22 levels (p = 0.0001). PBMC stimulated with PMA/ionomycin expressed higher levels of IL-22 in patients with RA than controls but this was not significant (mean 584.75 pg/ml and 295.57 pg/ml; p = 0.553). CONCLUSION: IL-22 is elevated in the serum of patients with established RA. Elevated serum IL-22 allows discrimination between patients with different clinical and laboratory measures and indicates the potential of IL-22 as an additional tool for assessment of activity in RA, particularly in patients with RF antibodies and longterm disease. IL-22 is associated with bone-destructive disease.

Pre-clinical pharmacokinetics of the acridine antitumour candidate AC04 and its 1-oxo-metabolite plasma profile.

This work aimed to investigate plasma pharmacokinetics and tissue distribution of a new acridine derivative 5-acridin-9-ylmethylene-3-(4-methyl-benzyl)-thiazolidine-2,4-dione (AC04) and its 1-oxo-AC04 metabolite disposition in Wistar rats. After a single AC04 1.5 mg/kg intravenous (i.v.) bolus dose, blood samples were taken up to 120 h. Plasma samples were deproteinization, and AC04 and metabolite were quantified by validated liquid chromatography in tandem with mass spectrometry method. Protein binding was determined by ultrafiltration. AC04 tissue disposition was evaluated after i.v. bolus dose. Individual AC04 concentration-time profiles were best fitted by a two-compartment model showing CL(tot) of 3.4 ± 3.4 L/h/kg, Vd(SS) of 137.9 ± 91.4 L/kg, AUC(0-∞) of 788 ± 483 ng·h/mL and a t(1/2) of 45.5 ± 31.5 h. Protein binding was 98.1 ± 1.6%. AC04 showed higher penetration into the lung, spleen and liver, with AUC(0-96) of 798,443, 263,211 and 303,722 ng·h/mL, respectively. The 1-oxo-AC04 metabolite represented 10% of AC04 plasma concentration, showing a t(1/2) of 23.2 ± 10.4 h. These results suggest that, despite the small free plasma fraction, AC04 penetrates extensively reaching high concentrations in most tissues residing for a long time, which is important for its activity on solid tumours. All results combined indicate that AC04 is potentially a good antitumour candidate.

Anti-inflammatory and antinociceptive activities of indole-imidazolidine derivatives.

Non-steroidal anti-inflammatory drugs (NSAIDs) represent a group of approximately 50 different medicines that are widely prescribed for the management of inflammation and that exhibit variable anti-inflammatory, anti-pyretic and analgesic activities. Most NSAIDs also exhibit a shared set of adverse effects, particularly related to gastrointestinal complications; thus, the development of new drugs for the treatment of chronic inflammation and pain continues to be an issue of high interest. Hydantoin and indole derivatives are reported to possess various pharmacological effects, including anti-inflammatory and analgesic activities. Therefore, the aim of this study was to evaluate the potential anti-inflammatory and antinociceptive activities of hybrid molecules containing imidazole and indole nuclei. The anti-inflammatory activities of 5-(1H-Indol-3-yl-methylene)-2-thioxo-imidazolidin-4-one (LPSF/NN-56) and 3-(4-Bromo-benzyl)-5-(1H-indol-3-yl-methylene)-2thioxo-imidazolidin-4-one (LPSF/NN-52) were evaluated using air pouch and carrageenan-induced peritonitis models as well as an acetic acid-induced vascular permeability model followed by IL-1ß and TNF-α quantification. To evaluate the antinociceptive activities of the compounds, acetic acid-induced nociception, formalin and hot plate tests were also performed. The anti-inflammatory activities of the compounds were evidenced by a reduction in both leukocyte migration and the release of TNF-α and IL-1ß in air pouch and peritonitis models. Upon acetic acid-induced nociception, a decrease in the level of abdominal writhing in the groups treated with LPSF/NN-52 (52.1%) or LPSF/NN-56 (63.1%) was observed. However, in the hot plate test, none of the derivatives tested exhibited an inhibition of nociception. These results indicate that the compounds tested exhibited promising anti-inflammatory and antinociceptive activities that likely involved the modulation of the immune system.

Metabolism evaluation of the anticancer candidate AC04 by biomimetic oxidative model and rat liver microsomes.

Jacobsen reagents, in the presence of monooxygen donors, appear as an alternative to produce metabolites from biological active compounds. This reaction may mimic the oxidation and oxygenation reactions of cytochrome P450 (CYP450) enzymes upon various drugs and biologically active compounds. Acridines represent a well-known group of polyaromatic compounds capable of acting as DNA intercalating agents. Viewing to search for new anticancer agents, one promising new acridine, the 5-acridin-9-ylmethylene-3-(4-methyl-benzyl)-thiazolidine-2,4-dione (AC04) (2), has been studied by our group and the in vitro metabolism was investigated in this work, aiming to advance in the pre-clinical pharmacokinetic investigation. A systematic investigation of the gas-phase reaction, supported by computational chemistry, of the AC04 (2) was studied to help the structure elucidation of possible in vivo metabolites. To confirm the methodology, the oxidized product was obtained in large scale for NMR analysis and the data confirmed the structure. In addition, AC04 (2) was submitted to an in vitro metabolism assay employing rat liver microsomes and also, a pilot study was conducted in rats after AC04 intravenous (i.v.) dosing of 1.5 mg/kg. A single oxidized product was obtained from microsomal metabolism and detected in rat plasma by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis corresponding to the same product formed by Jacobsen-catalyzed reaction. These results indicate that Jacobsen oxidation reactions, combined with in vitro metabolism assays employing isolated microsomes, might replace some in vivo metabolism studies, thus reducing the use of animals in new chemical entities pre-clinical investigation.

Antischistosomal action of thioxo-imidazolidine compounds: an ultrastructural and cytotoxicity study.

Schistosomiasis is a disease caused by helminthes of the genus Schistosoma, which threatens approximately 207 million people worldwide. Recently, strains of Schistosoma mansoni appear to be developing tolerance and resistance against Praziquantel, the most commonly available drug on the market used in the treatment of disease. This worrisome development justifies studies that seek alternatives for the prevention, treatment and cure of this disease. This study aimed to evaluate the in vitro activity of new imidazolidine compounds 1-benzyl-4-[(4-chloro-phenyl)-hydrazono]-5-thioxo-imidazolidin-2-one (LPSF/PT-5) and 1-(4-chloro-benzyl)-4-[(4-fluoro-phenyl)-hydrazono]-5-thioxo-imidazolidin-2-one (LPSF/PT-11) against adult worms of S. mansoni. LPSF/PT-5 and LPSF/PT-11 imidazolidine derivatives showed relevant schistosomicidal activity in vitro and induced significant ultrastructural alterations in worms and cell death: results similar to praziquantel. Thus, it is possible that these imidazolidine derivatives can be future candidates as schistosomotic drugs, but further studies are needed to elucidate the induced mechanisms behind this response.

Biological and immunological activity of new imidazolidines against adult worms of Schistosoma mansoni.

The only drug available for treating schistosomiasis is praziquantel, however there are already reports of resistance to its use in treatment, making it necessary to search and develop new compounds to combat schistosomiasis. We tested, in vitro, two new products, Laboratório de Planejamento de Síntese de Fármacos (LPSF)/5-(4-chloro-benzylidene-3-(4-nitrebenzyl)-4-thioxo-imidazolidin-2-one (RZS-2) and LPSF/5-(4-fluoride-benzylidene-3-(4-nitrebenzyl)-4-thioxo-imidazolidin-2-one (RZS-5) imidazolidines, against adult worms of Schistosoma mansoni. Efficacy and safety of these compounds were analyzed through IC50 cytotoxicity, immune response and cell viability tests. At different concentrations ranging from 40-640 microM, the imidazolidines produced motor abnormalities, inhibition of pairing and oviposition and mortality within 24 h at the higher concentrations. Although not triggering changes in IFN-gamma and IL-10, LPSF/RZS-2 and LPSF/RZS-5 induced production of nitric oxide and showed similar behavior to praziquantel in the cell death test.

Synthesis and anti-inflammatory activity of new arylidene-thiazolidine-2,4-diones as PPARgamma ligands.

Eight new 5-arylidene-3-benzyl-thiazolidine-2,4-diones with halide groups on their benzyl rings were synthesized and assayed in vivo to investigate their anti-inflammatory activities. These compounds showed considerable biological efficacy when compared to rosiglitazone, a potent and well-known agonist of PPARgamma, which was used as a reference drug. This suggests that the substituted 5-arylidene and 3-benzylidene groups play important roles in the anti-inflammatory properties of this class of compounds. Docking studies with these compounds indicated that they exhibit specific interactions with key residues located in the site of the PPARgamma structure, which corroborates the hypothesis that these molecules are potential ligands of PPARgamma. In addition, competition binding assays showed that four of these compounds bound directly to the ligand-binding domain of PPARgamma, with reduced affinity when compared to rosiglitazone. An important trend was observed between the docking scores and the anti-inflammatory activities of this set of molecules. The analysis of the docking results, which takes into account the hydrophilic and hydrophobic interactions between the ligands and the target, explained why the 3-(2-bromo-benzyl)-5-(4-methanesulfonyl-benzylidene)-thiazolidine-2,4-dione compound had the best activity and the best docking score. Almost all of the stronger hydrophilic interactions occurred between the substituted 5-arylidene group of this compound and the residues of the binding site.

Development of novel therapeutic drugs in humans from plant antimicrobial peptides.

All living organisms, ranging from microorganisms to plants and mammals, have evolved mechanisms to actively defend themselves against pathogen attack. A wide range of biological activities have been attributed to plant antimicrobial peptides (AMPs) including growth inhibitory effects on a broad range of fungi, Gram-positive and Gram-negative bacteria, viruses, neoplasic cells and parasitic protozoa. Classes of AMPs, their mechanisms of action, biological activity, and cytotoxicity towards host cells are discussed. A particular focus regards AMP candidates with potential for use in defense against biological warfare agents. This field is young, but provides additional stimulus to consideration of these molecules as a new class of therapeutic agents and promises to revolutionize treatment of many infectious diseases.

Overview on plant antimicrobial peptides.

Mechanisms related to biotic interactions, such as pathogen attack, herbivory and symbiosis are important challenges to higher plants and have been widely studied especially for breeding purposes. The present review focuses on a special category of defense molecules, the plant antimicrobial peptides, providing an overview of their main molecular features and structures.

Preclinical pharmacokinetic and pharmacodynamic evaluation of thiazolidinone PG15: an anti-inflammatory candidate.

OBJECTIVES: Novel 5-benzilidene thiazolidinones have been synthesized and exhibited anti-inflammatory activity. In this work one of the compounds of the thiazolidinone chemical series, (5Z,E)-3-[2-(4-chlorophenyl)-2-oxoethyl]-5-(1H-indol-3-ylmethylene)-thiazolidine-2,4-dione (PG15) was investigated aiming to determine the drug's anti-inflammatory potential in pre-clinical studies. METHODS: Methods used included the in-vitro inhibition of cyclooxygenase-1 and -2, in-vivo evaluation of anti-inflammatory activity by air pouch and peritonitis models and the pharmacokinetic profile after intravenous (3 mg/kg) and oral (3 and 6 mg/kg) dosing to rats. KEY FINDINGS: A two-compartment model with a fast distribution and an elimination half-life of 5.9 +/- 3.8 h described the PG15 plasma profile after intravenous dosing. PG15 showed an erratic and rapid absorption following oral administration with peak concentrations between 0.5 and 1 h. PG15 0.1 microM inhibited more than 30% and 13% of purified cyclooxygenase-1 and -2 activity in vitro, respectively. A lack of dose dependency was observed for the anti-inflammatory effect in the dose range investigated (0.8-50 mg/kg), with a maximum of 67.2 +/- 4.6% inhibition of leucocyte migration in the carrageenan-induced air pouch model obtained with the 3 mg/kg dose, similar to that observed for indometacin 10 mg/kg. CONCLUSIONS: The erratic absorption of PG15 observed after oral dosing could explain the lack of anti-inflammatory dose dependency.